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Intellectual Disability

Global developmental delay, highlights in this clinical report, chromosome microarray, screening for inborn errors of metabolism, genetic testing for mendelian disorders, male gender, genetic testing for nonspecific xlid, boys with suspected or known xlid, female gender and mecp2 testing, advances in diagnostic imaging, recommended approach, the shared evaluation and care plan for limited access, emerging technologies, conclusions, lead authors, american academy of pediatrics committee on genetics, 2013–2014, past committee members, contributor, comprehensive evaluation of the child with intellectual disability or global developmental delays.

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John B. Moeschler , Michael Shevell , COMMITTEE ON GENETICS , John B. Moeschler , Michael Shevell , Robert A. Saul , Emily Chen , Debra L. Freedenberg , Rizwan Hamid , Marilyn C. Jones , Joan M. Stoler , Beth Anne Tarini; Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays. Pediatrics September 2014; 134 (3): e903–e918. 10.1542/peds.2014-1839

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Global developmental delay and intellectual disability are relatively common pediatric conditions. This report describes the recommended clinical genetics diagnostic approach. The report is based on a review of published reports, most consisting of medium to large case series of diagnostic tests used, and the proportion of those that led to a diagnosis in such patients. Chromosome microarray is designated as a first-line test and replaces the standard karyotype and fluorescent in situ hybridization subtelomere tests for the child with intellectual disability of unknown etiology. Fragile X testing remains an important first-line test. The importance of considering testing for inborn errors of metabolism in this population is supported by a recent systematic review of the literature and several case series recently published. The role of brain MRI remains important in certain patients. There is also a discussion of the emerging literature on the use of whole-exome sequencing as a diagnostic test in this population. Finally, the importance of intentional comanagement among families, the medical home, and the clinical genetics specialty clinic is discussed.

The purpose of this clinical report of the American Academy of Pediatrics (AAP) is to describe an optimal medical genetics evaluation of the child with intellectual disability (ID) or global developmental delays (GDDs). The intention is to assist the medical home in preparing families properly for the medical genetics evaluation process. This report addresses the advances in diagnosis and treatment of children with intellectual disabilities since the publication of the original AAP clinical report in 2006 1 and provides current guidance for the medical genetics evaluation. One intention is to inform primary care providers in the setting of the medical home so that they and families are knowledgeable about the purpose and process of the genetics evaluation. This report will emphasize advances in genetic diagnosis while updating information regarding the appropriate evaluation for inborn errors of metabolism and the role of imaging in this context. The reader is referred to the 2006 clinical report for background information that remains relevant, including the roles of the medical home or pediatric primary care provider.

This clinical report will not address the importance of developmental screening in the medical home, nor will it address the diagnostic evaluation of the child with an autism spectrum disorder who happens to have ID as a co-occurring disability. (For AAP guidance related to Autism Spectrum Disorders, see Johnson and Myers. 2 )

For both pediatric primary care providers and families, there are specific benefits to establishing an etiologic diagnosis ( Table 1 ): clarification of etiology; provision of prognosis or expected clinical course; discussion of genetic mechanism(s) and recurrence risks; refined treatment options; the avoidance of unnecessary and redundant diagnostic tests; information regarding treatment, symptom management, or surveillance for known complications; provision of condition-specific family support; access to research treatment protocols; and the opportunity for comanagement of patients, as appropriate, in the context of a medical home to ensure the best health, social, and health care services satisfaction outcomes for the child and family. The presence of an accurate etiologic diagnosis along with a knowledgeable, experienced, expert clinician is one factor in improving the psychosocial outcomes for children and with intellectual disabilities and their families. 3 , – 5 Although perhaps difficult to measure, this “healing touch” contributes to the general well-being of the family. “As physicians we have experience with other children who have the same disorder, access to management programs, knowledge of the prognosis, awareness of research on understanding the disease and many other elements that when shared with the parents will give them a feeling that some control is possible.” 5  

The Purposes of the Comprehensive Medical Genetics Evaluation of the Young Child With GDD or ID

Makela et al 6 studied, in depth, 20 families of children with ID with and without an etiologic diagnosis and found that these families had specific stated needs and feelings about what a genetic diagnosis offers:

Validation: a diagnosis established that the problem (ID) was credible, which empowered them to advocate for their child.

Information: a diagnosis was felt to help guide expectations and management immediately and provide hope for treatment or cure in future.

Procuring services: the diagnosis assisted families in obtaining desired services, particularly in schools.

Support: families expressed the need for emotional companionship that a specific diagnosis (or “similar challenges”) assisted in accessing.

Need to know: families widely differed in their “need to know” a specific diagnosis, ranging from strong to indifferent.

Prenatal testing: families varied in their emotions, thoughts, and actions regarding prenatal genetic diagnosis.

For some families in the Makela et al 6 study, the clinical diagnosis of autism, for example, was sufficient and often more useful than “a rare but specific etiological diagnosis.” These authors report that “all of the families would have preferred to have an [etiologic] diagnosis, if given the option,” particularly early in the course of the symptoms.

As was true of the 2006 clinical report, this clinical report will not address the etiologic evaluation of young children who are diagnosed with cerebral palsy, autism, or a single-domain developmental delay (gross motor delay or specific language impairment). 1 Some children will present both with GDD and clinical features of autism. In such cases, the judgment of the clinical geneticist will be important in determining the evaluation of the child depending on the primary neurodevelopmental diagnosis. It is recognized that the determination that an infant or young child has a cognitive disability can be a matter of clinical judgment, and it is important for the pediatrician and consulting clinical geneticist to discuss this before deciding on the best approach to the diagnostic evaluation.” 1  

ID is a developmental disability presenting in infancy or the early childhood years, although in some cases, it cannot be diagnosed until the child is older than ∼5 years of age, when standardized measures of developmental skills become more reliable and valid. The American Association on Intellectual and Developmental Disability defines ID by using measures of 3 domains: intelligence (IQ), adaptive behavior, and systems of supports afforded the individual. 7 Thus, one cannot rely solely on the measure of IQ to define ID. More recently, the term ID has been suggested to replace “mental retardation.” 7 , 8 For the purposes of this clinical report, the American Association on Intellectual and Developmental Disability definition is used: “Intellectual disability is a disability characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social and practical adaptive skills. The disability originates before age 18 years.” 7 The prevalence of ID is estimated to be between 1% and 3%. Lifetime costs (direct and indirect) to support individuals with ID are large, estimated to be an average of approximately $1 million per person. 9  

Identifying the type of developmental delay is an important preliminary step, because typing influences the path of investigation later undertaken. GDD is defined as a significant delay in 2 or more developmental domains, including gross or fine motor, speech/language, cognitive, social/personal, and activities of daily living and is thought to predict a future diagnosis of ID. 10 Such delays require accurate documentation by using norm-referenced and age-appropriate standardized measures of development administered by experienced developmental specialists. The term GDD is reserved for younger children (ie, typically younger than 5 years), whereas the term ID is usually applied to older children for whom IQ testing is valid and reliable. Children with GDD are those who present with delays in the attainment of developmental milestones at the expected age; this implies deficits in learning and adaptation, which suggests that the delays are significant and predict later ID. However, delays in development, especially those that are mild, may be transient and lack predictive reliability for ID or other developmental disabilities. For the purposes of this report, children with delays in a single developmental domain (for example, isolated mild speech delay) should not be considered appropriate candidates for the comprehensive genetic evaluation process set forth here. The prevalence of GDD is estimated to be 1% to 3%, similar to that of ID.

Schaefer and Bodensteiner 11 wrote that a specific diagnosis is that which “can be translated into useful clinical information for the family, including providing information about prognosis, recurrence risks, and preferred modes of available therapy.” For example, agenesis of the corpus callosum is considered a sign and not a diagnosis, whereas the autosomal-recessive Acrocallosal syndrome (agenesis of the corpus callosum and polydactyly) is a clinical diagnosis. Van Karnebeek et al 12 defined etiologic diagnosis as “sufficient literature evidence…to make a causal relationship of the disorder with mental retardation likely, and if it met the Schaefer-Bodensteiner definition.” This clinical report will use this Van Karnebeek modification of the Schaefer–Bodensteiner definition and, thus, includes the etiology (genetic mutation or genomic abnormality) as an essential element to the definition of a diagnosis.

Recommendations are best when established from considerable empirical evidence on the quality, yield, and usefulness of the various diagnostic investigations appropriate to the clinical situation. The evidence for this clinical report is largely based on many small- or medium-size case series and on expert opinion. The report is based on a review of the literature by the authors.

Significant changes in genetic diagnosis in the last several years have made the 2006 clinical report out-of-date. First, the chromosome microarray (CMA) is now considered a first-line clinical diagnostic test for children who present with GDD/ID of unknown cause. Second, this report highlights a renewed emphasis on the identification of “treatable” causes of GDD/ID with the recommendation to consider screening for inborn errors of metabolism in all patients with unknown etiology for GDD/ID. 13  

Nevertheless, the approach to the patient remains familiar to pediatric primary care providers and includes the child’s medical history (including prenatal and birth histories); the family history, which includes construction and analysis of a pedigree of 3 generations or more; the physical and neurologic examinations emphasizing the examination for minor anomalies (the “dysmorphology examination”); and the examination for neurologic or behavioral signs that might suggest a specific recognizable syndrome or diagnosis. After the clinical genetic evaluation, judicious use of laboratory tests, imaging, and other consultations on the basis of best evidence are important in establishing the diagnosis and for care planning.

CMA now should be considered a first-tier diagnostic test in all children with GDD/ID for whom the causal diagnosis is not known. G-banded karyotyping historically has been the standard first-tier test for detection of genetic imbalance in patients with GDD/ID for more than 35 years. CMA is now the standard for diagnosis of patients with GDD/ID, as well as other conditions, such as autism spectrum disorders or multiple congenital anomalies. 14 , – 24 The G-banded karyotype allows a cytogeneticist to visualize and analyze chromosomes for chromosomal rearrangements, including chromosomal gains (duplications) and losses (deletions). CMA performs a similar function, but at a much “higher resolution,” for genomic imbalances, thus increasing the sensitivity substantially. In their recent review of the CMA literature, Vissers et al 25 report the diagnostic rate of CMA to be at least twice that of the standard karyotype. CMA, as used in this clinical report, encompasses all current types of array-based genomic copy number analyses, including array-based comparative genomic hybridization and single-nucleotide polymorphism arrays (see Miller et al 15 for a review of array types). With these techniques, a patient’s genome is examined for detection of gains or losses of genome material, including those too small to be detectable by standard G-banded chromosome studies. 26 , 27 CMA replaces the standard karyotype (“chromosomes”) and fluorescent in situ hybridization (FISH) testing for patients presenting with GDD/ID of unknown cause. The standard karyotype and certain FISH tests remain important to diagnostic testing but now only in limited clinical situations (see Manning and Hudgins 14 ) in which a specific condition is suspected (eg, Down syndrome or Williams syndrome). The discussion of CMA does not include whole-genome sequencing, exome sequencing, or “next-generation” genome sequencing; these are discussed in the “emerging technologies” section of this report.

Twenty-eight case series have been published addressing the rate of diagnosis by CMA of patients presenting with GDD/ID. 28 The studies vary by subject criteria and type of microarray technique and reflect rapid changes in technology over recent years. Nevertheless, the diagnostic yield for all current CMA is estimated at 12% for patients with GDD/ID. 14 , – 29 CMA is the single most efficient diagnostic test, after the history and examination by a specialist in GDD/ID.

CMA techniques or “platforms” vary. Generally, CMA compares DNA content from 2 differentially labeled genomes: the patient and a control. In the early techniques, 2 genomes were cohybridized, typically onto a glass microscope slide on which cloned or synthesized control DNA fragments had been immobilized. Arrays have been built with a variety of DNA substrates that may include oligonucleotides, complementary DNAs, or bacterial artificial chromosomes. The arrays might be whole-genome arrays, which are designed to cover the entire genome, or targeted arrays, which target known pathologic loci, the telomeres, and pericentromeric regions. Some laboratories offer chromosome-specific arrays (eg, for nonsyndromic X-linked ID [XLID]). 30 The primary advantage of CMA over the standard karyotype or later FISH techniques is the ability of CMA to detect DNA copy changes simultaneously at multiple loci in a genome in one “experiment” or test. The copy number change (or copy number variant [CNV]) may include deletions, duplications, or amplifications at any locus, as long as that region is represented on the array. CMA, independent of whether it is “whole genome” or “targeted” and what type of DNA substrate (single-nucleotide polymorphisms, 31 oligonucleotides, complementary DNAs, or bacterial artificial chromosomes), 32 identifies deletions and/or duplications of chromosome material with a high degree of sensitivity in a more efficient manner than FISH techniques. Two main factors define the resolution of CMA: (1) the size of the nucleic acid targets; and (2) the density of coverage over the genome. The smaller the size of the nucleic acid targets and the more contiguous the targets on the native chromosome are, the higher the resolution is. As with the standard karyotype, one result of the CMA test can be “of uncertain significance,” (ie, expert interpretation is required, because some deletions or duplications may not be clearly pathogenic or benign). Miller et al 15 describe an effort to develop an international consortium of laboratories to address questions surrounding array-based testing interpretation. This International Standard Cytogenomic Array Consortium 15 ( www.iscaconsortium.org ) is investigating the feasibility of establishing a standardized, universal system of reporting and cataloging CMA results, both pathologic and benign, to provide the physician with the most accurate and up-to-date information.

It is important for the primary care pediatrician to work closely with the clinical geneticist and the diagnostic laboratory when interpreting CMA test results, particularly when “variants of unknown significance” are identified. In general, CNVs are assigned the following interpretations: (1) pathogenic (ie, abnormal, well-established syndromes, de novo variants, and large changes); (2) variants of unknown significance; and (3) likely benign. 15 These interpretations are not essentially different than those seen in the standard G-banded karyotype. It is important to note that not all commercial health plans in the United States include this testing as a covered benefit when ordered by the primary care pediatrician; others do not cover it even when ordered by the medical geneticist. Typically, the medical genetics team has knowledge and experience in matters of payment for testing.

The literature does not stratify the diagnostic rates of CMA by severity of disability. In addition, there is substantial literature supporting the multiple factors (eg, social, environmental, economic, genetic) that contribute to mild disability. 33 Consequently, it remains within the judgment of the medical geneticist as to whether it is warranted to test the patient with mild (and familial) ID for pathogenic CNVs. In their review, Vissers et al 25 reported on several recurrent deletion or duplication syndromes with mild disability and commented on the variable penetrance of the more common CNV conditions, such as 1q21.1 microdeletion, 1q21.1 microduplication, 3q29 microduplication, and 12q14 microdeletion. Some of these are also inherited. Consequently, among families with more than one member with disability, it remains challenging for the medical geneticist to know for which patient with GDD/ID CMA testing is not warranted.

Recent efforts to evaluate reporting of CNVs among clinical laboratories indicate variability of interpretation because of platform variability in sensitivity. 34 , 35 Thus, the interpretation of CMA test abnormal results and variants of unknown significance, and the subsequent counseling of families should be performed in all cases by a medical geneticist and certified genetic counselor in collaboration with the reference laboratory and platform used. Test variability is resolving as a result of international collaborations. 36 With large data sets, the functional impact (or lack thereof) of very rare CNVs is better understood. Still, there will continue to be rare or unique CNVs for which interpretation remain ambiguous. The medical geneticist is best equipped to interpret such information to families and the medical home.

Since the 2006 AAP clinical report, several additional reports have been published regarding metabolic testing for a cause of ID. 13 , 37 , – 40 The percentage of patients with identifiable metabolic disorders as cause of the ID ranges from 1% to 5% in these reports, a range similar to those studies included in the 2006 clinical report. Likewise, these newer published case series varied by site, age range of patients, time frame, study protocol, and results. However, they do bring renewed focus to treatable metabolic disorders. 13 Furthermore, some of the disorders identified are not included currently in any newborn screening blood spot panels. Although the prevalence of inherited metabolic conditions is relatively low (0% to 5% in these studies), the potential for improved outcomes after diagnosis and treatment is high. 41  

In 2005, Van Karnebeek et al 40 reported on a comprehensive genetic diagnostic evaluation of 281 consecutive patients referred to an academic center in the Netherlands. All patients were subjected to a protocol for evaluation and studies were performed for all patients with an initially unrecognized cause of mental retardation and included urinary screen for amino acids, organic acids, oligosaccharides, acid mucopolysaccharides, and uric acid; plasma concentrations of total cholesterol and diene sterols of 7- and 8-dehydrocholesterol to identify defects in the distal cholesterol pathway; and a serum test to screen for congenital disorders of glycosylation (test names such as “carbohydrate-deficient transferrin”). In individual patients, other searches were performed as deemed necessary depending on results of earlier studies. This approach identified 7 (4.6%) subjects with “certain or probable” metabolic disorders among those who completed the metabolic screening ( n = 216). None of the 176 screening tests for plasma amino acids and urine organic acids was abnormal. Four children (1.4%) with congenital disorders of glycosylation were identified by serum sialotransferrins, 2 children had abnormal serum cholesterol and 7-dehydrocholesterol concentrations suggestive of Smith-Lemli-Opitz syndrome, 2 had evidence of a mitochondrial disorder, 1 had evidence of a peroxisomal disorder, and 1 had abnormal cerebrospinal fluid biogenic amine concentrations. These authors concluded that “screening for glycosylation defects proved useful, whereas the yield of organic acid and amino acid screening was negligible.”

In a similar study from the Netherlands done more recently, Engbers et al 39 reported on metabolic testing that was performed in 433 children whose GDD/ID remained unexplained after genetic/metabolic testing, which included a standard karyotype; urine screen for amino acids, organic acids, mucopolysaccharides, oligosaccharides, uric acid, sialic acid, purines, and pyrimidines; and plasma for amino acids, acylcarnitines, and sialotransferrins. Screenings were repeated, and additional testing, including cerebrospinal fluid studies, was guided by clinical suspicion. Metabolic disorders were identified and confirmed in 12 of these patients (2.7%), including 3 with mitochondrial disorders; 2 with creatine transporter disorders; 2 with short-chain acyl-coenzyme A dehydrogenase deficiency; and 1 each with Sanfilippo IIIa, a peroxisomal disorder; a congenital disorder of glycosylation; 5-methyltetrahydrofolate reductase deficiency; and deficiency of the GLUT1 glucose transporter.

Other studies have focused on the prevalence of disorders of creatine synthesis and transport. Lion-François et al 37 reported on 188 children referred over a period of 18 months with “unexplained mild to severe mental retardation, normal karyotype, and absence of fragile X syndrome” who were prospectively screened for congenital creatine deficiency syndromes. Children were from diverse ethnic backgrounds. Children with “polymalformative syndromes” were excluded. There were 114 boys (61%) and 74 girls (39%) studied. Creatine metabolism was evaluated by using creatine/creatinine and guanidinoacetate (GAA)-to-creatine ratios on a spot urine screen. Diagnosis was further confirmed by using brain proton magnetic resonance spectroscopy and mutation screening by DNA sequence analysis in either the SLC6A8 (creatine transporter defect) or the GAMT genes. This resulted in a diagnosis in 5 boys (2.7% of all; 4.4% of boys). No affected girls were identified among the 74 studied. All 5 boys also were late to walk, and 3 had “autistic features.” The authors concluded that all patients with undiagnosed ID have urine screened for creatine-to-creatinine ratio and GAA-to-creatine ratio. Similarly, Caldeira Arauja et al 38 studied 180 adults with ID institutionalized in Portugal, screening them for congenital creatine deficiency syndromes. Their protocol involved screening all subjects for urine and plasma uric acid and creatinine. Patients with an increased urinary uric acid-to-creatinine ratio and/or decreased creatinine were subjected to the analysis of GAA. GAMT activity was measured in lymphocytes and followed by GAMT gene analysis. This resulted in identifying 5 individuals (2.8%) from 2 families with GAMT deficiency. A larger but less selective study of 1600 unrelated male and female children with GDD/ID and/or autism found that 34 (2.1%) had abnormal urine creatine-to-creatinine ratios, although only 10 (0.6%) had abnormal repeat tests and only 3 (0.2%) were found to have an SLC6A8 mutation. 42 Clark et al 43 identified SLC6A8 mutations in 0.5% of 478 unrelated boys with unexplained GDD/ID.

Recently, van Karnebeek and Stockler reported 13 , 42 on a systematic literature review of metabolic disorders “presenting with intellectual disability as a major feature.” The authors identified 81 treatable genetic metabolic disorders presenting with ID as a major feature. Of these disorders, 50 conditions (62%) were identified by routinely available tests ( Tables 2 and 3 ). Therapeutic modalities with proven effect included diet, cofactor/vitamin supplements, substrate inhibition, enzyme replacement, and hematopoietic stem cell transplant. The effect on outcome (IQ, developmental performance, behavior, epilepsy, and neuroimaging) varied from improvement to halting or slowing neurocognitive regression. The authors emphasized the approach as one that potentially has significant impact on patient outcomes: “This approach revisits current paradigms for the diagnostic evaluation of ID. It implies treatability as the premise in the etiologic work-up and applies evidence-based medicine to rare diseases.” Van Karnebeek and Stockler 13 , 42 reported on 130 patients with ID who were “tested” per this metabolic protocol; of these, 6 (4.6%) had confirmed treatable inborn errors of metabolism and another 5 (3.8%) had “probable” treatable inborn error of metabolism.

Metabolic Screening Tests

See Fig 1 .

Serum lead, thyroid function studies not included as “metabolic tests” and to be ordered per clinician judgment.

Metabolic Conditions Identified by Tests Listed

Adapted from van Karnebeek and Stockler. 41  

Acylcarn, acylcarnitine profile; CPS, carbamyl phosphate synthetase; GA, glutaric acidemia; HHH, hyperornithinemia-hyperammonemia-homocitrullinuria; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; MHBD, 2-methyl-3-hydroxybutyryl CoA dehydrogenase; MMA, methylmalonic acidemia; MTHFR, methylenetetrahydrofolate reductase; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase; PAA, plasma amino acids; PDH, pyruvate dehydrogenase; P-HCY, plasma homocysteine; PKU; phenylketonuria; PPA, propionic acid; SCOT, succinyl-CoA:3-ketoacid CoA transferase; SSADH, succinic semialdehyde dehydrogenase; UGAA/creat; urine guanidino acid/creatine metabolites; UMPS, urine mucopolysaccharides qualitative screen (glycosaminoglycans); UOA, urine organic acids; UOGS, urine oligosaccharides; UPP, urine purines and pyrimidines.

Late-onset form of condition listed; some conditions are identified by more than 1 metabolic test.

This literature supports the need to consider screening children presenting with GDD/ID for treatable metabolic conditions. Many metabolic screening tests are readily available to the medical home and/or local hospital laboratory service. Furthermore, the costs for these metabolic screening tests are relatively low.

For patients in whom a diagnosis is suspected, diagnostic molecular genetic testing is required to confirm the diagnosis so that proper health care is implemented and so that reliable genetic counseling can be provided. For patients with a clinical diagnosis of a Mendelian disorder that is certain, molecular genetic diagnostic testing usually is not required to establish the diagnosis but may be useful for health care planning. However, for carrier testing or for genetic counseling of family members, it is often essential to know the specific gene mutation in the proband.

For patients with GDD/ID for whom the diagnosis is not known, molecular genetic diagnostic testing is necessary, under certain circumstances, which is discussed in the next section.

There is an approximate 40% excess of boys in all studies of prevalence and incidence of ID. 44 , 45 Part of this distortion of the gender ratio is attributable to X-linked genetic disorders. 46 Consequently, genetic testing for X-linked genes in boys with GDD/ID is often warranted, particularly in patients whose pedigree is suggestive of an X-linked condition. In addition, for several reasons, research in X-linked genes that cause ID is advanced over autosomal genes, 46 , 47 thus accelerating the clinical capacity to diagnose XLID over autosomal forms.

Most common of these is fragile X syndrome, although the prevalence of all other X-linked genes involved in ID far exceeds that of fragile X syndrome alone. 46 Fragile X testing should be performed in all boys and girls with GDD/ID of unknown cause. Of boys with GDD/ID of uncertain cause, 2% to 3% will have fragile X syndrome (full mutation of FMR1 , >200 CGG repeats), as will 1% to 2% of girls (full mutation). 48  

Stevenson and Schwartz 49 suggest 2 clinical categories for those with XLID: syndromal and nonsyndromal. Syndromal refers to patients in whom physical or neurologic signs suggest a specific diagnosis; nonsyndromal refers to those with no signs or symptoms to guide the diagnostic process. Using this classification has practical applicability, because the pediatric primary care provider can establish a specific XLID syndrome on the basis of clinical findings. In contrast, nonsyndromal conditions can only be distinguished on the basis of the knowledge of their causative gene. 50 In excess of 215 XLID conditions have been recorded, and >90 XLID genes have been identified. 46 , 50  

To address male patients with GDD/ID and X-linked inheritance, there are molecular genetic diagnostic “panels” of X-linked genes available clinically. These panels examine many genes in 1 “test sample.” The problem for the clinical evaluation is in which patient to use which test panel, because there is no literature on head-to-head performance of test panels, and the test panels differ somewhat by genes included, test methods used, and the rate of a true pathogenic genetic diagnosis. Nevertheless, the imperative for the diagnostic evaluation remains the same for families and physicians, and there is a place for such testing in the clinical evaluation of children with GDD/ID. For patients with an X-linked pedigree, genetic testing using one of the panels is clinically indicated. The clinical geneticist is best suited to guide this genetic testing of patients with possible XLID. For patients with “syndromal” XLID (eg, Coffin-Lowry syndrome), a single gene test rather than a gene panel is indicated. Whereas those patients with “nonsyndromal” presentation might best be assessed by using a multigene panel comprising many of the more common nonsyndromal XLID genes. The expected rate of the diagnosis may be high. Stevenson and Schwartz 46 reported, for example, on 113 cases of nonspecific ID testing using a 9-gene panel of whom 9 (14.2%) had pathogenic mutations identified. de Brouwer et al 51 reported on 600 families with multiple boys with GDD/ID and normal karyotype and FMR1 testing. Among those families with “an obligate female carrier” (defined by pedigree analysis and linkage studies), a specific gene mutation was identified in 42%. In addition, in those families with more than 2 boys with ID and no obligate female carrier or without linkage to the X chromosome, 17% of the ID cases could be explained by X-linked gene mutations. This very large study suggested that testing of individual boys for X-linked gene mutations is warranted.

Recently, clinical laboratories have begun offering “high-density” X-CMAs to assess for pathogenic CNVs (see previous discussion regarding microarrays) specifically for patients with XLID. Wibley et al 30 (2010) reported on CNVs in 251 families with evidence of XLID who were investigated by array comparative genomic hybridization on a high-density oligonucleotide X-chromosome array platform. They identified pathogenic CNVs in 10% of families. The high-density arrays for XLID are appropriate in those patients with syndromal or nonsyndromal XLID. The expected diagnostic rate remains uncertain, although many pathogenic segmental duplications are reported (for a catalog of X-linked mutations and CNVs, see http://www.ggc.org/research/molecular-studies/xlid.html ).

Whole exome sequencing and whole-genome sequencing are emerging testing technologies for patients with nonspecific XLID. Recently, Tarpey et al 52 have reported the results of the large-scale systematic resequencing of the coding X chromosome to identify novel genes underlying XLID. Gene coding sequences of 718 X-chromosome genes were screened via Sanger sequencing technology in probands from 208 families with probable XLID. This resequencing screen contributed to the identification of 9 novel XLID-associated genes but identified pathogenic sequence variants in only 35 of 208 (17%) of the cohort families. This figure likely underestimates the general contribution of sequence variants to XLID given the subjects were selected from a pool that had had previous clinical and molecular genetic screening. 30  

Table 4 lists some common XLID conditions. In cases in which the diagnosis is not certain, molecular genetic testing of patients for the specific gene is indicated, even if the pedigree does not indicate other affected boys (ie, cannot confirm X-linked inheritance). 46  

Common Recognizable XLID Syndromes

Reproduced with permission from Stevenson and Schwartz. 46  

Rett syndrome is an X-linked condition that affects girls and results from MECP2 gene mutations primarily (at least 1 other gene has been determined causal in some patients with typical and atypical Rett syndrome: CDKL5) . Girls with mutations in the MECP2 gene do not always present clinically with classic Rett syndrome. Several large case series have examined the rate of pathogenic MECP2 mutations in girls and boys with ID. The proportion of MECP2 mutations in these series ranged from 0% to 4.4% with the average of 1.5% among girls with moderate to severe ID. 53 , – 62   MECP2 mutations in boys present with severe neonatal encephalopathy and not with GDD/ID.

Currently, the literature does not indicate consensus on the role that neuroimaging, either by computed tomography (CT) or MRI, can play in the evaluation of children with GDD/ID. Current recommendations range from performing brain imaging on all patients with GDD/ID, 63 to performing it only on those with indications on clinical examination, 12 to being considered as a second-line investigation to be undertaken when features in addition to GDD are detected either on history or physical examination. The finding of a brain abnormality or anomaly on neuroimaging may lead to the recognition of a specific cause of an individual child’s developmental delay/ID in the same way that a dysmorphologic examination might lead to the inference of a particular clinical diagnosis. However, like other major or minor anomalies noted on physical examination, abnormalities on neuroimaging typically are not sufficient for determining the cause of the developmental delay/ID; the underlying precise, and presumably frequently genetic in origin, cause of the brain anomaly is often left unknown. Thus, although a central nervous system (CNS) anomaly (often also called a “CNS dysgenesis”) is a useful finding and indeed may be considered, according to the definition of Schaefer and Bodensteiner, 11 a useful “diagnosis.” However, it is frequently not an etiologic or syndromic diagnosis. This distinction is not always made in the literature on the utility of neuroimaging in the evaluation of children with developmental delay/ID. The lack of a consistent use of this distinction has led to confusion regarding this particular issue.

Early studies on the use of CT in the evaluation of children with idiopathic ID 64 indicated a low diagnostic yield for the nonspecific finding of “cerebral atrophy,” which did not contribute to clarifying the precise cause of the ID. 65 Later studies that used MRI to detect CNS abnormalities suggested that MRI was more sensitive than CT, with an increased diagnostic yield. 10 , 66 The rate of abnormalities actually detected on imaging varies widely in the literature as a result of many factors, such as subject selection and the method of imaging used (ie, CT or MRI). Schaefer and Bodensteiner, 63 in their literature review, found reported ranges of abnormalities from 9% to 80% of those patients studied. Shevell et al 10 reported a similar range of finding in their review. For example, in 3 studies totaling 329 children with developmental delay in which CT was used in almost all patients and MRI was used in but a small sample, a specific cause was determined in 31.4%, 67 27%, 68 and 30% 69 of the children. In their systematic review of the literature, van Karnebeek et al 12 reported on 9 studies that used MRI in children with ID. The mean rate of abnormalities found was 30%, with a range of 6.2% to 48.7%. These investigators noted that more abnormalities were found in children with moderate to profound ID versus those with borderline to mild ID (mean yield of 30% and 21.2%, respectively). These authors also noted that none of the studies reported on the value of the absence of any neurologic abnormality for a diagnostic workup and concluded that “the value for finding abnormalities or the absence of abnormalities must be higher” than the 30% mean rate implied.

If neuroimaging is performed in only selected cases, such as children with an abnormal head circumference or an abnormal focal neurologic finding, the rate of abnormalities detected is increased further than when used on a screening basis in children with a normal neurologic examination except for the documentation of developmental delay. Shevell et al 68 reported that the percentage of abnormalities were 13.9% if neuroimaging was performed on a “screening basis” but increased to 41.2% if performed on “an indicated basis.” Griffiths et al 70 highlighted that the overall risk of having a specific structural abnormality found on MRI scanning was 28% if neurologic symptoms and signs other than developmental delay were present, but if the developmental delay was isolated, the yield was reduced to 7.5%. In a series of 109 children, Verbruggen et al 71 reported an etiologic yield on MRI of 9%. They noted that all of these children had neurologic signs or an abnormal head circumference. In their practice parameter, the American Academy of Neurology and the Child Neurology Society 10 discussed other studies on smaller numbers of patients who showed similar results, which led to their recommendation that “neuroimaging is a recommended part of the diagnostic evaluation,” particularly should there be abnormal findings on examination (ie, microcephaly, macrocephaly, focal motor findings, pyramidal signs, extrapyramidal signs) and that MRI is preferable to CT. However, the authors of the American College of Medical Genetics Consensus Conference Report 10 stated that neuroimaging by CT or MRI in normocephalic patients without focal neurologic signs should not be considered a “standard of practice” or mandatory and believed that decisions regarding “cranial imaging will need to follow (not precede) a thorough assessment of the patient and the clinical presentation.” In contrast, van Karnebeek et al 12 found that MRI alone leads to an etiologic diagnosis in a much lower percentage of patients studied. They cited Kjos et al, 72 who reported diagnoses in 3.9% of patients who had no known cause for their ID and who did not manifest either a progressive or degenerative course in terms of their neurologic symptomatology. Bouhadiba et al 73 reported diagnoses in 0.9% of patients with neurologic symptoms, and in 4 additional studies, no etiologic or syndromic diagnosis on the basis of neuroimaging alone was found. 65 , 69 , 74 , 75 The authors of 3 studies reported the results on unselected patients; Majnemer and Shevell 67 reported a diagnosis by this typed unselected investigation in 0.2%, Stromme 76 reported a diagnosis in 1.4% of patients, and van Karnebeek et al 40 reported a diagnosis in 2.2% of patients.

Although a considerable evolution has occurred over the past 2 decades in neuroimaging techniques and modalities, for the most part with the exception of proton magnetic resonance spectroscopy, this has not been applied or reported in the clinical situation of developmental delay/ID in childhood. Proton resonance spectroscopy provides a noninvasive mechanism of measuring brain metabolites, such as lactate, using technical modifications to MRI. Martin et al 77 did not detect any differences in brain metabolite concentrations among stratifications of GDD/ID into mild, moderate, and severe levels. Furthermore, they did not detect any significant differences in brain metabolite concentration between children with GDD/ID and age-matched typically developing control children. Thus, these authors concluded that proton resonance spectroscopy “has little information concerning cause of unexplained DD.” Similarly, the studies by Martin et al 77 and Verbruggen et al 71 did not reveal that proton magnetic resonance spectroscopy was particularly useful in the determination of an underlying etiologic diagnosis in children with unexplained developmental delay/ID.

All of these findings suggest that abnormal findings on MRI are seen in ∼30% of children with developmental delay/ID. However, only in a fraction of these children does MRI lead to an etiologic or syndromic diagnosis. The precise value of a negative MRI result in leading to a diagnosis has not yet been studied in detail. In addition, MRI in the young child with developmental delay/ID invariably requires sedation or, in some cases, anesthesia to immobilize the child to accomplish the imaging study. This need, however, is decreasing with faster acquisition times provided by more modern imaging technology. Although the risk of sedation or anesthesia is small, it still merits consideration within the decision calculus for practitioners and the child’s family. 63 , 78 , 79 Thus, although MRI is often useful in the evaluation of the child with developmental delay/ID, at present, it cannot be definitively recommended as a mandatory study, and it certainly has higher diagnostic yields when concurrent neurologic indications exist derived from a careful physical examination of the child (ie, microcephaly, microcephaly, seizures, or focal motor findings).

The following is the recommended medical genetic diagnostic evaluation flow process for a new patient with GDD/ID. All patients with ID, irrespective of degree of disability, merit a comprehensive medical evaluation coordinated by the medical home in conjunction with the medical genetics specialist. What follows is the clinical genetics evaluation ( Fig 1 ):

Diagnostic process and care planning. Metabolic test 1: blood homocysteine, acylcarnitine profile, amino acids; and, urine organic acids, glycosaminoglycans, oligosaccharides, purines, pyrimidines, GAA/creatine metabolites. Metabolic test 2 based on clinical signs and symptoms. FH, family history; MH, medical history; NE, neurologic examination; PE, physical and dysmorphology examination.

Complete medical history; 3-generation family history; and physical, dysmorphologic, and neurologic examinations.

If the specific diagnosis is certain, inform the family and the medical home, providing informational resources for both; set in place an explicit shared health care plan 80 with the medical home and family, including role definitions; provide sources of information and support to the family; provide genetic counseling services by a certified genetic counselor; and discuss treatment and prognosis. Confirm the clinical diagnosis with the appropriate genetic testing, as warranted by clinical circumstances.

If a specific diagnosis is suspected, arrange for the appropriate diagnostic studies to confirm including single-gene tests or chromosomal microarray test.

If diagnosis is unknown and no clinical diagnosis is strongly suspected, begin the stepwise evaluation process:

Chromosomal microarray should be performed in all.

Specific metabolic testing should be considered and should include serum total homocysteine, acyl-carnitine profile, amino acids; and urine organic acids, glycosaminoglycans, oligosaccharides, purines, pyrimidines, GAA/creatine metabolites.

Fragile X genetic testing should be performed in all.

If no diagnosis is established:

Male gender and family history suggestive X-linkage, complete XLID panel that contains genes causal of nonsyndromic XLID and complete high-density X-CMA. Consider X-inactivation skewing in the mother of the proband.

Female gender: complete MECP2 deletion, duplication, and sequencing study.

If microcephaly, macrocephaly, or abnormal findings on neurologic examination (focal motor findings, pyramidal signs, extrapyramidal signs, intractable epilepsy, or focal seizures), perform brain MRI.

If brain MRI findings are negative or normal, review status of diagnostic evaluation with family and medical home.

Consider referrals to other specialists, signs of inborn errors of metabolism for which screening has not yet been performed, etc.

If no further studies appear warranted, develop a plan with the family and medical home for needed services for child and family; also develop a plan for diagnostic reevaluation.

Health care systems, processes, and outcomes vary geographically, and not all of what is recommended in this clinical report is easily accessible in all regions of the United States. 21 , 81 , – 84 Consequently, local factors affect the process of evaluation and care. These arrangements are largely by local custom or design. In some areas, there may be quick access and intimate coordination between the medical home and medical genetics specialist, but in other regions, access may be constrained by distance or by decreased capacity, making for long wait times for appointments. Some general pediatricians have the ability to interpret the results of genetic testing that they may order. In addition, children with GDD or ID are often referred by pediatricians to developmental pediatricians, child neurologists, or other subspecialists. It is appropriate for some elements of the medical genetic evaluation to be performed by physicians other than medical geneticists if they have the ability to interpret the test results and provide appropriate counseling to the families. In such circumstances, the diagnostic evaluation process can be designed to address local particularities. The medical home is responsible for referrals of the family and child to the appropriate special education or early developmental services professional for individualized services. In addition, the medical home can begin the process of the diagnostic evaluation if access is a problem and in coordination with colleagues in medical genetics. 80 , 85 What follows is a suggested process for the evaluation by the medical home and the medical genetics specialist and only applies where access is a problem; any such process is better established with local particularities in mind:

Medical home completes the medical evaluation, determines that GDD/ID is present, counsels family, refers to educational services, completes a 3-generation family history, and completes the physical examination and addresses the following questions:

Does the child have abnormalities on the dysmorphologic examination?

If no or uncertain, obtain microarray, perform fragile X testing, and consider the metabolic testing listed previously. Confirm that newborn screening was completed and reported negative. Refer to medical genetics while testing is pending.

If yes, send case summary and clinical photo to medical genetics center for review for syndrome identification. If diagnosis is suspected, arrange for expedited medical genetics referral and hold all testing listed above. Medical geneticist to arrange visit with genetic counselor for testing for suspected condition.

Does the child have microcephaly, macrocephaly, or abnormal neurologic examination (listed above)? If “yes,” measure parental head circumferences and review the family history for affected and unaffected members. If normal head circumferences in both parents and negative family history, obtain brain MRI and refer to medical genetics.

Does child also have features of autism, cerebral palsy, epilepsy, or sensory disorders (deafness, blindness)? This protocol does not address these patients; manage and refer as per local circumstances.

As above are arranged and completed and negative, refer to medical genetics and hold on additional diagnostic testing until consultation completed. Continue with current medical home family support services and health care.

Should a diagnosis be established, the medical home, medical geneticist, and family might then agree to a care plan with explicit roles and responsibilities of all.

Should a diagnosis not be established by medical genetics consultation, the medical home, family, and medical geneticist can then agree on the frequency and timing of diagnostic reevaluation while providing the family and child services needed.

Several research reports have cited whole-exome sequencing and whole-genome sequencing in patients with known clinical syndromes for whom the causative gene was unknown. These research reports identified the causative genes in patients with rare syndromes (eg, Miller syndrome, 86 Charcot-Marie-Tooth disease, 87 and a child with severe inflammatory bowel disease 88 ). Applying similar whole-genome sequencing of a family of 4 with 1 affected individual, Roach et al 86 identified the genes for Miller syndrome and primary ciliary dyskinesia. The ability to do whole-genome sequencing and interpretation at an acceptable price is on the horizon. 87 , 89 The use of exome or whole-genome sequencing challenges the field of medical genetics in ways not yet fully understood. When a child presents with ID and whole-genome sequencing is applied, one will identify mutations that are unrelated to the question being addressed, in this case “What is the cause of the child’s intellectual disability?” One assumes that this will include mutations that families do not want to have (eg, adult-onset disorders for which no treatment now exists). This is a sea change for the field of medical genetics, and the implications of this new technology have not been fully explored. In addition, ethical issues regarding validity of new tests, uncertainty, and use of resources will need to be addressed as these technologies become available for clinical use. 90 , 91  

The medical genetic diagnostic evaluation of the child with GDD/ID is best accomplished in collaboration with the medical home and family by using this clinical report to guide the process. The manner in which the elements of this clinical protocol are applied is subject to local circumstances, as well as the decision-making by the involved pediatric primary care provider and family. The goals and the process of the diagnostic evaluation are unchanged: to improve the health and well-being of those with GDD/ID. It is important to emphasize the new role of the genomic microarray as a first-line test, as well as the renewal of efforts to identify the child with an inborn error of metabolism. The future use of whole-genome sequencing offers promise and challenges needing to be addressed before regular implementation in the clinic.

John B. Moeschler, MD, MS, FAAP, FACMG

Michael Shevell, MDCM, FRCP

Robert A. Saul, MD, FAAP, Chairperson

Emily Chen, MD, PhD, FAAP

Debra L. Freedenberg, MD, FAAP

Rizwan Hamid, MD, FAAP

Marilyn C. Jones, MD, FAAP

Joan M. Stoler, MD, FAAP

Beth Anne Tarini, MD, MS, FAAP

Stephen R. Braddock, MD

Katrina M. Dipple, MD, PhD – American College of Medical Genetics

Melissa A. Parisi, MD, PhD – Eunice Kennedy Shriver National Institute of Child Health and Human Development

Nancy Rose, MD – American College of Obstetricians and Gynecologists

Joan A. Scott, MS, CGC – Health Resources and Services Administration, Maternal and Child Health Bureau

Stuart K. Shapira, MD, PhD – Centers for Disease Control and Prevention

American Academy of Pediatrics

chromosome microarray

central nervous system

copy number variant

computed tomography

fluorescent in situ hybridization

guanidinoacetate

global developmental delay

intellectual disability

X-linked intellectual disability

This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.

The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

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• Published: 18 May 2020

Clinical Characteristics of Developmentally Delayed Children based on Interdisciplinary Evaluation

• S. W. Kim 1 ,
• H. R. Jeon 1 ,
• H. J. Jung 2 ,
• J. A. Kim 2 ,
• J.-E. Song 3 &
• J. Kim   ORCID: orcid.org/0000-0003-4693-8400 4  

Scientific Reports volume  10 , Article number:  8148 ( 2020 ) Cite this article

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• Autism spectrum disorders
• Risk factors

The aim of this study is to examine the clinical characteristics of children suspected to have neurodevelopmental disorders and to present features that could be helpful diagnostic clues at the clinical assessment stage. All children who visited the interdisciplinary clinic for developmental problems from May 2001 to December 2014 were eligible for this study. Medical records of the children were reviewed. A total of 1,877 children were enrolled in this study. Most children were classified into four major diagnostic groups: global developmental delay (GDD), autism spectrum disorder (ASD), developmental language disorder (DLD) and motor delay (MD). GDD was the most common (43.9%), and boys were significantly more predominant than girls in all groups. When evaluating the predictive power of numerous risk factors, the probability of GDD was lower than the probability of ASD among boys, while the probability of GDD increased as independent walking age increased. Compared with GDD and DLD, the probability of GDD was increased when there was neonatal history or when the independent walking age was late. Comparison of ASD and DLD showed that the probability of ASD decreased when a maternal history was present, whereas the probability of ASD increased with male gender. To conclude, the present study revealed the clinical features of children with various neurodevelopmental disorders. These results are expected to be helpful for more effectively flagging children with potential neurodevelopmental disorders in the clinical setting.

Introduction

Developmental disabilities caused by dysfunction of the central nervous system, including the brain, are called neurodevelopmental disorders, and children with neurodevelopmental disorders have difficulties in various fields including physical, linguistic, behavior and learning 1 . According to a previous study conducted in the United States, 5–17% of children suffer from developmental disabilities, and recent trends have shown a gradual increase 2 . Limitations due to neurodevelopmental disorders might continue throughout life, and individuals with these disorders may require special services, health care and support 3 . These factors cause enormous social costs to a country as well as economic and psychological burdens for the families of children with developmental disabilities 4 .

The cause of neurodevelopmental disorders varies, and it is difficult to distinguish between children with neurodevelopmental disorders and typically developing children in early infancy. Even if the neurodevelopmental disorder is caused by nonprogressive factors, the clinical phenotype may change over time as the central nervous system matures 5 . Therefore, children’s symptoms are different according to their age and severity, and the necessary interventions will vary accordingly. As a result, the diagnosis of a neurodevelopmental disorder can vary greatly depending on the clinician’s perspective, and the treatment or intervention or social support offered may differ according to diagnosis. The time at which an expert is consulted varies widely from newborn to school-aged 6 . As shown in previous studies 7 , 8 , intervention during the period when the brain is developing rapidly can minimize disabilities and reduce the gap in developmental delay; as such, it is important to start precise intervention early. Neurodevelopmental disorders express various features, and the degree of influence by developmental domain varies from case to case. Because of the multi-morbidity feature, attempting to intervene by focusing on only one problem can lead to not only overlooking other accompanying problems but also a problem of inefficient use of limited intervention resources.

To compensate for difficulties in dealing with the complexity of neurodevelopmental disorders, an interdisciplinary clinic named the Developmental Delay Clinic (DDC) has been operating in our hospital. In this clinic, three specialists (a pediatric neurologist, pediatric physiatrist and pediatric psychologist) work together to provide comprehensive diagnoses and intervention plans. The three specialists, depending on area of expertise, each examine children, prescribe necessary tests, share and discuss the results of physical and neurological examinations and various tests and produce a precise diagnosis with a balanced intervention plan for each child. In this study, the authors aimed to identify meaningful factors for diagnosis and to determine if it is possible to distinguish major neurodevelopmental disorders at the clinical assessment stage.

Children who visited the DDC in our hospital with complaints of any developmental problems from May 2001 to December 2014 were included in this study. The total number of subjects was 1,877. Approval to perform this retrospective study was obtained from our Institutional Review Board (IRB) and research ethics committee (National Health Insurance Medical Center, NHIMC 2015-09-016). The need for informed consent was formally waived by the IRB and research ethics committee. All methods were performed in accordance with relevant guidelines and regulations.

All patients who visited the DDC for the first time had a history taken, and data were gathered according to the prescribed protocol. Data such as birth history, prenatal history, family history and other medical history were collected from a paper questionnaire. Birth history included intrauterine period and birth weight. Prenatal history included fetal distress, problems related to amniotic fluid or placenta, intrauterine growth retardation (IUGR), and fetal movement abnormality. Events such as fetal apnea, meconium aspiration and neonatal seizures were considered in the neonatal history. Postnatal history included infections such as sepsis, infantile spasm, and febrile convulsion. The presence of family history, such as language delay, autism spectrum disorder, and intellectual disability, and maternal history during the pregnancy period, such as anxiety or insomnia, depression, smoking and drinking, were also assessed in the survey.

After assessing histories through the questionnaire, the three specialists examined the child and prescribed necessary tests according to protocol. The diagnostic protocol was composed of two categories: required tests applied to all children and selective tests applied to some patients who needed those tests, based on each specialist’s judgment 9 (Fig.  1 , Supplementary 1).

Diagnostic protocol for children visited developmental delay clinic.

The diagnosis was determined by discussion among the three specialists in reference to each child’s clinical findings and standardized developmental assessment results. The diagnoses were divided into two categories: either a phenomenological diagnosis based on the child’s current condition or an etiological diagnosis based on the pathophysiology of the condition. All these phenomenological diagnoses were classified into four major groups according to the child’s main features: global developmental delay (GDD), autism spectrum disorder (ASD), developmental language disorder (DLD) and motor delay (MD). The GDD group included diagnoses such as GDD and intellectual disability. GDD refers to children with significant delays in more than two of the following developmental domains: gross motor/fine motor, speech/language, intelligence, social interaction and self-care. In general, children under five years of age who met the requirements were diagnosed with GDD, while older children who could be examined using a reliable and formal intelligence test were diagnosed with intellectual disability 10 . Diagnoses such as reactive attachment disorder and social communication disorder were included in the ASD group. Those in the ASD group were diagnosed based on diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition (DSM-IV) 11 . However, since it has been updated from DSM-IV to DSM-V, the term ASD is used in this paper to prevent confusion. MD was defined as significant impairment of gross and/or fine-motor function compared with other developmental domains. Cerebral palsy and developmental coordination disorder were included in this group. DLD was defined as significant impairment of speech and language ability compared with other developmental domains. In this context, “significant” meant more than two standard deviations below the average value for the same age 10 . Etiological diagnoses included chromosomal and genetic anomalies, myopathy, and metabolic disease, among others.

Statistical analysis

SAS ver. 9.2 (SAS Institute, Cary, NC, USA) was used for statistical analysis. The results of the survey were obtained using the Kruskal-Wallis test with Bonferroni correction and logistic regression analysis. The level of significance was set at p < 0.05.

A total of 1,877 children were enrolled in this study. When divided into classes according to major phenomenological diagnosis, GDD accounted for the largest number, with 824 children (43.9%), followed by ASD with 430 (22.9%), DLD with 389 (20.7%) and MD with 72 (3.8%). Only 16 children (0.9%) were finally diagnosed as developing normally after all tests and examinations were given. Boys were more predominant than girls, with 1,316 (70.1%) and 561 (29.9%), respectively (p < 0.05). The age at which children visited the DDC ranged from 2 months to 192 months, and the average age was 50.9 ± 30.0 months. The corrected age was used for preterm children until they reached two years old. Two hundred thirty-four children (12.5%) out of the total could be diagnosed with an etiological diagnosis. Among these, hypoxic ischemic encephalopathy accounted for the largest number, with 58 children (24.8%), followed by chromosomal and/or genetic abnormalities with 53 children (22.6%) and congenital anomalies of the brain with 33 children (14.0%). Among the children who underwent a brain MRI, abnormal findings were mostly found in MD with 27.8%, which was significantly higher than ASD and DLD (p < 0.05) (Table  1 ).

With respect to preterm birth (gestational age less than 37 weeks), the history of preterm birth was the most prevalent in MD (29.2%), which was significantly higher than that in GDD (12.5%), ASD (10.9%) and DLD (8.7%) (p < 0.05). A history of low birth weight (LBW, birth weight less than 2,500 grams) was most common in MD (44.4%), which was significantly higher than that in ASD (20.9%) and DLD (25.4%) (p < 0.05) but not GDD (32.5%) (p = 0.426). Prenatal histories were most prevalent in MD (5.6%), which was significantly higher than in ASD and DLD (p < 0.05). Neonatal histories were also most prevalent in MD (29.2%), which was significantly higher than in the other three groups (p < 0.05). GDD and MD had a significantly higher prevalence of postnatal history compared with ASD and DLD (p < 0.05), but the difference between GDD and MD was not significant. Among family histories, language delay was the most common across all diagnosis groups, but the prevalence of having a family history did not differ significantly among the groups (p = 0.445). With regard to maternal histories, a maternal history of having anxiety or insomnia was the most common type in GDD, ASD and DLD, but drugs or drinking alcohol were the most common in MD. The percentage of cases with a maternal history did not differ significantly across the groups (p = 0.294) (Table  2 ).

Among the various risk factors mentioned above, logistic regression analysis performed to compare the groups and to determine if certain risk factors contributed to being diagnosed with GDD, ASD and DLD. When comparing GDD with ASD, the risk of having GDD decreased with boys and the presence of family history, while the risk increased with the presence of neonatal, postnatal and maternal history, later independent walking age (a representation of delayed motor milestone) and abnormal findings in the brain MRI. After controlling for confounders, gender and independent walking age showed significant between-group differences. When comparing GDD with DLD, the risk of having GDD was lower in boys and with the presence of a family history, while the risk increased with presence of the prenatal, neonatal and postnatal history, later independent walking age and abnormal findings in the brain MRI. After controlling for confounders, neonatal history and independent walking age showed significant between-group differences. When comparing ASD with DLD, the risk of having ASD was higher in boys, while the risk decreased with the presence of maternal history. The results were the same after controlling for confounders (Table  3 , Fig.  2 ).

Distinctive clinical features among different diagnosis.

When receiver operating characteristic (ROC) curve analysis was performed to confirm the predictive power of these models, the model comparison of GDD vs. ASD and the model comparison of GDD vs. DLD showed good predictive power, while the model comparison of ASD vs. DLD had poor predictive power. Hosmer and Lemeshow’s Goodness-of-Fit Test revealed that all three logistic regression models were fit to predict the risk factors (Table  4 ).

The prevalence of developmental disabilities has risen in recent years with increases in high-risk pregnancies such as aged pregnancy, improved survival of high-risk infants due to medical technology advancement, and improved awareness and diagnosis of developmental disabilities 2 . The goal of early intervention for children with developmental disabilities is to prevent or minimize delays in all developmental domains, and early intervention allows children to achieve developmental milestones through the provision of enriched environments. Additionally, such interventions help caregivers cope efficiently with their children in daily life 12 . As seen in this study, the symptoms of children with neurodevelopmental disorders are very diverse, and the timing and symptoms of caregivers’ perception of something wrong in their children also vary. In addition, during the brain development period, one developmental domain affects the development of other domains, thus indicating multi-morbidity features. Proper intervention is important, but intervention is not always necessary. In some cases, it is more important to educate parents and modify the home environment than to use special resources. To effectively use limited resources, it is important to accurately diagnose neurodevelopmental disorders, which represent a multi-morbidity feature.

Among the patients who visited the DDC during the past 14 years, boys outnumbered girls in all diagnostic groups, which is consistent with previous studies 2 , 13 . Regarding etiological diagnosis, hypoxic ischemic encephalopathy was the most prevalent, followed by chromosomal and genetic abnormalities and congenital anomalies of the brain. These three factors accounted for 61.5% of the total etiologic causes. This outcome is similar to that of a study conducted by Shevell et al . 14 indicating that four causes, i.e., the three causes mentioned above plus poisoning, accounted for 68.9% of total cases with a known etiological basis. There were no children with poisoning in the present study, which could be due to differences in socio-cultural backgrounds. However, more attention to antenatal poisoning might be needed, based on the recent increase in poisoning cases in Korea 15 .

In cases of preterm birth and LBW, which are known as the strongest risk factors for developmental disabilities 16 , a history of preterm birth was significantly more common in MD than in GDD, ASD and DLD. In contrast, a history of LBW was not significantly different between MD and GDD. It could be posited that the risk of GDD increased in cases of small for gestational age even in full-term births. Arcangeli et al . 17 reported that compared with children of appropriate size for their gestational age, children who had a history of being small for their gestational age or who had fetal growth retardation, even in full-term births, showed lower neurodevelopmental scores. Takeuchi et al . 18 reported that being small for gestational age is a risk factor for developmental disabilities, even in full-term babies. These results were consistent with the present study, and more attentive follow-up regarding developmental course is needed for children with a history of being small for gestational age.

Kumar et al . 19 reported that the prevalence of neurodevelopmental disorders was higher in groups having family histories of neurodevelopmental disorders, such as epilepsy, GDD, MD, vision or hearing defects, compared with groups without such histories. Among the types of family histories, a history of language delay was seen the most in all diagnostic groups in this study. This finding could be explained by several factors: language delay is often present in various neurodevelopmental disorders, and the recognition and diagnosis of various neurodevelopmental disorders has improved in recent years, but this was not the case before. It may have been diagnosed as language delay 13 . In addition, it is possible that ASD has been diagnosed as other diseases, such as GDD or language delay, due to negative social perception of the diagnosis in Korea. Several studies have previously revealed that delay in one developmental domain often correlates with delay in other domains. Rechetnikov et al . 20 stated that there was a correlation between motor impairment and speech and language disorder. Wang et al . 21 reported that motor skill and communication skill were correlated with each other and that the motor skill of a one-and-a-half-year-old could predict the communication skill of a three-year-old. Language delay was predominant among the chief complaints of children who visited the DDC, but their final diagnosis was not limited to DLD. Shevell et al . 22 reported that approximately three-quarters of children who were diagnosed with DLD before their fifth birthday showed some limitation of not only language but also communication, motor skill and social function at an early school age. Overall, the physicians would carefully assess all of the developmental domains, even if the chief complaints of parents were language delay, and would also give them a proper intervention plan focusing on the other domains.

This study has a few limitations. First, it is a single-center study, and most of the included children were from a metropolitan area in the Northern Gyeonggi territory. Second, children suspected to have cerebral palsy often visited the outpatient clinic of the rehabilitation department instead of the DDC for their initial evaluation, so the proportion of children with cerebral palsy was low in this study. Third, although the diagnosis may change over time, the study was conducted based on the initial diagnosis. Nevertheless, this study is meaningful in that it is the first study to present a probabilistic model in the clinical evaluation of children with suspected neurodevelopmental disorders. Several papers on the diagnosis of neurodevelopmental disorders that suggest diagnostic steps for GDD and ASD have been published thus far 23 , 24 , 25 , 26 , 27 . However, in contrast to the present study, there were no articles suggesting probabilistic models that included comprehensive history taking and clinical diagnosis. Additionally, most previous studies were confined to one diagnosis, such as cerebral palsy or intellectual disabilities, whereas this study represents the many children who visited interdisciplinary clinics for 14 years with various chief complaints about development.

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S.W., H.J. and J.-E. conceived of the presented concept and revised the article. J.K. and H.R. developed the theory, interpreted of data and drafted the article. J.A. collected and analyzed the data and drafted the article. All authors discussed the results and contributed to the final manuscript and had complete access to the study data that support the publication. All authors read and approved the final manuscript.

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Kim, S.W., Jeon, H.R., Jung, H.J. et al. Clinical Characteristics of Developmentally Delayed Children based on Interdisciplinary Evaluation. Sci Rep 10 , 8148 (2020). https://doi.org/10.1038/s41598-020-64875-8

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Article Contents

Etiology of gdd and id, additional investigations, recommendations, acknowledgements, canadian paediatric society mental health and developmental disabilities committee.

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Evaluation of the child with global developmental delay and intellectual disability

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Stacey A Bélanger, Joannie Caron, Evaluation of the child with global developmental delay and intellectual disability, Paediatrics & Child Health , Volume 23, Issue 6, September 2018, Pages 403–410, https://doi.org/10.1093/pch/pxy093

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Global developmental delay (GDD) and intellectual disability (ID) are common concerns in the paediatric setting. Etiologies of both conditions are highly heterogeneous. The American Academy of Pediatrics, the American Academy of Neurology and the British Columbia-based Treatable Intellectual Disability Endeavor (TIDE) protocol have each proposed multitiered investigations of GDD/ID to guide physicians toward an understanding of etiology that optimizes therapeutic yield. This statement provides a framework for the clinical investigation of GDD/ID in children, along with an updated protocol for Canadian physicians to follow in the etiological investigation of GDD/ID. The revised protocol is based on current knowledge and existing guidelines. Key elements of investigation include formal vision and hearing testing, chromosomal microarray, Fragile-X DNA testing and first-tier testing for treatable inborn errors of metabolism. Brain imaging is recommended in the presence of specific neurological findings.

Global developmental delay (GDD) and intellectual disability (ID) affect up to three per cent of the paediatric population ( 1 , 2 ). The diagnosis of GDD is limited to children younger than 5 years old, but these children often evolve to meet diagnostic criteria for ID and probably represent the same population ( Table 1 ). Because the etiological diagnoses of GDD and ID overlap, it is natural that investigations in pursuit of a definitive diagnosis for either disorder are similar. Early detection is crucial for initiating rehabilitation services and treatment as soon as possible. The etiology of GDD/ID can be identified in many cases (40% to 80%) ( 3 ). Therefore, it is essential that general paediatricians in Canada coordinate the etiological evaluation of this patient population with subspecialists, using an integrative approach.

Diagnostic criteria

Data taken from refs. ( 1 , 2 ). SD Standard deviation

*The various levels of severity are no longer based on the intellectual quotient (IQ) but are, rather, defined by adaptive functioning ( 1 ).

A diagnosis is critical because it allows for ( 2 ):

Timely initiation of causal treatment or supportive management,

Prevention of complications,

Improved prognostication,

Accurate genetic counselling regarding recurrence risk and prenatal/preimplantation genetic diagnosis, when indicated,

Better access to services in the community, and

Resolution of a diagnostic odyssey or (better still) avoidance of inappropriate, costly and traumatizing tests.

The goal of this statement is to provide a framework for etiological investigation of GDD/ID in children that helps clinicians to implement evidence-based guidelines. We also propose a stepwise approach suited for clinical practice in Canada, always understanding that it must be tailored to the specific clinical context and availability of local resources.

The probability of finding an etiological diagnosis varies in different studies and according to the kind of investigation and the severity of GDD/ID. In severe ID (as defined in DSM-5), an identifiable cause was detected in up to 80% of cases ( 4 , 5 ). The yield appears to be lower in mild ID, with a cause identified in approximately 24% of cases ( 6 ). The categories of etiological diagnosis and proportion of diagnostic yield for the most common diagnoses are presented in Table 2 .

Causes of global developmental delay/intellectual disability

Data taken from ref. ( 3 ).

*Percentage of total cases of GDD/ID with an identified etiologic diagnosis who fall into this specific category.

Etiological investigation

Algorithms recommended by the American Academy of Pediatrics (AAP) ( 2 ), the American Academy of Neurology (AAN) ( 4 ) and the Treatable Intellectual Disability Endeavour (TIDE) protocol ( 5 ) are intended to simplify investigation of GDD/ID by limiting tests that are time-consuming or not clinically relevant and to promote efficient use of limited health care resources.

Each algorithm was developed to screen for the most common or treatable etiologies first. By contrast, other pathways propose an approach based on checklists and likelihood ratio models, stopping investigation when the clinician feels that it would not alter outcome, even without a diagnosis ( 3 ). One important ‘clinical pearl’ is to look for clinical characteristics pointing toward a specific etiology and order testing for that diagnosis first. When no apparent cause can be identified, a stepwise approach—conducted in collaboration with a geneticist—is recommended, with paediatricians leading the investigation whenever possible. See Figure 1 for a suggested approach to testing.

Algorithm for investigating global developmental delay or intellectual disability. Figure available in colour online. EEG Electroencephalogram; GDD Global developmental delay; ID Intellectual disability; MRI magnetic resonance imaging; XLID X-linked intellectual disability

History and physical examination

In one recent review, an etiological diagnosis based on history and physical examination was found in 12.5% to 38.6% of cases ( 3 ), confirming that these steps mark the most important phase of investigation ( 2 , 3 , 7 , 8 ). A three-generation family history, a psychosocial history, detailed prenatal and birth histories and the timing of major milestones should be recorded as accurately as possible ( Table 3 ). A neurodevelopmental assessment, including current developmental level and a systematic physical examination ( Table 3 ) can either point toward a specific diagnosis or guide laboratory testing. When a specific etiology is suspected at that point or when a family history of disorder associated with GDD/ID has been established, specific testing for this disorder should be ordered first ( Figure 1 ).

History and physical and neurodevelopmental exams

GDD Global developmental delay; ID Intellectual disability

Sensory evaluation

According to the AAN ( 4 ) and other reviews ( 5 , 7 , 9 ), children with GDD/ID should be referred for a formal assessment of their vision (optometry or ophthalmology) and hearing. Identifying a sight or hearing deficit can alter management course and guide further investigation.

Genetic testing

Chromosome microarray.

The use of chromosome microarray (CMA, also referred to as comparative genomic hybridization or CGH) as a first-line investigation in children with GDD/ID, is endorsed by the AAP, the AAN, the International Standard Cytogenetic Array and the American College of Medical Genetics ( 2 , 4 , 9 , 10 ). It is the single test with the best diagnostic yield ( 7 , 8 ) (at 8% to 20%), exceeded in efficacy only by clinical evaluation from an experienced clinician specializing in GDD/ID ( 2 , 4 , 11 ). The variation in yield reported in different studies can be explained by the absence of stratification for severity and the presence of other anomalies. Therefore, it remains uncertain whether CMA is useful in mild (according to DSM-5) familial ID. Those patients could simply represent the lower percentiles of the IQ Gauss curve and the etiologies are often multifactorial. When multiple congenital anomalies are present, the American College of Medical Genetics still recommends CMA as a first-line investigation, unless a specific diagnosis is being considered ( 10 ).

The use of standard karyotyping is not recommended as a first-line test, because its sensitivity is less than one-half that of CMA in children diagnosed with GDD/ID. The resolution of conventional chromosomal analysis is 5 Mb to 10 Mb compared with 0.05 Mb to 0.1 Mb with CMA. However, karyotyping is recommended instead of CMA for clinically suspected aneuploidy (e.g., Turner syndrome, trisomy 21) or a family history of chromosomal rearrangements or multiple spontaneous abortions ( 4 , 12 ). For the latter scenario, parental chromosome karyotyping should be ordered first.

Fragile X DNA testing

For children with ID, Fragile X is the most common genetic cause, representing 2% to 6% of affected boys and 1% to 4% of affected girls. Because the clinical phenotype is often nonspecific in infants and young children with Fragile X, AAP and AAN guidelines both recommend that Fragile X DNA (FMR1) testing be considered as part of first-line investigation for boys and girls with GDD/ID as defined in the DSM-5 ( 1 , 2 , 4 , 9 , 12 , 13 ). Panels for X-linked ID exist but should only be considered for families with two or more affected males. They should be guided by a geneticist ( 2 ).

Rett syndrome testing

Rett syndrome is found in 1.5% of girls with moderate-to-severe ID ( 2 ). According to the AAP and the AAN, MECP2 molecular analysis should be ordered when characteristic symptomatology is present (i.e., initially normal development followed by loss of speech and purposeful hand use, stereotypical hand movement, gait abnormalities) or for moderately-to-severely affected girls ( 2 , 4 ).

Whole-exome or -genome sequencing

Whole-exome sequencing permits analysis of coding regions for known genes and the identification of causal mutations in up to 40% of patients with severe ID ( 14 ). This relatively new technique is becoming clinically accessible at lower cost in some regions of Canada. Variations of unknown significance are still a challenge and need to be interpreted with caution. Given these limitations, exome or genome sequencing is not actually recommended for primary care physicians but may become a first-line investigation in the near future. Use of this test by medical geneticists in moderate-to-severe ID or in syndromic cases is endorsed by the Canadian College of Medical Geneticists ( 15 ).

Metabolic workup

Red flags suggestive of an inborn error of metabolism (IEM) are listed in Table 4 . Even if these findings, when present, raise the diagnostic yield of a metabolic workup, some IEMs present in a more subtle manner ( 5 ). In 2011, the AAN recommended that metabolic testing be performed only in the presence of strong clinical suspicion, in the absence of neonatal screening or after genetic testing and neuroimaging have not been diagnostic ( 4 ). As Canada does not have a universal newborn screening panel for hereditary disorders, neonatal screening programs vary among provinces/territories. Even with an effective screening program, some IEMs are easy to miss ( 2 , 5 ).

Red flags suggestive of inborn errors of metabolism

Data taken from ref. ( 5 ).

IEM Inborn error of metabolism ; SD Standard deviation.

While rapid access to a clinical geneticist or metabolic specialist for an evaluation identifying the most probable IEM would be ideal, it is not a reality in most of Canada. Also striking is that as much as two-thirds of children with GDD/ID have no recognizable pattern of symptoms pointing toward a specific diagnosis. Nonspecificity often precludes the timely identification of a potentially treatable disorder, especially in late-onset disorders or in milder cases, where complete symptomatology has not developed. The typical metabolic workup (lactate, ammonia, chromatography of plasma amino acids and urinary organic acids) has a diagnostic yield of less than 1% to 5% ( 7 ), therefore supporting testing only when clinical red flags are present. However, previous studies were designed to identify an etiological yield and ignored the ‘therapeutic yield’ (i.e., the identification of a treatable disorder). Series with a more extended metabolic workup revealed a yield of more than 5% ( 5 ). It is also known that many treatable causes of GDD/ID do not present with developmental regression ( 5 ). One Canadian initiative from the B.C. Children’s Hospital ( 5 ), based on a review of the literature ( 16 , 17 ) identifying 89 IEMs amenable to treatment ( 17 ), aims to identify diseases before they become severe or irremediable complications develop. This protocol proposes a two-tiered algorithm. Tier 1 comprises a group of tests capable of identifying at least three IEMs, along with being readily accessible, minimally invasive and economical (in Vancouver, the whole test group costs about $528).

First-tier tests can identify 60% of currently known treatable IEMs causing ID. TreatableID.org is a web app ( www.treatable-id.org ) containing an algorithm that is regularly updated and describes 81 treatable IDs by their biochemical defects, diagnostic tests, clinical features and treatment modalities ( 17 ). The algorithm developers recommend tier-1 testing before genetic testing and neuroimaging, emphasizing the treatable nature of the disorders included and the relative urgency to identify them. The AAP recommends considering a metabolic workup at the same time or soon after CMA and Fragile X DNA testing ( 2 ). Tier-1 content is the same for both groups, except for the addition of copper and ceruloplasmin in the TIDE protocol. The AAN adds basic metabolic tests that can guide further testing: blood sugar, blood gas, lactate and creatine kinase. Table 5 and Figure 1 summarize first-tier laboratory investigations that should be ordered for all patients whose GDD/ID presents without a recognizable constellation of symptoms. An evaluation or a discussion with a metabolics specialist should be considered in the presence of red flags to tailor the laboratory investigation to that specific patient.

Tier-1 laboratory investigations for unexplained GDD/ID

ALT Alanine aminotransferase; AST Aspartate aminotransferase; GDD Global developmental delay; ID Intellectual disability; TSH Thyroid-stimulating hormone .

*Perform testing after 4 h to 8 h of fasting. **Recommended tier-1 test in the TIDE protocol, but not by AAP, AAN. Consider as a first-line investigation when hepatomegaly, dystonia, abnormal liver function findings are present. ***Clinical expert recommendation only. Consider biotinidase testing when severe hypotonia, seizures are present.

Thyroid testing

Hypothyroidism is a common, reversible cause of GDD/ID, with an incidence of approximately 1 out of 3,500 live births. Many study authors recommend screening for thyroid function ( 9 ), but the AAN states that the test does not need to be repeated when newborn screening is present ( 4 ). It is included in tier 1 ( Table 5 ) whether or not newborn screening is performed, such that acquired cases and hypothyroidism cases of hypothalamic or pituitary origin are not missed.

Iron, vitamin B12

An Australian group ( 9 ) recommends including complete blood count, ferritin and vitamin B12 in the initial workup of children with GDD/ID, especially when there is a history of pica or feeding restrictions. Iron deficiency anemia is an easily identifiable and treatable cause of altered development.

Lead poisoning can affect mental and physical development severely, especially in children younger than 5 years of age, leading to conditions such as autism spectrum disorder, loss of milestones (particularly related to language) and encephalopathy ( 18 ). The AAN is the only association to recommend lead level dosing in children with risk factors for exposure.

Testing for congenital infections

One study ( 9 ) suggests evaluating for congenital infections (TORCH: toxoplasmosis, others, rubella, CMV, herpes) when neurological anomalies, microcephaly, hearing and/or vision loss are present. Consider consulting with infectious disease specialists whenever a congenital infection is suspected.

Neuroimaging

Neuroimaging studies, including computed tomography or magnetic resonance imaging (MRI) reveal nonspecific abnormalities in approximately 30% of children with GDD/ID ([6], anywhere between 2% and 80%, depending on the study), but neuroimaging contributes to understanding the etiology underlying GDD/ID in only 0.2% to 2.2% of cases ( 2 ). The diagnostic yield for neuroimaging improves when an abnormal neurological examination, seizures or macro- or microcephaly are present. MRI is preferred to computed tomography because it is more sensitive for identifying clinically significant structural abnormalities and anomalies related to myelination and neuronal migration ( 2 , 4 , 9 ). Because sedation is often required to perform an MRI and finding an abnormality rarely leads to an etiological diagnosis, the AAP does not recommend neuroimaging as a routine investigation for children with GDD/ID. While the AAN recommends performing an MRI on all patients when chromosomal microarray, Fragile X testing and MECP2 (if indicated) have been inconclusive ( 4 ), others recommend this test only when neurological findings are present ( 9 ). According to expert opinion, a brain MRI with spectroscopy is indicated in all cases of intractable epilepsy or developmental regression.

Electroencephalogram

Uncontrolled epilepsy or epileptic syndromes, such as Landau-Kleffner syndrome, can be associated with developmental delays or regression. Seizures are a common symptom of IEMs. An electroencephalogram is justified when there is clinical suspicion of seizures, speech regression or neurodegenerative disorder ( 9 ).

A testing algorithm

A stepwise approach, based on the AAP’s 2014 policy statement, AAN’s 2011 guidelines and the TIDE protocol, with some modifications arising from the literature and expert consensus, is outlined above ( Figure 1 ).

GDD and ID are common disorders in children, and paediatricians are often involved in the etiological workup needed for diagnosis and next steps. Even if early identification and stimulation are of paramount importance, establishing an etiological diagnosis can help relieve family stress, limit invasive and inappropriate testing, guide prognosis and, in some cases, alter management and treatment and prevent complications. ‘Therapeutic yield’ is gaining on pure diagnostics as grounds for testing in this rapidly evolving field, and children with suspected GDD/ID are sure to benefit from the newer approaches described here.

The following recommendations are based on evidence-based clinical practice guidelines and expert opinion.

History and physical examination are still the best first steps for establishing a diagnosis and should be systematically conducted for each child with suspected global developmental delay (GDD) and intellectual disability (ID). When a more specific diagnosis is suspected following clinical evaluation, investigation to confirm that etiology should be ordered first.

When a specific diagnosis is not suspected following clinical evaluation, consider a stepwise approach to investigation. The scope of investigation will depend on paediatric experience, the accessibility of subspecialists and the availability of resources.

To promote an evidence-based approach to evaluating children with GDD/ID, coordinating physician efforts with testing at provincial/territorial or regional referring centres is essential.

Formal vision and hearing testing is critical for all patients with suspected GDD/ID.

When no etiological diagnosis has been identified following history and physical examination, Fragile X, chromosomal microarray, Tier-1 metabolic testing, +/- brain imaging is recommended. If the diagnosis is not established, consider consultation with genetics/metabolic specialist.

Chromosomal microarray and Fragile X DNA testing are first-line investigations for children with unexplained GDD/ID.

Evidence supports Tier-1 ( Table 5 ) testing for treatable inborn errors of metabolism (IEMs) in children with unexplained GDD/ID, even when clinical red flags are absent and a normal newborn screen has been obtained.

Brain imaging is recommended as a first-line investigation for patients with microcephaly, macrocephaly, seizures or abnormal neurological findings. For others, imaging may be postponed until first-line genetic and metabolic investigations have been performed. Consider the risks and benefits of sedation in each case. Magnetic resonance imaging (MRI) is the modality of choice.

Order lead level and iron studies for children at risk.

Whole-exome or -genome sequencing may be indicated in the clinical setting in future, when these tests are more readily available

All Canadian Paediatric Society position statements and practice points are reviewed regularly and revised as needed. Consult the Position Statements section of the CPS website www.cps.ca/en/ documents for the most current version. Retired statements are removed from the website.

This position statement has been reviewed by the Community Paediatrics Committee and the Early Years Task Force of the Canadian Paediatric Society.

Members: Debra Andrews MD (Chair), Stacey A. Bélanger MD (past Chair), Alice Charach MD, Brenda Clark MD (past member), Mark Feldman MD (Board Representative), Benjamin Klein MD, Daphne Korczak MD (past member), Oliva Ortiz-Alvarez MD

Liaisons: Sophia Hrycko MD, Canadian Academy of Child and Adolescent Psychiatry; Angie Ip MD, CPS Developmental Paediatrics Section; Aven Poynter MD, CPS Mental Health Section

Principal authors : Stacey A. Bélanger MD PhD, Joannie Caron MD

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Wright CF , McRae JF , Clayton S , et al.  Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders . Genet Med 2018 .

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van Karnebeek CD , Shevell M , Zschocke J , Moeschler JB , Stockler S . The metabolic evaluation of the child with an intellectual developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource . Mol Genet Metab 2014 ; 111 ( 4 ): 428 – 38 .

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An evaluation of the effectiveness of a therapeutic program for children with global developmental delay

Arab Gulf Journal of Scientific Research

ISSN : 1985-9899

Article publication date: 30 January 2023

Issue publication date: 25 October 2023

Global developmental delay (GDD) is highly prevalent among patients at child psychiatry clinics. However, preschool day treatment centers are currently scarce. As such, this study aimed to evaluate a program that was designed for children with GDD in order to improve their global skills and prepare them to join the school system.

Design/methodology/approach

This study utilized an observation retrospective design with a comparative group sample and included all children aged between 3 and 6 years who participated in the program for at least one academic year (experimental group). Their GDD diagnoses were based on the DSM-5 criteria (Diagnostic and Statistical Manual of Mental Disorders). Children with similar diagnoses who were on the waiting list constituted the control group. Pre- and post-scoring of the Children’s Global Assessment Scale (CGAS) were conducted by the children’s teacher and blinded investigator for the experimental group, while the children’s mothers conducted the post-CGAS scoring for the control group.

The pre- and post-CGAS scores for the experimental group were 49.5 ± 12.8 and 58.3 ± 12.7 and 47.3 ± 17.3 and 66.6 ± 17.3 for the control group, respectively ( p  = 0.001). The children in the experimental group scored significantly better than the control group with respect to securing places in integrated, regular classes in the education system ( p  = 0.001).

Research limitations/implications

This study had certain limitations. First, the number of children in the control group was relatively small. Second, the baseline skill levels of some of the children in the control group may have been lower than those of the children in the experimental group at the beginning of the evaluation; this may explain why they had been put on the waiting list. Third, the information was gathered retrospectively; this is a method that is known to have its own limitations.

Practical implications

The clinical implications of the study are that the early identification and referral of GDD are key elements in the rehabilitation of these children and that early intervention programs are necessary for cases of moderate and severe GDD. Primary care physicians should follow up with GDD patients to ensure that referrals are being appropriately sought (Choo et al ., 2019).

Originality/value

The program was effective in both increasing the general functioning skills of the children in the experimental group and preparing them to attend regular, integrated classes. The program should be expanded and made available to more children with GDD.

• Educational outcome
• Global development delay
• Preschool children

Al-Yamani, A.I. , Sulaiman, N.A. and Al-Ansari, A.M. (2023), "An evaluation of the effectiveness of a therapeutic program for children with global developmental delay", Arab Gulf Journal of Scientific Research , Vol. 41 No. 4, pp. 627-637. https://doi.org/10.1108/AGJSR-09-2022-0195

Emerald Publishing Limited

Copyright © 2023, Abyan Ismail Al-Yamani, Nabil Ali Sulaiman and Ahmed Malalla Al-Ansari

Published in Arab Gulf Journal of Scientific Research . Published by Emerald Publishing Limited. This article is published under the Creative Commons Attribution (CC BY 4.0) licence. Anyone may reproduce, distribute, translate and create derivative works of this article (for both commercial and non-commercial purposes), subject to full attribution to the original publication and authors. The full terms of this licence may be seen at http://creativecommons.org/licences/by/4.0/legalcode

1. Introduction

Global developmental delay (GDD) can be seen in children aged under 5 years who fail to meet expected developmental milestones in multiple intellectual and functional areas ( American Psychiatric Association, 2013 ). Children with GDD experience significant developmental delays in at least two developmental areas; these include physical, cognitive, communication, social or emotional, and adaptive skills ( Bryson et al. , 2018 ; Moeschler et al. , 2014 ). Children with GDD are considered a marginalized group with ignored specific needs ( Daelmans et al. , 2017 ). GDD affects 1–3 % of children under 5 years of age, making it one of the most prevalent conditions at pediatric clinics ( Mithyantha et al. , 2017 ). The majority of children with GDD live in low-income countries and are from families that experience high levels of poverty, lack education and do not have access to developmental evaluation tools and services ( Banks et al. , 2017 ). Possible etiologies of GDD include genetic disorders, perinatal asphyxia, toxin exposure, cerebral dysgenesis, metabolic disorders, neglect and psychosocial factors ( Jimenez-Gomez & Standridge, 2014 ). In cases without a specific etiology, prematurity and intrauterine growth restrictions are more frequently observed in patients with severe cases ( Thomaidis et al. , 2014 ). Specific diagnoses, including those with no known etiology, and early detection can provide parents with information on treatment options and enable them to access special education and social support resources ( Scherzer et al. , 2012 ; Suri & Vasudevan, 2017 ).

A Brazilian study that focused on the evaluation of functional and developmental prognoses of children with GDD as they entered school found that 80% had their diagnosis changed within their first 3 years of life; their mother’s age at birth, assistance to perform cognitive tasks and poor balance were determinant outcome factors ( Dornelas et al. , 2016 ). A Portage early education program for children with GDD in China succeeded in increasing their developmental quotient scores in gross and fine motor skills, adaptability, language and social abilities ( Liu et al. , 2018 ). Another study focused specifically on the improvement of social skills in children with GDD with or without developmental co-ordination disorder ( Tal-Saban et al. , 2021 ). In sum, there are inadequate results from evidence-based approaches; the effectiveness of early childhood delay projects in low-income countries cannot be evaluated. In high-income countries, the majority of intervention programs are family-based, and, even though such interventions occur in low-income countries as well, they are less than effective ( Smythe et al. , 2021 ). Regionally, a study in the United Arab Emirates estimated the weighted prevalence of clinically significant developmental delays to be 2.44% ( Eapen et al. , 2006 ), while a prospective study in Oman revealed that the most common etiology was perinatal asphyxia and that children predominantly presented clinically with abnormal neurological findings and microcephaly ( Koul et al. , 2012 ). An earlier study conducted in Bahrain that examined the etiology of mild type intellectual disability in school-age children found that 42% of the sample had no traceable etiology ( Al-Ansari, 1993 ).

In this study, we aimed to evaluate the effectiveness of a program that began in 2014 with the goal of making up for the deficits in children with GDD in two respects. The first indicator of effectiveness involved evaluating improvements in the children’s developmental spheres and general functioning, and the second involved examining their education placement outcomes at school entry age (i.e. 6 years). This program is the first of its kind in Bahrain and likely in the Arabian Gulf region as a whole.

2.1 Participants

This observational retrospective case control study was conducted in the GDD kindergarten unit at the Al Wafaa Centre at the Bahrain Association for Intellectual Disability and Autism in Bahrain during September 2021. The study included 82 children with GDD aged 3–6 years who were divided into two groups; there were 56 children in the experimental group and 26 in the control group. All 82 children had been diagnosed with GDD between 2016 and 2020 according to the relevant criteria of the fifth edition of the Diagnostic and Statistics Manual of Mental Disorders ( American Psychiatric Association, 2013 ). The final experimental group was reduced from 62 to 56 children with GDD that had been registered with the therapeutic kindergarten for at least one year. The control group of 26 children with GDD was on the waiting list for the therapeutic kindergarten due to either limited capacity or parents’ refusal a spot in the kindergarten.

2.2 Therapeutic program curriculum

Level 1: children with severe developmental delays

Level 2: children with moderate developmental delays

Level 3: children with mild developmental delays

Each level has a comprehensive compensatory plan that covers nine aspects related to child development, including visual sensation, tactile sensation, auditory sensation, body control, arithmetic ability, language ability, life skills, social ability and motor ability.

2.3 Data collection and procedures

A working team, including four teachers, two blind investigators and authors was established to discuss the operation procedures. The team finalized the data collection sheet and trained the team members on both Children’s Global Assessment Scale (CGAS) forms and how to fill it out. The team members examined the medical referral form and notes on the children’s progress throughout their time in the program. They also regularly reviewed the pre- and post-scores and CGAS scores for every child during data collection. The blind investigators were in charge of calculating the final scores, with the help of the children’s mothers, and defining the educational outcome for the control group. For the experimental group, the blind investigators and teachers calculated their pre- and post-scores separately. The mean of the scores from the teacher and the blind investigator was then calculated. Ethical approval for the study was obtained from the Administrative Council of the Bahrain Association for Intellectual Disability and Autism.

2.4.1 Data collection sheet

A data collection sheet was developed to assess the five main spheres used to define children’s levels of development (i.e. cognitive ability, language ability, motor ability, self-help and social ability). Each child’s performance for each ability was assessed in line with their age and determined to be either very good, good, acceptable, poor or very poor. The final score ranged from 1 to 100. We also collected demographic data on each child’s age, gender and family income, as well as on their father’s employment and education level.

Teacher assessment form A ( Appendix 1 ),

Blinded investigator assessment form B ( Appendix 2 ) and

Final assessment form C ( Appendix 3 ).

Finally, each child’s mother was asked to indicate whether their child was at home or was attending either regular school classes, integrated school classes, regular kindergarten or special needs kindergarten.

2.4.2 Children’s Global Assessment Scale

The Children’s Global Assessment Scale (CGAS; Appendix 4) was published in 1983 by Shaffer et al . with the aim of providing a standardized method for assessing the functioning abilities of children aged 4–16 years worldwide. This scale allows investigators to assess different aspects of a patient’s social and psychiatric functioning to provide a single, clinically expressive index of the severity of the disturbance. Final scores on the CGAS range from 1 to 100 ( Shaffer et al. , 1983 ).

2.5 Assessments

The teacher assessments were conducted by the centre’s kindergarten teachers. Two medical students from the Arabian Gulf University were asked to participate in the assessment of the children as blinded investigators. The assessment process was explained to both the teachers and the blinded investigators. For the experimental group, the investigators assessed the pre- and post-program scores, which were based on the performance of each child before and after the program, respectively. For the control group, the investigators assessed pre-program scores, which were based on written records, while the post-program scores were determined using interviews conducted by the blinded investigators with the mothers. A mean score from both the teachers and blinded investigators was then calculated.

The experimental and control groups were comparable in terms of age, gender and social status ( Table 1 ). The experimental group comprised 56 children, and there were 26 children in the control group. The mean ages of the children in the experimental and control groups were 4.21 ± 1.00 years and 5.56 ± 1.63 years, respectively. Boys accounted for 83% of the experimental group and 58% of the control group. The average family income of the children was around 500 BHD for both groups.

4. Discussion

The program in question is the first of its kind in Bahrain and likely the Arabic Gulf region as a whole. Overall, evaluation showed an increase in skills across all the measured areas as well as an increase in the children’s chances of enrolling in the regular school system as compared to the children in the control group. In the experimental group, fewer children remained at home by the time they turned six. This is the case when children do not pass the first assessment by a teacher at school entry, and it is not related to a child’s age. It is worth mentioning that the gain in skills in both groups was not related to the age factor. Similar studies describing a similar curriculum in the region could not be found, and so these results could not be compared to analogous others. Some studies conducted in the region have assessed GDD from different perspectives, such as the prevalence rate and causes in referred clinical cases ( Al-Ansari, 1993 ; Eapen et al. , 2006 ; Koul et al. , 2012 ). Prospective studies, although limited in number, showed similar results. For example, a study in China on the effect of a portage early education program on children with GDD showed a significant positive change after six months of application. The program under evaluation is family- and hospital-based, meaning that it cannot be accurately compared with this study ( Liu et al. , 2018 ). In this study, an increase in general functioning measured by the CGAS was documented in both groups, but was more pronounced in the control group; however, the marked increase in the post-scores of the control group could also reflect the mothers’ subjective responses. This increase in the post-scores in the control group was not re-examined by an independent objective evaluation, as were the scores from the experimental group. In the experimental group, the final post-score was the mean of the scores from the teacher and the independent blinded evaluator. The progress in the general functioning of both groups partially supported the study hypothesis; however, in this study the final one of the outcomes measured was the educational placement. Outcomes regarding educational placement were significantly higher among the experimental group, which further adds support to the study hypothesis. The skill levels in each examined category (i.e. motor, self-help, cognitive, social and psychological skills) were not precisely determined for the control group, and so the difference between the two groups could not be examined to assess the determinant factors and what exactly was responsible for the developmental progress ( Dornelas et al. , 2016 ). The clinical implications of the study are that the early identification and referral of GDD are key elements in the rehabilitation of these children and that early intervention programs are necessary for cases of moderate and severe GDD. Primary care physicians should follow up with GDD patients to ensure that referrals are being appropriately sought ( Choo et al. , 2019 ).

5. Conclusion

In this study, a comprehensive training program targeting preschool children with GDD was evaluated. The results demonstrated that the program was successful in enhancing the children’s overall skills. The program helped children integrate more smoothly into the regular school system as compared to the control group. Primary care physicians are the ones most responsible for the referral of children with GDD to these programs, and so they should be familiar with the options. At present, the program is able to accommodate only a small number of children with GDD, so future efforts should focus on expanding the program to reach a wider population. The main obstacle in expanding the program is that it requires a high teacher–child ratio as trained teachers are difficult to recruit. In the future, the research community should focus on early intervention for children with GDD in low-income settings.

Group demographics by age, gender and family income

Pre- and post-program: CGAS scores by group

Appendix 1 Teacher assessment form A

Appendix 2 Blinded investigator assessment form B

Al-Ansari , A. ( 1993 ). Etiology of mild mental retardation among Bahraini children: A community-based case control study . Mental Retardation , 31 ( 3 ), 140 .

American Psychiatric Association . ( 2013 ). Diagnostic and statistical manual of mental disorders ( 5th ed. ). Arlington, VA : American Psychiatric Association .

Banks , L. M. , Kuper , H. , & Polack , S. ( 2017 ). Poverty and disability in low-and middle-income countries: A systematic review . PloS One , 12 ( 12 ), e0189996 .

Bryson , L. , Dukes , L. , Kelley , L. , Rodden-Perinka , A. , Richardson , L. , & Sharpe , M. ( 2018 ). Developmental delay evaluation guidance . Tennessee : Tennessee Department of Education, Government of Tennessee .

Choo , Y.Y. , Agarwal , P. , How , C. H. , & Yeleswarapu , S. P. ( 2019 ). Developmental delay: Identification and management at primary care level . Singapore Medical Journal , 60 ( 3 ), 119 .

Daelmans , B. , Britto , P. R. , Black , M. M. , Darmstadt , G. L. , Lombardi , J. , Lye , S. , and … Richter , L. M. ( 2017 ). Early childhood development: The foundation of sustainable development . The Lancet , 389 ( 10064 ), 9 – 11 .

Dornelas , L. F. , Araújo , R. R. , Duarte , N. M. , Magalhães , L. C. Morales , N. M. , Pereira , S. A. , & Pinto , R. M. ( 2016 ). Functional outcome of school children with history of global developmental delay . Journal of Child Neurology , 31 ( 8 ), 1041 - 1051 .

Eapen , V. , Ghubash , R. , Gururaj , A. K. , Sabri , S. , Yunis , F. , & Zoubeidi , T. ( 2006 ). Prevalence and psychosocial correlates of global developmental delay in 3-year-old children in the United Arab Emirates . Journal of Psychosomatic Research , 61 ( 3 ), 321 – 326 .

Jimenez-Gomez , A. , & Standridge , S. M. ( 2014 ). A refined approach to evaluating global developmental delay for the international medical community . Pediatric Neurology , 51 ( 2 ), 198 – 206 .

Koul , R. , Al-Yahmedy , M. , & Al-Futaisi , A. ( 2012 ). Evaluation children with global developmental delay: A prospective study at Sultan Qaboos University Hospital . Oman Medical Journal , 27 ( 4 ), 310 .

Liu , X. , Dong , X. , Q. , Ge , J. J. , Wang , X. M. ( 2018 ). Effects of the portage early education program on Chinese children with global developmental delay . Medicine , 97 ( 41 ), 1 – 6 .

Mithyantha , R. , Gladstone , M. , & McCann , E. ( 2017 ). Current evidence-based recommendations on investigating children with global developmental delay . Archives of Disease in Childhood , 102 ( 11 ), 1071 – 1076 .

Moeschler , J. , Shevell , M. , Saul , R. A. , Chen , E. , Freedenberg , D. L. , Hamid , R. , & Anne , B. T. ( 2014 ). Comprehensive evaluation of the child with intellectual disability or global developmental delays . Pediatrics , 134 ( 3 ), e903 – e918 .

Scherzer , A. L. , Chhagan , M. , Kauchali , S. , & Susser , E. ( 2012 ). Global perspective on early diagnosis and intervention for children with developmental delays and disabilities . Developmental Medicine and Child Neurology , 54 ( 12 ), 1079 – 1084 .

Shaffer , D. , Ambrosini , P. , Aluwahlia , S. , Bird , H. , Brasic , J. , & Gould , M. S. ( 1983 ). A children’s global assessment scale (CGAS) . Archives of General Psychiatry , 40 ( 11 ), 1228 – 1231 .

Smythe , T. , Gladstone , M. , Kuper , H. , Tann , C. J. , & Zuurmond , M. ( 2021 ). Early intervention for children with developmental disabilities in low and middle-income countries–The case for action . International Health , 13 ( 3 ), 222 – 231 .

Suri , M. , & Vasudevan , P. ( 2017 ). A clinical approach to developmental delay and intellectual disability . Clinical Medicine , 17 ( 6 ), 558 .

Tal-Saban , M. , Moshkovitz , M. , Yochman , A. , & Zaguri-Vittenberg , S. ( 2021 ). Social skills of kindergarten children with Global Developmental Delay (GDD), with and without Developmental Coordination Disorder (DCD) . Research in Developmental Disabilities , 119 , 104105 .

Thomaidis , L. , Bakoula , C. , Fouzas , S. , Mantagou , L. , & Zantopoulos , G. Z. ( 2014 ). Predictors of severity and outcome of global developmental delay without definitive etiologic yield: A prospective observational study . BMC Pediatrics , 14 ( 1 ), 1 – 7 .

Acknowledgements

The authors would like to acknowledge the help of Dr. Haitham Ali Jahrami in data management.

Corresponding author

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• Volume 102, Issue 11
• Current evidence-based recommendations on investigating children with global developmental delay
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• Renuka Mithyantha 1 ,
• Rachel Kneen 2 , 3 ,
• Emma McCann 4 ,
• http://orcid.org/0000-0002-2579-9301 Melissa Gladstone 1 , 5
• 1 Department of Developmental Paediatrics , Alder Hey Children’s NHS Foundation Trust , Liverpool , UK
• 2 Department of Paediatric Neurology , Alder Hey Children’s NHS Foundation Trust , Liverpool , UK
• 3 Institute of Infection and Global Health, University of Liverpool , Liverpool , UK
• 4 Department of Clinical Genetics , Liverpool Women’s Hospital , Liverpool , UK
• 5 Department of Women and Children’s Health , Institute of Translational Medicine, University of Liverpool, Alder Hey Children’s NHS Foundation Trust , Liverpool , UK
• Correspondence to Dr Melissa Gladstone, Department of Women and Children’s Health, Institute of Translational Medicine, University of Liverpool, Alder Hey Children’s NHS Foundation Trust, Liverpool, L14 5AB, UK; M.J.Gladstone{at}liverpool.ac.uk

Introduction Global developmental delay (GDD) affects 1%–3% of the population of children under 5 years of age, making it one of the most common conditions presenting in paediatric clinics; causes are exogenous, genetic (non-metabolic) or genetic (metabolic). Recent advances in biotechnology and genetic testing mean that the investigations available to perform for children under 5 years are increasing and are more sensitive than previously. This change in availability and type of testing necessitates an update in the recommendations for investigating GDD.

Methods We conducted a review of the literature from 2006 to 2016 to identify articles with evidence relating to the investigation of developmental delay in children under the age of 5 years. We collated the evidence into first-line and second-line investigations and, where available, on their yield and cost implications.

Results We have provided up-to-date guidance for first-line and second-line investigations for children with GDD under the age of 5 years. Recent evidence demonstrates that genetic testing for all children with unexplained GDD should be first line, if an exogenous cause is not already established. Our review of the literature demonstrates that all patients, irrespective of severity of GDD, should have investigations for treatable conditions. Evidence demonstrates that the yield for treatable conditions is higher than previously thought and that investigations for these metabolic conditions should be considered as first line. Additional second-line investigations can be led by history, examination and developmental trajectories.

Discussion We may need to update present recommendations in the UK for investigation of developmental delay. This would include microarray testing as first line and a more thorough approach to investigations for metabolic disorders that can be treated. Clinical assessment remains vital for guiding investigations.

• neurodevelopment
• neurodisability

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http://dx.doi.org/10.1136/archdischild-2016-311271

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Introduction

Global developmental delay (GDD) is defined as a delay in two or more developmental domains of gross/fine motor, speech/language, cognition, social/personal and activities of daily living, affecting children under the age of 5 years. 1 2 The degree of developmental delay is further subclassified as: mild (functional age <33% below chronological age), moderate (functional age 34%–66% of chronological age) and severe (functional age <66% of chronological age). 1 GDD is considered significant when there is a deficit in performance of at least 2 SD below the age appropriate mean on accepted standardised assessment tests. 3 With a prevalence of 1%–3%, GDD is one of the the most common conditions encountered in paediatrics with genetic and structural brain abnormalities being the most frequent causes. 1 Establishing a diagnosis enables clinicians to define treatment options and conduct surveillance for known complications as well as provide prognosis and condition-specific family support (including family planning choices). This ensures the best overall outcomes for the child and their families/carers. 4 A diagnosis may also provide an explanation, a source of closure or acceptance to parents and stops clinicians advancing to potentially more expensive and invasive tests 5–7

Previous estimates for the yield of investigations for GDD are broad (10%–81%). 2 The variability may be due to differences in patient populations, clinical settings where tests are performed and the range of tests undertaken. 2 The last evidence-based UK guideline for investigation of developmental delay was published 10 years ago. 8 With the advent of more recent techniques in genetics and a recent burgeoning of guidelines in other countries, 4 9 10 there is a need to review our practice in the UK.

The primary objective of this paper is to provide (1) an update of the latest evidence for investigation of GDD, (2) recommendations for investigations and (3) evidence relating to yield and cost from literature presently available.

We conducted a systematic review of the literature relating to the investigation of GDD published in the last 10 years (since the McDonald review in 2006). We searched Pubmed, Google Scholar and Embase using the MESH terms: ‘developmental delay’, ‘developmental disorders’, ‘mental retardation’, ‘intellectual disability’, ‘learning disorders’ AND ‘guidelines’ AND ‘investigations’. ‘Cost’ and ‘yield’ were included along with the MESH terms. Papers included were reviews, consensus recommendations, retrospective or prospective studies. Relevant articles from reference lists were also included. We included papers published in English that were relevant to children that included investigations for GDD. We excluded papers that targeted specific metabolic, genetic or neurological conditions. We used the term GDD as meaning: delayed developmental domains in children under the age of 5 years and intellectual disability (ID) as the term used after this age when IQ can be reliably tested. 11

For this review, we discuss and categorise investigations into first-line and second-line tests and subcategorised them to genetics, metabolic and imaging. See table 1 for recommended first-line investigations to be considered prior to referral to specialist services. We show a flowchart and decision-making tree for investigations in figure 1 .

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Flow chart for decision making for investigations for global developmental delay in young children.

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Table demonstrating recommendations for first-line investigations for global developmental delay from four guidelines and our proposed recommendations

First-line assessment and investigations

History and examination.

Comprehensive clinical assessment remains the core to planning investigations in young children presenting with GDD. 4 8–10 Aetiology can be categorised into exogenous, genetic (non-metabolic) and genetic (metabolic). 11 The diagnosis of exogenous causes includes teratogenic agents (alcohol and drugs); prenatal, perinatal causes (prematurity, infections); and social causes often best assessed by history but must not be assumed.

Investigations following a thorough clinical history (including a family pedigree, pregnancy and birth history) and a detailed physical examination by a trained specialist lead to a higher diagnostic yield. 3 12 Identification and correction of sensory deficits are essential, while evaluating these children and may provide pointers to the underlying aetiology. 2 6

An examination of the child’s developmental status in all domains (gross motor, fine motor, language, socioemotional and cognitive skills) using a recognised tool to provide a normative comparison should also be conducted. Repeated clinical/dysmorphology and developmental assessments over time are more informative than one-off assessments in planning investigations and management.

It is important that the clinician consider investigations in all levels of developmental delay including those with persistent mild GDD, given the variable phenotypic presentations of genetic and metabolic conditions. Some studies, although from tertiary centres, have found that severity did not impact on the diagnostic rate of investigations, 12 while others report higher yield in patients with moderate-to-severe GDD. 13 Serial assessment enables clinicians to identify changing phenotypes over time. When metabolic conditions are clinically suspected, annual evaluation after the first year of life until school age is recommended. 14

Some studies have demonstrated that we can identify the cause of developmental or cognitive delay in a one-third of cases by history and examination alone. With clinical evaluation prompting investigations, we can identify another one-third. It is only the latter one-third that are identified by investigations only. 12 The presence of abnormal neurology, microcephaly, female gender, dysmorphism, abnormal prenatal or perinatal history and absence of autistic features are linked with higher aetiological yield of investigations. 15 Investigations following comprehensive clinical evaluation are also cost effective. 16

Genetic testing

First-line tests .

Genetic investigation by means of standard karyotyping was recommended as a first-line investigation in the UK guidance from 2006. 8 The implementation of ‘molecular karyotyping’ or chromosome microarray (array-based comparative genomic hybridisation (aCGH)) has changed the state of play. Recent evidence-based international guidelines promote the use of aCGH as a first-tier investigation for GDD if no aetiological indicators from history and examination are found. 4 9 10 The higher sensitivity that it has for identifying submicroscopic deletions and duplications (than standard karyotyping methods) and better definition of the breakpoints and size of imbalances all make microarray a suitable first-line test. 4 17 18

Chromosome microarray has been described to be the ‘single most efficient diagnostic test’ for GDD after history and examination. 4 A literature search of 33 studies that used this technique in nearly 22 000 patients has demonstrated that the diagnostic yield of aCGH is between 15% and 20%, while karyotyping is 3%. 18 The diagnostic yield of microarray is supported by a health economics report, which showed cost saving when comparing a National Health Service (NHS) clinical genetics service use of aCGH as a first-tier test while evaluating learning disability, compared with CGH as second line after negative karyotyping. 19

Molecular karyotyping will not detect conditions where structural changes in the chromosomes result in no loss or gain of genetic material such as balanced translocations or inversions, ring chromosomes and low-level mosaicism. 18 20 A standard karyotype is still required if such a disorder is suspected (eg, refractory epilepsy, if a family is known to have a balanced translocation associated with a phenotype, a history of multiple miscarriages or clinical features to suggest mosaicism). Syndromes caused by methylation defects (eg, Beckwith-Wiedemann, Angelman syndrome) or mutations in single genes will also go undetected unless specifically tested.

Fragile X syndrome affects approximately 1/5000 births, typically causing moderate ID in boys and a variable phenotype in girls (unaffected to significant). Phenotypic features evolve and are not as apparent in younger children. 9 The UK genetic testing network and international guidelines therefore do promote testing for fragile X for children with moderate-to-severe GDD, without profound physical disability, as an additional first-tier genetic investigation. 4 9 10 21 Testing criteria are available to help aid clinical decisions in older children. 21

Second-line tests

Clinical syndromes can present with variable phenotypes, and children who have a normal aCGH and FMR1 may be best assessed by a clinical geneticist to ensure that the most appropriate and cost-effective additional tests are undertaken. 22 Use of specific gene tests such as those for Rett syndrome (or its variants) or gene panels for ID has been proposed as second-line tests. 4 There is an increasing number of panels and exome sequencing tests available for ID (UK Genetic Testing Network; http://www.ukgtn.nhs.uk ) or private providers, but specialist services (clinical genetics or paediatric neurology) do most requests for these tests, although this is likely to change as mainstreaming of these investigations advances.

Metabolic and biochemical investigations

There is limited good quality evidence for first-line metabolic investigations. Recommendations from Ireland are based on evidence review by expert committee, 10 while those from Australia are based on a literature review, quoting grade III–IV evidence. 9

Inborn errors of metabolism (IEMs) are rare, their prevalence likely to vary in different populations. There is limited UK data on detecting metabolic disorders in patients with GDD. 14 IEMs are usually associated with systemic features, and previous guidelines recommend selective metabolic investigations. 2 8 Some IEMs are now (partially) treatable, and for others, treatment is in the research stages. Treatment includes dietary supplements (folinic acid for cerebral folate deficiency, pyridoxine or pyridoxal phosphate for B6-responsive epilepsy, creatine in creatine transporter deficiency, uridine in pyrimidine 5-nucleotidase super activity), dietary restriction (homocystinuria, glutaricacidaemia) and ketogenic diet (pyruvate dehydrogenase deficiency, Glut1 transporter deficiency). Other treatments include: haematopoietic stem cell transplantation (mucopolysaccharidoses, metachromatic leucodystrophy), enzyme replacement (Fabry’s disease, Gaucher’s disease, neuronal ceroid lipofuscinosis) or gene therapy (adrenoleucodystophy, lysosomal storage disorders). 23–25

A systematic review of literature by van Karnebeek et al identified 89 conditions presenting with ID as a major feature, which are susceptible to treatment. Of these, 60% could be identified by non-targeted urine and blood tests. Some of these conditions (eg, creatine transporter defects, mild homocystinuria, female ornithine transcarbamylase deficiency) can initially present as GDD alone. 25 26 While individual treatable IEMs are extremely rare in the general population, the prevalence will be higher in the at-risk population. Hence, though small in number, these treatable causes of GDD have been the focus of the more recent US guidance, with recommendations that screening for IEM should be used in all patients with GDD of unknown aetiology. 4 24 A list of tests with treatable conditions they identify is shown in table 2 .

Table demonstrating IEM tested for by first-line metabolic investigations 25

The neonatal screening programme in the UK (Guthrie test) currently includes six IEMs (phenyketonuria, medium-chain acyl-CoA dehydrogenase deficiency, maple syrup urine disease, isovaleric acidaemia, glutaricaciduria type 1, homocystinuria (pyridoxine unresponsive)) and congenital hypothyroidism. It is restricted when compared with other countries (eg, Canada, the USA, The Netherlands), which offer a wider range including urea cycle disorders, organic and some amino acid disorders. Testing for these is, therefore, more relevant in UK patients with GDD, and IEMs should be considered in symptomatic children. 14

There are also some conditions where early diagnosis can be made from simple and cheap biochemical screening tests. This includes creatine kinase and thyroid function tests as well as ferritin, vitamin B12 and lead on a selective basis when Pica, dietary restrictions (vegan diet in child/mother) or environmental exposure risk is possible. 9 While these tests seldom lead to a diagnosis, they also may add to a diagnosis (eg, macrocytic anaemia in organic acidaemias, abnormal triiodothyronine in Allan-Herdon-Dudley syndrome). 10 27

There is limited research on comprehensive metabolic evaluation in larger groups of individuals with GDD. It is, therefore, difficult to estimate the yield of many of the proposed first-line metabolic tests. A recent systematic review conducted for the American Academy of Neurology found that yield of metabolic investigations varied between 0.2% and 4.6%, based on clinical signs and range of tests undertaken in the studies (grade III evidence). 28 Second-line individually tailored testing in a tertiary setting in the Netherlands produced an overall yield of 2.8% for metabolic investigations. 11

Individually tailored second-line testing 4 14 26 and referral to a specialist service is recommended, 4 9 when clinical suspicion remains. An evidence-based, free web-based application ( http://www.treatable-id.org ) may be useful to tailor investigations for treatable IEMs not covered by first-line tests. 29

Neuroimaging

MRI of the brain has been used selectively and non-selectively in evaluating patients with GDD. The diagnostic yield of MRI is higher when used in patients where GDD is associated with clinical signs such as abnormal head circumference (microcephaly, non-familial macrocephaly, rapid change in head circumference), focal neurological signs or epilepsy. Targeted imaging was hence advocated by previous guidelines. 2 8 Previous studies have demonstrated abnormal results in targeted imaging in about 41% compared with 14% with non-selective screening. 3 Recent studies continue to demonstrate higher abnormality detection rates when MRI is performed in patients with GDD with additional clinical/neurological signs. 30 31 More complex MRI protocols (eg, proton magnetic resonance spectroscopy) are promising tools to investigate GDD and enable a non-invasive measure of brain metabolites such as lactate or white matter choline, 32 but studies have so far failed to show an increased diagnostic yield, 31 33 and hence these are best used as second line in selected patients.

MRI is a more sensitive test and has no radiation exposure, making it a preferred choice over CT. However, all children under 5 years will need sedation or a general anaesthetic, which has a slim risk attached, and some children will need further investigations including a lumbar puncture. There is an argument, therefore, that children requiring brain imaging should see a specialist prior to imaging, if an anaesthetic is required.

Special considerations

Ten most common causes of progressive intellectual and neurological deterioration.

10 most common causes of PIND reported in the PIND study in the UK ( www.rcpch.ac.uk/pind ) 34

NCL late infantile

Mucopolysaccharidosis IIIA (San Filippo)

Rett syndrome

Metachromatic leucodystrophy

Adrenoleucodystrophy

NCL juvenile

GM2 gangliosidosis type 1 (Tay-Sachs)

Niemann-Pick type C

GM2 gangliosidosis type 2 (Sandhoff)

NCL, neuronal ceroid lipofuscinosis; PIND, progressive intellectual and neurological deterioration.

Children that should be referred to a specialist in neurodisability or neurology are shown on table 3 . Investigations should be individualised and targeted as they can be invasive (eg, LP, muscle/skin biopsy) or painful (eg, nerve conduction studies and electromyography) and are expensive and time consuming for medical staff and families. Children with regression may also be referred to the clinical genetics team where specific next-generation sequencing panels can be undertaken and, at present, considered for the 100 000 Genome Project ( www.genomicsengland.co.uk/the-100000-genomes-project ).

Clinical pointers to consider referral to a specialist in neurodisability or neurology

Immigrant children

Immigrant children are exposed to a combination of biological, socioeconomical, emotional and environmental adverse events placing them at higher risk of developmental problems. This includes malnutrition and disability from trauma, overcrowding and toxin exposure and loss of parents or trauma from lack of stability. 35 Furthermore, children may have missed new-born screens and vaccinations and been exposed to infectious diseases. In these children, comprehensive clinical assessments should consider all these factors while planning individual investigations.

Despite new advances in technology, particularly in the realm of genetic investigation, clinical assessment continues to be vital in guiding investigation. Clues to investigation may lie in the history and examination with clinical judgement being essential to enabling the right pathways to be taken in making a diagnosis. A good history can help direct which route to take in terms of investigation, particularly when exogenous causes are identified. Assessment over a period will provide clarity as to whether a condition is resolving, static or deteriorating. Assessment over time enables the phenotype to evolve and more appropriate targeting of investigations.

It is clear that establishing a diagnosis enables us to answer questions on: why it has happened (aetiology), what does it mean for our child (prognosis), what treatments might be available (precision medicine) and whether it can be prevented in the future (prenatal testing and preimplantation genetic diagnosis).

In these recommendations, we have also highlighted the recent evidence that promotes metabolic screening tests to detect treatable conditions. This is a move away from older guidance where metabolic investigations were not recommended for children with no features/risk factors other than GDD. 2 Though rare, the possibility of presentation as stable developmental delay and potential for treatment merits their inclusion as first-line tests. Treatment outcomes vary but can potentially improve cognitive development, slow deterioration, prevent metabolic decompensation and improve seizure control and systemic manifestations. 25 26

GDD and ID affect 2%–3% of the worldwide population with a lifetime cost of up to US$1 million. 36 First-line metabolic investigations to identify treatable IEMs cost approximately $C568, 26 with costs in Ireland for all first-line tests at €1335. 10 Costs in the UK NHS laboratory for aCGH are not astronomical (£338–£350), 37 38 with the majority of combined metabolic tests costing under £1000. 38 Not all children will get a diagnosis and cost per diagnosis may be high, but there are obvious long-term cost savings if early diagnosis and treatment are possible. The options of genetic counselling and support for young families also make diagnosis invaluable.

Recent advances in genomic medicine are transforming the investigation of children with significant developmental delay and are likely to transform the way we assess and investigate children. Traditional models of care have relied on history and examination with broad and then specific investigations to funnel down to specific diagnoses. The advent of rapid genetic testing and ‘omic’ medicine is likely to turn this paradigm on its head with whole genome/exome sequencing identifying genes, which may be causing the phenotype in an individual. The clinician will then use knowledge of their patient to make a judgement about whether this is the cause for their patient—‘reverse dysmorphology’.

These advances in genomic medicine will lead to an increase in diagnoses that will modify how the individual is clinically cared for (precision medicine). The Deciphering Developmental Disorders study and the 100 000 Genome Project will both aid our understanding of disorders. We predict that, with time, whole genome sequencing/exome sequencing may become the first-line investigation of choice for all children with unexplained GDD and that other investigations will be secondary to this and used primarily for phenotyping. These will provide answers for families about the underlying cause of their child’s condition and will prevent further costly and potentially distressing investigations taking place.

Conclusions

In this paper, we have outlined the present evidence and recommendations for both first-line and second-line investigations for GDD in children in the UK. We have provided new evidence relating to the use of genetic testing techniques and have demonstrated that this should be a first-line investigation for all children with GDD. Second to this, any treatable metabolic conditions should be always considered. With time, it is likely that the investigation of children with developmental delay will be turned on its head and we will be going from genetic diagnosis to phenotypic diagnosis. Despite this, history and examination will always be crucial for defining the condition and the change over time.

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Contributors RM, RK, EM and MG contributed to the initial idea for the paper, wrote and reviewed sections of the paper and approved the final version. RM conducted the literature review with the support of MG and wrote the first draft of the paper.

Funding None declared.

Competing interests None declared.

Provenance and peer review Commissioned; externally peer reviewed.

Linked Articles

• Original article Aetiological investigations in early developmental impairment: are they worth it? Anthony Richard Hart Ruchi Sharma Mark Atherton Samer Alabed Sally Simpson Stuart Barfield Judith Cohen Nicholas McGlashan Asha Ravi Michael James Parker Daniel JA Connolly Archives of Disease in Childhood 2017; 102 1004-1013 Published Online First: 22 Jul 2017. doi: 10.1136/archdischild-2017-312843

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Diagnosis and Management of Global Development Delay: Consensus Guidelines of Growth, Development and Behavioral Pediatrics Chapter, Neurology Chapter and Neurodevelopment Pediatrics Chapter of the Indian Academy of Pediatrics

Affiliations.

• 1 Department of Pediatrics, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi. Correspondence to: Dr Monica Juneja, Director-Professor and Head, Department of Pediatrics, Maulana Azad Medical College, New Delhi. [email protected].
• 2 Department of Pediatrics, Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi.
• 3 Department of Pediatrics, Christian Medical College, Ludhiana.
• 4 Niramaya Hospital and Guidance Clinic, Chembur, Mumbai, Maharashtra.
• 5 Ummeed Child Development Centre, Mumbai, Maharashtra.
• 6 Rainbow Children's Hospital, Hyderabad.
• 7 Indian Academy of Pediatrics, Neurodevelopment Chapter.
• 8 Department of Pediatrics, MP Shah Government Medical College, Jamnagar, Gujarat.
• 9 Department of Pediatrics, MGM Medical College, Kolkata, West Bengal.
• 10 New Horizons Child Development Centre, Mumbai, Maharashtra.
• 11 Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi.
• 12 GCS Medical College, Hospital and Research Centre, Ahmedabad, Gujarat.
• 13 Department of Medical Genetics, Kasturba Medical College, Manipal, Karnataka.
• 14 Mumbai Port Trust Hospital, Mumbai, Maharashtra.
• 15 Department of Pediatric Neurology, Medical College Thiruvananthapuram, Kerala.
• 16 Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh.
• 17 Ummeid Group of Child Development Centers, Bhopal, Madhya Pradesh.
• 18 Center for Child Development and Disabilities (CCDD) Bengaluru, Karnataka.
• 19 NIMS-SPECTRUM-Child Development Research Centre (CDRC) NIMS Medicity, Thiruvananthapuram, Kerala.
• 20 Christian Medical College, Vellore, Tamil Nadu.
• 21 ASHA, Centre for Autism and Intellectual Developmental Disorders, Chandigarh.
• 22 All India Institute of Medical Sciences, Jodhpur, Rajasthan.
• 23 Bharati Vidyapeeth Medical College and Hospital, Pune, Maharashtra.
• 24 Child Development Centre, Sir Gangaram Hospital, New Delhi.
• 25 The Children's Neurodevelopmental Centre, Patna, Bihar.
• PMID: 35188106

Justification: Global developmental delay (GDD) is a relatively common neurodevelopmental disorder; however, paucity of published literature and absence of uniform guidelines increases the complexity of clinical management of this condition. Hence, there is a need of practical guidelines for the pediatrician on the diagnosis and management of GDD, summarizing the available evidence, and filling in the gaps in existing knowledge and practices.

Process: Seven subcommittees of subject experts comprising of writing and expert group from among members of Indian Academy of Pediatrics (IAP) and its chapters of Neurology, Neurodevelopment Pediatrics and Growth Development and Behavioral Pediatrics were constituted, who reviewed literature, developed key questions and prepared the first draft on guidelines after multiple rounds of discussion. The guidelines were then discussed by the whole group in an online meeting. The points of contention were discussed and a general consensus was arrived at, after which final guidelines were drafted by the writing group and approved by all contributors. The guidelines were then approved by the Executive Board of IAP.

Guidelines: GDD is defined as significant delay (at least 2 standard deviations below the mean with standardized developmental tests) in at least two developmental domains in children under 5 years of age; however, children whose delay can be explained primarily by motor issues or severe uncorrected visual/hearing impairment are excluded. Severity of GDD can be classified as mild, moderate, severe and profound on adaptive functioning. For all children, in addition to routine surveillance, developmental screening using standardized tools should be done at 9-12 months,18-24 months, and at school entry; whereas, for high risk infants, it should be done 6-monthly till 24 months and yearly till 5 years of age; in addition to once at school entry. All children, especially those diagnosed with GDD, should be screened for ASD at 18-24 months, and if screen negative, again at 3 years of age. It is recommended that investigations should always follow a careful history and examination to plan targeted testing and, vision and hearing screening should be done in all cases prior to standardized tests of development. Neuro-imaging, preferably magnetic resonance imaging of the brain, should be obtained when specific clinical indicators are present. Biochemical and metabolic investigations should be targeted towards identifying treatable conditions and genetic tests are recommended in presence of clinical suspicion of a genetic syndrome and/or in the absence of a clear etiology. Multidisciplinary intervention should be initiated soon after the delay is recognized even before a formal diagnosis is made, and early intervention for high risk infants should start in the nursery with developmentally supportive care. Detailed structured counselling of family regarding the diagnosis, etiology, comorbidities, investigations, management, prognosis and follow-up is recommended. Regular targeted follow-up should be done, preferably in consultation with a team of experts led by a developmental pediatrician/ pediatric neurologist.

Publication types

• Practice Guideline
• Child, Preschool
• Comorbidity
• Pediatrics*

Symptom-Based Approach to Pediatric Neurology pp 25–45 Cite as

Child with Global Developmental Delay

• Leigh Anne Flore 3 , 4 &
• Stephanie Campbell 5  
• First Online: 01 January 2023

606 Accesses

Global developmental delay (GDD) is a common finding in the pediatric population and is found in 1–3% of children under the age of 5 years. GDD is etiologically diverse. A comprehensive assessment with thorough history and physical examination can help determine the next best diagnostic steps for evaluating these patients. Up to 25–50% of children with GDD will have an identified genetic etiology. Specific guidelines exist for recommended genetic testing in this population, though these are likely to change with recent advances in genetic medicine. Early diagnosis of GDD and identification of the specific etiology can help improve outcomes in many cases, allowing for earlier therapeutic intervention and identifying other associated health issues that may be subsequently managed.

• Global developmental delay
• Intellectual disability
• Neurodevelopmental disorder

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Division of Genetic, Genomic and Metabolic Disorders, Children’s Hospital of Michigan, Detroit, MI, USA

Leigh Anne Flore

Central Michigan University, College of Medicine, Mt. Pleasant, MI, USA

Division of Genetic, Genomic and Metabolic Disorders, Detroit Medical Center/Wayne State University, Detroit, MI, USA

Stephanie Campbell

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Flore, L.A., Campbell, S. (2022). Child with Global Developmental Delay. In: Kamat, D.M., Sivaswamy, L. (eds) Symptom-Based Approach to Pediatric Neurology . Springer, Cham. https://doi.org/10.1007/978-3-031-10494-7_3

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How Global Developmental Disorder Impacts Child Development

Dr. Amy Marschall is an autistic clinical psychologist with ADHD, working with children and adolescents who also identify with these neurotypes among others. She is certified in TF-CBT and telemental health.

Yolanda Renteria, LPC, is a licensed therapist, somatic practitioner, national certified counselor, adjunct faculty professor, speaker specializing in the treatment of trauma and intergenerational trauma.

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• Characteristics
• Getting Support

Global developmental delay (GDD), sometimes referred to as global developmental disorder, is a neurodevelopmental diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). GDD is a form of intellectual disability , which is diagnosed when an individual under age five exhibits clear signs of a developmental delay but cannot be evaluated for a more specific diagnosis due to their age.

For an individual to meet the criteria for GDD, they must experience delays in achieving milestones in several areas of intellectual functioning and learning. A provider will re-evaluate someone with a diagnosis of GDD as they get older to obtain a more specific and accurate diagnosis.

Characteristics of Global Developmental Disorder

According to the DSM-5, “Global developmental delay, as its name implies, is diagnosed when an individual fails to meet expected developmental milestones in several areas of intellectual functioning.”

GDD does not have a specific set of symptoms like other DSM diagnoses but instead refers to general delays that cannot be more specifically identified at the time of the assessment.

Symptoms of GDD can include, but are not limited to:

• Delays in motor skills (including crawling and walking)
• Difficulty with fine motor skills
• Language and communication delays
• Difficulty understanding communication
• Difficulty with problem-solving
• Difficulty with social skills

Identifying and Diagnosing Global Developmental Disorder

Providers diagnose intellectual disabilities by assessing an individual’s cognitive and adaptive functioning. Although adaptive functioning can be evaluated from birth, many cognitive tests (also referred to as IQ tests) require that a child be at least six years old for testing.

Some IQ tests can evaluate children younger than six, but long-term research shows that these scores do not accurately predict future learning prior to age six.

Providers can identify developmental delays in many different ways, including:

• Diagnostic Interview with the Parent or Guardian: This interview consists of gathering extensive, detailed information about the child’s history so far, developmental progress, and any known medical issues or injuries.
• Vineland-3: The Vineland-3 measures adaptive functioning in several domains, including communication, daily life skills, social skills, and motor skills. There is a parent form that can be administered as early as birth, and there is a teacher form that can be administered starting at age three.
• Adaptive Behavior Assessment System-3: The ABAS-3 measures an individual’s adaptive skills from birth through their lifespan and assesses for developmental and learning disabilities, neuropsychological disorders, and physical impairments.
• Bayley-4: The Bayley scales measure cognitive, language, motor, social, emotional, and adaptive behavioral growth in preschool-age children to determine whether developmental delays are present.

Causes of Global Developmental Delay

Because GDD is a general term and not a specific diagnosis, many different things can cause a child to experience a delay with this label. Sometimes, genetics can cause developmental delays. Other times, the environment can cause GDD, both before and after the child is born.

GDD can begin before birth when caused by exposure to drugs or other toxic substances, premature birth, prenatal infections, or hemorrhages. Following birth, head traumas or certain infections such as meningitis can cause GDD. Finally, malnutrition, abuse , or physical neglect can cause a child to experience developmental delays.

Treatment for Global Developmental Disorder

Sometimes, children outgrow developmental delays and catch up to their peers with minimal intervention. However, many benefit from treatments and services to help them reach their full potential.

Because “Global Developmental Disorder” is a general term for delays that can manifest in many different ways, providers determine the most appropriate interventions on a case-by-case basis.

Treatments that can help with GDDs include:

• Birth to Three Programs: These programs emphasize helping a child reach missed milestones and catch up to their peers.
• Early Childhood Special Education : Preschool and kindergarten programs can offer individual special education to help meet a child’s specific needs when the child exhibits developmental delays.
• Physical Therapy: Physical therapists can help a child by teaching them exercises and skills to catch up on motor delays or recover from an injury that might be causing a delay.
• Speech Therapy: Speech therapists can help children learn to use language to express their needs by emphasizing articulation, vocabulary, or other forms of communication.
• Occupational Therapy (OT): Occupational therapists help with adaptive skills. OT can help alleviate sensory issues, develop fine motor skills, or complete other functional tasks.
• Re-Evaluation: Because GDD is a general term for unspecified developmental delays, as the child gets older and can undergo more specific assessments, re-evaluation can help identify and understand their delays and provide a more specific diagnosis.

As the child gets older, they will need re-assessment to gather more specific information about their delays and get more specific information about their diagnosis or diagnoses.

Support for Global Developmental Disorder

Some children diagnosed with GDD are able to catch up developmentally and will no longer meet the criteria for a developmental disorder as they get older. Others continue to experience mild, moderate, or severe difficulties throughout their lifetime.

Parents and caregivers whose child has a diagnosis of GDD can ask their treatment team questions they have about their child’s specific delays and what interventions might help them catch up. They may also benefit from support groups where they can connect with other families going through similar situations.

Early intervention is important in helping children live their best lives. Understanding a child’s developmental delays and offering appropriate treatment can prevent future delays and allow them to catch up to their peers.

Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed., American Psychiatric Association, 2013. DSM-V, doi-org.db29.linccweb.org/10.1176/ appi

National Research Center on the Gifted and Talented.  Assessing and advocating for gifted students: Perspectives for school and clinical psychologists .

Habibullah H, Albradie R, Bashir S. Identifying pattern in global developmental delay children: A retrospective study at King Fahad specialist hospital, Dammam (Saudi Arabia) .  Pediatr Rep . 2019;11(4):8251. Published 2019 Dec 2. doi:10.4081/pr.2019.8251

Choo Y, Agarwal P, How C, Yeleswarapu S. Developmental delay: identification and management at primary care level .  smedj . 2019;60(3):119-123.

Mithyantha R, Kneen R, McCann E, Gladstone M. Current evidence-based recommendations on investigating children with global developmental delay .  Archives of Disease in Childhood . 2017;102(11):1071-1076.

By Amy Marschall, PsyD Dr. Amy Marschall is an autistic clinical psychologist with ADHD, working with children and adolescents who also identify with these neurotypes among others. She is certified in TF-CBT and telemental health.

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Case report article, case report: traumatic stress and developmental regression: an unintended consequence of complex cardiac care.

• 1 Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
• 2 Division of Pediatric Cardiovascular Surgery, Masonic Children's Hospital, Minneapolis, MN, United States
• 3 Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, United States

This brief case report outlines a novel approach to supporting the development of a pediatric complex cardiac care patient. Patient X is a 19-month old patient who spent 5.5 months in hospital and underwent multiple surgeries including heart transplantation. This case report explores the impacts of his condition and care on his development and family functioning within the framework of an integrated care model. This case report is uniquely complimented by outpatient neurodevelopmental follow up, dyadic trauma-informed intervention and use of telemedicine allowing for a deeper understanding of the family adaptation that provide novel insight into long-term trajectory beyond discharge. Throughout care Patient X met criteria for both a traumatic stress disorder and global developmental delay. This case study highlights the threat complex care poses to neurodevelopment, pediatric mental health and family dynamics as well as opportunities for intervention.

Introduction

Hospitalization in childhood disrupts normative developmental processes and induces significant stressors on both children and their parents. Necessary but uncomfortable therapeutic interventions, the loss of a familiar and predictable environment, and the limited opportunities for exploration all contribute to an abnormal developmental environment. Separation from primary caregivers further exacerbates possible threats to normal development in this environment. An optimal caregiver-child relationship is one of the strongest protective factors against comprised development and detrimental psychological and physical consequences ( 1 – 3 ). The following case report exemplifies the implications of inpatient stress on long-term outpatient child development. This case is uniquely complimenting by long-term outpatient neurodevelopmental and mental health follow-up and interventions allowing for perspectives in post-discharge functioning. It is instructive that the stress and challenges associated with acute and chronic hospitalization can impact the patient's developmental trajectory as well as the parent-child relationship. Given the lack of a standardized approach to mitigate such challenges, opportunities for early recognition are identified in order that intervention maybe leveraged in the inpatient environment and post-discharge to optimize outcomes.

Case Description

The parents of this patient provided informed consent for data collection, chart review and presentation of findings. A timeline of care is outlined in Figure 1 .

Figure 1 . Timeline of care.

Medical History

P is a 19-month-old, ex-37 week, small for gestational age male; with a birth weight of 2,220 grams. Labor was induced due to poor fetal growth. Although initial APGAR scores were reassuring; shortly after birth, difficulty with feeds and respiratory distress necessitated transfer to a Level IV NICU for suspected esophageal atresia (EA) with tracheoesophageal fistula (TEF). This was confirmed and surgical repair was undertaken without complications. Post-natal echocardiogram demonstrated large perimembranous ventricular septal defect (VSD) and mild left ventricular enlargement managed with furosemide. P was discharged from the NICU at 41-weeks corrected gestational age, and was compliant with follow-up appointments.

At his 4-month follow-up appointment the patient was seen by an early childhood mental health clinician (PhD, LP) where a slight delay in social-emotional development was noted via Ages and Stages Developmental Questionnaire ( 4 ). The patient displayed age-appropriate social behavior (smiles, responding to voices) but was behind expectations on self-regulatory skills (self-soothing). Identified family stressors included strained financial resources, limited access to care due to rural residence, and pending maternal immigration status. Please see Figure 2 for a summary of intersecting stressors influencing and compounding clinical presentation. Referral was made for local state supportive intervention services.

Figure 2 . Impact of stressors on Neurodevelopment in hospitalized children.

At 10 months of age an abnormal ECHO demonstrated significant large left-to-right shunt secondary to a large VSD, and right ventricular outflow tract (RVOT) obstruction and a subaortic gradient, requiring surgical resection of right ventricular outflow tract muscle bundles and of the subaortic membrane and VSD closure. This procedure (on 7/15/20) was uncomplicated with good results on postoperative transesophageal echocardiogram. However, his post-op course was complicated by bradycardic cardiac arrest of unknown etiology on the first postoperative night requiring extracorporeal membrane oxygenator (ECMO) support, and thereafter left ventricular assist device (LVAD) support. He was able to be weaned off the LVAD but had ongoing severe systolic and diastolic dysfunction requiring inotropes and ongoing mechanical ventilation. His course was complicated by a stable subdural hemorrhage with mirco-hemorrhages throughout the cerebral, midbrain and cerebellum. He was listed for heart transplant. Decompensation led to a Berlin LVAD placement on 8/26/20, followed by heart transplant on 8/30. Post-transplant imaging displayed global cerebral volume loss with confluent hypodensity of the periventricular white matter. He required prolonged post-transplant hospitalization given his deconditioning, oral aversion, aspiration risk and required supportive care. He was discharged on 11/10/2020 at 14.5 months of age. He presented back to the hospital for three brief stays due to dehydration, fever, and feeding intolerance, respectively. Overall, this patient spent ~5.5 months in inpatient care.

During hospitalization, a childhood mental health clinician was consulted due to poor parental coping, post-transplant concerns of developmental regression and an abnormal stress response. At this time the family reported that they had been unable to fulfill the referral for supportive services in their area that had been recommended at 4-months. A detailed developmental assessment, including parent interview, observations of the child and the parent-child dyad and consultation with medical team was conducted. This assessment revealed increased social withdrawal (interacting solely with his iPad and not parents or social partners), reduced positive affect (decrease in positive displays of emotions), fearful behaviors (withdraw and dysregulation in response to medical staff or new people), hypervigilance (constant awareness of changes in the environment) and difficulties with concentration (he could only display maintained attention with the iPad) and disordered sleep—all manifestations that are characteristic of Post-Traumatic Stress Disorder (PTSD). However, he did not meet full PTSD criteria (namely re-experiencing trauma and avoidance of reminders), and thus, was diagnosed with Other Trauma, Stress and Deprivation Disorder of Early Childhood. The slight delay in social and emotional development that was noted at 4 months had progressed to a diagnosis of global developmental delay by 14 months of age due to the absence of social, cognitive, motor and language skills.

Family Functioning at Second Hospitalization

The consultation with this family at 10.5 month of age illustrates challenges faced by the family and possible gaps in the system. Paternal mental health challenges, aversions to hospital visits, maternal anxiety and a distrust of medical system were noted; all complicated by cultural and language barriers. This is also encapsulated in Figure 2 . The clinician noted that the patient rarely looked to parents for emotional support or security. The child was utilizing a screen for regulation rather than reaching out to his parents for support. This accentuated their feelings of helplessness and made them feel dispensable in his care; further promoting a cycle of isolation.

Due to symptoms of trauma in this patient and the level of parental distress the clinician recommended trauma-informed dyadic intervention (see Table 1 ). Unfortunately, there are currently no standardized dyadic psychological interventions formalized for children in the critical care environment. The clinician saw the family approximately twice per month while the patient was still in the hospital, offering supportive resources for the parents and suggestions on how to enhance interactions. Both parents were receptive to these services.

Table 1 . Trauma-informed relational interventions.

Outpatient Course

At the point of discharge, the family began trauma informed dyadic intervention with the same clinician primarily via telemedicine (and which continued over the next 12 months). The patient continued to show an abnormal stress response with hypervigilance, hyperactivity or complete passivity. This is noteworthy as the child attended these visits with both parents from his home, where environmental components should be supportive. Once an intensive stressor is removed (such as the hospital environment) ideally children are expected to signal their distress to primary caregivers and seek comfort ( 5 ). The continuation of abnormal stress responses in the absence of the inpatient environment and in the presence of his parents was of concern; capacity to find comfort in a caregiver when stressed is an important developmental skill to reduce emotional and physiological distress ( 2 , 6 , 7 ). The family is now engaging in weekly therapy with the clinician, following the Parent-Child Psychotherapy intervention model ( 8 ). Of note, the Covid-19 pandemic necessitated weekly therapy appointments via a tele-health model. As restrictions were lifted the goal was to alternate therapy sessions weekly between in-person and tele-health. While disadvantages to tele-medicine have been reported ( 9 ), the flexibility of telemedicine allowed for higher compliance with scheduled visits and a lower likelihood of cancellation due to maternal anxiety, family schedule or illness. Telemedicine may have a particular advantage in this population of vulnerable children as both the child and the parents may be hesitant to return to the hospital environment given associated triggers or stressors. Continued work to attenuate such hospital avoidance is vital to allow for a full in-person developmental assessments to optimize cognitive and social functioning. Advances have been made in helping the patient's parents identify his irregular indicators of stress and maladaptive responses as well as how they may best respond. Through the development of this ongoing therapeutic process a deeper understanding of the parent's perspective, emotions and experience was gained. Further goals are centered around decreasing parental distress and enhancing the family's ability to engage in synchronous dyadic interactions.

This case study highlights the threat hospitalization and complex care pose to neurodevelopment and pediatric mental health as well as opportunities for intervention. When the family was seen at their four-month follow up appointment they were undoubtedly experiencing stress and social isolation, but it was manageable. However, they did not connect with supportive services and were unable to develop effective coping strategies. In the absence of these strategies and with the additional stressors of re-admission and cardiac transplantation they struggled to regulate their own stress and were unable to help co-regulate their son's stress. Furthermore, despite what many medical professionals may hope, the child's stress and trauma symptoms did not resolve upon discharge and removal from a “stressful environment.” Indeed, ongoing and unmanaged stressors continued to put his development at risk. Effective consultation and intervention are needed both in the inpatient stay and upon discharge in order to ensure that parents and their children do not continue to struggle with concerning mental health symptoms.

While the themes in this case are commonly identified in complex chronic hospitalized pediatric patients, the specific diagnosis of Other Trauma, Stress Disorder of Early Childhood is both a significant and escalating factor in the assessment and care of this patient, and is indicative of detrimental implications in his post-discharge course. These maladaptive stress responses, even in the home environment, is a marker of the severity of his accumulated insults and may serve as a poor prognostic indicator in terms of future development and adaption in the absence of intervention ( 2 , 3 , 6 ). It is important to note that there is no clear etiologic factor as to what element of critical care or hospitalization primarily impact development, and such an answer likely does not exit. A variety of components of critical cardiac care can have an adverse impact on neurological and neuropsychological development including, surgery, anesthetics and bypass interventions ( 10 – 13 ). Additionally, children born with complex congenital heart lesions are frequently born with brain immaturity and with ongoing relative hypoxemia ( 14 – 16 ). Teasing apart the impact of neuro-organic insults as opposed to stress and environmental factors is a clear limitation in this case study. These organic factors alone do not fully explain the developmental delay seen in this patient or many of those who experienced similar care. Additionally, such neuronal insults are not commonly seen to elicit the trauma response seen in this patient. Specific factors (over both the inpatient course and in the post-discharge home environment) that contribute to adversely impacting neurodevelopment beyond the neuro-organic insults are outlined in Figure 2 . This inability to tease apart and quantify specific elements of an experience is a challenge that has been noted consistently in the developmental trauma literature ( 17 , 18 ).

Early childhood is a period of in which neurodevelopment is uniquely vulnerable to insult. The brain utilizes early plasticity to promote learning and adaptation, however this plasticity also leaves the brain open to impacts that can cascade through later development. A child's developing stress system was not designed for chronic or incredibly heightened activation Extreme stress in the absence of a safe and predictable caregiving relationship can lead to an inability to regulate the developing stress system ( 6 ). A dysregulated stress system may have adverse impacts on brain, immune, hormonal and behavioral development throughout the lifespan ( 1 , 19 , 20 ). Given the plastic nature of early brain development young children can also display outstanding capacity for recovery and resilience ( 21 ). Evidence based dyadic interventions (as described in Table 1 ) show promise in reducing children's behavioral manifestations of past trauma, promoting a more well-regulated physiological stress system and enhancing capacity for learning ( 22 – 24 ). Selecting the dyadic relationships as a point of intervention offers opportunity to support both young patients and their parents. The trauma and stressed faced by children experiencing complex critical care cannot be completely removed; however, trauma informed dyadic intervention can alleviate the toll of this experience and attenuate adverse sequelae.

While developmental concerns are acknowledged by medical professions in post-cardiac surgery populations, the severity of the developmental delay and the prolonged symptoms of post-traumatic stress disorder in this case are both significant and novel enough to warrant discussion. The possible impact on the child's development due to long hospitalization related to complex and repeat cardiac surgical procedures should be disclosed as part of the consent process. Furthermore, despite a level of acknowledgment among medical care providers there is little in the literature on the psychological and developmental consequences of complex cardiac care. Limited research suggests that childhood hospitalization is correlated with learning delays ( 25 ), heightened physiological stress response ( 26 ) and/or increased levels of psychosocial stress ( 27 ). Further research is needed to appropriately understand and address the needs of this vulnerable population. In the field overall, long-term neurodevelopmental follow-up is not the current standard of care. However, patients may undoubtedly benefit from developmental follow-up and care post-surgery and hospitalization. The program through which patient X was managed is unique in its capacity to meet families during hospitalization and provide support post-discharge. During hospitalization the primary focus is on the child's physical health and survival; however, failure to address mental health concerns in these families will place the child's long-term development at risk. As such, early identification and intervention with long-term follow up should be an ideal model for care for these families.

This case highlights the potential impact of intense and complex cardiac care on neurodevelopment, pediatric mental health and family dynamics, as well as novel intervention mechanisms.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

CD conceptualized and drafted the initial manuscript and additionally contributed critical revisions. MK played a vital role in conceptualization, patient identification, and critical manuscript drafting and revision. SS substantially contributed to conceptualization and critical manuscript revision. AS made substantial contributions to conceptualization, patient identification, manuscript drafting, and critical revision. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Conflict of Interest

SS is a consultant for Stryker and Cryolife.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

EA, esophageal atresia; TEF, tracheoesophageal fistula; VSD, ventricular septal defect; NICU, neonatal intensive care unit; RVOT, right ventricular outflow tract; ECMO, extracorporeal membrane oxygenator; LVAD, left ventricular assist device; PTSD, posttraumatic stress disorder.

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Keywords: case report, mental health, pediatric development, critical care, pediatric intensive care unit

Citation: Dahl CM, Kroupina M, Said SM and Somani A (2021) Case Report: Traumatic Stress and Developmental Regression: An Unintended Consequence of Complex Cardiac Care. Front. Pediatr. 9:790066. doi: 10.3389/fped.2021.790066

Received: 06 October 2021; Accepted: 06 December 2021; Published: 24 December 2021.

Reviewed by:

Copyright © 2021 Dahl, Kroupina, Said and Somani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Arif Somani, soman007@umn.edu

• Open access
• Published: 16 November 2023

Perampanel effectiveness in treating ROGDI -related Kohlschütter-Tönz syndrome: first reported case in China and literature review

• Linxue Meng 1 , 2 , 3 , 4 , 5   na1 ,
• Dishu Huang 1 , 2 , 3 , 4 , 5   na1 ,
• Lingling Xie 1 , 2 , 3 , 4 , 5 ,
• Xiaojie Song 1 , 2 , 3 , 4 , 5 ,
• Hanyu Luo 1 , 2 , 3 , 4 , 5 ,
• Jianxiong Gui 1 , 2 , 3 , 4 , 5 ,
• Ran Ding 1 , 2 , 3 , 4 , 5 ,
• Xiaofang Zhang 1 , 2 , 3 , 4 , 5 &
• Li Jiang 1 , 2 , 3 , 4 , 5  

BMC Medical Genomics volume  16 , Article number:  292 ( 2023 ) Cite this article

Metrics details

This study reported the first case of Kohlschütter-Tönz syndrome (KTS) in China and reviewed the literature of the reported cases.

This patient was registered at the Children’s Hospital of Chongqing Medical University. The patient’s symptoms and treatments were recorded in detail, and the patient was monitored for six years. We employed a combination of the following search terms and Boolean operators in our search strategy: Kohlschütter-Tönz syndrome, KTS, and ROGDI . These terms were carefully selected to capture a broad range of relevant publications in PubMed, Web of Science, WHO Global Health Library, and China National Knowledge Infrastructure, including synonyms, variations, and specific terms related to KTS. The pathogenicity of the variants was predicted using SpliceAI and MutationTaster, and the structures of the ROGDI mutations were constructed using I-TASSER.

This is the first case report of KTS in China. Our patient presented with epilepsy, global developmental delay, and amelogenesis imperfecta. A trio-WES revealed homozygous mutations in ROGDI (c.46-37_46-30del). The brain magnetic resonance imaging (MRI) and video electroencephalogram (VEEG) were normal. The efficacy of perampanel (PMP) in treating seizures and intellectual disability was apparent. Furthermore, 43 cases of ROGDI -related KTS were retrieved. 100% exhibited epilepsy, global developmental delay, and amelogenesis imperfecta. 17.2% received a diagnosis of attention deficit hyperactivity disorder (ADHD), and 3.4% were under suspicion of autism spectrum disorder (ASD). Language disorders were observed in all patients. Emotional disorders, notably self-harm behaviors (9.1%), were also reported.

ROGDI -related KTS is a rare neurodegenerative disorder, characterized by three classic clinical manifestations: epilepsy, global developmental delay, and amelogenesis imperfecta. Moreover, patients could present comorbidities, including ADHD, ASD, emotional disorders, and language disorders. PMP may be a potential drug with relatively good efficacy, but long-term clinical trials are still needed.

Peer Review reports

What is known

Kohlschütter-Tönz syndrome (KTS) is an autosomal recessive disorder that manifests with severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta, leading to the discoloration of both primary and secondary teeth (yellow or brown) (OMIM, 2022).

Research has demonstrated that the primary genetic cause of KTS is linked to biallelic mutations in the ROGDI gene.

The genotype-phenotype correlation of ROGDI- related KTS remains unclear.

What is new

In this study, we presented the first case of ROGDI -related KTS in the Chinese population, which added to the existing knowledge of this spectrum disorder. The intronic variant c.46-37_46-30del was detected and predicted to be pathogenic by causing loss of function of ROGDI.

Clinicians may contemplate perampanel therapy for KTS patients with epilepsy as it could potentially decrease seizure frequency and enhance motor development.

We speculate that there may be a link between KTS and comorbidities, therefore, we advocate for strengthening psychological interventions and adopting multidisciplinary management approaches for KTS patients to prevent accidental injury.

Introduction

Kohlschütter-Tönz syndrome (KTS) is an autosomal recessive disorder, initially reported in a Swiss family by Kohlschütter in 1974 [ 1 ]. KTS is a rare disorder that manifests with severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta, leading to the discoloration of both primary and secondary teeth (yellow or brown) (OMIM, 2022). KTS is clinically heterogeneous, with varying ages of onset of epilepsy, diverse manifestations of seizures, and varied relationships between intellectual disability and seizures [ 2 , 3 ]. To date, research has demonstrated that the primary genetic cause of KTS is linked to biallelic mutations in the ROGDI gene. The vast majority of KTS patients who had undergone genetic testing were found to have ROGDI mutations [ 4 , 5 , 6 ].

Owing to the rarity of KTS, there was relatively little treatment evidence provided by case reports. Currently, there is no specific treatment available for KTS. In addition, the disease's clinical phenotype is heterogeneous, which leads to delays in diagnosis. As a result, clinicians often relied on symptomatic treatment methods, including the administration of anti-seizure medications (ASMs). Regrettably, the prognosis for patients with KTS was typically unfavorable. KTS patients often experienced not only global developmental delay but also develop refractory epilepsy (RE) and even died early due to progressive mental deterioration, which undoubtedly causes heavy psychological and economic burdens for patients and their families [ 1 ].

To improve the management of children with KTS, this study presented the clinical and genetic features of the first reported KTS patient in China, a young Chinese girl with homozygous ROGDI mutations. We observed that the patient responded well to perampanel (PMP), which may serve as a useful reference for treating KTS-related epilepsy. Additionally, we compiled data on all previously reported patients with ROGDI -related KTS, including their genotypes, phenotypes, treatments, and prognosis. We also discussed and summarized the possible mechanisms of PMP effectiveness in treatment from the perspective of molecular mechanisms. This study aimed to facilitate early diagnosis and treatment of KTS, ultimately improving patient prognosis and reducing suffering.

Materials and methods

The patient was registered at the Children’s Hospital of Chongqing Medical University (CHCMU), the largest pediatric medical center in Southwest China. We obtained her detailed clinical and genetic information and performed six years of follow-up.

The diagnostic criteria for KTS have not been clearly established yet. However, the main genetic etiology has been identified as ROGDI mutations. The patient’s clinical features manifest three core symptoms of KTS: global developmental delay, early-onset intractable seizures, and amelogenesis imperfecta [ 5 ]. Therefore, the patient's diagnosis was based on both genetic test results and clinical symptoms.

Next-generation sequencing (NGS)

Before performing the study, written informed consent was obtained from legal guardians. This study was approved by the CHCMU Ethics Committee. The targeted NGS was performed following previously reported experimental procedures [ 7 ]. The average sequencing depth of the WES was 123.810. The sequencing result was aligned to the Genome Reference Consortium Homo sapiens (human) genome assembly GRCh37 (GRCh37/hg19) and compared with the established human ROGDI sequence (NM_024589).

Sanger sequencing

Sanger sequencing was performed to validate the variant identified by NGS and for segregation analysis. Amino acid sequence alignment was performed using Genedoc software ( https://github.com/karlnicholas/GeneDoc ) for conservative analysis. Then we used SpliceAI and MutationTaster to predict the pathogenicity of the variants [ 7 ].

Quality control

The patient was evaluated by two psychiatrists, and at least one family member accompanied her to the clinic visit. Follow-up care was primarily conducted on an outpatient basis. A designated primary caregiver was requested to conduct the follow-up interviews. All clinical data were meticulously organized, cross-checked, and independently analyzed by two investigators.

Data retrieval methodology

We conducted an extensive search to identify relevant cases of KTS in the Chinese population. Our search strategy involved utilizing multiple databases, including PubMed, Web of Science, WHO Global Health Library, and China National Knowledge Infrastructure. We employed a combination of search terms, including Kohlschütter-Tönz syndrome, KTS, and ROGDI to ensure a comprehensive and systematic retrieval of relevant literature. Additionally, we manually reviewed the reference lists of identified articles to identify any additional pertinent studies. The period of retrieval was up to June 2023. By conducting a meticulous review of the available literature and analyzing the clinical data from the case presented here, we aim to shed light on the underreported aspects of KTS within the Chinese population, ultimately filling a crucial knowledge gap in this field.

Case report

This is a female from China. No obvious abnormality was found during her mother's gestation period. Due to a fetal heart rate of fewer than 120 beats per minute, her mother underwent a cesarean section delivery. The child was born with a birth weight of 2.87 kg. There is no history of seizures or intellectual disability in her family. The parents of this patient are not endogamy or consanguinity.

At the age of seven months, the child was admitted to our hospital’s neurology clinic due to developmental delay. She exhibited an inability to raise her head, laugh, or grab objects. Physical examination revealed decreased muscle tension of limbs and laxity of the Achilles tendon. Gesell Developmental Schedules (GDS) assessment showed her total developmental quotient (DQ) was only 38.8 points, indicating a developmental delay. Peabody's developmental motor scale (PDMS) also showed her fine motor and gross motor abilities were only equivalent to those of a two-month-old child. After conducting a magnetic resonance imaging (MRI) scan of the brain, no abnormalities were detected. No discharges were found through a video electroencephalogram (VEEG). Consequently, on the recommendation of the neurology clinic, she began rehabilitation training.

At the age of 10 months, the patient experienced her first unprovoked generalized seizure, characterized by cyanosis of the face and lips, lips smacking, eyes staring, loss of consciousness, and no convulsive limb movements. The seizure occurred without a fever and lasted for nearly one minute. The patient's VEEG revealed an increase in δ and θ waves of 3–4 Hz during wakefulness, along with clinical symptoms, leading to a diagnosis of epilepsy. Treatment was initiated with valproic acid (VPA) at a dose of 17 mg/kg/d, which initially proved effective. The seizures were well controlled at the beginning. The longest time of seizure-free was 7 months with a maintenance dose of 27 mg/kg/d.

Uniform yellow discoloration and carious changes in her teeth were observed at the age of one. Although the epilepsy was controlled to some extent, she exhibited significant developmental delays compared to her peers. Despite the aid of VPA and rehabilitation therapy, her mental and motor functions still progressed slowly. At 1.3 years of age, she could hold, chase, laugh, and sit with her back arched at that time. The PDMS showed her gross motor function was only equivalent to a 5-month-old infant, and her fine motor function was only equivalent to a 7-month-old infant. The GDS indicated a DQ of 47, showing that her motor function and cognition progressed more slowly than before. The patient is 7 years old now and continues to exhibit profound global developmental delays. Her comprehension is limited to basic instructions, and she is unable to perform self-care tasks such as independent eating or managing urinary and bowel functions. Throughout our thorough and ongoing monitoring, the patient has not displayed any comorbid conditions, including ADHD, or ASD, except for a language disorder.

The patient remained seizure-free until she reached 1.5 years of age. Subsequently, for the following four years, she began to experience recurrent seizures with a consistent pattern. These seizures were consistently triggered by fever following respiratory or digestive tract infections. Notably, there were no seizures reported after the fever subsided. In response to this recurring pattern, the patient was maintained on VPA as a treatment. At the age of five, the patient began experiencing afebrile convulsions once a week. These seizures were characterized by facial and labial cyanosis, staring eyes, or sometimes only peri-labial cyanosis. As a result, the patient's anti-seizure therapy was modified to include a combination of levetiracetam (LEV) at a dose of 20 mg/kg/d along with VPA. After the addition of LEV, the child's motor and communication functions reportedly improved. However, the frequency of seizures increased, occurring two or three times a night. During the VEEG, discharge was observed on the right side of the frontal lobe during sleep, with occasional discharge seen on the left side of the frontal lobe. As a result, at the age of six, the patient's treatment regimen was adjusted. PMP was introduced as part of her treatment plan, and concurrently, the dosage of VPA was gradually reduced as the child approached her sixth year. The initial and maintenance dose of PMP was 2 mg/n. The patient had been seizure-free for nearly seven months and showed significant improvement in gross motor skills after receiving PMP treatment. Currently, the patient is receiving a combination of PMP with a maintenance dose of 2 mg/n and LEV with a maintenance dose of 43 mg/kg/d for anti-seizure therapy. The efficacy of PMP in treating seizures and intellectual disability was apparent.

The MRI was normal. Mild regurgitation of the tricuspid and pulmonary valves was detected through a cardiac ultrasound. The immune-related examination did not mention any obvious immune abnormalities. Blood metabolism screening at 10 months of age indicated a possible diagnosis of citrullinemia, but subsequent examinations were normal. During the course of the disease, the patient's blood ammonia levels exhibited multiple instances of increase, occurring on five occasions, with the highest recorded level peaking at 79.4 μmol/L, the patient has been receiving L-carnitine supplementation for a duration of approximately 9 months as part of her treatment regimen to address specific metabolic needs. After repeated examinations, the blood ammonia returned to normal, so the L-carnitine was gradually stopped. The blood ammonia level remained stable without L-carnitine and the result of trio-WES did not indicate the causative gene for citrullinemia.

When the patient was three years old, a trio whole exome sequencing (trio-WES) genetic examination was performed, which revealed homozygous mutations in ROGDI (c.46–37_46–30delGGCGGGGC) (Fig.  1 ). The patient's mother had heterozygous mutations at this site, while her father did not have any mutations at this site. Therefore, it is suspected that there may be a parental-single diploid on chromosome 16 in this patient. This variation was previously reported as a pathogenic mutation in a KTS patient. As shown in Fig.  2 , The molecular structures resulting from nonsense variants in ROGDI were predicted by a hierarchical approach using I-TASSER. ( https://seq2fun.dcmb.med.umich.edu//I-TASSER/ ).

DNA sequence chromatogram of the ROGDI mutations. The circles indicate the position of the mutation. G: guanine; T: thymine; C: cytosine

Molecular analysis of ROGDI missense variants. A Normal ROGDI protein structure. B c.286C > T/p. Gln96Ter, the peptide chain terminates at Gln96. C c.402C > G/p. Tyr134Ter, the peptide chain terminates at Tyr134. D c.469C > T/p. Arg157Ter, the peptide chain terminates at Arg157

In conclusion, the patient presented with the three core symptoms of KTS, including epilepsy, global developmental delay, and amelogenesis imperfecta. The patient's diagnosis of KTS was confirmed by the genetic examination results, which showed a homozygous deletion mutation of ROGDI . According to our follow-up, the patient has been seizure-free for seven months and meanwhile her gross motor skills had significant improvement after receiving a PMP treatment.

Literature review

Forty-three cases of ROGDI -related KTS were retrieved. To comprehend the features of ROGDI gene mutations, we analyzed all KTS cases reported until June 2023 with pathogenic or likely pathogenic mutations of ROGDI, including the basic information (e.g., sex, age of onset, age of diagnosis), characteristics of seizures, comorbidities, and auxiliary examination. The neurologic manifestations of 44 KTS patients with pathogenic ROGDI variants were summarized in Table 1 (including our case) [ 1 , 2 , 3 , 4 , 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. We summarized a total of 44 KTS patients with ROGDI mutations (including our case), consisting of 25 (56.8%) males and 19 (43.2%) females. There was no clear chronological relationship between the onset of intellectual and developmental disabilities (IDDs) and epilepsy. Ten (22.7%) patients started with IDDs, and 34 (77.3%) patients started with epilepsy. The median age of seizure onset was 10 months (range: birth–48 months). It took an average of 37 months (range: birth–75 months) from seizure onset to establish the diagnosis of KTS. The seizure onset was triggered by fever in nine (20.5%) patients, and 11 (25.0%) patients had a history of febrile convulsions. The patterns of epilepsy were diverse, with six (40%) patients having generalized seizures, five (33.3%) patients having focal seizures, six (40%) patients having generalized tonic–clonic seizures, three (20%) patients having myoclonic seizures, one (6.7%) patient having unilateral tonic–clonic seizures, and one patient (6.7%) having generalized atonic seizures. Among those patients whose clinical information was available, three (6.8%) patients had status epilepticus, 24 (61.5%) patients developed RE, and three (7.7%) patients became seizure-free. Two (5.1%) patients had a history of encephalopathy. Descriptions of dystonia were reported in 34 patients, with 18 (52.9%) having dystonia and 16 (47.1%) not. Excluding one patient with incomplete documentation, 43 (100%) patients had IDDs. In those detailed cases reported, we also identified five (17.2%) patients with attention deficit hyperactivity disorder (ADHD) and one (3.4%) with suspected autism spectrum disorder (ASD). All 29 (100%) patients had language disorders, characterized by no or limited verbal language and communicated by shouting. Three (9.1%) patients had self-harm behaviors and showed more aggression than before, one (3.0%) had impulsiveness, and one (3.0%) showed a hyperactive temper. Based on the limited description, there is currently one case of hearing loss, and no visual impairment has been reported yet. There was no particular pattern of electrical discharge in the electroencephalogram (EEG). Of the 20 patients with VEEG or EEG descriptions, 17 (85%) patients had abnormal discharges. Brain MRI was described in 19 patients, of whom five (26.3%) were normal and 14 (73.7%) had diverse manifestations, including ventricular enlargement (28.6%), brain atrophy (35.7%), cortical atrophy (7.1%), delayed myelination (7.1%), marginally hypoplastic vermis (14.3%), corpus callosum agenesis (7.1%), and thickening of the right temporal lobe surface (7.1%). All the patients (100%) whose clinical data were available had amelogenesis imperfecta.

To better comprehend the relationship between ROGDI genotypes and phenotypes, we summarized the genotypes of 44 patients in Table 2 and predicted their pathogenicity. Of the 44 patients, 15 (34.1%) had homozygous intronic variants, nine (20.1%) had homozygous frameshift mutations, 18 (40.9%) had homozygous nonsense mutations, one (2.3%) had heterozygous intronic mutations, and one (2.3%) had compound heterozygous mutations. It is noteworthy that all patients inherited mutations rather than de novo mutations. The ROGDI nonsense variants were located at extremely conserved positions (Fig.  3 ) All the nonsense mutations were predicted to be disease-causing by Mutation Taster. The protein structures resulting from nonsense mutations (Fig.  2 ) indicated a decrease in the effective ROGDI protein, which suggests the loss of ROGDI function. SpliceAI was used to predict the pathogenicity of intronic variants. All four intronic variants were predicted to affect splice sites, indicating their potential pathogenicity.

Conservation analysis of ROGDI nonsense variants. Conservation of the altered amino acid was shown in the MUSCLE alignment

To provide insights into the treatment strategies for KTS, we collected information on the treatment of 44 patients, and detailed descriptions of 15 of them are summarized in Table 3 . Except for two patients who only used one anti-seizure medication (ASM), all other patients used at least two ASMs combined with antiepileptic therapy, and one patient used a maximum of five ASMs. None of the patients received adrenocorticotropic hormone (ACTH) treatment. One patient underwent vagus nerve stimulation (VNS) and adopted a ketogenic diet (KD), but this treatment did not have a satisfactory curative effect, and the patient still had RE. Seven patients (46.7%) responded well to ASMs, and six of them had a seizure frequency reduction of over 50%, with one becoming seizure-free at four years old. The seven patients responded well to different combinations of ASMs: one responded well to VPA combined with clobazam (CLB), one responded well to CLB, one responded well to phenobarbital (PHB), and vigabatrin (VGB), one responded well to CLB combined with phenytoin, one responded well to PHB combined with LEV, and two (including our case) responded well to PMP.

The ROGDI gene consists of 11 exons and codes for a 287 amino acid protein. It is highly conserved across various species, mainly expressed in the human brain and spinal cord [ 16 ]. Prior to 2017, little was known about the protein encoded by ROGDI . However, the ROGDI protein is enriched at synaptic sites and co-localizes with the presynaptic scaffolding Bassoon protein, as well as the synaptic vesicle markers Synaptophysin, Synapsin-1, VAMP2/Synaptobrevin, and Mover [ 17 ]. ROGDI plays a crucial role in presynaptic targeting and facilitates efficient signal transmission.

ROGDI -related KTS has been reported in 43 cases, and the loss of function (LOF) has been proposed as a pathological mechanism [ 3 ]. Null mutations, including deletions, duplications, frameshifts, and intronic variations, have been identified in various cases of ROGDI mutations and may potentially lead to the complete LOF [ 5 ]. The c.507del deletion variant (located in exon 7) was found to be the genetic cause in 15.9% of KTS cases, leading to a frameshift mutation of ROGDI and LOF. Additionally, the c.229_230del deletion variant (located in exon 4) and the intronic variant c.531 + 5G > C (located in intron 7) were identified in 4.5% and 13.6% of KTS cases, respectively, and the latter was predicted to disrupt the splice donor site of ROGDI , both resulting in LOF. The c.45 + 9_45 + 20del intronic variant (located in intron 1) was identified in 6.8% of KTS cases, which might cause a splicing error that led to LOF of ROGDI . Furthermore, the nonsense variant c.469C > T (located in exon 7) was identified in 36.4% of KTS cases, predicted to cause premature termination of the peptide chain. The c.201-1G > T intronic variant (located in exon 3) was identified in 6.8% of KTS cases, predicted to have disrupted the splice acceptor site in exon 4, resulting in LOF of ROGDI . In this study, we also identified a homozygous variant (c.46–37_46–30del) in intron 1, predicted to have disrupted the splice acceptor site in exon 2, causing complete LOF of ROGDI . The pathogenicity of the homozygous variant has been confirmed in a previous KTS patient, leaving no room for doubt. One mutation site originated from the patient's asymptomatic heterozygous mother. It is speculated that the other mutation site also has maternal origin due to the exceedingly low probability of both alleles sharing the same mutation. This suggests a possible case of maternal uniparental disomy (mUPD) on chromosome 16. Uniparental disomy (UPD) is the inheritance of both copies of a chromosome or a chromosomal region from a single parent, as opposed to the typical inheritance of one copy from each parent. UPD occurs in two forms: paternal UPD (pUPD) and maternal UPD (mUPD), depending on whether the duplicated chromosomes originate from the father or mother. In cases of mUPD, individuals inherit both copies of a chromosome or chromosomal region exclusively from the mother, with no genetic contribution from the father, similar to the scenario in this case. mUPD can result from various mechanisms, including meiotic errors, non-disjunction events, and chromosomal rearrangements. Although our research did not entail a dedicated marker study, we advocate for future investigations to delve more comprehensively into this aspect. The rest variants listed in Table 2 were identified once. However, the number of cases is not sufficient for a possible mutational hot spot definition [ 2 ].

Epilepsy is the most common initial symptom in KTS patients. The age of seizure onset varies widely, with a median age of 10 months (range: 0–48 months). At present, no evidence indicates that early-onset seizures are a risk factor for a negative prognosis [ 1 , 13 , 14 ]. Seizure frequency typically decreases with age, expect individuals with RE [ 5 , 13 ]. Our knowledge of KTS-related epilepsy is limited, and seizures can manifest in diverse forms without discernible patterns, as noted in prior studies [ 12 , 14 , 18 ]. Furthermore, the existing evidence does not adequately account for the relationship between genotype and seizure phenotype. This is exemplified by the observation that families with the same variation c.46–37_ 46–30del display diverse seizure patterns [ 14 ]. The assistance offered by VEEG/EEG results is also severely limited [ 5 , 10 , 12 , 13 , 14 , 18 ]. Based on our summary of the VEEG/EEG results of the 44 KTS patients, we did not find any correlation between genotypes and discharge patterns. The exact pathogenesis of epilepsy in KTS patients caused by ROGDI gene mutations remains unknown. In view of the exocytosis of neurotransmitters and synaptic vesicle recycling are hallmarks of presynaptic function at mature synapses, Donatus Riemann et al. put forward one possibility that ROGDI may regulate exocytosis in neurons and the dysfunctional exocytosis would affect neural development and synaptic function [ 17 ]. Notably, BASSOON , which encodes the BASSOON protein and co-localizes with the ROGDI protein, has been recently identified as an epilepsy gene [ 19 ]. Additionally, ROGDI is involved in sleep regulation via dopaminergic signaling mediated by GABAergic pathways [ 20 ]. Therefore, ROGDI gene mutation might affect the expression of the ROGDI protein, affect the expression of the co-located BASSOON protein, and disrupt the ROGDI -GABAergic signaling pathway, ultimately leading to epilepsy. Nevertheless, this hypothesis needs further functional validation through experiments on animals or cells by silencing ROGDI expression and monitoring changes in BASSOON expression and the GABAergic signaling pathway.

Amelogenesis imperfecta is another significant symptom of KTS. To date, all KTS patients involve amelogenesis imperfecta. However, the underlying mechanism of ROGDI -related amelogenesis imperfecta remains unknown. KTS patients had very thin, soft, rough enamel and brown-stained enamel, which is susceptible to disintegration [ 1 ]. Yellow enamel was discovered when our patient was one year old. She was already displaying global developmental delay and epilepsy. However, due to the rarity of KTS and the lack of awareness among clinicians, a diagnosis of KTS was not made, and genetic testing was not completed at once. It is advisable to remain vigilant about the potential for KTS and complete genetic testing as soon as possible when there is a link between amelogenesis imperfecta, global developmental delay, and epilepsy.

Global developmental delay frequently causes significant distress for both KTS patients and their families. While most KTS cases exhibited global developmental delay or regression after the onset of epilepsy, approximately 20% of patients showed global retardation before epilepsy occurred [ 2 , 3 , 4 , 5 , 11 , 13 , 14 , 18 ]. According to the reported cases, such children usually start walking at 2–5 years of age [ 5 , 8 , 11 , 13 , 21 ], and some may lose the ability to walk during long-term follow-up due to spasms and abnormal gait [ 2 , 13 ]. With a long period of uninterrupted rehabilitation training, our patient started walking when she was 25 months old. She could walk alone without spasms and abnormal gait for now, but his gait was not very stable yet (Supplementary material: Video 1 ). No genotype has been found to be associated with the degree of dyskinesia so far. Even patients with the same genotype can exhibit varying degrees of dyskinesia. For instance, two patients with the same mutation as in this study started walking independently at 24 and 21 months, respectively, which were similar to our patient [ 14 ]. However, one of the two patients was unable to stand up even at six years old. Therefore, we believe that this phenomenon is not only associated with the heterogeneity of clinical presentation but also with the persistence of rehabilitation training over six years.

Additionally, the language disabilities of KTS patients are significantly impacted. The ROGDI gene codes for a protein involved in the development of glial cells and neuron migration. Mutations in this gene may result in connectivity and communication issues between brain regions, which can affect both language development and comprehension [ 22 , 23 ]. Table 1 presented a summary of our findings that indicated varying degrees of language impairment among all KTS patients for whom data was available. Language impairment manifests as either a complete absence of verbal communication or severely limited verbal abilities. The patient in our study also exhibited limited verbal communication skills.

There is currently no evidence that the frequency of seizures is associated with early-onset developmental delays in KTS patients [ 3 , 5 , 13 , 18 ]. However, when it comes to epilepsy and developmental delays, epilepsy may lead to developmental delay, particularly with prolonged or frequent seizures. Conversely, developmental delay may increase the risk of epilepsy. Some genetic mutations, including ROGDI gene mutations, can result in the simultaneous occurrence of epilepsy and developmental delay. Hence, it is crucial to consider and manage both conditions concurrently in clinical management.

It is not clear whether KTS is associated with any comorbidities. However, our analysis of the limited number of cases available (Table 1 ) suggested that five patients had ADHD and one patient had suspected ASD [ 2 , 8 , 13 , 18 ]. Although this evidence is not definitive, we speculate that there may be a link between KTS and comorbidities. Given that some KTS patients have exhibited self-harm behaviors, aggression, or impulsivity, it is strongly recommended to pay close attention to the possible presence of comorbidities [ 2 , 11 , 12 , 13 ]. We advocate for strengthening psychological interventions and adopting multidisciplinary management approaches for KTS patients to prevent accidental injury.

Currently, no recommendations exist regarding the use of ASMs for these patients. However, we observed a positive response to PMP in the patient described in this report, which is consistent with a case reported by Lelde Liepina [ 12 ]. Following PMP treatment, the patient remained seizure-free for seven months and exhibited a significant reduction in epileptic discharges, as evidenced by VEEG results. Moreover, the patient’s mother reported that her child made notable improvements in gross motor development following PMP treatment. PMP is an anticonvulsant with a unique pharmacological profile. It acts as a non-competitive antagonist of AMPA receptors, which inhibits the AMPA receptor-mediated current in single neurons [ 24 , 25 ]. The anticonvulsant effect of PMP is due to its ability to disrupt the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations. This disruption is achieved through dynamic glutamatergic and GABAergic transmission [ 26 ]. Given that ROGDI can influence GABA neurotransmission and the mechanism of PMP in treating epilepsy, we speculate that this may explain why PMP is effective in treating KTS patients [ 20 ]. The long-term effectiveness of PMP needs to be verified by longer follow-up. Nonetheless, the exact pharmacological mechanisms require additional investigation and clinical evidence. Regardless, we suggest that clinicians may contemplate PMP therapy for KTS patients with epilepsy as it could potentially decrease seizure frequency and enhance motor development.

Our study reported the first case of ROGDI -related KTS in the Chinese population, which enriched the content of the spectrum disorder. We acknowledged the limitations of the single case report, as personalized treatment strategies must be developed based on the individual characteristics of each patient. Prospective multicenter clinical studies should be conducted to clarify the pathogenesis of KTS and the pharmacological effects of PMP treatment, which will assist clinical physicians in developing better disease management strategies.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author, Li Jiang, upon reasonable request. The datasets generated during the current study are available in the UNIPROT repository ( https://www.uniprot.org/uniprotkb/Q14738/entry#sequences ).

Abbreviations

Attention deficit hyperactivity disorder

Autism spectrum disorder

Anti-seizure medication

Adrenocorticotropic hormone

Children’s Hospital of Chongqing Medical University

Developmental quotient

Electroencephalogram

Gesell Developmental Schedules

Intellectual and developmental disabilities

• Kohlschütter-Tönz syndrome

Ketogenic diet

Levetiracetam

Loss of function

Medical University

Magnetic resonance imaging

Next-generation sequencing

Peabody's developmental motor scale

Phenobarbital

Refractory epilepsy

Trio whole exome sequencing

Video electroencephalogram

Valproic acid

Vagus nerve stimulation

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Acknowledgements

We thank this patient and her parents for their generous contribution and cooperation. We also thank all the clinicians and therapists treated this patient for six years. We would also like to thank all the authors of the review articles and the patients they reported for their extended coverage of the disease.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Linxue Meng and Dishu Huang were equally responsible for the work described in this paper.

Authors and Affiliations

Department of Neurology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

Linxue Meng, Dishu Huang, Lingling Xie, Xiaojie Song, Hanyu Luo, Jianxiong Gui, Ran Ding, Xiaofang Zhang & Li Jiang

National Clinical Research Center for Child Health and Disorders, Chongqing, People’s Republic of China

China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People’s Republic of China

Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People’s Republic of China

Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of China

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Contributions

All authors contributed to the study conception and design. Li Jiang designed the study. Lingling Xie, Xiaojie Song, Hanyu Luo and Jianxiong Gui collected the patients and; clinical information. Linxue Meng and Dishu Huang performed the statistical analysis and drafted the first version of the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Li Jiang .

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This is an observational study and has been performed in accordance with the declaration of Helsinki. The Ethics Committee of the Children’s Hospital affiliated with Chongqing University of Medical Sciences has approved this study. Informed consent was obtained from this patient’s parents. The authors affirm that human research participants provided informed consent for publication of the video in Supplementary material: Video 1 . A copy of the consent form is available for review by the Editor of this journal.

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Supplementary Information

Additional file 1: Supplementary material: Video 1 . The child's walking performance at age of six.

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Meng, L., Huang, D., Xie, L. et al. Perampanel effectiveness in treating ROGDI -related Kohlschütter-Tönz syndrome: first reported case in China and literature review. BMC Med Genomics 16 , 292 (2023). https://doi.org/10.1186/s12920-023-01728-z

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Published : 16 November 2023

DOI : https://doi.org/10.1186/s12920-023-01728-z

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Case 2: Developmental delay, especially language, in a toddler

An 18-month-old girl was first referred at eight months of age to a developmental centre because of general developmental delay. She was born after a normal pregnancy and delivery. Her birth weight was 3.7 kg, with Apgar scores of 9 and 10 at 1 min and 5 min, respectively. The neonatal period was uneventful. Her parents are non-consanguineous and have two older healthy sons. There are no known individuals with developmental delay or mental retardation in the enlarged families of both parents.

Beginning at four months of age, the infant suffered recurrent episodes of otitis media, and was hospitalized twice with pneumonia and purulent otitis media. A hearing test performed at seven months of age revealed profound hearing loss mainly in her right ear (70 dB), and a brainstem auditory evoked response test confirmed the hearing loss; ventilatory tubes were inserted. Her physical examination when she was first seen in the developmental centre was normal, with no dysmorphic features or abnormal neurological signs. Repeated developmental examinations and follow-up at 18 months of age confirmed a general developmental delay corresponding to motor developmental skills of a 12-month level and language skills at a nine-month level. The neurological examination showed mild hypotonia. Laboratory tests including a complete blood count, chemistry, thyroid function and urinalysis were normal. Toxoplasma, rubella, cytomegalovirus and herpes simplex virus titres were negative. Metabolic work-up including lactate, ammonia, amino acids and biotinidase in the blood, and organic and amino acids in the urine were normal. At this point, a blood test was ordered, which confirmed the suspected diagnosis.

CASE 2 DIAGNOSIS: FEMALE FRAGILE X SYNDROME

The developmental delay and recurrent episodes of otitis media, with hearing loss that persisted after the ventilatory tubes were inserted, led us to think of a syndromic cause for the patient’s symptoms. Chromosomal analysis revealed a normal female 46,XX karyotype, and molecular studies found a full mutation in the FMR1 gene (more than 200 copies of the CGG trinucleotide repeat sequence at the fragile X locus on the X chromosome), thus establishing the diagnosis of fragile X syndrome (FXS).

In 1991, the gene for FXS, designated FMR1 , which codes for the fragile X MR protein (FMRP) was discovered. The lack of FMRP production causes the syndrome. The DNA sequence at the FMR1 gene is a CGG trinucleotide repeat sequence. Normal individuals have between six and 55 CGG repeats, and carriers of the ‘premutation’ have 56 to 199 repeats, in which FMRP production still occurs. Those who have 200 CGG repeats or more have the ‘full mutation’, and in this situation, the DNA nucleotides are methylated, resulting in the absence of the FMRP. Forty per cent of patients with the full mutation are mosaics with cells containing variable length of full or premutation alleles.

FXS is the most common inherited cause of intellectual disability affecting males and females, with a prevalence of 1:3500 to 1:4000 in males, and 1:8000 to 1:9000 in females who show the full mutation. The overall prevalence may be as high as 1:2000 to 1:3000 because many prevalence studies have not screened children with milder cognitive deficits. The syndrome is characterized by certain physical features and impaired cognition, with language and behavioural problems. Approximately 80% of males have a dysmorphic appearance in contrast with most females who are not dysmorphic. Physical features may not be apparent at an early age. The characteristic facies are usually apparent by eight to 10 years of age, and may consist of macrocephaly, long face, prominent forehead, epicanthal folds, prognathism, dental crowding and large protruding ears. Entering puberty at approximately nine years of age, macroorchidism may become evident, increasing until a mean testicular volume of 50 mL in adulthood. Other features that may be seen in FXS include strabismus, mitral valve prolapse, high arched palate, soft velvety skin over the dorsum of the hands, hyperextensible joints, flat feet, scoliosis and simian creases of the palms. Recurrent otitis media (in 60% to 80% of individuals) and sinusitis (in 23% of individuals) are common in infancy and childhood.

Neurological abnormalities such as seizures (25%), hypotonia and motor dyspraxia may occur. The seizures appear mainly in boys. Partial seizures have been described in two girls who are fragile X carriers. In girls with the pre-mutation, the typical physical characteristics are more subtle, and they may exhibit premature ovarian insufficiency later in life. Approximately 30% of males who carry a pre-mutation allele will develop fragile X-associated tremor and ataxia syndrome after 50 years of age. Cognitive function in boys is more severely impaired, and most of them have moderate to severe intellectual disability with an average IQ of 30, whereas girls are borderline to mild, and 35% to 50% of those with the full mutation may have IQ scores of less than 85. With regard to language skills, boys may show greater delays in gaining expressive language skills compared with receptive language. Their speech may be rapid; dysfluent; characterized by repetitions of sounds, words and phrases; and they occasionally may have garbled, slurred and disorganized speech. Language impairment is also noted in affected girls.

Behavioural problems in boys are manifested by social avoidance, and deficits in attention and hyperactivity. Nearly 25% of boys meet the criteria for autism. Girls express social anxiety, social avoidance, withdrawal and depression. Shyness and social discomfort appear more in those with the premutation. Selective mutism has also been described in girls with the full mutation. Girls express more attentional difficulties, without the hyperactivity and impulsivity of attention-deficit hyperactivity disorder. Autistic behaviours may be reported in girls by six to 16 years of age, but unlike boys with the syndrome, they are usually not severly affected.

There are still reports in the literature of delayed diagnosis of the syndrome because of nonspecific features, unremarkable physical examination, noncontributory family history and delayed molecular testing. The case presented is one of the earliest ages of diagnosis in a female described in the literature.

There is no specific treatment for the syndrome. However, affected children do benefit from early developmental treatments in physical, speech and occupational therapy. More specific therapy includes psychopharmacological treatments for those with attention-deficit hyperactivity disorder symptoms; selective serotonin reuptake inhibitors for those with anxiety, perseveration, compulsive and depressive symptoms; and risperidone for aggressive behaviours.

CLINICAL PEARLS

• Consider FXS in any child, boy or girl, with a delay in language, social anxiety, hyperactivity or hand flapping.
• Girls generally have a milder presentation than boys because they have two X chromosomes and the normal X produces variable amounts of FMRP, depending on the amount of X inactivation. The level of FMRP correlates with the degree of cognitive involvement in both males and females.
• Early diagnosis is important for genetic counselling, particularly in young couples, and it is also useful for early intervention for those children who have special educational and psychosocial needs.
• In girls presenting with partial seizures of unknown cause, consider the possibility that they may be fragile X carriers.

RECOMMENDED READING

DNB Pediatrics

Global developmental delay - history taking and examination.

Table of contents

Introduction.

• Chief complaints, HOPI and OPD structure
• Other histories
• Signposting
• Examination - General, Neurological and other systems
• Diagnosis & Differential
• Approaching a child with GDD

Often a case with Global developmental delay is kept in the exam for history taking and physical examination. Taking a full history and finishing the examination is a relatively time taking exercise in CNS cases. Therefore remembering a structured format is very important. The post focuses on this .

Following is the history taking and examination guide for a child with Global developmental delay.

Before moving on to the case presentation, let us be clear on when to call it a Global developmental delay in a child.

Developmental delay vs global developmental delay - To be called it a global developmental delay, the child must have a functional delay in two or more domains of development.

Intellectual disability vs global developmental delay - For children less than 5 years of age the term global developmental delay is used, If the child is more than 5 years, it's called an Intellectual disability.

So, this time our dummy patient is Laila, she is 4 yr old little girl currently undergoing therapy for walking and speech.

Laila, 4 yr old girl, 1 st born out to consanguineous parents, Muslim by religion, resident of Park circus, Kolkata came to OPD with her mother for her scheduled therapy today. Informant being the mother who seems to be very reliable. Avoid using terms like patient relatives, instead use specifc terms like mum or father or aunt. Also avoid refering "patient" repeatedly, instead use the name, like 'Laila' in this case

Chief complaints

• Inability to walk
• Inability to speak words

Avoid using - 'Not attaining age-appropriate milestones', rather use specific issues in each domain.

History of present Illness

There are two ways to describe HOPI in this case.

• Start from birth history if it is significant, say, for example, neonatal asphyxia or bilirubin induced neural damage.
• Start from the point where the caregiver first doubted the delay and then go back in the past.

The history of present illness should be like a story, a story which links step by step rather than an unorganized one.

ODP is a good structure format to organize HOPI, it's a sequence of Onset, Duration followed by progression.

Laila was first suspected to have a delay in development by her grandma when she was not able to hold her neck even at the age of 6 months, also she was quieter than other babies, not making much sound.

D Duration- continued

Define the timeline of various symptoms and problems observed by parents or carer and how long they continued, whether some problems resolved over a period of time or they continued.

P Progression

This will elaborate how the symptomatology, severity progressed,

Let us try to present Laila's symptom progression.

Laila was taken to doctors at the age of 6 months of age and she underwent some tests along with a scan of the brain. But all of those came out to be normal.

Her mother noticed that she was slipping from her lap sometimes and felt very loose. She was able to hold her neck for a few seconds by 1 year of age. 

Laila was not gaining enough weight also. By her 2 nd birthday, they went to another doctor and found she has a problem with hearing and was given a hearing aid in both ears.

Eventually, she could sit with support, can transfer objects from one hand to the other, and produce some cooing sound, She also started playing with some bright colored toys. With ongoing physiotherapy, the limpness started getting better.

Now she can stand on her own and walk a few steps with support, can utter few monosyllables, can eat a biscuit by herself, and is afraid of strangers as a social behavior.

She takes feed well but prefers semisolid food. She sleeps well and does not have any history suggestive of sleep-disordered breathing.

There is no functional problem with the bladder, bowel habits although She can only sometimes tell that she has to pee. 

History on leading questions

There is no h/o seizure, drooling of saliva, frequent cough during feeding.There is no h/o birth trauma, delayed cry, NICU stay, no postnatal complication other than difficulty in breastfeeding (To rule out HIE, kernicterus, infection)

No h/o constipation (not hypothyroidism)No h/o loss of attained milestones (not degenerative)No h/o similar problem in the family (It does not completely rule out genetic disease)Functional disability and the impact of the disease on the family must be mentioned.

H/o past illness Like frequent respiratory infections,  Mention if relevant.

Pre-natal, intra-natal, post-natal history

This is very very important in this case, Teke detail the history of

• Age of parents at conception
• Any previous abortion or stillbirth
• Periconceptional folic acid
• Diagnosis of pregnancy when?
• All trimester any complication fever, bleeding?
• Routine blood test, USG, medication if any?
• The anomaly scan is done or not?
• Quickening felt at what time?
• Adequate fetal movements felt?
• Mode of delivery? Any instrumentation?
• Any Fever around delivery at all?
• First feeding when? Any prelacteal feed? Any dysmorphic look? Edema?
• What feeding difficulty? Coordination problem of suckling swallowing.
• Movement of all 4 limbs after birth
• Neonatal vistits, vaccines

Nutritional history

Leila was not gaining weight, Nutritional history is significant and should be taken in detail in this particular case so as to know what impacted her weight gain.

Full 24-hour recall with calorie and protein deficit should be calculated. Remember a child with a genetic disease can have very little weight even with adequate nutritional intake due to other issues like malabsorption

Developmental history

Discuss all 4 domain one by one in order, Tell what is are the current milestone child has achieved and what she should have achieved normally. This leaves no further questions in the examiner's mind.

DQ can be calculated from history ( mention the DQ is based on history) but better to comment after a physical examination. Sometimes parents do not exactly remember the milestones and this might give a wrong developmental quotient.

Immunization history

Mention vaccines and the time is given, or if anything is missed. If missed why?

Family history

Since this is a CNS case, better to draw, 3 generation pedigree. Consanguinity needs to be proved.Mention if anyone has a similar illness in the family tree, or any congenital disease.

Socio-economic history

Socioeconomic status of the father,/mother/carer., Monthly expenses for the child are going to be more than usual, mention that. The attitude of the caregiver toward the child need to be mentioned. Any safeguarding issues at home.

Treatment/Drug history

Mention types of physiotherapy is being given, What other treatment like speech therapy the child is receiving at present. How frequently the sessions are planned. Etc.

Signposting/Summarizing after history

Laila, a 4yr old girl born out of 3rd consanguineous marriage, with global developmental delay without any significant birth or family history seems to have dysmorphic features probably pointing towards a genetic syndrome that cannot be named based on history.

Examination

Start with the opening remark, the first impression or thing you felt of the child, like dysmorphic, hypotonic, what was the posture when you were interacting etc.

A. General examination

A1. anthropometry.

Mention Height, weight, head circumference of a child in the usual manner. Mention the previous record and classify the growth status.

Use PICCLE to remember, the sequence for mentioning vitals. 

A3. Head to toe examination

Mention the dysmorphic feature from head to toe and see if it fits under specific syndrome-like DOWNs, Hypothyroidism etc. If you cannot determine, mention your inability. Even the finest neurologist will take some time and details to diagnose a syndromic child, Do not worry.

A4. Development Quotient

Examine all domains and confirm with history, mention it like 50% in Gross motor, 40% in language, cover all the domains. (Its good to mention DQ before neurological examination coz a child with DQ of 50% is not expected to cooperate examination)

B. Neurological examination

There will be the case with a lot of neurological signs and there will be some, where most of the things are just based on observations.

B1. Higher function

Alert, active, oriented to self, whether taking interest in the surrounding.

B2. Cranial nerve

No apparent cranial nerve palsy

B3. Motor system

Make a 2/2 table for documenting the findings your demonstrated

B4. Sensory system

Response to touch and pain. In most of these cases, detailed examination findings could not be obtained as mostly the kids are under 5 and they cannot give answers to question. Mostly state your observation and mention the incapabilities.

B5. Cerebellar signs

Could not be tested for Laila.

B6. Cranium n spine

Mention shape, size, and visible abnormalities. Microcephaly, macrocephaly, sutures, scoliosis, kyphosis.

C. Other Systemic Examination

C1. respiratory.

Mention finding of recurrent respiratory infection etc, There was none in case of laila.

C2. Cardiovascular

These kids might have congenital heart disease as well, so look carefully for murmurs.

C3. Abdomen

Look for organomegaly. here is the history taking for hepatosplenomegaly If present, it goes in favor of storage disorder associated with developmental delay. Here is the list of a genetic syndrome in children

Summarise your findings.

Diagnosis and differntials

Diagnosis in the case of Laila can be put this way

A case of global development delay born out of consanguineous marriage with dysmorphic facies, hypotonia, feeding difficulty with grade 1 malnutrition with a functional disability of …(degree) without apparent skeletal abnormality or other major system involvement, most probably a case of inherited genetic disease/ syndrome.

Approach to the child with global developmental delay

More on history taking

• Hepatosplenomegaly
• Jaundiced Infant
• Brainstem Glioma

Mandira Roy | DNB(Pediatrics), fellowship in Devlopemental Pediatrics

Mandira has completed her pediatric residency at the Institute of Child health Kolkata and currently working as a Pediatrician with special focus on developmental medicine

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