Comprehensive Evaluation of the Child with Intellectual Disability Or Global Developmental Delays

FROM THE AMERICAN ACADEMY OF PEDIATRICS

Guidance for the Clinician in Rendering Pediatric Care

CLINICAL REPORT Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

John B. Moeschler, MD, MS, FAAP, FACMG, Michael Shevell, MDCM, FRCP, and COMMITTEE ON GENETICS abstract ABBREVIATIONS Global developmental delay and intellectual disability are relatively — AAP American Academy of Pediatrics common pediatric conditions. This report describes the recommended CMA—chromosome microarray CNS—central nervous system clinical genetics diagnostic approach. The report is based on a review CNV—copy number variant of published reports, most consisting of medium to large case series of CT—computed tomography diagnostic tests used, and the proportion of those that led to a diag- FISH—fluorescent in situ hybridization GAA—guanidinoacetate nosis in such patients. Chromosome microarray is designated as GDD—global developmental delay a first-line test and replaces the standard karyotype and fluorescent ID—intellectual disability in situ hybridization subtelomere tests for the child with intellectual XLID—X-linked intellectual disability disability of unknown etiology. Fragile X testing remains an important This document is copyrighted and is property of the American first-line test. The importance of considering testing for inborn errors Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American of metabolism in this population is supported by a recent systematic Academy of Pediatrics. Any conflicts have been resolved through review of the literature and several case series recently published. The a process approved by the Board of Directors. The American role of brain MRI remains important in certain patients. There is also Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of a discussion of the emerging literature on the use of whole-exome se- this publication. quencing as a diagnostic test in this population. Finally, the importance The guidance in this report does not indicate an exclusive of intentional comanagement among families, the medical home, course of treatment or serve as a standard of medical care. and the clinical genetics specialty clinic is discussed. Pediatrics Variations, taking into account individual circumstances, may be 2014;134:e903–e918 appropriate.

The purpose of this clinical report of the American Academy of Pe- diatrics (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 www.pediatrics.org/cgi/doi/10.1542/peds.2014-1839 clinical report in 20061 and provides current guidance for the medical doi:10.1542/peds.2014-1839 genetics evaluation. One intention is to inform primary care providers All clinical reports from the American Academy of Pediatrics in the setting of the medical home so that they and families are automatically expire 5 years after publication unless reafﬁrmed, knowledgeable about the purpose and process of the genetics eval- revised, or retired at or before that time. uation. This report will emphasize advances in genetic diagnosis while PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). updating information regarding the appropriate evaluation for inborn Copyright © 2014 by the American Academy of Pediatrics 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

PEDIATRICS Volume 134, Number 3, September 2014 e903 Downloaded from www.aappublications.org/news by guest on March 4, 2020 evaluation of the child with an autism intellectual disabilities and their fami- have preferred to have an [etiologic] spectrum disorder who happens to lies.3–5 Although perhaps difficult to diagnosis, if given the option,” partic- have ID as a co-occurring disability. measure, this “healing touch” contrib- ularly early in the course of the (For AAP guidance related to Autism utes to the general well-being of the symptoms. Spectrum Disorders, see Johnson and family. “As physicians we have experi- As was true of the 2006 clinical report, Myers.2) ence with other children who have the this clinical report will not address the For both pediatric primary care pro- same disorder, access to management etiologic evaluation of young children viders and families, there are specific programs, knowledge of the prognosis, who are diagnosed with cerebral palsy, benefits to establishing an etiologic awareness of research on understanding autism, or a single-domain develop- diagnosis (Table 1): clarification of eti- the disease and many other elements mental delay (gross motor delay or ology; provision of prognosis or ex- that when shared with the parents will specific language impairment).1 Some pected clinical course; discussion of give them a feeling that some control children will present both with GDD genetic mechanism(s) and recurrence is possible.”5 and clinical features of autism. In risks; refined treatment options; the Makela et al6 studied, in depth, 20 such cases, the judgment of the clin- avoidance of unnecessary and re- families of children with ID with and ical geneticist will be important in dundant diagnostic tests; information without an etiologic diagnosis and determining the evaluation of the child regarding treatment, symptom man- found that these families had specific depending on the primary neuro- agement, or surveillance for known stated needs and feelings about what developmental diagnosis. It is recog- complications; provision of condition- a genetic diagnosis offers: nized that the determination that an fi speci c family support; access to re- 1. Validation: a diagnosis established infant or young child has a cognitive search treatment protocols; and the that the problem (ID) was credible, disability can be a matter of clinical opportunity for comanagement of pa- which empowered them to advo- judgment, and it is important for the tients, as appropriate, in the context of cate for their child. pediatrician and consulting clinical a medical home to ensure the best geneticist to discuss this before de- 2. Information: a diagnosis was felt to health, social, and health care services ciding on the best approach to the help guide expectations and man- satisfaction outcomes for the child and diagnostic evaluation.”1 agement immediately and provide family. The presence of an accurate hope for treatment or cure in fu- etiologic diagnosis along with a knowl- ture. INTELLECTUAL DISABILITY edgeable, experienced, expert clinician is one factor in improving the psycho- 3. Procuring services: the diagnosis ID is a developmental disability pre- social outcomes for children and with assisted families in obtaining desired senting in infancy or the early child- services, particularly in schools. hood years, although in some cases, it 4. Support: families expressed the need cannot be diagnosed until the child is ∼ TABLE 1 The Purposes of the for emotional companionship that a older than 5 years of age, when Comprehensive Medical Genetics fi “ standardized measures of develop- Evaluation of the Young Child With speci c diagnosis (or similar chal- GDD or ID lenges”) assisted in accessing. mental skills become more reliable and valid. The American Association 5. Need to know: families widely dif- 1. Clarification of etiology on Intellectual and Developmental 2. Provision of prognosis or expected clinical fered in their “need to know” aspe- Disability defines ID by using mea- course cific diagnosis, ranging from strong 3. Discussion of genetic mechanism(s) and sures of 3 domains: intelligence (IQ), to indifferent. recurrence risks adaptive behavior, and systems of 4. Refined treatment options 6. Prenatal testing: families varied in supports afforded the individual.7 5. Avoidance of unnecessary or redundant their emotions, thoughts, and actions diagnostic tests Thus, one cannot rely solely on the 6. Information regarding treatment, symptom regarding prenatal genetic diagno- measure of IQ to define ID. More re- management, or surveillance for known sis. cently, the term ID has been suggested complications 6 7,8 7. Provision of condition-specific family support For some families in the Makela et al to replace “mental retardation.” For 8. Access to research treatment protocols study, the clinical diagnosis of autism, the purposes of this clinical report, 9. Opportunity for comanagement of appropriate for example, was sufficient and often the American Association on Intel- patients in the context of a medical home to “ fi ensure the best health, social, and health care more useful than a rare but speci c lectual and Developmental Disability services satisfaction outcomes for the child and etiological diagnosis.” These authors definition is used: “Intellectual dis- family report that “all of the families would ability is a disability characterized by

e904 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on March 4, 2020 FROM THE AMERICAN ACADEMY OF PEDIATRICS significant limitations both in intel- of GDD is estimated to be 1% to 3%, highlights a renewed emphasis on the lectual functioning and in adaptive be- similar to that of ID. identification of “treatable” causes of havior as expressed in conceptual, GDD/ID with the recommendation to social and practical adaptive skills. Diagnosis consider screening for inborn errors The disability originates before age 18 of metabolism in all patients with Schaefer and Bodensteiner11 wrote ”7 13 years. The prevalence of ID is esti- that a specific diagnosis is that which unknown etiology for GDD/ID. mated to be between 1% and 3%. “can be translated into useful clinical Nevertheless, the approach to the Lifetime costs (direct and indirect) to information for the family, including patient remains familiar to pediatric support individuals with ID are large, providing information about progno- primary care providers and includes estimated to be an average of ap- sis, recurrence risks, and preferred the child’s medical history (including 9 proximately $1 million per person. modes of available therapy.” For ex- prenatal and birth histories); the ample, agenesis of the corpus callosum family history, which includes con- struction and analysis of a pedigree of Global Developmental Delay is considered a sign and not a diagnosis, whereas the autosomal-recessive Acro- 3 generations or more; the physical Identifying the type of developmental callosal syndrome (agenesis of the and neurologic examinations empha- delay is an important preliminary step, corpus callosum and polydactyly) is sizing the examination for minor anom- fl because typing in uences the path of a clinical diagnosis. Van Karnebeek alies (the “dysmorphology examination”); investigation later undertaken. GDD is et al12 defined etiologic diagnosis as and the examination for neurologic or fi fi de ned as a signi cant delay in 2 or “sufficient literature evidence…to behavioral signs that might suggest more developmental domains, including make a causal relationship of the dis- a specific recognizable syndrome or fi gross or ne motor, speech/language, order with mental retardation likely, diagnosis. After the clinical genetic cognitive, social/personal, and activi- and if it met the Schaefer-Bodensteiner evaluation, judicious use of laboratory ties of daily living and is thought to definition.” This clinical report will use tests, imaging, and other consulta- 10 predict a future diagnosis of ID. Such this Van Karnebeek modification of the tions on the basis of best evidence are delays require accurate documenta- Schaefer–Bodensteiner definition and, important in establishing the diagno- tion by using norm-referenced and age- thus, includes the etiology (genetic sis and for care planning. appropriate standardized measures mutation or genomic abnormality) as of development administered by ex- fi an essential element to the de nition of CHROMOSOME MICROARRAY perienced developmental specialists. a diagnosis. The term GDD is reserved for younger CMA now should be considered a first- Recommendations are best when es- children (ie, typically younger than 5 tier diagnostic test in all children with tablished from considerable empirical years), whereas the term ID is usually GDD/ID for whom the causal diagnosis evidence on the quality, yield, and applied to older children for whom IQ is not known. G-banded karyotyping usefulness of the various diagnostic testing is valid and reliable. Children historically has been the standard first- investigations appropriate to the with GDD are those who present with tier test for detection of genetic im- clinical situation. The evidence for this delays in the attainment of develop- balance in patients with GDD/ID for clinical report is largely based on mental milestones at the expected more than 35 years. CMA is now the many small- or medium-size case se- age; this implies deficits in learning standard for diagnosis of patients with ries and on expert opinion. The report and adaptation, which suggests that GDD/ID, as well as other conditions, is based on a review of the literature the delays are significant and predict such as autism spectrum disorders or by the authors. later ID. However, delays in development, multiple congenital anomalies.14–24 especially those that are mild, may be The G-banded karyotype allows a cyto- transient and lack predictive reliability Highlights in This Clinical Report geneticist to visualize and analyze for ID or other developmental disabil- Significant changes in genetic di- chromosomes for chromosomal rear- ities. For the purposes of this report, agnosis in the last several years have rangements, including chromosomal children with delays in a single devel- made the 2006 clinical report out- gains (duplications) and losses (dele- opmental domain (for example, iso- of-date. First, the chromosome mi- tions). CMA performs a similar function, lated mild speech delay) should not be croarray (CMA) is now considered a but at a much “higher resolution,” for considered appropriate candidates for first-line clinical diagnostic test for genomic imbalances, thus increasing the comprehensive genetic evaluation children who present with GDD/ID of the sensitivity substantially. In their process set forth here. The prevalence unknown cause. Second, this report recent review of the CMA literature,

PEDIATRICS Volume 134, Number 3, September 2014 e905 Downloaded from www.aappublications.org/news by guest on March 4, 2020 Vissers et al25 report the diagnostic rate slide on which cloned or synthesized International Standard Cytogenomic Ar- of CMA to be at least twice that of the control DNA fragments had been ray Consortium15 (www.iscaconsortium. standard karyotype. CMA, as used in immobilized. Arrays have been built org) is investigating the feasibility of this clinical report, encompasses all with a variety of DNA substrates that establishing a standardized, univer- current types of array-based genomic may include oligonucleotides, com- sal system of reporting and catalog- copy number analyses, including array- plementary DNAs, or bacterial artifi- ing CMA results, both pathologic and based comparative genomic hybridiza- cial chromosomes. The arrays might benign, to provide the physician with tion and single-nucleotide polymorphism be whole-genome arrays, which are the most accurate and up-to-date in- arrays (see Miller et al15 for a review of designed to cover the entire genome, formation. array types). With these techniques, or targeted arrays, which target It is important for the primary care a patient’s genome is examined for known pathologic loci, the telomeres, pediatrician to work closely with the detection of gains or losses of ge- and pericentromeric regions. Some clinical geneticist and the diagnostic fi nome material, including those too laboratories offer chromosome-speci c laboratory when interpreting CMA test small to be detectable by standard arrays (eg, for nonsyndromic X-linked results, particularly when “variants of 26,27 ID [XLID]).30 The primary advantage of G-banded chromosome studies. unknown significance” are identified. CMA over the standard karyotype or CMA replaces the standard karyotype In general, CNVs are assigned the later FISH techniques is the ability of (“chromosomes”)and fluorescent in following interpretations: (1) patho- CMA to detect DNA copy changes si- situ hybridization (FISH) testing for genic (ie, abnormal, well-established multaneously at multiple loci in a ge- patients presenting with GDD/ID of un- syndromes, de novo variants, and large nome in one “experiment” or test. The known cause. The standard karyotype changes); (2) variants of unknown sig- copy number change (or copy number and certain FISH tests remain important nificance; and (3) likely benign.15 These variant [CNV]) may include deletions, to diagnostic testing but now only in interpretations are not essentially duplications, or amplifications at any limited clinical situations (see Manning different than those seen in the stan- 14 locus, as long as that region is rep- and Hudgins ) in which a specificcon- dard G-banded karyotype. It is impor- resented on the array. CMA, indepen- dition is suspected (eg, Down syndrome tant to note that not all commercial dent of whether it is “whole genome” or Williams syndrome). The discussion health plans in the United States in- or “targeted” and what type of DNA sub- of CMA does not include whole-genome clude this testing as a covered benefit strate (single-nucleotide polymorphisms,31 sequencing, exome sequencing, or “next- when ordered by the primary care oligonucleotides, complementary DNAs, generation” genome sequencing; these pediatrician; others do not cover it or bacterial artificial chromosomes),32 are discussed in the “emerging tech- even when ordered by the medical identifies deletions and/or duplications nologies” section of this report. geneticist. Typically, the medical ge- of chromosome material with a high Twenty-eight case series have been netics team has knowledge and ex- degree of sensitivity in a more efficient published addressing the rate of di- perience in matters of payment for manner than FISH techniques. Two main agnosis by CMA of patients presenting testing. factors define the resolution of CMA: (1) with GDD/ID.28 The studies vary by the size of the nucleic acid targets; and The literature does not stratify the di- subject criteria and type of microarray (2) the density of coverage over the agnostic rates of CMA by severity of technique and reflect rapid changes in genome. The smaller the size of the disability. In addition, there is substantial technology over recent years. Never- nucleic acid targets and the more con- literature supporting the multiple fac- theless, the diagnostic yield for all tiguous the targets on the native chro- tors (eg, social, environmental, eco- current CMA is estimated at 12% for mosome are, the higher the resolution nomic, genetic) that contribute to mild 14–29 patients with GDD/ID. CMA is the is. As with the standard karyotype, one disability.33 Consequently, it remains fi single most ef cient diagnostic test, result of the CMA test can be “of un- within the judgment of the medical ge- after the history and examination by certain significance,” (ie, expert inter- neticist as to whether it is warranted to a specialist in GDD/ID. pretation is required, because some test the patient with mild (and familial) CMA techniques or “platforms” vary. deletions or duplications may not be ID for pathogenic CNVs. In their review, Generally, CMA compares DNA content clearly pathogenic or benign). Miller Vissers et al25 reported on several recur- from 2 differentially labeled genomes: et al15 describe an effort to develop an rent deletion or duplication syndromes the patient and a control. In the early international consortium of laborato- with mild disability and commented on techniques, 2 genomes were cohybrid- ries to address questions surrounding thevariablepenetranceofthe more ized, typically onto a glass microscope array-based testing interpretation. This common CNV conditions, such as 1q21.1

e906 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on March 4, 2020 FROM THE AMERICAN ACADEMY OF PEDIATRICS microdeletion, 1q21.1 microduplication, are not included currently in any whereas the yield of organic acid and 3q29 microduplication, and 12q14 micro- newborn screening blood spot pan- amino acid screening was negligible.” deletion. Some of these are also inheri- els. Although the prevalence of In a similar study from the Netherlands ted. Consequently, among families with inherited metabolic conditions is done more recently, Engbers et al39 more than one member with disability, relatively low (0% to 5% in these reported on metabolic testing that was it remains challenging for the medical studies), the potential for improved performed in 433 children whose GDD/ geneticist to know for which patient outcomes after diagnosis and treat- ID remained unexplained after genetic/ with GDD/ID CMA testing is not war- ment is high.41 metabolic testing, which included ranted. In 2005, Van Karnebeek et al40 reported a standard karyotype; urine screen for Recent efforts to evaluate reporting on a comprehensive genetic diagnostic amino acids, organic acids, mucopoly- of CNVs among clinical laboratories evaluation of 281 consecutive patients saccharides, oligosaccharides, uric indicate variability of interpretation referred to an academic center in the acid, sialic acid, purines, and pyrim- because of platform variability in sen- Netherlands. All patients were sub- idines; and plasma for amino acids, sitivity.34,35 Thus, the interpretation of jected to a protocol for evaluation and acylcarnitines, and sialotransferrins. CMA test abnormal results and var- studies were performed for all patients Screenings were repeated, and addi- iants of unknown significance, and the with an initially unrecognized cause of tional testing, including cerebrospinal subsequent counseling of families mental retardation and included uri- fluid studies, was guided by clinical should be performed in all cases by nary screen for amino acids, organic suspicion. Metabolic disorders were fi fi fi a medical geneticist and certi ed ge- acids, oligosaccharides, acid mucopoly- identi ed and con rmed in 12 of these netic counselor in collaboration with saccharides, and uric acid; plasma con- patients (2.7%), including 3 with mito- the reference laboratory and platform centrations of total cholesterol and diene chondrial disorders; 2 with creatine used. Test variability is resolving as sterols of 7- and 8-dehydrocholesterol to transporter disorders; 2 with short-chain fi a result of international collabora- identify defects in the distal choles- acyl-coenzyme A dehydrogenase de ciency; 36 fi tions. With large data sets, the terol pathway; and a serum test to and 1 each with San lippo IIIa, a per- functional impact (or lack thereof) of screen for congenital disorders of oxisomal disorder; a congenital disorder very rare CNVs is better understood. of glycosylation; 5-methyltetrahydrofolate glycosylation (test names such as Still, there will continue to be rare or reductase deficiency; and deficiency of the “carbohydrate-deficient transferrin”). unique CNVs for which interpretation GLUT1 glucose transporter. In individual patients, other searches remain ambiguous. The medical ge- were performed as deemed necessary Other studies have focused on the neticist is best equipped to interpret depending on results of earlier stud- prevalence of disorders of creatine such information to families and the ies. This approach identified 7 (4.6%) synthesis and transport. Lion-François medical home. 37 subjects with “certain or probable” et al reported on 188 children re- metabolic disorders among those who ferred over a period of 18 months SCREENING FOR INBORN ERRORS completed the metabolic screening with “unexplained mild to severe OF METABOLISM (n = 216). None of the 176 screening mental retardation, normal karyotype, and absence of fragile X syndrome” Since the 2006 AAP clinical report, sev- tests for plasma amino acids and eral additional reports have been pub- urine organic acids was abnormal. who were prospectively screened for fi lished regarding metabolic testing for Four children (1.4%) with congenital congenital creatine de ciency syn- a cause of ID.13,37–40 The percentage of disorders of glycosylation were iden- dromes. Children were from diverse patients with identifiable metabolic dis- tified by serum sialotransferrins, 2 ethnic backgrounds. Children with “ ” orders as cause of the ID ranges from children had abnormal serum choles- polymalformative syndromes were 1% to 5% in these reports, a range terol and 7-dehydrocholesterol concen- excluded. There were 114 boys (61%) similar to those studies included in trations suggestive of Smith-Lemli- and 74 girls (39%) studied. Creatine the 2006 clinical report. Likewise, these Opitz syndrome, 2 had evidence of a metabolism was evaluated by using newer published case series varied by mitochondrial disorder, 1 had evi- creatine/creatinine and guanidinoacetate site, age range of patients, time frame, dence of a peroxisomal disorder, and (GAA)-to-creatine ratios on a spot urine study protocol, and results. However, 1 had abnormal cerebrospinal fluid screen. Diagnosis was further con- they do bring renewed focus to treat- biogenic amine concentrations. These firmed by using brain proton magnetic able metabolic disorders.13 Further- authors concluded that “screening for resonance spectroscopy and mutation more, some of the disorders identified glycosylation defects proved useful, screening by DNA sequence analysis in

PEDIATRICS Volume 134, Number 3, September 2014 e907 Downloaded from www.aappublications.org/news by guest on March 4, 2020 either the SLC6A8 (creatine trans- zyme replacement, and hematopoietic implemented and so that reliable ge- porter defect) or the GAMT genes. This stem cell transplant. The effect on netic counseling can be provided. For resulted in a diagnosis in 5 boys (2.7% outcome (IQ, developmental perfor- patients with a clinical diagnosis of of all; 4.4% of boys). No affected girls mance, behavior, epilepsy, and neuro- a Mendelian disorder that is certain, were identified among the 74 studied. imaging) varied from improvement to molecular genetic diagnostic testing All 5 boys also were late to walk, and 3 halting or slowing neurocognitive re- usually is not required to establish the had “autistic features.” The authors gression. The authors emphasized the diagnosis but may be useful for health concluded that all patients with un- approach as one that potentially has care planning. However, for carrier diagnosed ID have urine screened for significant impact on patient out- testing or for genetic counseling of creatine-to-creatinine ratio and GAA- comes: “This approach revisits cur- family members, it is often essential to to-creatine ratio. Similarly, Caldeira rent paradigms for the diagnostic know the specific gene mutation in the Arauja et al38 studied 180 adults with evaluation of ID. It implies treatability proband. ID institutionalized in Portugal, screen- as the premise in the etiologic work- ForpatientswithGDD/ID forwhom ing them for congenital creatine de- up and applies evidence-based medi- the diagnosis is not known, molec- ” ficiency syndromes. Their protocol cine to rare diseases. Van Karnebeek ular genetic diagnostic testing is involved screening all subjects for and Stockler13,42 reported on 130 necessary, under certain circum- “ ” urine and plasma uric acid and cre- patients with ID who were tested per stances, which is discussed in the atinine. Patients with an increased this metabolic protocol; of these, 6 next section. fi urinary uric acid-to-creatinine ratio and/ (4.6%) had con rmed treatable inborn or decreased creatinine were sub- errors of metabolism and another 5 “ ” MALE GENDER jected to the analysis of GAA. GAMT (3.8%) had probable treatable inborn activity was measured in lymphocytes error of metabolism. There is an approximate 40% excess of and followed by GAMT gene analysis. This literature supports the need boys in all studies of prevalence and This resulted in identifying 5 individ- to consider screening children pre- incidence of ID.44,45 Part of this distor- uals (2.8%) from 2 families with GAMT senting with GDD/ID for treatable tion of the gender ratio is attributable deficiency. A larger but less selective metabolic conditions. Many meta- to X-linked genetic disorders.46 Conse- study of 1600 unrelated male and bolic screening tests are readily quently, genetic testing for X-linked female children with GDD/ID and/or available to the medical home and/ genes in boys with GDD/ID is often autism found that 34 (2.1%) had or local hospital laboratory service. warranted, particularly in patients abnormal urine creatine-to-creatinine Furthermore, the costs for these met- whose pedigree is suggestive of an ratios, although only 10 (0.6%) had abolic screening tests are relatively X-linked condition. In addition, for sev- abnormal repeat tests and only 3 low. eral reasons, research in X-linked genes (0.2%) were found to have an that cause ID is advanced over autoso- GENETIC TESTING FOR MENDELIAN 46,47 SLC6A8 mutation.42 Clark et al43 mal genes, thus accelerating the DISORDERS identified SLC6A8 mutations in 0.5% clinical capacity to diagnose XLID over of 478 unrelated boys with unexplained For patients in whom a diagnosis is autosomal forms. GDD/ID. suspected, diagnostic molecular ge- Most common of these is fragile X netic testing is required to confirm the syndrome, although the prevalence of Recently, van Karnebeek and Stockler diagnosis so that proper health care is all other X-linked genes involved in ID reported13,42 on a systematic literature review of metabolic disorders “presenting with intellectual disability TABLE 2 Metabolic Screening Tests as a major feature.” The authors Specimena Test Notes identified 81 treatable genetic meta- Blood Amino acids See Table 3 bolic disorders presenting with ID as Homocysteine fi a major feature. Of these disorders, 50 Acylcarnitine pro le Urine Organic acids conditions (62%) were identified by GAA/creatine metabolites routinely available tests (Tables 2 and 3). Purines and pyrimidines Therapeutic modalities with proven Mucopolysaccharide screen Oligosaccharide screen effect included diet, cofactor/vitamin See Fig 1. supplements, substrate inhibition, en- a Serum lead, thyroid function studies not included as “metabolic tests” and to be ordered per clinician judgment.

e908 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on March 4, 2020 PEDIATRICS TABLE 3 Metabolic Conditions Identified by Tests Listed PAAs P-HCY Acylcarn UOA UPP UGAA/Cr UMPS UOligo fi β fi ′ fi α Volume Argininosuccinic Cobalamin C Cobalamin C de ciency -ketothiolase de ciency Pyrimidine 5 nucleotidase AGAT de ciency Hurler -mannosidosis aciduriaa deficiency superactivity Citrullinemiaa Cobalamin D Cobalamin D deficiency Cobalamin A deficiency Molybdenum cofactor type GAMT deficiency Hunter Aspartylglucosaminuria 134, deficiency Adeficiency a fi fi fi Number Citrullinemia, type II Cobalamin F Cobalamin F de ciency Cobalamin B de ciency Creatine transporter San lippo deficiency defect A, B, C CPS deficiency a Cobalamin E Ethylmalonic Cobalamin C deficiency Sly (MPS

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September a a Downloaded from Argininemia Cobalamin G Isovaleric acidemia Cobalamin D deficiency deficiency HHH syndrome MTHFR deficiency a 3-methylcrotonyl Cobalamin F deficiency

2014 glycinuria Maple syrup urine Homocystinuria PPAa Ethylmalonic encephalopathy disease, variant fi a www.aappublications.org/news NAGS de ciency Tyrosinemia, type II GA, type I MTHFR deficiency a GA, type II OTC deficiency a HMG-CoA Lyase deficiency PKU Holocarboxylase synthetase deficiency PDH complex defi ciency Homocystinuria Tyrosinemia, type II Isovaleric acidemiaa 3-methylcrotonyl glycinuria 3-methylglutaconic aciduria MMAa MHBD deficiency by gueston March4,2020 PPAa SCOT deficiency

SSADH deficiency FROM Tyrosinemia, type II Adapted from van Karnebeek and Stockler.41 Acylcarn, acylcarnitine profi le; 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 THE 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 AMERICAN (glycosaminoglycans); UOA, urine organic acids; UOGS, urine oligosaccharides; UPP, urine purines and pyrimidines. a Late-onset form of condition listed; some conditions are identifi ed by more than 1 metabolic test. ACADEMY OF PEDIATRICS e909 far exceeds that of fragile X syndrome X-linked pedigree, genetic testing using The expected diagnostic rate remains alone.46 Fragile X testing should be one of the panels is clinically indicated. uncertain, although many pathogenic performed in all boys and girls with The clinical geneticist is best suited to segmental duplications are reported GDD/ID of unknown cause. Of boys guide this genetic testing of patients (for a catalog of X-linked mutations with GDD/ID of uncertain cause, 2% to with possible XLID. For patients with and CNVs, see http://www.ggc.org/re- 3% will have fragile X syndrome (full “syndromal” XLID (eg, Coffin-Lowry search/molecular-studies/xlid.html). > mutation of FMR1, 200 CGG repeats), syndrome), a single gene test rather Whole exome sequencing and whole- as will 1% to 2% of girls (full muta- than a gene panel is indicated. Whereas genome sequencing are emerging tion).48 those patients with “nonsyndromal” testing technologies for patients with presentation might best be assessed nonspecific XLID. Recently, Tarpey et al52 GENETIC TESTING FOR by using a multigene panel compris- have reported the results of the large- NONSPECIFIC XLID ing many of the more common non- scale systematic resequencing of the syndromal XLID genes. The expected coding X chromosome to identify novel Stevenson and Schwartz49 suggest 2 rate of the diagnosis may be high. genes underlying XLID. Gene coding clinical categories for those with XLID: Stevenson and Schwartz46 reported, sequences of 718 X-chromosome genes syndromal and nonsyndromal. Syn- for example, on 113 cases of non- were screened via Sanger sequenc- dromal refers to patients in whom specific ID testing using a 9-gene panel ing technology in probands from 208 physical or neurologic signs suggest of whom 9 (14.2%) had pathogenic families with probable XLID. This re- a specific diagnosis; nonsyndromal mutations identified. de Brouwer et al51 sequencing screen contributed to the refers to those with no signs or reported on 600 families with multiple identification of 9 novel XLID-associated symptoms to guide the diagnostic boys with GDD/ID and normal karyo- genes but identified pathogenic se- process. Using this classification has type and FMR1 testing. Among those quence variants in only 35 of 208 practical applicability, because the families with “an obligate female (17%) of the cohort families. This pediatric primary care provider can carrier” (defined by pedigree analysis figure likely underestimates the gen- establish a specific XLID syndrome on and linkage studies), a specific gene eral contribution of sequence var- the basis of clinical findings. In con- mutation was identified in 42%. In iants to XLID given the subjects were trast, nonsyndromal conditions can selected from a pool that had had only be distinguished on the basis of addition, in those families with more previous clinical and molecular ge- the knowledge of their causative than 2 boys with ID and no obligate netic screening.30 gene.50 In excess of 215 XLID con- female carrier or without linkage to ditions have been recorded, and >90 the X chromosome, 17% of the ID XLID genes have been identified.46,50 cases could be explained by X-linked BOYS WITH SUSPECTED OR KNOWN gene mutations. This very large study To address male patients with GDD/ID XLID suggested that testing of individual and X-linked inheritance, there are Table 4 lists some common XLID con- boys for X-linked gene mutations is molecular genetic diagnostic “panels” ditions. In cases in which the diagnosis warranted. of X-linked genes available clinically. is not certain, molecular genetic test- These panels examine many genes in Recently, clinical laboratories have being of patients for the specificgeneis “ ” 1 “test sample.” The problem for the gun offering high-density X-CMAs to indicated, even if the pedigree does not clinical evaluation is in which patient assess for pathogenic CNVs (see pre- indicate other affected boys (ie, cannot to use which test panel, because there vious discussion regarding micro- confirm X-linked inheritance).46 is no literature on head-to-head per- arrays) specifically for patients with formance of test panels, and the test XLID. Wibley et al30 (2010) reported on FEMALE GENDER AND MECP2 panels differ somewhat by genes in- CNVs in 251 families with evidence of TESTING cluded, test methods used, and the XLID who were investigated by array rate of a true pathogenic genetic di- comparative genomic hybridization Rett syndrome is an X-linked condition agnosis. Nevertheless, the imperative on a high-density oligonucleotide X- that affects girls and results from for the diagnostic evaluation remains chromosome array platform. They MECP2 gene mutations primarily (at the same for families and physicians, identified pathogenic CNVs in 10% of least 1 other gene has been de- and there is a place for such testing families. The high-density arrays for termined causal in some patients with in the clinical evaluation of children XLID are appropriate in those patients typical and atypical Rett syndrome: with GDD/ID. For patients with an with syndromal or nonsyndromal XLID. CDKL5). Girls with mutations in the

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MECP2 gene do not always present However, it is frequently not an etio- concluded that “the value for finding clinically with classic Rett syndrome. logic or syndromic diagnosis. This abnormalities or the absence of ab- Several large case series have exam- distinction is not always made in the normalities must be higher” than the ined the rate of pathogenic MECP2 literature on the utility of neuro- 30% mean rate implied. mutations in girls and boys with ID. The imaging in the evaluation of children If neuroimaging is performed in only proportion of MECP2 mutations in with developmental delay/ID. The lack selected cases, such as children with an these series ranged from 0% to 4.4% of a consistent use of this distinction abnormal head circumference or an with the average of 1.5% among girls has led to confusion regarding this abnormal focal neurologic finding, the 53–62 with moderate to severe ID. MECP2 particular issue. rate of abnormalities detected is in- mutations in boys present with severe Early studies on the use of CT in the creased further than when used on neonatal encephalopathy and not with evaluation of children with idiopathic a screening basis in children with GDD/ID. ID64 indicated a low diagnostic yield for a normal neurologic examination except the nonspecific finding of “cerebral for the documentation of developmental ADVANCES IN DIAGNOSTIC atrophy,” which did not contribute to delay. Shevell et al68 reported that IMAGING clarifying the precise cause of the ID.65 the percentage of abnormalities were Later studies that used MRI to detect 13.9% if neuroimaging was performed Currently, the literature does not in- CNS abnormalities suggested that MRI on a “screening basis” but increased to dicate consensus on the role that was more sensitive than CT, with an 41.2% if performed on “an indicated neuroimaging, either by computed to- increased diagnostic yield.10,66 The rate basis.” Griffiths et al70 highlighted that mography (CT) or MRI, can play in the of abnormalities actually detected on the overall risk of having a specific evaluation of children with GDD/ID. imaging varies widely in the literature structural abnormality found on MRI Current recommendations range from as a result of many factors, such as scanning was 28% if neurologic symp- performing brain imaging on all patients subject selection and the method of toms and signs other than develop- with GDD/ID,63 to performing it only on imaging used (ie, CT or MRI). Schaefer mental delay were present, but if the those with indications on clinical ex- and Bodensteiner,63 in their literature developmental delay was isolated, the amination,12 to being considered as review, found reported ranges of ab- yield was reduced to 7.5%. In a series a second-line investigation to be un- normalities from 9% to 80% of those of 109 children, Verbruggen et al71 re- dertaken when features in addition to patients studied. Shevell et al10 reported an etiologic yield on MRI of 9%. GDD are detected either on history or fi physical examination. The finding of ported a similar range of nding in They noted that all of these children had a brain abnormality or anomaly on their review. For example, in 3 studies neurologic signs or an abnormal head neuroimaging may lead to the recogni- totaling 329 children with develop- circumference. In their practice pa- tion of a specific cause of an individual mental delay in which CT was used in rameter, the American Academy of child’s developmental delay/ID in the almost all patients and MRI was used Neurology and the Child Neurology fi 10 same way that a dysmorphologic ex- in but a small sample, a speci ccause Society discussed other studies on amination might lead to the inference of was determined in 31.4%,67 27%,68 and smaller numbers of patients who a particular clinical diagnosis. However, 30%69 of the children. In their systematic showed similar results, which led to like other major or minor anomalies review of the literature, van Karnebeek their recommendation that “neuro- noted on physical examination, abnor- et al12 reported on 9 studies that used imaging is a recommended part of malities on neuroimaging typically are MRI in children with ID. The mean rate the diagnostic evaluation,” particularly not sufficient for determining the cause of abnormalities found was 30%, with should therebeabnormal findings on of the developmental delay/ID; the un- a range of 6.2% to 48.7%. These in- examination (ie, microcephaly, macro- derlying precise, and presumably fre- vestigators noted that more abnor- cephaly, focal motor findings, pyramidal quently genetic in origin, cause of the malities were found in children with signs, extrapyramidal signs) and that brain anomaly is often left unknown. moderate to profound ID versus those MRI is preferable to CT. However, the Thus, although a central nervous sys- with borderline to mild ID (mean yield authors of the American College of tem (CNS) anomaly (often also called a of 30% and 21.2%, respectively). These Medical Genetics Consensus Conference “CNS dysgenesis”)isauseful finding authors also noted that none of Report10 stated that neuroimaging by and indeed may be considered, ac- the studies reported on the value of CT or MRI in normocephalic patients cording to the definition of Schaefer the absence of any neurologic abnor- without focal neurologic signs should and Bodensteiner,11 auseful “diagnosis.” mality for a diagnostic workup and not be considered a “standard of

PEDIATRICS Volume 134, Number 3, September 2014 e911 Downloaded from www.aappublications.org/news by guest on March 4, 2020 TABLE 4 Common Recognizable XLID Syndromes Syndrome Common Manifestations Gene, Location Aarskog syndrome Short stature, hypertelorism, downslanting palpebral fissures, FGD1, Xp11.21 joint hyperextensibility, shawl scrotum Adrenoleukodystrophy Variable and progressive vision and hearing loss, spasticity, ABCD1, Xq28 neurological deterioration associated with demyelination of the central nervous system and adrenal insufficiency Aicardi syndrome Agenesis of the corpus callosum, lacunar chorioretinopathy, _____, Xp22 costovertebral anomalies, seizures in females Allan–Herndon syndrome Generalized muscle hypoplasia, childhood hypotonia, ataxia, MCT8 (SLC16A2), Xq13 athetosis, dysarthria, progressing to spastic paraplegia ARX-related syndromes Partington: dysarthria, dystonia, hyperreflexia, seizures. West: ARX, Xp22.3 (includes Partington, Proud, West, infantile spasms, hypsarrhythmia. Proud: microcephaly, XLAG syndromes and nonsyndromal XLMR) ACC, spasticity, seizures, ataxia, genital anomalies. XLAG: lissencephaly, seizures, genital anomalies ATRX syndrome (includes Short stature, microcephaly, hypotonic facies with XNP, (XH2) Xq13.3 ARTX, Chudley–Lowry, Carpenter–Waziri, hypertelorism, small nose, open mouth and prominent lips, Holmes–Gang, and Martinez spastic brachydactyly, genital anomalies, hypotonia, in some cases paraplegia syndromes and hemoglobin H inclusions in erythrocytes nonsyndromal XLMR) Christianson syndrome Short stature, microcephaly, long narrow face, large ears, long SLC9A6, Xq26 straight nose, prominent mandible, general asthenia, narrow chest, long thin digits, adducted thumbs, contractures, seizures, autistic features, truncal ataxia, ophthalmoplegia, mutism, incontinence, hypoplasia of the cerebellum, and brain stem Coffin–Lowry syndrome Short stature, distinctive facies, large soft hands, hypotonia, RSK2, Xp22 joint hyperextensibility, skeletal changes Creatine transporter deficiency Nondysmorphic, autistic, possibly progressive SLC6A8, Xq28 Duchenne muscular dystrophy Pseudohypertrophic muscular dystrophy DMD, Xp21.3 Fragile X syndrome Prominent forehead, long face, recessed midface, large ears, FMR1, Xq27.3 prominent mandible, macroorchidism Hunter syndrome Progressive coarsening of face, thick skin, cardiac valve disease, IDS, Xq28 joint stiffening, dysostosis multiplex Incontinentia pigmenti Sequence of cutaneous blistering, verrucous thickening, and NEMO (IKB6KG), Xq28 irregular pigmentation. May have associated CNS, ocular abnormalities Lesch–Nyhan syndrome Choreoathetosis, spasticity, seizures, self-mutilation, uric acid HPRT, Xq26 urinary stones Lowe syndrome Short stature, cataracts, hypotonia, renal tubular dysfunction OCRL, Xq26.1 MECP2 duplication syndrome Hypotonia, progressing to spastic paraplegia, recurrent MECP2, Xq28 infections Menkes syndrome Growth deficiency, full cheeks, sparse kinky hair, metaphyseal ATP7A, Xpl3.3 changes, limited spontaneous movement, hypertonicity, seizures, hypothermia, lethargy, arterial tortuosity, death in early childhood Pelizaeus–Merzbacher disease Nystagmus, truncal hypotonia, progressive spastic paraplegia, PLP, Xq21.1 ataxia, dystonia Renpenning syndrome (includes Short stature, microcephaly, small testes. May PQBP1, Xp11.3 Sutherland–Haan, cerebropalatocardiac, have ocular or genital abnormalities Golabi–Ito–Hall, Porteous syndrome Rett syndrome XLMR in girls, cessation and regression of development in early MECP2, Xq28 childhood, truncal ataxia, autistic features, acquired microcephaly X-linked hydrocephaly-MASA spectrum Hydrocephalus, adducted thumbs, spastic paraplegia L1CAM, Xq28 Reproduced with permission from Stevenson and Schwartz.46 practice” or mandatory and believed MRI alone leads to an etiologic di- a progressive or degenerative course in that decisions regarding “cranial im- agnosis in a much lower percentage of terms of their neurologic symptom- aging will need to follow (not precede) patients studied. They cited Kjos et al,72 atology. Bouhadiba et al73 reported a thorough assessment of the patient who reported diagnoses in 3.9% of diagnoses in 0.9% of patients with and the clinical presentation.” In con- patients who had no known cause for neurologic symptoms, and in 4 addi- trast, van Karnebeek et al12 found that their ID and who did not manifest either tional studies, no etiologic or syndromic

e912 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on March 4, 2020 FROM THE AMERICAN ACADEMY OF PEDIATRICS diagnosis on the basis of neuroimaging been studied in detail. In addition, MRI treatment and prognosis. Confirm alone was found.65,69,74,75 The authors in the young child with developmental the clinical diagnosis with the ap- of 3 studies reported the results on delay/ID invariably requires sedation propriate genetic testing, as war- unselected patients; Majnemer and or, in some cases, anesthesia to im- ranted by clinical circumstances. Shevell67 reported a diagnosis by this mobilize the child to accomplish the 3. If a specific diagnosis is suspected, typed unselected investigation in 0.2%, imaging study. This need, however, is arrange for the appropriate diag- Stromme76 reported a diagnosis in decreasing with faster acquisition nostic studies to confirm including 1.4% of patients, and van Karnebeek times provided by more modern im- single-gene tests or chromosomal et al40 reported a diagnosis in 2.2% of aging technology. Although the risk of microarray test. patients. sedation or anesthesia is small, it still 4. If diagnosis is unknown and no merits consideration within the de- Although a considerable evolution has clinical diagnosis is strongly sus- cision calculus for practitioners and occurred over the past 2 decades in pected, begin the stepwise evalua- the child’s family.63,78,79 Thus, although neuroimaging techniques and modali- tion process: ties, for the most part with the ex- MRI is often useful in the evaluation of the child with developmental delay/ID, a. Chromosomal microarray should ception of proton magnetic resonance at present, it cannot be definitively be performed in all. spectroscopy, this has not been applied recommended as a mandatory study, fi or reported in the clinical situation of b. Speci c metabolic testing should and it certainly has higher diagnostic developmental delay/ID in childhood. be considered and should in- yields when concurrent neurologic Proton resonance spectroscopy provides clude serum total homocysteine, indications exist derived from a care- fi a noninvasive mechanism of measuring acyl-carnitine pro le, amino acids; ful physical examination of the child brain metabolites, such as lactate, using and urine organic acids, glycos- (ie, microcephaly, microcephaly, seizures, technical modifications to MRI. Martin aminoglycans, oligosaccharides, or focal motor findings). et al77 did not detect any differences purines, pyrimidines, GAA/creatine in brain metabolite concentrations metabolites. among stratifications of GDD/ID into RECOMMENDED APPROACH c. Fragile X genetic testing should mild, moderate, and severe levels. The following is the recommended be performed in all. Furthermore, they did not detect any medical genetic diagnostic evaluation 5. If no diagnosis is established: fi fl signi cant differences in brain me- ow process for a new patient with a. Male gender and family history tabolite concentration between chil- GDD/ID. All patients with ID, irre- suggestive X-linkage, complete dren with GDD/ID and age-matched spective of degree of disability, merit XLID panel that contains genes typically developing control children. a comprehensive medical evaluation causal of nonsyndromic XLID and coordinated by the medical home in Thus, these authors concluded that complete high-density X-CMA. Con- “ conjunction with the medical genetics proton resonance spectroscopy has sider X-inactivation skewing in the specialist. What follows is the clinical little information concerning cause of mother of the proband. unexplained DD.” Similarly, the studies genetics evaluation (Fig 1): b. Female gender: complete MECP2 by Martin et al77 and Verbruggen 1. Complete medical history; 3-generation deletion, duplication, and sequenc- et al71 did not reveal that proton mag- family history; and physical, dys- ing study. netic resonance spectroscopy was morphologic, and neurologic exami- particularly useful in the determina- nations. 6. If microcephaly, macrocephaly, or abnormal findings on neurologic tion of an underlying etiologic diag- 2. If the specific diagnosis is certain, examination (focal motor findings, nosis in children with unexplained inform the family and the medical pyramidal signs, extrapyramidal developmental delay/ID. home, providing informational re- signs, intractable epilepsy, or focal All of these findings suggest that ab- sources for both; set in place an seizures), perform brain MRI. normal findings on MRI are seen in explicit shared health care plan80 fi ∼30% of children with developmental with the medical home and family, 7. If brain MRI ndings are negative delay/ID. However, only in a fraction of including role definitions; provide or normal, review status of diag- these children does MRI lead to an sources of information and sup- nostic evaluation with family and etiologic or syndromic diagnosis. The port to the family; provide genetic medical home. precise value of a negative MRI result counseling services by a certified 8. Consider referrals to other specialists, in leading to a diagnosis has not yet genetic counselor; and discuss signs of inborn errors of metabolism

PEDIATRICS Volume 134, Number 3, September 2014 e913 Downloaded from www.aappublications.org/news by guest on March 4, 2020 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 con- strained 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 FIGURE 1 genetics specialist and only applies Diagnostic process and care planning. Metabolic test 1: blood homocysteine, acylcarnitine proﬁle, amino acids; and, urine organic acids, glycosaminoglycans, oligosaccharides, purines, pyrimidines, where access is a problem; any such GAA/creatine metabolites. Metabolic test 2 based on clinical signs and symptoms. FH, family history; process is better established with local MH, medical history; NE, neurologic examination; PE, physical and dysmorphology examination. particularities in mind: Medical home completes the medical for which screening has not yet been THE SHARED EVALUATION AND evaluation, determines that GDD/ID is performed, etc. CARE PLAN FOR LIMITED ACCESS present, counsels family, refers to 9. If no further studies appear war- Health care systems, processes, and educational services, completes a 3- ranted, develop a plan with the outcomes vary geographically, and not generation family history, and com- family and medical home for all of what is recommended in this pletes the physical examination and needed services for child and fam- clinical report is easily accessible in all addresses the following questions: ily; also develop a plan for diagnos- regions of the United States.21,81–84 1. Does the child have abnormalities on tic reevaluation. Consequently, local factors affect the the dysmorphologic examination?

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a. If no or uncertain, obtain micro- medical geneticist can then agree on clinical report to guide the process. array, perform fragile X testing, the frequency and timing of diagnos- The manner in which the elements of and consider the metabolic test- tic reevaluation while providing the this clinical protocol are applied is ing listed previously. Confirm family and child services needed. subject to local circumstances, as well that newborn screening was as the decision-making by the involved completed and reported nega- EMERGING TECHNOLOGIES pediatric primary care provider and tive. Refer to medical genetics family. The goals and the process of the Several research reports have cited while testing is pending. diagnostic evaluation are unchanged: whole-exome sequencing and whole- to improve the health and well-being of b. If yes, send case summary and genome sequencing in patients with those with GDD/ID. It is important to clinical photo to medical genetics known clinical syndromes for whom the emphasize the new role of the genomic center for review for syndrome causative gene was unknown. These re- microarray as a first-line test, as well identification. If diagnosis is sus- search reports identified the causative as the renewal of efforts to identify the pected, arrange for expedited genes in patients with rare syndromes child with an inborn error of metab- medical genetics referral and (eg, Miller syndrome,86 Charcot-Marie- olism. The future use of whole-genome hold all testing listed above. Med- Tooth disease,87 and a child with se- sequencing offers promise and chal- ical geneticist to arrange visit vere inflammatory bowel disease88). lenges needing to be addressed before with genetic counselor for testing Applying similar whole-genome se- regular implementation in the clinic. for suspected condition. quencing of a family of 4 with 1 affected individual, Roach et al86 identified the 2. Does the child have microcephaly, LEAD AUTHORS macrocephaly, or abnormal neuro- genes for Miller syndrome and primary John B. Moeschler, MD, MS, FAAP, FACMG logic examination (listed above)? If ciliary dyskinesia. The ability to do Michael Shevell, MDCM, FRCP “yes,” measure parental head cir- whole-genome sequencing and inter- pretationatanacceptablepriceison AMERICAN ACADEMY OF PEDIATRICS cumferences and review the family – the horizon.87,89 The use of exome or COMMITTEE ON GENETICS, 2013 history for affected and unaffected 2014 members. If normal head circum- whole-genome sequencing challenges fi Robert A. Saul, MD, FAAP, Chairperson ferences in both parents and neg- the eld of medical genetics in ways Emily Chen, MD, PhD, FAAP ative family history, obtain brain not yet fully understood. When a child Debra L. Freedenberg, MD, FAAP Rizwan Hamid, MD, FAAP MRI and refer to medical genetics. presents with ID and whole-genome sequencing is applied, one will identify Marilyn C. Jones, MD, FAAP 3. Does child also have features of au- Joan M. Stoler, MD, FAAP mutations that are unrelated to the tism, cerebral palsy, epilepsy, or Beth Anne Tarini, MD, MS, FAAP question being addressed, in this case sensory disorders (deafness, blind- “What is the cause of the child’sin- PAST COMMITTEE MEMBERS ness)? This protocol does not ad- tellectual disability?” One assumes that Stephen R. Braddock, MD dress these patients; manage and this will include mutations that families John B. Moeschler, MD, MS, FAAP, FACMG refer as per local circumstances. do not want to have (eg, adult-onset CONTRIBUTOR 4. As above are arranged and completed disorders for which no treatment now Michael Shevell, MDCM, FRCP and negative, refer to medical ge- exists). This is a sea change for the field netics and hold on additional diag- of medical genetics, and the implications LIAISONS nostic testing until consultation of this new technology have not been Katrina M. Dipple, MD, PhD – American College completed. Continue with current fully explored. In addition, ethical issues of Medical Genetics Melissa A. Parisi, MD, PhD – Eunice Kennedy medical home family support ser- regarding validity of new tests, un- Shriver National Institute of Child Health and vices and health care. certainty, and use of resources will need Human Development 5. Should a diagnosis be established, to be addressed as these technologies Nancy Rose, MD – American College of Obste- the medical home, medical geneti- become available for clinical use.90,91 tricians and Gynecologists Joan A. Scott, MS, CGC – Health Resources and cist, and family might then agree to Services Administration, Maternal and Child a care plan with explicit roles and CONCLUSIONS Health Bureau Stuart K. Shapira, MD, PhD – Centers for Disease responsibilities of all. The medical genetic diagnostic evalu- Control and Prevention 6. Should a diagnosis not be estab- ation of the child with GDD/ID is best lished by medical genetics consulta- accomplished in collaboration with the STAFF tion, the medical home, family, and medical home and family by using this Paul Spire

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Downloaded from www.aappublications.org/news by guest on March 4, 2020 Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays John B. Moeschler, Michael Shevell and COMMITTEE ON GENETICS Pediatrics 2014;134;e903 DOI: 10.1542/peds.2014-1839 originally published online August 25, 2014;

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