clinical report ...pediatrics.aappublications.org/content/pediatrics/early/2014/08/19/... ·...
Post on 24-Mar-2019
220 Views
Preview:
TRANSCRIPT
CLINICAL REPORT
Comprehensive Evaluation of the Child With IntellectualDisability or Global Developmental Delays
abstractGlobal developmental delay and intellectual disability are relativelycommon pediatric conditions. This report describes the recommendedclinical genetics diagnostic approach. The report is based on a reviewof published reports, most consisting of medium to large case series ofdiagnostic tests used, and the proportion of those that led to a diag-nosis in such patients. Chromosome microarray is designated asa first-line test and replaces the standard karyotype and fluorescentin situ hybridization subtelomere tests for the child with intellectualdisability of unknown etiology. Fragile X testing remains an importantfirst-line test. The importance of considering testing for inborn errorsof metabolism in this population is supported by a recent systematicreview of the literature and several case series recently published. Therole of brain MRI remains important in certain patients. There is alsoa discussion of the emerging literature on the use of whole-exome se-quencing as a diagnostic test in this population. Finally, the importanceof intentional comanagement among families, the medical home,and the clinical genetics specialty clinic is discussed. Pediatrics2014;134:e903–e918
The purpose of this clinical report of the American Academy of Pe-diatrics (AAP) is to describe an optimal medical genetics evaluation ofthe child with intellectual disability (ID) or global developmental delays(GDDs). The intention is to assist the medical home in preparingfamilies properly for the medical genetics evaluation process. Thisreport addresses the advances in diagnosis and treatment of childrenwith intellectual disabilities since the publication of the original AAPclinical report in 20061 and provides current guidance for the medicalgenetics evaluation. One intention is to inform primary care providersin the setting of the medical home so that they and families areknowledgeable about the purpose and process of the genetics eval-uation. This report will emphasize advances in genetic diagnosis whileupdating information regarding the appropriate evaluation for inbornerrors of metabolism and the role of imaging in this context. Thereader is referred to the 2006 clinical report for background in-formation that remains relevant, including the roles of the medicalhome or pediatric primary care provider.
This clinical report will not address the importance of developmentalscreening in the medical home, nor will it address the diagnostic
John B. Moeschler, MD, MS, FAAP, FACMG, Michael Shevell,MDCM, FRCP, and COMMITTEE ON GENETICS
ABBREVIATIONSAAP—American Academy of PediatricsCMA—chromosome microarrayCNS—central nervous systemCNV—copy number variantCT—computed tomographyFISH—fluorescent in situ hybridizationGAA—guanidinoacetateGDD—global developmental delayID—intellectual disabilityXLID—X-linked intellectual disability
This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.
The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.
www.pediatrics.org/cgi/doi/10.1542/peds.2014-1839
doi:10.1542/peds.2014-1839
All clinical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2014 by the American Academy of Pediatrics
PEDIATRICS Volume 134, Number 3, September 2014 e903
FROM THE AMERICAN ACADEMY OF PEDIATRICS
Guidance for the Clinician inRendering Pediatric Care
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
evaluation of the child with an autismspectrum disorder who happens tohave ID as a co-occurring disability.(For AAP guidance related to AutismSpectrum Disorders, see Johnson andMyers.2)
For both pediatric primary care pro-viders and families, there are specificbenefits to establishing an etiologicdiagnosis (Table 1): clarification of eti-ology; provision of prognosis or ex-pected clinical course; discussion ofgenetic mechanism(s) and recurrencerisks; refined treatment options; theavoidance of unnecessary and re-dundant diagnostic tests; informationregarding treatment, symptom man-agement, or surveillance for knowncomplications; provision of condition-specific family support; access to re-search treatment protocols; and theopportunity for comanagement of pa-tients, as appropriate, in the context ofa medical home to ensure the besthealth, social, and health care servicessatisfaction outcomes for the child andfamily. The presence of an accurateetiologic diagnosis along with a knowl-edgeable, experienced, expert clinicianis one factor in improving the psycho-social outcomes for children and with
intellectual disabilities and their fami-lies.3–5 Although perhaps difficult tomeasure, this “healing touch” contrib-utes to the general well-being of thefamily. “As physicians we have experi-ence with other children who have thesame disorder, access to managementprograms, knowledge of the prognosis,awareness of research on understandingthe disease and many other elementsthat when shared with the parents willgive them a feeling that some controlis possible.”5
Makela et al6 studied, in depth, 20families of children with ID with andwithout an etiologic diagnosis andfound that these families had specificstated needs and feelings about whata genetic diagnosis offers:
1. Validation: a diagnosis establishedthat the problem (ID) was credible,which empowered them to advo-cate for their child.
2. Information: a diagnosis was felt tohelp guide expectations and man-agement immediately and providehope for treatment or cure in fu-ture.
3. Procuring services: the diagnosisassisted families in obtaining desiredservices, particularly in schools.
4. Support: families expressed the needfor emotional companionship that aspecific diagnosis (or “similar chal-lenges”) assisted in accessing.
5. Need to know: families widely dif-fered in their “need to know” a spe-cific diagnosis, ranging from strongto indifferent.
6. Prenatal testing: families varied intheir emotions, thoughts, and actionsregarding prenatal genetic diagno-sis.
For some families in the Makela et al6
study, the clinical diagnosis of autism,for example, was sufficient and oftenmore useful than “a rare but specificetiological diagnosis.” These authorsreport that “all of the families would
have preferred to have an [etiologic]diagnosis, if given the option,” partic-ularly early in the course of thesymptoms.
As was true of the 2006 clinical report,this clinical report will not address theetiologic evaluation of young childrenwho are diagnosed with cerebral palsy,autism, or a single-domain develop-mental delay (gross motor delay orspecific language impairment).1 Somechildren will present both with GDDand clinical features of autism. Insuch cases, the judgment of the clin-ical geneticist will be important indetermining the evaluation of the childdepending on the primary neuro-developmental diagnosis. It is recog-nized that the determination that aninfant or young child has a cognitivedisability can be a matter of clinicaljudgment, and it is important for thepediatrician and consulting clinicalgeneticist to discuss this before de-ciding on the best approach to thediagnostic evaluation.”1
INTELLECTUAL DISABILITY
ID is a developmental disability pre-senting in infancy or the early child-hood years, although in some cases, itcannot be diagnosed until the child isolder than ∼5 years of age, whenstandardized measures of develop-mental skills become more reliableand valid. The American Associationon Intellectual and DevelopmentalDisability defines ID by using mea-sures of 3 domains: intelligence (IQ),adaptive behavior, and systems ofsupports afforded the individual.7
Thus, one cannot rely solely on themeasure of IQ to define ID. More re-cently, the term ID has been suggestedto replace “mental retardation.”7,8 Forthe purposes of this clinical report,the American Association on Intel-lectual and Developmental Disabilitydefinition is used: “Intellectual dis-ability is a disability characterized by
TABLE 1 The Purposes of theComprehensive Medical GeneticsEvaluation of the Young Child WithGDD or ID
1. Clarification of etiology2. Provision of prognosis or expected clinicalcourse
3. Discussion of genetic mechanism(s) andrecurrence risks
4. Refined treatment options5. Avoidance of unnecessary or redundantdiagnostic tests
6. Information regarding treatment, symptommanagement, or surveillance for knowncomplications
7. Provision of condition-specific family support8. Access to research treatment protocols9. Opportunity for comanagement of appropriatepatients in the context of a medical home toensure the best health, social, and health careservices satisfaction outcomes for the child andfamily
e904 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on March 23, 2019www.aappublications.org/newsDownloaded from
significant limitations both in intel-lectual functioning and in adaptive be-havior as expressed in conceptual,social and practical adaptive skills.The disability originates before age 18years.”7 The prevalence of ID is esti-mated to be between 1% and 3%.Lifetime costs (direct and indirect) tosupport individuals with ID are large,estimated to be an average of ap-proximately $1 million per person.9
Global Developmental Delay
Identifying the type of developmentaldelay is an important preliminary step,because typing influences the path ofinvestigation later undertaken. GDD isdefined as a significant delay in 2 ormore developmental domains, includinggross or fine motor, speech/language,cognitive, social/personal, and activi-ties of daily living and is thought topredict a future diagnosis of ID.10 Suchdelays require accurate documenta-tion by using norm-referenced and age-appropriate standardized measuresof development administered by ex-perienced developmental specialists.The term GDD is reserved for youngerchildren (ie, typically younger than 5years), whereas the term ID is usuallyapplied to older children for whom IQtesting is valid and reliable. Childrenwith GDD are those who present withdelays in the attainment of develop-mental milestones at the expectedage; this implies deficits in learningand adaptation, which suggests thatthe delays are significant and predictlater ID. However, delays in development,especially those that are mild, may betransient and lack predictive reliabilityfor ID or other developmental disabil-ities. For the purposes of this report,children with delays in a single devel-opmental domain (for example, iso-lated mild speech delay) should not beconsidered appropriate candidates forthe comprehensive genetic evaluationprocess set forth here. The prevalence
of GDD is estimated to be 1% to 3%,similar to that of ID.
Diagnosis
Schaefer and Bodensteiner11 wrotethat a specific diagnosis is that which“can be translated into useful clinicalinformation for the family, includingproviding information about progno-sis, recurrence risks, and preferredmodes of available therapy.” For ex-ample, agenesis of the corpus callosumis considered a sign and not a diagnosis,whereas the autosomal-recessive Acro-callosal syndrome (agenesis of thecorpus callosum and polydactyly) isa clinical diagnosis. Van Karnebeeket al12 defined etiologic diagnosis as“sufficient literature evidence…tomake a causal relationship of the dis-order with mental retardation likely,and if it met the Schaefer-Bodensteinerdefinition.” This clinical report will usethis Van Karnebeek modification of theSchaefer–Bodensteiner definition and,thus, includes the etiology (geneticmutation or genomic abnormality) asan essential element to the definition ofa diagnosis.
Recommendations are best when es-tablished from considerable empiricalevidence on the quality, yield, andusefulness of the various diagnosticinvestigations appropriate to theclinical situation. The evidence for thisclinical report is largely based onmany small- or medium-size case se-ries and on expert opinion. The reportis based on a review of the literatureby the authors.
Highlights in This Clinical Report
Significant changes in genetic di-agnosis in the last several years havemade the 2006 clinical report out-of-date. First, the chromosome mi-croarray (CMA) is now considered afirst-line clinical diagnostic test forchildren who present with GDD/ID ofunknown cause. Second, this report
highlights a renewed emphasis on theidentification of “treatable” causes ofGDD/ID with the recommendation toconsider screening for inborn errorsof metabolism in all patients withunknown etiology for GDD/ID.13
Nevertheless, the approach to thepatient remains familiar to pediatricprimary care providers and includesthe child’s medical history (includingprenatal and birth histories); thefamily history, which includes con-struction and analysis of a pedigree of3 generations or more; the physicaland neurologic examinations empha-sizing the examination for minor anom-alies (the “dysmorphology examination”);and the examination for neurologic orbehavioral signs that might suggesta specific recognizable syndrome ordiagnosis. After the clinical geneticevaluation, judicious use of laboratorytests, imaging, and other consulta-tions on the basis of best evidence areimportant in establishing the diagno-sis and for care planning.
CHROMOSOME MICROARRAY
CMA now should be considered a first-tier diagnostic test in all children withGDD/ID for whom the causal diagnosisis not known. G-banded karyotypinghistorically has been the standard first-tier test for detection of genetic im-balance in patients with GDD/ID formore than 35 years. CMA is now thestandard for diagnosis of patients withGDD/ID, as well as other conditions,such as autism spectrum disorders ormultiple congenital anomalies.14–24
The G-banded karyotype allows a cyto-geneticist to visualize and analyzechromosomes for chromosomal rear-rangements, including chromosomalgains (duplications) and losses (dele-tions). CMA performs a similar function,but at a much “higher resolution,” forgenomic imbalances, thus increasingthe sensitivity substantially. In theirrecent review of the CMA literature,
PEDIATRICS Volume 134, Number 3, September 2014 e905
FROM THE AMERICAN ACADEMY OF PEDIATRICS
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
Vissers et al25 report the diagnostic rateof CMA to be at least twice that of thestandard karyotype. CMA, as used inthis clinical report, encompasses allcurrent types of array-based genomiccopy number analyses, including array-based comparative genomic hybridiza-tion and single-nucleotide polymorphismarrays (see Miller et al15 for a review ofarray types). With these techniques,a patient’s genome is examined fordetection of gains or losses of ge-nome material, including those toosmall to be detectable by standardG-banded chromosome studies.26,27
CMA replaces the standard karyotype(“chromosomes”) and fluorescent insitu hybridization (FISH) testing forpatients presenting with GDD/ID of un-known cause. The standard karyotypeand certain FISH tests remain importantto diagnostic testing but now only inlimited clinical situations (see Manningand Hudgins14) in which a specific con-dition is suspected (eg, Down syndromeor Williams syndrome). The discussionof CMA does not include whole-genomesequencing, exome sequencing, or “next-generation” genome sequencing; theseare discussed in the “emerging tech-nologies” section of this report.
Twenty-eight case series have beenpublished addressing the rate of di-agnosis by CMA of patients presentingwith GDD/ID.28 The studies vary bysubject criteria and type of microarraytechnique and reflect rapid changes intechnology over recent years. Never-theless, the diagnostic yield for allcurrent CMA is estimated at 12% forpatients with GDD/ID.14–29 CMA is thesingle most efficient diagnostic test,after the history and examination bya specialist in GDD/ID.
CMA techniques or “platforms” vary.Generally, CMA compares DNA contentfrom 2 differentially labeled genomes:the patient and a control. In the earlytechniques, 2 genomes were cohybrid-ized, typically onto a glass microscope
slide on which cloned or synthesizedcontrol DNA fragments had beenimmobilized. Arrays have been builtwith a variety of DNA substrates thatmay include oligonucleotides, com-plementary DNAs, or bacterial artifi-cial chromosomes. The arrays mightbe whole-genome arrays, which aredesigned to cover the entire genome,or targeted arrays, which targetknown pathologic loci, the telomeres,and pericentromeric regions. Somelaboratories offer chromosome-specificarrays (eg, for nonsyndromic X-linkedID [XLID]).30 The primary advantage ofCMA over the standard karyotype orlater FISH techniques is the ability ofCMA to detect DNA copy changes si-multaneously at multiple loci in a ge-nome in one “experiment” or test. Thecopy number change (or copy numbervariant [CNV]) may include deletions,duplications, or amplifications at anylocus, as long as that region is rep-resented on the array. CMA, indepen-dent of whether it is “whole genome”or “targeted” and what type of DNA sub-strate (single-nucleotide polymorphisms,31
oligonucleotides, complementary DNAs,or bacterial artificial chromosomes),32
identifies deletions and/or duplicationsof chromosome material with a highdegree of sensitivity in a more efficientmanner than FISH techniques. Two mainfactors define the resolution of CMA: (1)the size of the nucleic acid targets; and(2) the density of coverage over thegenome. The smaller the size of thenucleic acid targets and the more con-tiguous the targets on the native chro-mosome are, the higher the resolutionis. As with the standard karyotype, oneresult of the CMA test can be “of un-certain significance,” (ie, expert inter-pretation is required, because somedeletions or duplications may not beclearly pathogenic or benign). Milleret al15 describe an effort to develop aninternational consortium of laborato-ries to address questions surroundingarray-based testing interpretation. This
International Standard Cytogenomic Ar-ray Consortium15 (www.iscaconsortium.org) is investigating the feasibility ofestablishing a standardized, univer-sal system of reporting and catalog-ing CMA results, both pathologic andbenign, to provide the physician withthe most accurate and up-to-date in-formation.
It is important for the primary carepediatrician to work closely with theclinical geneticist and the diagnosticlaboratory when interpreting CMA testresults, particularly when “variants ofunknown significance” are identified.In general, CNVs are assigned thefollowing interpretations: (1) patho-genic (ie, abnormal, well-establishedsyndromes, de novo variants, and largechanges); (2) variants of unknown sig-nificance; and (3) likely benign.15 Theseinterpretations are not essentiallydifferent than those seen in the stan-dard G-banded karyotype. It is impor-tant to note that not all commercialhealth plans in the United States in-clude this testing as a covered benefitwhen ordered by the primary carepediatrician; others do not cover iteven when ordered by the medicalgeneticist. Typically, the medical ge-netics team has knowledge and ex-perience in matters of payment fortesting.
The literature does not stratify the di-agnostic rates of CMA by severity ofdisability. In addition, there is substantialliterature supporting the multiple fac-tors (eg, social, environmental, eco-nomic, genetic) that contribute to milddisability.33 Consequently, it remainswithin the judgment of the medical ge-neticist as to whether it is warranted totest the patient with mild (and familial)ID for pathogenic CNVs. In their review,Vissers et al25 reported on several recur-rent deletion or duplication syndromeswith mild disability and commented onthe variable penetrance of the morecommon CNV conditions, such as 1q21.1
e906 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on March 23, 2019www.aappublications.org/newsDownloaded from
microdeletion, 1q21.1 microduplication,3q29 microduplication, and 12q14 micro-deletion. Some of these are also inheri-ted. Consequently, among families withmore than one member with disability,it remains challenging for the medicalgeneticist to know for which patientwith GDD/ID CMA testing is not war-ranted.
Recent efforts to evaluate reportingof CNVs among clinical laboratoriesindicate variability of interpretationbecause of platform variability in sen-sitivity.34,35 Thus, the interpretation ofCMA test abnormal results and var-iants of unknown significance, and thesubsequent counseling of familiesshould be performed in all cases bya medical geneticist and certified ge-netic counselor in collaboration withthe reference laboratory and platformused. Test variability is resolving asa result of international collabora-tions.36 With large data sets, thefunctional impact (or lack thereof) ofvery rare CNVs is better understood.Still, there will continue to be rare orunique CNVs for which interpretationremain ambiguous. The medical ge-neticist is best equipped to interpretsuch information to families and themedical home.
SCREENING FOR INBORN ERRORSOF METABOLISM
Since the 2006 AAP clinical report, sev-eral additional reports have been pub-lished regarding metabolic testing fora cause of ID.13,37–40 The percentage ofpatients with identifiable metabolic dis-orders as cause of the ID ranges from1% to 5% in these reports, a rangesimilar to those studies included inthe 2006 clinical report. Likewise, thesenewer published case series varied bysite, age range of patients, time frame,study protocol, and results. However,they do bring renewed focus to treat-able metabolic disorders.13 Further-more, some of the disorders identified
are not included currently in anynewborn screening blood spot pan-els. Although the prevalence ofinherited metabolic conditions isrelatively low (0% to 5% in thesestudies), the potential for improvedoutcomes after diagnosis and treat-ment is high.41
In 2005, Van Karnebeek et al40 reportedon a comprehensive genetic diagnosticevaluation of 281 consecutive patientsreferred to an academic center in theNetherlands. All patients were sub-jected to a protocol for evaluation andstudies were performed for all patientswith an initially unrecognized cause ofmental retardation and included uri-nary screen for amino acids, organicacids, oligosaccharides, acid mucopoly-saccharides, and uric acid; plasma con-centrations of total cholesterol and dienesterols of 7- and 8-dehydrocholesterol toidentify defects in the distal choles-terol pathway; and a serum test toscreen for congenital disorders ofglycosylation (test names such as“carbohydrate-deficient transferrin”).In individual patients, other searcheswere performed as deemed necessarydepending on results of earlier stud-ies. This approach identified 7 (4.6%)subjects with “certain or probable”metabolic disorders among those whocompleted the metabolic screening(n = 216). None of the 176 screeningtests for plasma amino acids andurine organic acids was abnormal.Four children (1.4%) with congenitaldisorders of glycosylation were iden-tified by serum sialotransferrins, 2children had abnormal serum choles-terol and 7-dehydrocholesterol concen-trations suggestive of Smith-Lemli-Opitz syndrome, 2 had evidence of amitochondrial disorder, 1 had evi-dence of a peroxisomal disorder, and1 had abnormal cerebrospinal fluidbiogenic amine concentrations. Theseauthors concluded that “screening forglycosylation defects proved useful,
whereas the yield of organic acid andamino acid screening was negligible.”
In a similar study from the Netherlandsdone more recently, Engbers et al39
reported on metabolic testing that wasperformed in 433 children whose GDD/ID remained unexplained after genetic/metabolic testing, which includeda standard karyotype; urine screen foramino acids, organic acids, mucopoly-saccharides, oligosaccharides, uricacid, sialic acid, purines, and pyrim-idines; and plasma for amino acids,acylcarnitines, and sialotransferrins.Screenings were repeated, and addi-tional testing, including cerebrospinalfluid studies, was guided by clinicalsuspicion. Metabolic disorders wereidentified and confirmed in 12 of thesepatients (2.7%), including 3 with mito-chondrial disorders; 2 with creatinetransporter disorders; 2 with short-chainacyl-coenzyme A dehydrogenase deficiency;and 1 each with Sanfilippo IIIa, a per-oxisomal disorder; a congenital disorderof glycosylation; 5-methyltetrahydrofolatereductase deficiency; and deficiency of theGLUT1 glucose transporter.
Other studies have focused on theprevalence of disorders of creatinesynthesis and transport. Lion-Françoiset al37 reported on 188 children re-ferred over a period of 18 monthswith “unexplained mild to severemental retardation, normal karyotype,and absence of fragile X syndrome”who were prospectively screened forcongenital creatine deficiency syn-dromes. Children were from diverseethnic backgrounds. Children with“polymalformative syndromes” wereexcluded. There were 114 boys (61%)and 74 girls (39%) studied. Creatinemetabolism was evaluated by usingcreatine/creatinine and guanidinoacetate(GAA)-to-creatine ratios on a spot urinescreen. Diagnosis was further con-firmed by using brain proton magneticresonance spectroscopy and mutationscreening by DNA sequence analysis in
PEDIATRICS Volume 134, Number 3, September 2014 e907
FROM THE AMERICAN ACADEMY OF PEDIATRICS
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
either the SLC6A8 (creatine trans-porter defect) or the GAMT genes. Thisresulted in a diagnosis in 5 boys (2.7%of all; 4.4% of boys). No affected girlswere identified among the 74 studied.All 5 boys also were late to walk, and 3had “autistic features.” The authorsconcluded that all patients with un-diagnosed ID have urine screened forcreatine-to-creatinine ratio and GAA-to-creatine ratio. Similarly, CaldeiraArauja et al38 studied 180 adults withID institutionalized in Portugal, screen-ing them for congenital creatine de-ficiency syndromes. Their protocolinvolved screening all subjects forurine and plasma uric acid and cre-atinine. Patients with an increasedurinary uric acid-to-creatinine ratio and/or decreased creatinine were sub-jected to the analysis of GAA. GAMTactivity was measured in lymphocytesand followed by GAMT gene analysis.This resulted in identifying 5 individ-uals (2.8%) from 2 families with GAMTdeficiency. A larger but less selectivestudy of 1600 unrelated male andfemale children with GDD/ID and/orautism found that 34 (2.1%) hadabnormal urine creatine-to-creatinineratios, although only 10 (0.6%) hadabnormal repeat tests and only 3(0.2%) were found to have anSLC6A8 mutation.42 Clark et al43
identified SLC6A8 mutations in 0.5%of 478 unrelated boys with unexplainedGDD/ID.
Recently, van Karnebeek and Stocklerreported13,42 on a systematic litera-ture review of metabolic disorders“presenting with intellectual disabilityas a major feature.” The authorsidentified 81 treatable genetic meta-bolic disorders presenting with ID asa major feature. Of these disorders, 50conditions (62%) were identified byroutinely available tests (Tables 2 and 3).Therapeutic modalities with proveneffect included diet, cofactor/vitaminsupplements, substrate inhibition, en-
zyme replacement, and hematopoieticstem cell transplant. The effect onoutcome (IQ, developmental perfor-mance, behavior, epilepsy, and neuro-imaging) varied from improvement tohalting or slowing neurocognitive re-gression. The authors emphasized theapproach as one that potentially hassignificant impact on patient out-comes: “This approach revisits cur-rent paradigms for the diagnosticevaluation of ID. It implies treatabilityas the premise in the etiologic work-up and applies evidence-based medi-cine to rare diseases.” Van Karnebeekand Stockler13,42 reported on 130patients with ID who were “tested” perthis metabolic protocol; of these, 6(4.6%) had confirmed treatable inbornerrors of metabolism and another 5(3.8%) had “probable” treatable inbornerror of metabolism.
This literature supports the needto consider screening children pre-senting with GDD/ID for treatablemetabolic conditions. Many meta-bolic screening tests are readilyavailable to the medical home and/or local hospital laboratory service.Furthermore, the costs for these met-abolic screening tests are relativelylow.
GENETIC TESTING FOR MENDELIANDISORDERS
For patients in whom a diagnosis issuspected, diagnostic molecular ge-netic testing is required to confirm thediagnosis so that proper health care is
implemented and so that reliable ge-netic counseling can be provided. Forpatients with a clinical diagnosis ofa Mendelian disorder that is certain,molecular genetic diagnostic testingusually is not required to establish thediagnosis but may be useful for healthcare planning. However, for carriertesting or for genetic counseling offamily members, it is often essential toknow the specific gene mutation in theproband.
For patients with GDD/ID for whomthe diagnosis is not known, molec-ular genetic diagnostic testing isnecessary, under certain circum-stances, which is discussed in thenext section.
MALE GENDER
There is an approximate 40% excess ofboys in all studies of prevalence andincidence of ID.44,45 Part of this distor-tion of the gender ratio is attributableto X-linked genetic disorders.46 Conse-quently, genetic testing for X-linkedgenes in boys with GDD/ID is oftenwarranted, particularly in patientswhose pedigree is suggestive of anX-linked condition. In addition, for sev-eral reasons, research in X-linked genesthat cause ID is advanced over autoso-mal genes,46,47 thus accelerating theclinical capacity to diagnose XLID overautosomal forms.
Most common of these is fragile Xsyndrome, although the prevalence ofall other X-linked genes involved in ID
TABLE 2 Metabolic Screening Tests
Specimena Test Notes
Blood Amino acids See Table 3HomocysteineAcylcarnitine profile
Urine Organic acidsGAA/creatine metabolitesPurines and pyrimidinesMucopolysaccharide screenOligosaccharide screen
See Fig 1.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 by guest on March 23, 2019www.aappublications.org/newsDownloaded from
TABLE3
MetabolicConditionsIdentified
byTestsListed
PAAs
P-HCY
Acylcarn
UOA
UPP
UGAA/Cr
UMPS
UOligo
Argininosuccinic
aciduriaa
Cobalamin
Cdeficiency
Cobalamin
Cdeficiency
β-ketothiolase
deficiency
Pyrimidine5′nucleotidase
superactivity
AGAT
deficiency
Hurler
α-mannosidosis
Citrullinem
iaa
Cobalamin
Ddeficiency
Cobalamin
Ddeficiency
Cobalamin
Adeficiency
Molybdenum
cofactor
type
Adeficiency
GAMTdeficiency
Hunter
Aspartylglucosam
inuria
Citrullinem
ia,typeIIa
Cobalamin
Fdeficiency
Cobalamin
Fdeficiency
Cobalamin
Bdeficiency
Creatinetransporter
defect
Sanfilippo
A,B,
CCPSdeficiency
aCobalamin
Edeficiency
Ethylmalonic
encephalopathy
Cobalamin
Cdeficiency
Sly(M
PSVI)
Argininemiaa
Cobalamin
Gdeficiency
Isovalericacidem
iaa
Cobalamin
Ddeficiency
HHHsyndrome
MTHFR
deficiency
a3-methylcrotonyl
glycinuria
Cobalamin
Fdeficiency
Maple
syrupurine
disease,variant
Homocystinuria
PPAa
Ethylmalonicencephalopathy
NAGS
deficiency
aTyrosinemia,typeII
GA,typeI
MTHFR
deficiency
aGA,typeII
OTCdeficiency
aHM
G-CoALyasedeficiency
PKU
Holocarboxylasesynthetase
deficiency
PDHcomplex
deficiency
Homocystinuria
Tyrosinemia,typeII
Isovalericacidem
iaa
3-methylcrotonylglycinuria
3-methylglutaconicaciduria
MMAa
MHB
Ddeficiency
PPAa
SCOT
deficiency
SSADHdeficiency
Tyrosinemia,typeII
Adaptedfrom
vanKarnebeekandStockler.41
Acylcarn,acylcarnitine
profile;CPS,
carbam
ylphosphatesynthetase;GA,glutaric
acidem
ia;HH
H,hyperornithinem
ia-hyperam
monem
ia-hom
ocitrullinuria;HM
G-CoA,
3-hydroxy-3-methylglutaryl-coenzym
eA;
MHB
D,2-methyl-3-hydroxybutyrylCoA
dehydrogenase;MMA,methylmalonicacidem
ia;M
THFR,m
ethylenetetrahydrofolatereductase;NAGS,N-acetylglutamatesynthase;OTC,ornithinetranscarbamylase;PAA,plasmaam
inoacids;PDH,pyruvatedehydrogenase;P-HCY,plasmahomocysteine;
PKU;
phenylketonuria;PPA,propionicacid;SCOT,succinyl-CoA:3-ketoacidCoAtransferase;SSADH,
succinicsemialdehydedehydrogenase;UG
AA/creat;urine
guanidinoacid/creatinemetabolites;UM
PS,urine
mucopolysaccharides
qualitativescreen
(glycosaminoglycans);UO
A,urineorganicacids;UO
GS,urine
oligosaccharides;U
PP,urine
purinesandpyrimidines.
aLate-onset
form
ofcondition
listed;
someconditionsareidentified
bymorethan
1metabolictest.
PEDIATRICS Volume 134, Number 3, September 2014 e909
FROM THE AMERICAN ACADEMY OF PEDIATRICS
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
far exceeds that of fragile X syndromealone.46 Fragile X testing should beperformed in all boys and girls withGDD/ID of unknown cause. Of boyswith GDD/ID of uncertain cause, 2% to3% will have fragile X syndrome (fullmutation of FMR1, >200 CGG repeats),as will 1% to 2% of girls (full muta-tion).48
GENETIC TESTING FORNONSPECIFIC XLID
Stevenson and Schwartz49 suggest 2clinical categories for those with XLID:syndromal and nonsyndromal. Syn-dromal refers to patients in whomphysical or neurologic signs suggesta specific diagnosis; nonsyndromalrefers to those with no signs orsymptoms to guide the diagnosticprocess. Using this classification haspractical applicability, because thepediatric primary care provider canestablish a specific XLID syndrome onthe basis of clinical findings. In con-trast, nonsyndromal conditions canonly be distinguished on the basis ofthe knowledge of their causativegene.50 In excess of 215 XLID con-ditions have been recorded, and >90XLID genes have been identified.46,50
To address male patients with GDD/IDand X-linked inheritance, there aremolecular genetic diagnostic “panels”of X-linked genes available clinically.These panels examine many genes in1 “test sample.” The problem for theclinical evaluation is in which patientto use which test panel, because thereis no literature on head-to-head per-formance of test panels, and the testpanels differ somewhat by genes in-cluded, test methods used, and therate of a true pathogenic genetic di-agnosis. Nevertheless, the imperativefor the diagnostic evaluation remainsthe same for families and physicians,and there is a place for such testingin the clinical evaluation of childrenwith GDD/ID. For patients with an
X-linked pedigree, genetic testing usingone of the panels is clinically indicated.The clinical geneticist is best suited toguide this genetic testing of patientswith possible XLID. For patients with“syndromal” XLID (eg, Coffin-Lowrysyndrome), a single gene test ratherthan a gene panel is indicated. Whereasthose patients with “nonsyndromal”presentation might best be assessedby using a multigene panel compris-ing many of the more common non-syndromal XLID genes. The expectedrate of the diagnosis may be high.Stevenson and Schwartz46 reported,for example, on 113 cases of non-specific ID testing using a 9-gene panelof whom 9 (14.2%) had pathogenicmutations identified. de Brouwer et al51
reported on 600 families with multipleboys with GDD/ID and normal karyo-type and FMR1 testing. Among thosefamilies with “an obligate femalecarrier” (defined by pedigree analysisand linkage studies), a specific genemutation was identified in 42%. Inaddition, in those families with morethan 2 boys with ID and no obligatefemale carrier or without linkage tothe X chromosome, 17% of the IDcases could be explained by X-linkedgene mutations. This very large studysuggested that testing of individualboys for X-linked gene mutations iswarranted.
Recently, clinical laboratories have be-gun offering “high-density” X-CMAs toassess for pathogenic CNVs (see pre-vious discussion regarding micro-arrays) specifically for patients withXLID. Wibley et al30 (2010) reported onCNVs in 251 families with evidence ofXLID who were investigated by arraycomparative genomic hybridizationon a high-density oligonucleotide X-chromosome array platform. Theyidentified pathogenic CNVs in 10% offamilies. The high-density arrays forXLID are appropriate in those patientswith syndromal or nonsyndromal XLID.
The expected diagnostic rate remainsuncertain, although many pathogenicsegmental duplications are reported(for a catalog of X-linked mutationsand CNVs, see http://www.ggc.org/re-search/molecular-studies/xlid.html).
Whole exome sequencing and whole-genome sequencing are emergingtesting technologies for patients withnonspecific XLID. Recently, Tarpey et al52
have reported the results of the large-scale systematic resequencing of thecoding X chromosome to identify novelgenes underlying XLID. Gene codingsequences of 718 X-chromosome geneswere screened via Sanger sequenc-ing technology in probands from 208families with probable XLID. This re-sequencing screen contributed to theidentification of 9 novel XLID-associatedgenes but identified pathogenic se-quence variants in only 35 of 208(17%) of the cohort families. Thisfigure likely underestimates the gen-eral contribution of sequence var-iants to XLID given the subjects wereselected from a pool that had hadprevious clinical and molecular ge-netic screening.30
BOYS WITH SUSPECTED OR KNOWNXLID
Table 4 lists some common XLID con-ditions. In cases in which the diagnosisis not certain, molecular genetic test-ing of patients for the specific gene isindicated, even if the pedigree does notindicate other affected boys (ie, cannotconfirm X-linked inheritance).46
FEMALE GENDER AND MECP2TESTING
Rett syndrome is an X-linked conditionthat affects girls and results fromMECP2 gene mutations primarily (atleast 1 other gene has been de-termined causal in some patients withtypical and atypical Rett syndrome:CDKL5). Girls with mutations in the
e910 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on March 23, 2019www.aappublications.org/newsDownloaded from
MECP2 gene do not always presentclinically with classic Rett syndrome.Several large case series have exam-ined the rate of pathogenic MECP2mutations in girls and boys with ID. Theproportion of MECP2 mutations inthese series ranged from 0% to 4.4%with the average of 1.5% among girlswith moderate to severe ID.53–62 MECP2mutations in boys present with severeneonatal encephalopathy and not withGDD/ID.
ADVANCES IN DIAGNOSTICIMAGING
Currently, the literature does not in-dicate consensus on the role thatneuroimaging, either by computed to-mography (CT) or MRI, can play in theevaluation of children with GDD/ID.Current recommendations range fromperforming brain imaging on all patientswith GDD/ID,63 to performing it only onthose with indications on clinical ex-amination,12 to being considered asa second-line investigation to be un-dertaken when features in addition toGDD are detected either on history orphysical examination. The finding ofa brain abnormality or anomaly onneuroimaging may lead to the recogni-tion of a specific cause of an individualchild’s developmental delay/ID in thesame way that a dysmorphologic ex-amination might lead to the inference ofa particular clinical diagnosis. However,like other major or minor anomaliesnoted on physical examination, abnor-malities on neuroimaging typically arenot sufficient for determining the causeof the developmental delay/ID; the un-derlying precise, and presumably fre-quently genetic in origin, cause of thebrain anomaly is often left unknown.Thus, although a central nervous sys-tem (CNS) anomaly (often also called a“CNS dysgenesis”) is a useful findingand indeed may be considered, ac-cording to the definition of Schaeferand Bodensteiner,11 a useful “diagnosis.”
However, it is frequently not an etio-logic or syndromic diagnosis. Thisdistinction is not always made in theliterature on the utility of neuro-imaging in the evaluation of childrenwith developmental delay/ID. The lackof a consistent use of this distinctionhas led to confusion regarding thisparticular issue.
Early studies on the use of CT in theevaluation of children with idiopathicID64 indicated a low diagnostic yield forthe nonspecific finding of “cerebralatrophy,” which did not contribute toclarifying the precise cause of the ID.65
Later studies that used MRI to detectCNS abnormalities suggested that MRIwas more sensitive than CT, with anincreased diagnostic yield.10,66 The rateof abnormalities actually detected onimaging varies widely in the literatureas a result of many factors, such assubject selection and the method ofimaging used (ie, CT or MRI). Schaeferand Bodensteiner,63 in their literaturereview, found reported ranges of ab-normalities from 9% to 80% of thosepatients studied. Shevell et al10 re-ported a similar range of finding intheir review. For example, in 3 studiestotaling 329 children with develop-mental delay in which CT was used inalmost all patients and MRI was usedin but a small sample, a specific causewas determined in 31.4%,67 27%,68 and30%69 of the children. In their systematicreview of the literature, van Karnebeeket al12 reported on 9 studies that usedMRI in children with ID. The mean rateof abnormalities found was 30%, witha range of 6.2% to 48.7%. These in-vestigators noted that more abnor-malities were found in children withmoderate to profound ID versus thosewith borderline to mild ID (mean yieldof 30% and 21.2%, respectively). Theseauthors also noted that none ofthe studies reported on the value ofthe absence of any neurologic abnor-mality for a diagnostic workup and
concluded that “the value for findingabnormalities or the absence of ab-normalities must be higher” than the30% mean rate implied.
If neuroimaging is performed in onlyselected cases, such as children with anabnormal head circumference or anabnormal focal neurologic finding, therate of abnormalities detected is in-creased further than when used ona screening basis in children witha normal neurologic examination exceptfor the documentation of developmentaldelay. Shevell et al68 reported thatthe percentage of abnormalities were13.9% if neuroimaging was performedon a “screening basis” but increased to41.2% if performed on “an indicatedbasis.” Griffiths et al70 highlighted thatthe overall risk of having a specificstructural abnormality found on MRIscanning was 28% if neurologic symp-toms and signs other than develop-mental delay were present, but if thedevelopmental delay was isolated, theyield was reduced to 7.5%. In a seriesof 109 children, Verbruggen et al71 re-ported an etiologic yield on MRI of 9%.They noted that all of these children hadneurologic signs or an abnormal headcircumference. In their practice pa-rameter, the American Academy ofNeurology and the Child NeurologySociety10 discussed other studies onsmaller numbers of patients whoshowed similar results, which led totheir recommendation that “neuro-imaging is a recommended part ofthe diagnostic evaluation,” particularlyshould there be abnormal findings onexamination (ie, microcephaly, macro-cephaly, focal motor findings, pyramidalsigns, extrapyramidal signs) and thatMRI is preferable to CT. However, theauthors of the American College ofMedical Genetics Consensus ConferenceReport10 stated that neuroimaging byCT or MRI in normocephalic patientswithout focal neurologic signs shouldnot be considered a “standard of
PEDIATRICS Volume 134, Number 3, September 2014 e911
FROM THE AMERICAN ACADEMY OF PEDIATRICS
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
practice” or mandatory and believedthat decisions regarding “cranial im-aging will need to follow (not precede)a thorough assessment of the patientand the clinical presentation.” In con-trast, van Karnebeek et al12 found that
MRI alone leads to an etiologic di-agnosis in a much lower percentage ofpatients studied. They cited Kjos et al,72
who reported diagnoses in 3.9% ofpatients who had no known cause fortheir ID and who did not manifest either
a progressive or degenerative course interms of their neurologic symptom-atology. Bouhadiba et al73 reporteddiagnoses in 0.9% of patients withneurologic symptoms, and in 4 addi-tional studies, no etiologic or syndromic
TABLE 4 Common Recognizable XLID Syndromes
Syndrome Common Manifestations Gene, Location
Aarskog syndrome Short stature, hypertelorism, downslanting palpebral fissures,joint hyperextensibility, shawl scrotum
FGD1, Xp11.21
Adrenoleukodystrophy Variable and progressive vision and hearing loss, spasticity,neurological deterioration associated with demyelination ofthe central nervous system and adrenal insufficiency
ABCD1, Xq28
Aicardi syndrome Agenesis of the corpus callosum, lacunar chorioretinopathy,costovertebral anomalies, seizures in females
_____, Xp22
Allan–Herndon syndrome Generalized muscle hypoplasia, childhood hypotonia, ataxia,athetosis, dysarthria, progressing to spastic paraplegia
MCT8 (SLC16A2), Xq13
ARX-related syndromes(includes Partington, Proud, West,XLAG syndromes and nonsyndromal XLMR)
Partington: dysarthria, dystonia, hyperreflexia, seizures. West:infantile spasms, hypsarrhythmia. Proud: microcephaly,ACC, spasticity, seizures, ataxia, genital anomalies. XLAG:lissencephaly, seizures, genital anomalies
ARX, Xp22.3
ATRX syndrome (includesARTX, Chudley–Lowry, Carpenter–Waziri,Holmes–Gang, and Martinez spasticparaplegia syndromes andnonsyndromal XLMR)
Short stature, microcephaly, hypotonic facies withhypertelorism, small nose, open mouth and prominent lips,brachydactyly, genital anomalies, hypotonia, in some caseshemoglobin H inclusions in erythrocytes
XNP, (XH2) Xq13.3
Christianson syndrome Short stature, microcephaly, long narrow face, large ears, longstraight nose, prominent mandible, general asthenia, narrowchest, long thin digits, adducted thumbs, contractures,seizures, autistic features, truncal ataxia, ophthalmoplegia,mutism, incontinence, hypoplasia of the cerebellum, andbrain stem
SLC9A6, Xq26
Coffin–Lowry syndrome Short stature, distinctive facies, large soft hands, hypotonia,joint hyperextensibility, skeletal changes
RSK2, Xp22
Creatine transporter deficiency Nondysmorphic, autistic, possibly progressive SLC6A8, Xq28Duchenne muscular dystrophy Pseudohypertrophic muscular dystrophy DMD, Xp21.3Fragile X syndrome Prominent forehead, long face, recessed midface, large ears,
prominent mandible, macroorchidismFMR1, Xq27.3
Hunter syndrome Progressive coarsening of face, thick skin, cardiac valve disease,joint stiffening, dysostosis multiplex
IDS, Xq28
Incontinentia pigmenti Sequence of cutaneous blistering, verrucous thickening, andirregular pigmentation. May have associated CNS, ocularabnormalities
NEMO (IKB6KG), Xq28
Lesch–Nyhan syndrome Choreoathetosis, spasticity, seizures, self-mutilation, uric acidurinary stones
HPRT, Xq26
Lowe syndrome Short stature, cataracts, hypotonia, renal tubular dysfunction OCRL, Xq26.1MECP2 duplication syndrome Hypotonia, progressing to spastic paraplegia, recurrent
infectionsMECP2, Xq28
Menkes syndrome Growth deficiency, full cheeks, sparse kinky hair, metaphysealchanges, limited spontaneous movement, hypertonicity,seizures, hypothermia, lethargy, arterial tortuosity, death inearly childhood
ATP7A, Xpl3.3
Pelizaeus–Merzbacher disease Nystagmus, truncal hypotonia, progressive spastic paraplegia,ataxia, dystonia
PLP, Xq21.1
Renpenning syndrome (includesSutherland–Haan, cerebropalatocardiac,Golabi–Ito–Hall, Porteous syndrome
Short stature, microcephaly, small testes. Mayhave ocular or genital abnormalities
PQBP1, Xp11.3
Rett syndrome XLMR in girls, cessation and regression of development in earlychildhood, truncal ataxia, autistic features, acquiredmicrocephaly
MECP2, Xq28
X-linked hydrocephaly-MASA spectrum Hydrocephalus, adducted thumbs, spastic paraplegia L1CAM, Xq28
Reproduced with permission from Stevenson and Schwartz.46
e912 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on March 23, 2019www.aappublications.org/newsDownloaded from
diagnosis on the basis of neuroimagingalone was found.65,69,74,75 The authorsof 3 studies reported the results onunselected patients; Majnemer andShevell67 reported a diagnosis by thistyped unselected investigation in 0.2%,Stromme76 reported a diagnosis in1.4% of patients, and van Karnebeeket al40 reported a diagnosis in 2.2% ofpatients.
Although a considerable evolution hasoccurred over the past 2 decades inneuroimaging techniques and modali-ties, for the most part with the ex-ception of proton magnetic resonancespectroscopy, this has not been appliedor reported in the clinical situation ofdevelopmental delay/ID in childhood.Proton resonance spectroscopy providesa noninvasive mechanism of measuringbrain metabolites, such as lactate, usingtechnical modifications to MRI. Martinet al77 did not detect any differencesin brain metabolite concentrationsamong stratifications of GDD/ID intomild, moderate, and severe levels.Furthermore, they did not detect anysignificant differences in brain me-tabolite concentration between chil-dren with GDD/ID and age-matchedtypically developing control children.Thus, these authors concluded thatproton resonance spectroscopy “haslittle information concerning cause ofunexplained DD.” Similarly, the studiesby Martin et al77 and Verbruggenet al71 did not reveal that proton mag-netic resonance spectroscopy wasparticularly useful in the determina-tion of an underlying etiologic diag-nosis in children with unexplaineddevelopmental delay/ID.
All of these findings suggest that ab-normal findings on MRI are seen in∼30% of children with developmentaldelay/ID. However, only in a fraction ofthese children does MRI lead to anetiologic or syndromic diagnosis. Theprecise value of a negative MRI resultin leading to a diagnosis has not yet
been studied in detail. In addition, MRIin the young child with developmentaldelay/ID invariably requires sedationor, in some cases, anesthesia to im-mobilize the child to accomplish theimaging study. This need, however, isdecreasing with faster acquisitiontimes provided by more modern im-aging technology. Although the risk ofsedation or anesthesia is small, it stillmerits consideration within the de-cision calculus for practitioners andthe child’s family.63,78,79 Thus, althoughMRI is often useful in the evaluation ofthe child with developmental delay/ID,at present, it cannot be definitivelyrecommended as a mandatory study,and it certainly has higher diagnosticyields when concurrent neurologicindications exist derived from a care-ful physical examination of the child(ie, microcephaly, microcephaly, seizures,or focal motor findings).
RECOMMENDED APPROACH
The following is the recommendedmedical genetic diagnostic evaluationflow process for a new patient withGDD/ID. All patients with ID, irre-spective of degree of disability, merita comprehensive medical evaluationcoordinated by the medical home inconjunction with the medical geneticsspecialist. What follows is the clinicalgenetics evaluation (Fig 1):
1. Complete medical history; 3-generationfamily history; and physical, dys-morphologic, and neurologic exami-nations.
2. If the specific diagnosis is certain,inform the family and the medicalhome, providing informational re-sources for both; set in place anexplicit shared health care plan80
with the medical home and family,including role definitions; providesources of information and sup-port to the family; provide geneticcounseling services by a certifiedgenetic counselor; and discuss
treatment and prognosis. Confirmthe clinical diagnosis with the ap-propriate genetic testing, as war-ranted by clinical circumstances.
3. If a specific diagnosis is suspected,arrange for the appropriate diag-nostic studies to confirm includingsingle-gene tests or chromosomalmicroarray test.
4. If diagnosis is unknown and noclinical diagnosis is strongly sus-pected, begin the stepwise evalua-tion process:
a. Chromosomal microarray shouldbe performed in all.
b. Specific metabolic testing shouldbe considered and should in-clude serum total homocysteine,acyl-carnitine profile, amino acids;and urine organic acids, glycos-aminoglycans, oligosaccharides,purines, pyrimidines, GAA/creatinemetabolites.
c. Fragile X genetic testing shouldbe performed in all.
5. If no diagnosis is established:
a. Male gender and family historysuggestive X-linkage, completeXLID panel that contains genescausal of nonsyndromic XLID andcomplete high-density X-CMA. Con-sider X-inactivation skewing in themother of the proband.
b. Female gender: complete MECP2deletion, duplication, and sequenc-ing study.
6. If microcephaly, macrocephaly, orabnormal findings on neurologicexamination (focal motor findings,pyramidal signs, extrapyramidalsigns, intractable epilepsy, or focalseizures), perform brain MRI.
7. If brain MRI findings are negativeor normal, review status of diag-nostic evaluation with family andmedical home.
8. Consider referrals to other specialists,signs of inborn errors of metabolism
PEDIATRICS Volume 134, Number 3, September 2014 e913
FROM THE AMERICAN ACADEMY OF PEDIATRICS
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
for which screening has not yet beenperformed, etc.
9. If no further studies appear war-ranted, develop a plan with thefamily and medical home forneeded services for child and fam-ily; also develop a plan for diagnos-tic reevaluation.
THE SHARED EVALUATION ANDCARE PLAN FOR LIMITED ACCESS
Health care systems, processes, andoutcomes vary geographically, and notall of what is recommended in thisclinical report is easily accessible in allregions of the United States.21,81–84
Consequently, local factors affect the
process of evaluation and care. Thesearrangements are largely by localcustom or design. In some areas, theremay be quick access and intimate co-ordination between the medical homeand medical genetics specialist, but inother regions, access may be con-strained by distance or by decreasedcapacity, making for long wait times forappointments. Some general pedia-tricians have the ability to interpret theresults of genetic testing that they mayorder. In addition, children with GDD orID are often referred by pediatriciansto developmental pediatricians, childneurologists, or other subspecialists. Itis appropriate for some elements ofthe medical genetic evaluation to beperformed by physicians other thanmedical geneticists if they have theability to interpret the test results andprovide appropriate counseling to thefamilies. In such circumstances, thediagnostic evaluation process can bedesigned to address local particulari-ties. The medical home is responsiblefor referrals of the family and child tothe appropriate special education orearly developmental services profes-sional for individualized services. Inaddition, the medical home can beginthe process of the diagnostic evalua-tion if access is a problem and in co-ordination with colleagues in medicalgenetics.80,85 What follows is a sug-gested process for the evaluation bythe medical home and the medicalgenetics specialist and only applieswhere access is a problem; any suchprocess is better established with localparticularities in mind:
Medical home completes the medicalevaluation, determines that GDD/ID ispresent, counsels family, refers toeducational services, completes a 3-generation family history, and com-pletes the physical examination andaddresses the following questions:
1. Does the child have abnormalities onthe dysmorphologic examination?
FIGURE 1Diagnostic 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.
e914 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on March 23, 2019www.aappublications.org/newsDownloaded from
a. If no or uncertain, obtain micro-array, perform fragile X testing,and consider the metabolic test-ing listed previously. Confirmthat newborn screening wascompleted and reported nega-tive. Refer to medical geneticswhile testing is pending.
b. If yes, send case summary andclinical photo to medical geneticscenter for review for syndromeidentification. If diagnosis is sus-pected, arrange for expeditedmedical genetics referral andhold all testing listed above. Med-ical geneticist to arrange visitwith genetic counselor for testingfor suspected condition.
2. Does the child have microcephaly,macrocephaly, or abnormal neuro-logic examination (listed above)? If“yes,” measure parental head cir-cumferences and review the familyhistory for affected and unaffectedmembers. If normal head circum-ferences in both parents and neg-ative family history, obtain brainMRI and refer to medical genetics.
3. Does child also have features of au-tism, cerebral palsy, epilepsy, orsensory disorders (deafness, blind-ness)? This protocol does not ad-dress these patients; manage andrefer as per local circumstances.
4. As above are arranged and completedand negative, refer to medical ge-netics and hold on additional diag-nostic testing until consultationcompleted. Continue with currentmedical home family support ser-vices and health care.
5. Should a diagnosis be established,the medical home, medical geneti-cist, and family might then agree toa care plan with explicit roles andresponsibilities of all.
6. Should a diagnosis not be estab-lished by medical genetics consulta-tion, the medical home, family, and
medical geneticist can then agree onthe frequency and timing of diagnos-tic reevaluation while providing thefamily and child services needed.
EMERGING TECHNOLOGIES
Several research reports have citedwhole-exome sequencing and whole-genome sequencing in patients withknown clinical syndromes for whom thecausative gene was unknown. These re-search reports identified the causativegenes in patients with rare syndromes(eg, Miller syndrome,86 Charcot-Marie-Tooth disease,87 and a child with se-vere inflammatory bowel disease88).Applying similar whole-genome se-quencing of a family of 4 with 1 affectedindividual, Roach et al86 identified thegenes for Miller syndrome and primaryciliary dyskinesia. The ability to dowhole-genome sequencing and inter-pretation at an acceptable price is onthe horizon.87,89 The use of exome orwhole-genome sequencing challengesthe field of medical genetics in waysnot yet fully understood. When a childpresents with ID and whole-genome se-quencing is applied, one will identifymutations that are unrelated to thequestion being addressed, in this case“What is the cause of the child’s in-tellectual disability?” One assumes thatthis will include mutations that familiesdo not want to have (eg, adult-onsetdisorders for which no treatment nowexists). This is a sea change for the fieldof medical genetics, and the implicationsof this new technology have not beenfully explored. In addition, ethical issuesregarding validity of new tests, un-certainty, and use of resources will needto be addressed as these technologiesbecome available for clinical use.90,91
CONCLUSIONS
The medical genetic diagnostic evalu-ation of the child with GDD/ID is bestaccomplished in collaboration with themedical home and family by using this
clinical report to guide the process.The manner in which the elements ofthis clinical protocol are applied issubject to local circumstances, as wellas the decision-making by the involvedpediatric primary care provider andfamily. The goals and the process of thediagnostic evaluation are unchanged:to improve the health and well-being ofthose with GDD/ID. It is important toemphasize the new role of the genomicmicroarray as a first-line test, as wellas the renewal of efforts to identify thechild with an inborn error of metab-olism. The future use of whole-genomesequencing offers promise and chal-lenges needing to be addressed beforeregular implementation in the clinic.
LEAD AUTHORSJohn B. Moeschler, MD, MS, FAAP, FACMGMichael Shevell, MDCM, FRCP
AMERICAN ACADEMY OF PEDIATRICSCOMMITTEE ON GENETICS, 2013–2014Robert A. Saul, MD, FAAP, ChairpersonEmily Chen, MD, PhD, FAAPDebra L. Freedenberg, MD, FAAPRizwan Hamid, MD, FAAPMarilyn C. Jones, MD, FAAPJoan M. Stoler, MD, FAAPBeth Anne Tarini, MD, MS, FAAP
PAST COMMITTEE MEMBERSStephen R. Braddock, MDJohn B. Moeschler, MD, MS, FAAP, FACMG
CONTRIBUTORMichael Shevell, MDCM, FRCP
LIAISONSKatrina M. Dipple, MD, PhD – American Collegeof Medical GeneticsMelissa A. Parisi, MD, PhD – Eunice KennedyShriver National Institute of Child Health andHuman DevelopmentNancy Rose, MD – American College of Obste-tricians and GynecologistsJoan A. Scott, MS, CGC – Health Resources andServices Administration, Maternal and ChildHealth BureauStuart K. Shapira, MD, PhD – Centers for DiseaseControl and Prevention
STAFFPaul Spire
PEDIATRICS Volume 134, Number 3, September 2014 e915
FROM THE AMERICAN ACADEMY OF PEDIATRICS
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
REFERENCES
1. Moeschler JB, Shevell M; American Acad-emy of Pediatrics Committee on Genetics.Clinical genetic evaluation of the child withmental retardation or developmental delays.Pediatrics. 2006;117(6):2304–2316
2. Johnson CP, Myers SM; American Academyof Pediatrics Council on Children WithDisabilities. Identification and evaluation ofchildren with autism spectrum disorders.Pediatrics. 2007;120(5):1183–1215
3. Lopez-Rangel E, Mickelson E, Lewis MES. Thevalue of a genetic diagnosis for individualswith intellectual disabilities: optimising health-care and function across the lifespan. Br J DevDisabil. 2008;54(107 pt 2):69–82
4. Ronen GM, Fayed N, Rosenbaum PL. Out-comes in pediatric neurology: a review ofconceptual issues and recommendations.The 2010 Ronnie Mac Keith Lecture. DevMed Child Neurol. 2011;53(4):305–312
5. Rosenbaum PL. Prevention of psychosocialproblems in children with chronic illness.CMAJ. 1988;139(4):293–295
6. Makela NL, Birch PH, Friedman JM, MarraCA. Parental perceived value of a diagnosisfor intellectual disability (ID): a qualitativecomparison of families with and withouta diagnosis for their child’s ID. Am J MedGenet A. 2009;149A(11):2393–2402
7. Schalock RL, Luckasson RA, Shogren KA,et al. The renaming of mental retardation:understanding the change to the term in-tellectual disability. Intellect Dev Disabil.2007;45(2):116–124
8. Moeschler JB, Nisbeft J. Invited commenton terminology. Am J Med Genet A. 2011;155A(5):972–973
9. Centers for Disease Control and Pre-vention. Economic costs associated withmental retardation, cerebral palsy, hearingloss, and vision impairment—UnitedStates, 2003. MMWR Morb Mortal Wkly Rep.2004;53(3):57–59
10. Shevell M, Ashwal S, Donley D, et al; QualityStandards Subcommittee of the AmericanAcademy of Neurology; Practice Committeeof the Child Neurology Society. Practiceparameter: evaluation of the child withglobal developmental delay: report ofthe Quality Standards Subcommittee of theAmerican Academy of Neurology and ThePractice Committee of the Child NeurologySociety. Neurology. 2003;60(3):367–380
11. Schaefer GB, Bodensteiner JB. Evaluation ofthe child with idiopathic mental retardation.Pediatr Clin North Am. 1992;39(4):929–943
12. van Karnebeek CD, Jansweijer MC, LeendersAG, Offringa M, Hennekam RC. Diagnosticinvestigations in individuals with mental
retardation: a systematic literature reviewof their usefulness. Eur J Hum Genet. 2005;13(1):6–25
13. Van Karnebeek CS, Stockler IS. Evidence-based approach to identify treatable met-abolic diseases causing intellectual disability.Paper presented at: Annual Conference of theAmerican College of Medical Genetics; March11, 2011; Vancouver, BC, Canada
14. Manning M, Hudgins L; Professional Prac-tice and Guidelines Committee. Array-basedtechnology and recommendations for uti-lization in medical genetics practice fordetection of chromosomal abnormalities.Genet Med. 2010;12(11):742–745
15. Miller DT, Adam MP, Aradhya S, et al. Con-sensus statement: chromosomal micro-array is a first-tier clinical diagnostic testfor individuals with developmental dis-abilities or congenital anomalies. Am JHum Genet. 2010;86(5):749–764
16. Coulter ME, Miller DT, Harris DJ, et al.Chromosomal microarray testing influen-ces medical management. Genet Med. 2011;13(9):770–776
17. Nowakowska B, Stankiewicz P, Obersztyn E,et al. Application of metaphase HR-CGH andtargeted Chromosomal Microarray Analy-ses to genomic characterization of 116patients with mental retardation and dys-morphic features. Am J Med Genet A. 2008;146A(18):2361–2369
18. Pickering DL, Eudy JD, Olney AH, et al. Array-based comparative genomic hybridizationanalysis of 1176 consecutive clinical ge-netics investigations. Genet Med. 2008;10(4):262–266
19. Aradhya S, Manning MA, Splendore A,Cherry AM. Whole-genome array-CGH iden-tifies novel contiguous gene deletions andduplications associated with developmen-tal delay, mental retardation, and dysmor-phic features. Am J Med Genet A. 2007;143A(13):1431–1441
20. Adam MP, Justice AN, Schelley S, Kwan A,Hudgins L, Martin CL. Clinical utility of ar-ray comparative genomic hybridization:uncovering tumor susceptibility in individ-uals with developmental delay. J Pediatr.2009;154(1):143–146
21. Saul RA, Moeschler JB. How best to useCGH arrays in the clinical setting. GenetMed. 2009;11(5):371–, author reply 371–372
22. Bremer A, Giacobini M, Eriksson M, et al.Copy number variation characteristics insubpopulations of patients with autismspectrum disorders. Am J Med Genet BNeuropsychiatr Genet. 2011;156(2):115–124
23. Fan YS, Jayakar P, Zhu H, et al. Detection ofpathogenic gene copy number variations inpatients with mental retardation bygenomewide oligonucleotide array com-parative genomic hybridization. Hum Mutat.2007;28(11):1124–1132
24. Bar-Shira A, Rosner G, Rosner S, GoldsteinM, Orr-Urtreger A. Array-based compara-tive genome hybridization in clinical ge-netics. Pediatr Res. 2006;60(3):353–358
25. Vissers LE, de Vries BB, Veltman JA. Geno-mic microarrays in mental retardation:from copy number variation to gene, fromresearch to diagnosis. J Med Genet. 2010;47(5):289–297
26. Redon R, Ishikawa S, Fitch KR, et al. Globalvariation in copy number in the humangenome. Nature. 2006;444(7118):444–454
27. Iafrate AJ, Feuk L, Rivera MN, et al. Detectionof large-scale variation in the human ge-nome. Nat Genet. 2004;36(9):949–951
28. Michelson DJ, Shevell MI, Sherr EH,Moeschler JB, Gropman AL, Ashwal S. Evi-dence report: Genetic and metabolic test-ing on children with global developmentaldelay: report of the Quality StandardsSubcommittee of the American Academy ofNeurology and the Practice Committee ofthe Child Neurology Society. Neurology.2011;77(17):1629–1635
29. Taylor MR, Jirikowic J, Wells C, et al. Highprevalence of array comparative genomichybridization abnormalities in adults withunexplained intellectual disability. GenetMed. 2010;12(1):32–38
30. Whibley AC, Plagnol V, Tarpey PS, et al.Fine-scale survey of X chromosome copynumber variants and indels underlying in-tellectual disability. Am J Hum Genet. 2010;87(2):173–188
31. Hoyer J, Dreweke A, Becker C, et al. Mo-lecular karyotyping in patients with mentalretardation using 100K single-nucleotidepolymorphism arrays. J Med Genet. 2007;44(10):629–636
32. Lee C, Iafrate AJ, Brothman AR. Copy num-ber variations and clinical cytogenetic di-agnosis of constitutional disorders. NatGenet. 2007;39(suppl 7):S48–S54
33. Van Naarden Braun K, Yeargin-Allsopp M.Epidemiology of intellectual disabilities. In:Levene MI, Chervenak FA, eds. Fetal andNeonatal Neurology and Neurosurgery. 4thed . London: Elsevier; 2009:876–897
34. Tsuchiya KD, Shaffer LG, Aradhya S, et al.Variability in interpreting and reportingcopy number changes detected by array-based technology in clinical laboratories.Genet Med. 2009;11(12):866–873
e916 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on March 23, 2019www.aappublications.org/newsDownloaded from
35. Tucker T, Montpetit A, Chai D, et al. Com-parison of genome-wide array genomichybridization platforms for the detection ofcopy number variants in idiopathic mentalretardation. BMC Med Genomics. 2011;4:25
36. Kaminsky EB, Kaul V, Paschall J, et al. Anevidence-based approach to establish thefunctional and clinical significance of copynumber variants in intellectual and de-velopmental disabilities. Genet Med. 2011;13(9):777–784
37. Lion-François L, Cheillan D, Pitelet G, et al.High frequency of creatine deficiency syn-dromes in patients with unexplained mentalretardation. Neurology. 2006;67(9):1713–1714
38. Caldeira Araújo H, Smit W, Verhoeven NM,et al. Guanidinoacetate methyltransferasedeficiency identified in adults and a childwith mental retardation. Am J Med Genet A.2005;133A(2):122–127
39. Engbers HM, Berger R, van Hasselt P, et al.Yield of additional metabolic studies inneurodevelopmental disorders. Ann Neurol.2008;64(2):212–217
40. van Karnebeek CD, Scheper FY, Abeling NG,et al. Etiology of mental retardation inchildren referred to a tertiary care center:a prospective study. Am J Ment Retard.2005;110(4):253–267
41. van Karnebeek CD, Stockler S. Treatable in-born errors of metabolism causing in-tellectual disability: a systematic literaturereview. Mol Genet Metab. 2012;105(3):368–381
42. Arias A, Corbella M, Fons C, et al. Creatinetransporter deficiency: prevalence amongpatients with mental retardation and pit-falls in metabolite screening. Clin Biochem.2007;40(16–17):1328–1331
43. Clark AJ, Rosenberg EH, Almeida LS, et al.X-linked creatine transporter (SLC6A8) mu-tations in about 1% of males with mentalretardation of unknown etiology. Hum Genet.2006;119(6):604–610
44. Yeargin-Allsopp M, Murphy CC, Cordero JF,Decouflé P, Hollowell JG. Reported bio-medical causes and associated medicalconditions for mental retardation among10-year-old children, metropolitan Atlanta,1985 to 1987. Dev Med Child Neurol. 1997;39(3):142–149
45. Leonard H, Wen X. The epidemiology ofmental retardation: challenges and oppor-tunities in the new millennium. Ment Re-tard Dev Disabil Res Rev. 2002;8(3):117–134
46. Stevenson RE, Schwartz CE. X-linked in-tellectual disability: unique vulnerability ofthe male genome. Dev Disabil Res Rev.2009;15(4):361–368
47. Raymond FL. X linked mental retardation:a clinical guide. J Med Genet. 2006;43(3):193–200
48. Hersh JH, Saul RA; Committee on Genetics.Health supervision for children with fragile Xsyndrome. Pediatrics. 2011;127(5):994–1006
49. Stevenson RE, Schwartz CE. Clinical and mo-lecular contributions to the understanding ofX-linked mental retardation. Cytogenet Ge-nome Res. 2002;99(1–4):265–275
50. Chiurazzi P, Schwartz CE, Gecz J, Neri G.XLMR genes: update 2007. Eur J Hum Genet.2008;16(4):422–434
51. de Brouwer AP, Yntema HG, Kleefstra T,et al. Mutation frequencies of X-linkedmental retardation genes in families fromthe EuroMRX consortium. Hum Mutat. 2007;28(2):207–208
52. Tarpey PS, Smith R, Pleasance E, et al. Asystematic, large-scale resequencing screenof X-chromosome coding exons in mentalretardation. Nat Genet. 2009;41(5):535–543
53. Couvert P, Bienvenu T, Aquaviva C, et al.MECP2 is highly mutated in X-linked mentalretardation. Hum Mol Genet. 2001;10(9):941–946
54. Laccone F, Zoll B, Huppke P, Hanefeld F,Pepinski W, Trappe R. MECP2 gene nucleo-tide changes and their pathogenicity inmales: proceed with caution. J Med Genet.2002;39(8):586–588
55. Yntema HG, Kleefstra T, Oudakker AR, et al.Low frequency of MECP2 mutations inmentally retarded males. Eur J Hum Genet.2002;10(8):487–490
56. Bourdon V, Philippe C, Martin D, Verloès A,Grandemenge A, Jonveaux P. MECP2 muta-tions or polymorphisms in mentally re-tarded boys: diagnostic implications. MolDiagn. 2003;7(1):3–7
57. Kleefstra T, Yntema HG, Nillesen WM, et al.MECP2 analysis in mentally retardedpatients: implications for routine DNA diag-nostics. Eur J Hum Genet. 2004;12(1):24–28
58. dos Santos JM, Abdalla CB, Campos M, Jr,Santos-Rebouças CB, Pimentel MM. TheA140V mutation in the MECP2 gene is nota common etiological factor among Brazil-ian mentally retarded males. Neurosci Lett.2005;379(1):13–16
59. Ylisaukko-Oja T, Rehnström K, Vanhala R,et al. MECP2 mutation analysis in patientswith mental retardation. Am J Med Genet A.2005;132A(2):121–124
60. Donzel-Javouhey A, Thauvin-Robinet C,Cusin V, et al. A new cohort of MECP2 mu-tation screening in unexplained mentalretardation: careful re-evaluation is thebest indicator for molecular diagnosis. AmJ Med Genet A. 2006;140(14):1603–1607
61. Tejada MI, Peñagarikano O, Rodriguez-Revenga L, et al. Screening for MECP2mutations in Spanish patients with an un-
explained mental retardation. Clin Genet.2006;70(2):140–144
62. Campos M, Jr, Abdalla CB, Santos-RebouçasCB, et al. Low significance of MECP2 muta-tions as a cause of mental retardation inBrazilian males. Brain Dev. 2007;29(5):293–297
63. Schaefer GB, Bodensteiner JB. Radiologicalfindings in developmental delay. SeminPediatr Neurol. 1998;5(1):33–38
64. Moeschler JB, Bennett FC, Cromwell LD. Useof the CT scan in the medical evaluation ofthe mentally retarded child. J Pediatr. 1981;98(1):63–65
65. Lingam S, Read S, Holland IM, Wilson J,Brett EM, Hoare RD. Value of computerisedtomography in children with non-specificmental subnormally. Arch Dis Child. 1982;57(5):381–383
66. Gabrielli O, Salvolini U, Coppa GV, et al.Magnetic resonance imaging in the mal-formative syndromes with mental re-tardation. Pediatr Radiol. 1990;21(1):16–19
67. Majnemer A, Shevell MI. Diagnostic yield ofthe neurologic assessment of the de-velopmentally delayed child. J Pediatr.1995;127(2):193–199
68. Shevell MI, Majnemer A, Rosenbaum P,Abrahamowicz M. Etiologic yield of sub-specialists’ evaluation of young childrenwith global developmental delay. J Pediatr.2000;136(5):593–598
69. Demaerel P, Kingsley DP, Kendall BE. Iso-lated neurodevelopmental delay in child-hood: clinicoradiological correlation in 170patients. Pediatr Radiol. 1993;23(1):29–33
70. Griffiths PD, Batty R, Warren D, et al The useof MR imaging and spectroscopy of thebrain in children investigated for de-velopmental delay: what is the most ap-propriate imaging strategy? Eur Radiol.2011;21(9):1820–1830
71. Verbruggen KT, Meiners LC, Sijens PE,Lunsing RJ, van Spronsen FJ, Brouwer OF.Magnetic resonance imaging and protonmagnetic resonance spectroscopy of thebrain in the diagnostic evaluation of de-velopmental delay. Eur J Paediatr Neurol.2009;13(2):181–190
72. Kjos BO, Umansky R, Barkovich AJ. BrainMR imaging in children with developmentalretardation of unknown cause: results in76 cases. AJNR Am J Neuroradiol. 1990;11(5):1035–1040
73. Bouhadiba Z, Dacher J, Monroc M, Vanhulle C,Ménard JF, Kalifa G. [MRI of the brain in theevaluation of children with developmentaldelay]. J Radiol. 2000;81(8):870–873
74. Hunter AG. Outcome of the routine assess-ment of patients with mental retardation ina genetics clinic. Am J Med Genet. 2000;90(1):60–68
PEDIATRICS Volume 134, Number 3, September 2014 e917
FROM THE AMERICAN ACADEMY OF PEDIATRICS
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
75. Harbord MG, Finn JP, Hall-Craggs MA, RobbSA, Kendall BE, Boyd SG. Myelination pat-terns on magnetic resonance of childrenwith developmental delay. Dev Med ChildNeurol. 1990;32(4):295–303
76. Strømme P. Aetiology in severe and mildmental retardation: a population-based studyof Norwegian children. Dev Med Child Neurol.2000;42(2):76–86
77. Martin E, Keller M, Ritter S, Largo RH, Thiel T,Loenneker T. Contribution of proton magneticresonance spectroscopy to the evaluation ofchildren with unexplained developmental de-lay. Pediatr Res. 2005;58(4):754–760
78. Wilder RT, Flick RP, Sprung J, et al. Earlyexposure to anesthesia and learning dis-abilities in a population-based birth cohort.Anesthesiology. 2009;110(4):796–804
79. Sprung J, Flick RP, Katusic SK, et al. Attention-deficit/hyperactivity disorder after earlyexposure to procedures requiring generalanesthesia. Mayo Clin Proc. 2012;87(2):120–129
80. Turchi RM, Berhane Z, Bethell C, Pomponio A,Antonelli R, Minkovitz CS. Care coordination
for CSHCN: associations with family-providerrelations and family/child outcomes. Pediat-rics. 2009;124(suppl 4):S428–S434
81. Shipman SA, Lan J, Chang CH, Goodman DC.Geographic maldistribution of primary carefor children. Pediatrics. 2011;127(1):19–27
82. McGrath RJ, Laflamme DJ, Schwartz AP,Stransky M, Moeschler JB. Access to geneticcounseling for children with autism, Downsyndrome, and intellectual disabilities. Pedi-atrics. 2009;124(suppl 4):S443–S449
83. Hawkins AK, Hayden MR. A grand challenge:providing benefits of clinical genetics to thosein need. Genet Med. 2011;13(3):197–200
84. Ledbetter DH. Cytogenetic technology—genotype and phenotype. N Engl J Med. 2008;359(16):1728–1730
85. Cooley WC. Redefining primary pediatriccare for children with special health careneeds: the primary care medical home.Curr Opin Pediatr. 2004;16(6):689–692
86. Roach JC, Glusman G, Smit AF, et al. Anal-ysis of genetic inheritance in a family
quartet by whole-genome sequencing. Sci-ence. 2010;328(5978):636–639
87. Lupski JR, Reid JG, Gonzaga-Jauregui C,et al. Whole-genome sequencing in a pa-tient with Charcot-Marie-Tooth neuropathy.N Engl J Med. 2010;362(13):1181–1191
88. Worthey EA, Mayer AN, Syverson GD, et al.Making a definitive diagnosis: successfulclinical application of whole exome se-quencing in a child with intractable in-flammatory bowel disease. Genet Med.2011;13(3):255–262
89. Bamshad MJ, Ng SB, Bigham AW, et al.Exome sequencing as a tool for Mendeliandisease gene discovery. Nat Rev Genet.2011;12(11):745–755
90. Jacob HJ. Next-generation sequencing forclinical diagnostics. N Engl J Med. 2013;369(16):1557–1558
91. Yang Y, Muzny DM, Reid JG, et al. Clinicalwhole-exome sequencing for the diagnosisof Mendelian disorders. N Engl J Med. 2013;369(16):1502–1511
e918 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on March 23, 2019www.aappublications.org/newsDownloaded from
originally published online August 25, 2014; Pediatrics John B. Moeschler, Michael Shevell and COMMITTEE ON GENETICS
Developmental DelaysComprehensive Evaluation of the Child With Intellectual Disability or Global
ServicesUpdated Information &
014-1839http://pediatrics.aappublications.org/content/early/2014/08/19/peds.2including high resolution figures, can be found at:
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtmlin its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or
Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
originally published online August 25, 2014; Pediatrics John B. Moeschler, Michael Shevell and COMMITTEE ON GENETICS
Developmental DelaysComprehensive Evaluation of the Child With Intellectual Disability or Global
http://pediatrics.aappublications.org/content/early/2014/08/19/peds.2014-1839located on the World Wide Web at:
The online version of this article, along with updated information and services, is
ISSN: 1073-0397. 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
by guest on March 23, 2019www.aappublications.org/newsDownloaded from
top related