Definitions of the ratings of recommendations (A, B, C, U), translation of evidence to recommendations (A-C), and the classification scheme for a diagnostic article (Class I-IV) are provided at the end of the "Major Recommendations" field.
Recommendations
What is the diagnostic yield of metabolic genetic investigations in children with global developmental delay?
Recommendations
- Given the low yield of about 1%, routine metabolic screening for inborn errors of metabolism is not indicated in the initial evaluation of a child with global developmental delay provided that universal newborn screening was performed and the results are available for review. Metabolic testing may be pursued in the context of historical (parental consanguinity, family history, developmental regression, episodic decompensation) or physical examination findings that are suggestive of a specific etiology (or in the context of relatively homogeneous population groups) in which the yield approaches 5% (Level B recommendation; Class II and III evidence). If newborn screening was not performed, if it is uncertain whether a patient had testing, or if the results are unavailable, metabolic screening should be obtained in a child with global developmental delay.
- Routine cytogenetic testing (yield of 3.7%) is indicated in the evaluation of the child with developmental delay, even in the absence of dysmorphic features or clinical features suggestive of a specific syndrome (Level B recommendation; Class II and III evidence).
- Testing for the fragile X mutation (yield of 2.6%), particularly in the presence of a family history of developmental delay, may be considered in the evaluation of the child with global developmental delay. Clinical preselection may narrow the focus of who should be tested without sacrificing diagnostic yield. Although screening for fragile X is more commonly done in males because of the higher incidence and greater severity, females are frequently affected and may also be considered for testing. Because siblings of fragile X patients are at greater risk to be symptomatic or asymptomatic carriers, they can also be screened (Level B recommendation; Class II and Class III evidence).
- The diagnosis of Rett syndrome should be considered in females with unexplained moderate to severe mental retardation. If clinically indicated, testing for the MECP2 gene deletion may be obtained. Insufficient evidence exists to recommend testing of females with milder clinical phenotypes or males with moderate or severe developmental delay (Level B recommendation; Class II and Class III evidence).
- In children with unexplained moderate or severe developmental delay, additional testing using newer molecular techniques (e.g., fluorescence in situ hybridization [FISH], microsatellite markers) to assess for subtelomeric chromosomal rearrangements (6.6%) may be considered (Level B recommendation; Class II and Class III evidence).
What is the role of lead and thyroid screening in children with global developmental delay?
Recommendations
- Screening of children with developmental delay for lead toxicity may be targeted to those with known identifiable risk factors for excessive environmental lead exposure as per established current guidelines (Level B recommendation; Class II evidence).
- In the setting of existing newborn screening programs for congenital hypothyroidism, screening of children with developmental delay with thyroid function studies is not indicated unless there are systemic features suggestive of thyroid dysfunction (Level B recommendation; Class II evidence).
What is the diagnostic yield of electroencephalogram (EEG) in children with global developmental delay?
Recommendations
- An electroencephalogram can be obtained when a child with global developmental delay has a history or examination features suggesting the presence of epilepsy or a specific epileptic syndrome (Level C recommendation; Class III and IV evidence).
- Data are insufficient to permit making a recommendation regarding the role of electroencephalogram in a child with global developmental delay in whom there is no clinical evidence of epilepsy (Level U recommendation; Class III and IV evidence).
What is the diagnostic yield of neuroimaging in children with global developmental delay?
Recommendations
- Neuroimaging is recommended as part of the diagnostic evaluation of the child with global developmental delay (Level B recommendation; Class III evidence). As the presence of physical findings (e.g., microcephaly, focal motor findings) increases the yield of making a specific neuroimaging diagnosis, physicians can more readily consider obtaining a scan in this population (Level C recommendation; Class III evidence).
- If available, magnetic resonance imaging (MRI) should be obtained in preference to computed tomography (CT) scanning when a clinical decision has been made that neuroimaging is indicated (Level C recommendation; Class III evidence).
Are vision and hearing disorders common in children with global developmental delay?
Recommendations
- Children with global developmental delay may undergo appropriate vision and audiometric assessment at the time of their diagnosis (Level C recommendation; Class III evidence).
- Vision assessment can include vision screening and a full ophthalmologic examination (visual acuity, extraoculo-movements, fundoscopic) (Level C recommendation; Class III evidence).
- Audiometric assessment can include behavioral audiometry or brainstem auditory evoked response testing when feasible (Level C recommendation; Class III evidence). Early evidence from screening studies suggests that transient evoked otoacoustic emissions should offer an alternative when audiometry is not feasible (Level A recommendation; Class I and II evidence).
Recommendations for a Staged Approach to the Evaluation of the Child with Global Developmental Delay
Although there is insufficient evidence to recommend the optimal sequence of tests to determine the etiology of global developmental delay, taking into account diagnostic yield and potential treatability, the guideline committee members propose the following consensus-based schedule of testing as outlined in the algorithm in the original guideline document. Consensus-based recommendations relate to the order and timing of testing but not to the relative diagnostic yield of the specific tests themselves (refer to table 5 titled "Diagnostic yield of tests in children with global developmental delay" in the original guideline document).
All children should undergo a detailed history and physical examination, which may in itself suggest specific diagnostic possibilities. For all children with global developmental delay, auditory and visual integrity should be ascertained. If a child was born in a locale without universal newborn screening, a screening metabolic evaluation including capillary blood gas, serum lactate and ammonia levels, serum amino acids and urine organic acids, and thyroid function studies (thyroxine [T4] and thyroid stimulating hormone) may be considered. If a history of events suggestive of possible seizures, paroxysmal behaviors, or an underlying epilepsy syndrome is elicited, one can consider an electroencephalogram. In addition, screening for autism or a language disorder should be considered in any child presenting with global developmental delay (GDD). If there is a family history of a close family member (sibling, aunt/uncle, or first cousin) with global developmental delay on a known basis, testing specific for the known disorder may be ordered. When there is a family history of unexplained developmental delay, cytogenetic testing (which may include testing for subtelomeric rearrangements) may be obtained.
In the absence of a familial history of global developmental delay, specific historical or physical findings can be utilized to direct testing. Observed dysmorphic features may prompt specific testing for such entities as Down syndrome (karyotype), fragile X (FMR1), Rett syndrome (MECP2), Prader-Willi/Angelman (FISH), or hypothyroidism. Historical documentation of intrapartum asphyxia or ascertainment of physical findings such as microcephaly, cerebral palsy, or focal findings or focal seizures may suggest acquired central nervous system (CNS) injury or an underlying cerebral malformation and thus prompt neuroimaging study (magnetic resonance imaging preferable to computed tomography). Risk factors for lead exposure or findings suggestive of lead intoxication mandate lead screening.
Parental consanguinity, documentation of loss or regression of developmental milestones, or unexplained prior parental loss of a child are likely to be caused by a definable disease process and thus a comprehensive evaluation may be considered. This can include careful metabolic evaluation together with neuroimaging studies, electroencephalogram, cytogenetic studies, and genetic and ophthalmologic consultations.
The absence of any clinical features that suggest a specific diagnosis is less likely to be associated with a definable disease and thus a stepwise approach is recommended. This may include initial neuroimaging (magnetic resonance imaging preferred) and cytogenetic and fragile X screening. If these tests are negative, consideration may be given to metabolic evaluation, testing for subtelomeric rearrangements, and genetic consultation.
Definitions:
Evidence Classification Scheme for a Diagnostic Article
Class I: Evidence provided by a prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.
Class II: Evidence provided by a prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriated tests of diagnostic accuracy.
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation.
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).
Translation of Evidence to Recommendations
Level A rating requires at least one convincing Class I study or at least two consistent, convincing Class II studies.
Level B rating requires at least one convincing Class II study or overwhelming Class III evidence.
Level C rating requires at least two convincing Class III studies.
Rating of Recommendation
A = established as effective, ineffective, or harmful for the given condition in the specified population.
B = probably effective, ineffective, or harmful for the given condition in the specified population.
C = possibly effective, ineffective, or harmful for the given condition in the specified population.
U = data inadequate or conflicting. Given current knowledge, treatment is unproven.
