Global Developmental Delay Evaluation: Evidence-based Approach

Case

The parents of a 9-month old boy are concerned because he is unable to sit without support, does not actively reach for objects, and coos but does not babble. How would you evaluate this patient?

Definitions

  1. Significant developmental delay: defined as performance at least 2 SD’s below the age-appropriate mean in at least one of the following categories on the Denver Developmental Scale: gross/fine motor, speech/language, cognition, social/personal, and activities of daily living.
    1. Isolated delay in social/language development is characteristic of autism spectrum disorders or hearing loss.
    2. Isolated delay in motor development is characteristic of cerebral palsy (a static encephalopathy) or myopathy.
  2. Global developmental delay (GDD): a subset of DD defined as significant delay (by at least 2 SD’s) in two or more developmental categories.
    1. Note that the term “GDD” is usually reserved for children <5 y.o., while the term “mental retardation” is applied to older children >5 y.o, when MR severity is quantifiable with IQ testing.

Introduction

Developmental disabilities are relatively common in children, with a 5-10% prevalence. GDD is estimated to be prevalent in 1-3% children < 5 y.o, and it is estimated that between 40,000 - 120,000 children born each year in the U.S. and Canada will manifest GDD. There are many possible causes for the clinical picture of GDD and some causes are treatable. Therefore, early recognition and diagnosis is important. In addition, some of the etiologies are genetically transmitted and may affect future family members. An underlying etiology can be identified in approx 25% of cases of developmental delay, with higher rates (50%) in GDD and motor delays, and lower rates (<5%) in children with isolated language disorders.

Etiologies of GDD

  1. Genetic causes:
    1. Metabolic disorders, i.e. storage diseases, PKU, urea cycle disorders, etc. - normally picked up on newborn screening.
    2. Down syndrome (trisomy 21)
    3. Fragile X syndrome (FMR1 gene, CGG triplet repeat expansion, X-linked inheritance): arguably the most common cause of male GDD/MR after Down syndrome, but female sibs may also be affected; typical phenotype includes MR, long face, prominent ears and jaw, macroorchidism after puberty, hyperactivity, poor eye contact, and withdrawn social behavior.
    4. Rett syndrome (MECP2 gene mutation): arguably the most common cause of female GDD/MR after Down syndrome; typical history includes normal development up to 6-18 mo, then gradual loss of speech and purposeful hand use, deceleration of head growth/microcephaly, seizures, ataxia, autistic behavior, and stereotypic hand movements.
    5. 22q11 deletion syndrome, i.e. DiGeorge syndrome and velocardiofacial syndrome - typical features may include abnormal facies, cleft lip/palate, cardiac defects, recurrent infections due to lack of thymus, and hypocalcemia from hypoparathyroidism.
    6. Prader-Willi and Angelman syndromes
    7. Neurocutaneous syndromes, i.e. neurofibromatosis type I, tuberous sclerosis
    8. Leukodystrophy
  2. Acquired causes:
    1. Prenatal or perinatal causes:
      1. Exposure to teratogens or toxins (tobacco, alcohol, illicit drugs)
      2. Intrapartum asphyxia
      3. Prematurity
      4. Congenital infections
      5. Congenital hypothyroidism - normally picked up on newborn screening.
      6. Birth trauma
      7. Intracranial hemorrhage
    2. Postnatal causes:
      1. Infection (meningitis, encephalitis)
      2. Cranial trauma
      3. Environmental causes, i.e. poor nutrition, family stress, child abuse or neglect, severe poverty
      4. **Note that low-level lead poisoning is NOT associated with GDD although it may cause some cognitive deficits

Initial evaluation of GDD

  1. History:
    1. Obtain a comprehensive family history
      1. Ask about specific examples of neurologic disorders (i.e. epilepsy, mental retardation), any history of miscarriages or infant deaths, and any consanguinity in family.
    2. Construct a pedigree of at least 3 generations
    3. Obtain an accurate prenatal and birth history
      1. Include questions about: pregnancy complications; maternal medical conditions; maternal use of medications, alcohol, tobacco, and illicit drug use during pregnancy; preterm or term labor; any complications during delivery; Apgar scores; duration of postnatal hospital stay.
    4. Postnatal medical history
      1. Any hospitalizations, surgeries, medical conditions, current medication use; any seizures or feeding difficulties
    5. Social history
    6. Developmental history
      1. Assess the child’s developmental progress in each of the Denver Developmental Scale categories
      2. Specifically ask about any loss of milestones or developmental regression (could suggest neurodegenerative or metabolic disorder)
      3. Also ask specifically about the presence of any autistic features, i.e. poor eye contact, repetitive behaviors, or lack of appropriate social interaction.
      4. Ask about any co-existing behaviors, such as epilepsy, sleep disturbances, behavioral problems, and feeding difficulties.
  2. Physical exam:
    1. Weight and height (also look at growth charts) - for growth deficiency
    2. Head circumference - for microcephaly or macrocephaly
    3. Look for dysmorphic features - i.e. coarse facies, low-set ears, upslanting palpebral fissures
    4. Skin exam - for neurocutaneous lesions such as cafe-au-lait spots (neurofibromatosis) or hypopigmented “ash leaf spots” (tuberous sclerosis); findings over the spine/lower back can suggest spinal dysraphism
    5. Abdominal exam - for HSM (seen in storage disorders)
    6. Neurologic exam - for reflexes, tone, symmetry, strength
    7. Also observe the child’s spontaneous interaction with the environment and exploration of play opportunities
  3. Testing: (according to guidelines from the American Academy of Neurology and Child Neurology Society)
    1. Cytogenetic testing (high-resolution karyotyping) - routine testing is recommended even if dysmorphic and specific syndrome features are absent.
    2. Fragile X testing (FMR1 triplet repeat analysis) - recommended for both males and females, especially if there is a family history of developmental delay.
      1. 7 specific findings on history and exam increase diagnostic yield for Fragile X testing significantly:
        • Family hx of mental retardation
        • Long jaw or high forehead
        • Large or protuberant ears
        • Hyperextensible joints
        • Soft palmar skin
        • Large testes
        • Initial shyness followed by extreme verbosity
    3. Rett syndrome testing (testing for MECP2 gene deletion) - should be considered in females with unexplained moderate to severe mental retardation.
    4. Fluorescence In Situ Hybridization (FISH) to assess for subtelomeric abnormalities - may be considered in children with unexplained moderate or severe developmental delay.
    5. Metabolic screening - routine screening is NOT indicated unless newborn screening was not performed, the results of the newborn screen are unavailable, or there are historical or PE findings that suggest a metabolic disorder (i.e. consanguinity in family, family history of child loss, developmental regression, coarse facies, HSM).
    6. Neuroimaging - recommended in the initial evaluation of GDD, esp if physical findings are present (i.e. microcephaly, focal motor findings). If available, MRI is preferred to CT scan.
    7. EEG - only indicated if there is clinical evidence of seizures or epilepsy.
    8. Lead screening - only indicated if child has known identifiable risk factors for excessive lead exposure (low SES, housing built before 1950, developmentally delayed with oral affinity, children whose parents are exposed).
    9. Thyroid screening - only indicated if newborn screening was not performed or there are systemic features suggestive of thyroid dysfunction.
    10. Hearing and vision testing - recommended for all children with GDD, as they are more likely to have deficits than healthy kids, and these sensory deficits are likely to confound the picture of GDD.
    11. Autism or language disorder screening

***Summary Chart from American Academy of Neurology Practice Parameter:

http://www.neurology.org/content/vol60/issue3/images/large/6FF1.jpeg

Treatment

  1. Treat underlying cause of GDD if possible (i.e. thyroid hormone for congenital hypothyroidism)
  2. Enroll child in Early Intervention program
  3. Develop an individual family service plan (IFSP) if child is <3 y.o., or an individualized education plan (IEP) if child is older.
  4. Provide supportive services: physical therapy, occupational therapy, speech and language

References

  1. Shevell M. et al. Practice Parameter: Evaluation of the child with global developmental delay. Neurology February 2003
  2. Roberts G. et al. A rational approach to the medical evaluation of a child with developmental delay. Contemporary Pediatrics March 2004
  3. Committee on Genetics.  Clinical Genetic Evaluation of the Child with Mental Retardation or Developmenbtal Delays.  Pediatrics June 2006
  4. Srour M. et al. Analysis of Clinical Features Predicting Etiologic Yield in the Assessment of Global Developmental Delay. Pediatrics July 2006
  5. American Academy of Neurology. Evaluation of the Child with Global Developmental Delay
  6. Michaelson D.J. et al.  Genetic and Metabolic Testing on Children with Global  Developmental Delay.  Neurology 2011 

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