DESCRIPTION

• Microcephaly is a descriptive term denoting that the head is significantly smaller than expected, and it encompasses a broad range of etiologies.
• There is no consensus on the definition of microcephaly. The American Academy of Neurology and the Child Neurology Society defines microcephaly as a head circumference which is ≥2 standard deviations below the mean for age and sex, whereas other experts define it as ≥3 standard deviations below.
• Microcephaly is classified as congenital if it is present at birth, and postnatal if developed later. Postnatal microcephaly usually presents in the first 2 years of life, during which brain growth is most rapid. Postnatal microcephaly may result from abnormal neurodevelopment or early-onset neurodegenerative process.
• Either type of microcephaly may be due to genetic or nongenetic causes.

EPIDEMIOLOGY

• Found in both sexes and all racial and socioeconomic groups
• Reported incidence of microcephaly ranges from 1 in 200 to 1 in 5,000 live births, depending on the definition used.

ETIOLOGY

Specific causes are numerous. A partial list of the more common causes is presented.

• Genetic: There are >1,000 disorders associated with microcephaly. Among of the cases with known causes, genetic etiologies account for about half.
  • Syndromes
    • Congenital microcephaly
      • Down syndrome (trisomy 21)
      • Edwards syndrome (trisomy 18)
      • Patau syndrome (trisomy 13)
      • Smith-Lemli-Opitz syndrome
      • Cornelia de Lange syndrome
      • Cri-du-Chat (5p) syndrome
      • Wolf-Hirschhorn (4p) syndrome
    • Postnatal microcephaly
      • Angelman syndrome (most common syndrome of progressive microcephaly)
      • Rett syndrome
      • Williams syndrome
  • Familial (not associated with other comorbidities)
    • Autosomal recessive microcephaly
    • Autosomal dominant microcephaly
    • X-linked microcephaly
  • Inborn errors of metabolism account for 1–5% of all children with microcephaly. Microcephaly associated with metabolic disorders is more likely to be postnatal-onset rather than congenital.
• Nongenetic
  • Congenital infections
    • Zika virus
    • Cytomegalovirus (CMV)
    • Toxoplasmosis
    • Rubella
    • Varicella-zoster
    • Syphilis
    • HIV
    • Herpes simplex virus (HSV)
  • Other in utero exposures:
    • Maternal exposures to alcohol, cocaine, or certain antiseizure drugs (e.g., phenytoin, valproic acid)
    • Maternal hyperphenylalaninemia
    • Poorly controlled maternal diabetes
    • Radiation
  • Perinatal and postnatal brain injury
    • Meningitis
    • Encephalitis
    • Hypoxic-ischemic encephalopathy
    • Intraventricular hemorrhage
    • Traumatic brain injury
    • Hemorrhagic/ischemic insult
• Craniosynostosis: Premature closure of all cranial sutures can lead to microcephaly.
  • Isolated
  • Syndromic
    • Crouzon syndrome
    • Apert syndrome
• Idiopathic in up to 40% of children with microcephaly

RISK FACTORS

• Intrauterine insults such as infections (such as Zika virus and CMV) and exposure to drugs (such as cocaine)
• Perinatal infections (such as HSV) and postnatal infections (such as meningitis)
• Severe hypoxic-ischemic encephalopathy
• Family history of microcephaly
• Family history of consanguinity for certain autosomal recessive disorders

GENERAL PREVENTION

There is no known prevention of microcephaly itself other than prevention and treatment of some of the underlying causes (e.g., preventing infections, perinatal hypoxic injury, in utero exposures to drugs or toxins).

PATHOPHYSIOLOGY

• The pathophysiology depends on the underlying etiology.
• Congenital microcephaly may be secondary to abnormal development of the neurons in utero, leading to a small head circumference at birth.
• Postnatal-onset microcephaly may be secondary to perinatal insults to the CNS during a critical period of time of brain growth. It is often associated with neurodegenerative process resulting in neuronal loss and gliosis.

COMMONLY ASSOCIATED CONDITIONS

Some etiologies of microcephaly are associated with:

• Developmental delay and intellectual disability
• Epilepsy
• Cerebral palsy
• Hearing loss
• Ophthalmologic abnormalities

HISTORY

Detailed history should be taken and be guided by the suspected etiologies. In particular, consider the following elements:

• Prenatal history
  • Maternal health and medical diagnoses
  • Maternal exposures
  • Maternal irradiation
  • Maternal travel history
  • Prenatal serologies
  • Ultrasound findings
  • Genetic screening
• Birth history
  • Gestational age at delivery
  • Weight, length, and head circumference at birth
  • Hypoxia-ischemia, infections, and other perinatal complications
  • Newborn screening results
• Past medical history
  • CNS infections
  • Seizures
  • Head trauma
  • Prior neuroimaging
• Developmental history
  • Gross and fine motor, language, personal–social milestones
  • Developmental regression
• Review of systems
  • Feeding difficulties
  • Poor weight gain
  • Hearing issues
  • Vision issues
• Family history
  • Consanguinity
  • Recurrent miscarriages
  • Microcephaly
  • Developmental delays or intellectual disabilities
  • Neurologic disorders such as epilepsy with maternal exposure to antiseizure medications
  • Genetic syndromes
  • Inborn errors of metabolism

PHYSICAL EXAM

Thorough physical examination should be performed and be guided by the suspected etiologies. In particular, consider the following elements:

• Growth parameters
  • Weight
  • Length
  • Head circumference: Head circumference should be measured accurately by pulling a nonstretchable measuring tape tightly across the most prominent parts of the head from the occiput to supraorbital ridge. The trend of serial head circumference measurements over time is more meaningful than a single measurement.
  • Obtain the head circumference of parents and siblings if possible and compare with the patient’s head circumference percentile.
• Skull
  • Shape: symmetry
  • Sutures: bony ridges
  • Fontanelles
• Features of genetic syndromes
  • Characteristic facial features
  • Ocular
  • Cardiac
  • Genitourinary
  • Limbs, digits
  • Skin lesions such as café-au-lait spots or hypopigmented lesions
• Neurologic assessment
  • Developmental level
  • Cranial nerves
  • Tone
  • Strength
  • Persistence of primitive reflexes
  • Deep tendon reflexes
  • Sensation
  • Abnormal movements such as choreiform movements and hand wringing
• Other features of congenital infections in neonates
  • Rash
  • Hepatosplenomegaly

DIAGNOSTIC TESTS & INTERPRETATION

GENERAL MEASURES

• Treatment should be tailored to the underlying disorder if identified.
• Presently, there is no curative treatment for microcephaly itself. Individualized, multidisciplinary supportive care should be aimed at optimizing function and minimizing comorbidities.

FOLLOW-UP RECOMMENDATIONS

PATIENT EDUCATION

Monitor for signs and symptoms of seizures.

PROGNOSIS

Overall prognosis depends on the underlying etiology, severity, and comorbidities. Acquired microcephaly is often associated with a progressive disease which will be the major determinant of the outcome. Children with more severe microcephaly generally have a worse prognosis in terms of long-term neurologic function including intellectual disabilities, autistic features, motor deficits, and epilepsy.