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Microcephaly

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Neurological Presentations/Head size and structure

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Occipitofrontal head circumference more than 2 SD below the mean for age and sex (some sources use −3 SD for "severe"). Primary microcephaly is present at birth and reflects abnormal brain growth in utero; secondary microcephaly evolves postnatally and reflects a brain that started normal-sized but failed to grow. Distinguishing the two on the curve is the single most important first move.

The first split is timing:

  1. Microcephaly at birth (primary): the insult or genetic program affected fetal neurogenesis. Think congenital infection, teratogen, primary microcephaly genes (the MCPH family), holoprosencephaly, chromosomal.
  2. Microcephaly evolving postnatally (secondary): the brain stopped growing. Think Rett, Angelman, leukodystrophies, hypoxic-ischemic injury, metabolic / mitochondrial disease, neurodegeneration.

Then layer on proportionality: head circumference small and tracking with weight/length (proportionate, often syndromic or constitutional) versus head circumference disproportionately small for body (worse signal). And family history: a small head in a normally-developing child of small-headed parents is often benign familial.

Congenital (primary microcephaly)

Infectious / environmental (the TORCH-Z framework)

  • Cytomegalovirus (CMV): most common congenital infection cause of microcephaly. Periventricular calcifications, sensorineural hearing loss, chorioretinitis.
  • Zika virus: brain calcifications at the gray-white junction (CMV calcifications are periventricular), cerebellar hypoplasia, arthrogryposis.
  • Toxoplasmosis: diffuse intracranial calcifications, chorioretinitis, hydrocephalus (paradoxically can be macro).
  • Rubella, herpes: less common now.
  • Fetal alcohol spectrum: microcephaly + smooth philtrum + thin upper lip + small palpebral fissures. Ask the history.

Chromosomal

Primary microcephaly genes (MCPH family)

  • MCPH1, ASPM, WDR62, CDK5RAP2, CENPJ, others. Severe microcephaly at birth, often with proportionate body size, intact basic brain architecture but reduced cortical volume. Mostly AR.

Severe pre- and postnatal growth failure with microcephaly

  • Seckel syndrome, MOPD II (PCNT): severe pre- and postnatal growth failure + severe microcephaly + skeletal dysplasia. (MOPD II remains the established acronym for this entity in the literature.)

Brain malformation syndromes

  • Holoprosencephaly: failure of midline forebrain cleavage. SHH, ZIC2, SIX3, TGIF1.
  • Lissencephaly / migration disorders: LIS1, DCX, RELN.

Postnatal (secondary microcephaly)

Acquired brain injury

  • Hypoxic-ischemic encephalopathy: birth history is key.
  • Stroke, meningitis, traumatic injury.

Neurogenetic / neurodegenerative

  • Rett syndrome (MECP2): normal head at birth, deceleration starts ~6 months, regression of hand use, stereotypies, breathing dysrhythmia. Almost always female.
  • Angelman syndrome (15q11-q13 maternal): microcephaly + happy demeanor + ataxic gait + seizures.
  • Mowat-Wilson syndrome (ZEB2): microcephaly + Hirschsprung + distinctive facies.

Metabolic / mitochondrial

  • PKU and other amino acidopathies (untreated): microcephaly is preventable with newborn screening.
  • Mitochondrial disease, including Leigh.

Leukodystrophies (progressive)

  • Krabbe, MLD, Alexander: secondary microcephaly + regression.

Skeletal (small skull, normal brain)

  • Craniosynostosis (multiple sutures): the skull is too small but the brain may be normal. Suspicious for syndromic synostosis (Apert, Crouzon, Pfeiffer) which have hand/face findings.
  • Microcephaly + periventricular calcifications + SNHL → congenital CMV.
  • Microcephaly + cortical calcifications + Brazilian mother → congenital Zika.
  • Microcephaly + smooth philtrum + thin upper lip → fetal alcohol spectrum.
  • Microcephaly + deceleration after 6 months + hand stereotypies in a girl → Rett.
  • Microcephaly + Hirschsprung + characteristic uplifted earlobes → Mowat-Wilson.
  • Microcephaly + happy affect + ataxic gait + seizures → Angelman.
  • Severe symmetric microcephaly + intact major brain structures + proportionate body in a consanguineous family → MCPH gene panel.
  1. Plot the trajectory. Was the head small at birth (primary) or did it stop growing (secondary)? The growth chart is the most informative single piece of data.
  2. History: prenatal infections, maternal alcohol/drug use, perinatal events, family head sizes, consanguinity.
  3. Measure the parents. Familial microcephaly with normal development is benign.
  4. MRI brain: structural malformations, calcifications, white matter changes, cerebellar involvement.
  5. TORCH-Z workup if congenital: CMV PCR (urine in newborn; dried bloodspot retrospectively), Zika serology if exposure history, toxoplasmosis serology.
  6. Genetic testing: chromosomal microarray first-line for most. MECP2 if Rett picture; methylation / UBE3A if Angelman; targeted gene if syndrome recognizable; otherwise exome.
  7. Metabolic screen: plasma amino acids, urine organic acids, lactate, ammonia (especially if regression).
  • CMV calcifications are periventricular. Zika calcifications are at the gray-white junction. This is a frequent question.
  • A child with microcephaly + regression + hand-wringing is Rett until proven otherwise; check MECP2.
  • Untreated PKU causes severe microcephaly that is essentially preventable. Always check newborn screening history.
  • Familial microcephaly with normal development is real and common; benign by definition, but you have to actually examine the parents to make the diagnosis.