Microcephaly

1. Growth Velocity of Head Size From Birth

Head circumference (HC) is a surrogate marker for brain volume. Brain growth is maximal during the first 2 years of life.

Normal Values and Velocity

• At Birth: Mean HC is 34–35 cm.
• First Year Growth (Total gain ~12 cm):
  • 0–3 months: 2 cm/month (Maximum velocity).
  • 3–6 months: 1 cm/month.
  • 6–12 months: 0.5 cm/month.
  • At 1 Year: Mean HC is 46–47 cm.
• Second Year Growth:
  • Rate slows significantly.
  • Gain: 2 cm/year.
  • At 2 Years: Mean HC is 48–49 cm.
• Preschool to Adolescence:
  • Gain: < 1 cm/year (very slow).
  • At 5 Years: ~50–51 cm.
  • At 10 Years: ~52–53 cm.
  • Adult Size: Mean 55–57 cm (achieved by mid-adolescence).

Brain Weight Correlation

• Birth: 350 g (25% of adult weight).
• 1 Year: 925 g (60–70% of adult weight).
• 2 Years: 80% of adult weight.
• Reference Charts: WHO Growth Standards (0–5 years) and IAP/CDC charts (>5 years).

2. Definition of Microcephaly

Microcephaly is a clinical sign, not a diagnosis, indicating a small head size relative to age and sex.

• Statistical Definition: Occipitofrontal circumference (OFC) more than 2 Standard Deviations (SD) below the mean (< 3rd percentile) for age, sex, and ethnicity.
• Severe Microcephaly: OFC more than 3 SD below the mean.
• Relative Microcephaly: HC drops from a higher percentile to a lower percentile over time (crossing major centiles downward), even if absolute value is > -2 SD.

3. Etiology of Microcephaly

Classified based on timing (onset) and pathophysiology.

A. Primary Microcephaly (Congenital/Genetic)

Defect in neurogenesis or neuronal migration; usually present at birth.

1. Genetic (Isolated):
   • Autosomal Recessive Primary Microcephaly (MCPH): Genes ASPM (most common), MCPH1, WDR62.
2. Chromosomal/Syndromic:
   • Trisomies: Down (T21), Edwards (T18), Patau (T13).
   • Deletion Syndromes: Cri-du-chat (5p-), Wolf-Hirschhorn (4p-).
   • Mendelian Syndromes: Seckel syndrome ("Bird-headed dwarfism"), Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, Cornelia de Lange syndrome.
3. Disorders of Neuronal Migration/Structure:
   • Lissencephaly (Smooth brain).
   • Schizencephaly.
   • Holoprosencephaly.
   • Agenesis of Corpus Callosum.

B. Secondary Microcephaly (Acquired/Environmental)

Normal initial brain development followed by insult/destruction.

1. Intrauterine Infections (TORCH):
   • Cytomegalovirus (CMV) - most common infectious cause.
   • Zika virus (severe destruction).
   • Toxoplasmosis, Rubella, Varicella, Syphilis.
2. Teratogens/Maternal Factors:
   • Alcohol: Fetal Alcohol Spectrum Disorder (FAS).
   • Drugs: Phenytoin (Fetal Hydantoin Syndrome), Valproate.
   • Maternal Metabolic: Uncontrolled Phenylketonuria (PKU).
   • Radiation exposure.
3. Perinatal/Postnatal Insults:
   • Hypoxic Ischemic Encephalopathy (HIE).
   • Intracranial Hemorrhage (IVH Grade III/IV).
   • CNS Infections: Meningitis, Encephalitis.
   • Severe Malnutrition (leads to stunted brain growth).
4. Craniosynostosis:
   • Premature fusion of sutures (e.g., sagittal, coronal) restricting growth.

4. Diagnostic Approach to a Child with Microcephaly

Step 1: Confirmation of Microcephaly

• Measurement: Use non-stretchable tape. Measure maximum occipitofrontal circumference (glabella to most prominent point of occiput). Repeat three times.
• Plotting: Use appropriate chart (Fenton for preterm, WHO for <5y).
• Parental HC: Measure parents to rule out Benign Familial Microcephaly (use Weaver curves).

Step 2: Detailed History

• Antenatal: Maternal fever/rash (Zika/Rubella), drug intake (antiepileptics, alcohol), radiation, maternal PKU.
• Perinatal: Gestational age, birth weight (SGA?), history of asphyxia, NICU stay.
• Family: Consanguinity (suggests AR/MCPH), similar history in siblings, early deaths.
• Developmental: Global developmental delay vs. specific motor delay.

Step 3: Physical Examination

• Cranium: Shape (scaphocephaly/turricephaly in craniosynostosis), sutures, fontanelles (early closure?).
• Dysmorphism:
  • Down syndrome features: Flat facies, up-slanting eyes.
  • Fetal Alcohol: Smooth philtrum, thin upper lip.
  • Seckel: Beaked nose.
• Systemic:
  • Eyes: Chorioretinitis (CMV/Toxo), Cataracts (Rubella/Galactosemia).
  • Abdomen: Hepatosplenomegaly (TORCH).
  • Skin: Petechiae/Purpura (TORCH), Hypopigmented macules.
• Neurology: Tone (Spasticity in CP vs. Hypotonia in syndromes), reflexes, deficits.

Step 4: Diagnostic Algorithm & Investigations

A. Neuroimaging (First Line)

• MRI Brain (Gold Standard): Identifies migration disorders (lissencephaly), structural agenesis, myelination defects.
• CT Head: If TORCH suspected (identifies periventricular calcifications in CMV; diffuse calcifications in Toxo).
• USG Cranium: Screening tool if fontanelle is open.

B. Genetic Testing (If Dysmorphic or MRI abnormal)

• Karyotype: If Trisomy suspected.
• Chromosomal Microarray (CMA): First-line for developmental delay + dysmorphism (detects microdeletions).
• Whole Exome Sequencing (WES): For suspected Mendelian disorders or Primary Microcephaly (MCPH panel).

C. Infection Screen (If Calcifications/HSM present)

• TORCH titers: IgM/IgG.
• Urine CMV PCR: Most sensitive for congenital CMV.

D. Metabolic Screen (If recurrent seizures/regression/FTT)

• Serum Amino acids (PKU).
• Urine Organic acids.
• Ammonia/Lactate.

Summary Flowchart

1. Microcephaly Confirmed -> Check Parents.
2. Parents Small? -> Benign Familial -> Observation.
3. Parents Normal? -> Assess for Dysmorphism/Delay.
4. Dysmorphic? -> Genetic Workup (CMA/Karyotype).
5. Non-dysmorphic + Neurological signs? -> MRI Brain -> Etiologic specific (Infection/Ischemia/Structural).
6. Sutural ridging? -> Skull X-ray/CT 3D Recon -> Craniosynostosis repair.