Microcephaly

Susan I. Blaser, MD, FRCPC

DIFFERENTIAL DIAGNOSIS

Common

Secondary/Acquired from
- Hypoxic Ischemic Encephalopathy
- TORCH Infections
- Nonaccidental Trauma
- Meningitis
- Fetal Alcohol Syndrome

Less Common

Primary/Genetic with
- Gyral Simplification
- Cortical Dysplasia
- Midline Anomaly
- Cerebellar Hypoplasia
- Hypomyelination

Rare but Important

Microlissencephaly
Pseudo-TORCH
- Aicardi-Goutieres
Progeroid Syndromes
- Cockayne

ESSENTIAL INFORMATION

Key Differential Diagnosis Issues

Was head circumference ever normal?
Decreased cranio-facial ratio on sagittal view helpful, tape measure best

Helpful Clues for Common Diagnoses

Hypoxic Ischemic Encephalopathy
- Patterns helpful, even if no history
  - Profound: Atrophy, gliosis posterior putamen, lateral thalami, rolandic cortex
  - Prolonged progressive: Typical watershed encephalomalacia
  - Mixed: Features of both, ± calcified thalami
TORCH Infections
- Agents most frequently causing microcephaly
  - Cytomegalovirus (CMV) most common by far
  - Rubella (now rare)
- Look for cortical dysplasia, periventricular Ca++, hypomyelination (typically associated with CMV)
Nonaccidental Trauma
- History is crucial
- BUT look for evidence of trauma/fractures on ALL available films
- Brain imaging
  - Global atrophy or hemiatrophy
  - Hemosiderin
Meningitis
- Early infancy: Group B strep the most damaging
  - Hypothalamus
  - Chiasm
  - Inferior basal ganglia
  - Diffuse cortex, often asymmetric
Fetal Alcohol Syndrome
- Microcephaly
  - By tape measure or MR volumetrics
  - Anomalies may occur, but not specific
- Diffusion tensor imaging (DTI) reported to show abnormal connectivity

Helpful Clues for Less Common Diagnoses

Gyral Simplification
- Small, grossly normal brain
- Looks like “small, but perfect brain”
- Corpus callosum may appear thick, lack isthmus
Cortical Dysplasia
- Any severe, diffuse dysplasia
  - Lissencephaly
  - Pachygyria
Midline Anomaly
- Holoprosencephaly, agenesis CC
- Assess corpus callosum presence, size, shape
  - Is there an isthmus?
- Holoprosencephaly
  - Most severe are the smallest
Cerebellar Hypoplasia
- May be clue to rare disorders
  - Microlissencephaly
  - TUBA1A mutations: Lissencephaly PLUS cerebellar hypoplasia
- Assess degree of deficiency
  - Fastigial recess, primary fissure
  - Degree of vermian lobulation
  - Tegmento-vermian angle (is the inferior 4th ventricle open?)
Hypomyelination
- May be a clue to rare disorders
  - Early onset West syndrome with cerebral hypomyelination and reduced white matter
  - 3-phosphoglycerate dehydrogenase deficiency
  - Progressive encephalopathy, edema, hypsarrhythmia, optic atrophy (PEHO)

Helpful Clues for Rare Diagnoses

Microlissencephaly
- “Z-shaped” brainstem
- Callosal agenesis
- Surface often totally smooth
- Very small brain
Pseudo-TORCH
- Aicardi-Goutieres
  - Autosomal recessive, important to diagnose
  - Elevated CSF alpha-interferon
  - Early onset: TREX1 mutation
  - Late onset: RNASEH2B mutation
  - Imaging CMV-like
  - Ca++
  - Hypomyelination
  - Atrophy
Progeroid Syndromes
- Cockayne
  - Cachectic dwarfism with mental retardation
  - Disorder of DNA repair
  - Several mutations known
  - Lack phenotype-genotype correlation
  - Facies & neuroimaging progressive
  - Basal ganglia/dentate Ca++
  - Demyelination
  - Atrophy

SELECTED REFERENCES

1. Gul A et al: Novel protein-truncating mutations in the aspm gene in families with autosomal recessive primary microcephaly. J Neurogenet. 21(3):153-63, 2007

2. Hassan MJ et al: Previously described sequence variant in CDK5RAP2 gene in a pakistani family with autosomal recessive primary microcephaly. BMC Med Genet. 2007

3. Kure-Kageyama H et al: A patient with simplified gyral pattern followed by progressive brain atrophy. Brain Dev. 29(6):383-6, 2007

4. Ornoy A et al: Fetal effects of primary and secondary cytomegalovirus infection in pregnancy. Reprod Toxicol. 21(4):399-409, 2006

5. Tang BL: Molecular genetic determinants of human brain size. Biochem Biophys Res Commun. 345(3):911-6, 2006

6. Sztriha L et al: Extreme microcephaly with agyria-pachygyria, partial agenesis of the corpus callosum, and pontocerebellar dysplasia. J Child Neurol. 20(2):170-2, 2005

7. Abdel-Salam GM et al: Aicardi-Goutieres syndrome: clinical and neuroradiological findings of 10 new cases. Acta Paediatr. 93(7):929-36, 2004

8. de Vries LS et al: The spectrum of cranial ultrasound and magnetic resonance imaging abnormalities in congenital cytomegalovirus infection. Neuropediatrics. 35(2):113-9, 2004

9. Riley EP et al: Teratogenic effects of alcohol: a decade of brain imaging. Am J Med Genet C Semin Med Genet. 127(1):35-41, 2004

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