Autosomal recessive primary microcephaly

Most conditions are autosomal recessive, including . Parents are obligate heterozygotes, the recurrence risk for siblings is 25%, and carriers are unaffected. Parental consanguinity raises the probability of a recessive cause considerably. More recently, autosomal dominant forms of hereditary primary microcephaly with similar clinical features have also been incorporated into the MCPH spectrum.

5–20% of children with developmental delay have microcephaly, identified by serial measurement of the occipitofrontal circumference against population references. Whether it is present at birth or develops thereafter directs the differential. Assessment includes length and weight to establish whether the microcephaly is proportionate, brain MRI, and consideration of non-genetic causes. Where a genetic cause is suspected, the diagnosis can be established by molecular genetic analysis from a DNA sample. For , brain MR angiography becomes scheduled surveillance once the diagnosis is confirmed, because cerebrovascular lesions are frequently present before they become symptomatic.

Main differential diagnoses include:

• Meier-Gorlin syndrome is defined by growth restriction, microtia, and hypoplastic or absent patellae. Thirteen replication-machinery genes are associated with this entity.
• RNU4ATAC-related spliceosomopathies combine severe microcephaly and growth restriction with brain malformation, skeletal dysplasia, retinal anomalies, and immunodeficiency; the immunological and retinal findings separate them from .
• Seckel syndrome overlaps with the MCPH.

• Establishing the molecular diagnosis assigns the specific entity behind a congenital microcephaly and provides the basis for genetic counselling, including an accurate recurrence risk. That risk differs between the recessive (majority of genes) and the dominant forms, a distinction that cannot be made clinically.
• For , a confirmed result changes management directly, because the surveillance programme is entity-specific and largely preventive, covering the cerebral vessels, blood pressure, and heart, kidney function, glucose, and lipids, the skeleton, and the dentition. Where the result confirms MCPH without additional organ involvement, it ends the diagnostic process and allows carrier and prenatal testing to be offered within the family.

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