Macrocephaly

Macrocephaly is detected by routine occipitofrontal circumference (OFC) measurement on age- and sex-specific growth charts. Values exceeding 2 SD define macrocephaly, while values above 3 SD are regarded as clinically relevant and trigger further work-up. Macrocephaly encompasses a broad clinical range, from benign familial macrocephaly and benign external hydrocephalus to more than 200 genetic disorders alongside acquired causes such as progressive hydrocephalus, vascular anomalies, and intracranial masses. A useful diagnostic paradigm classifies macrocephaly by identifying which of the four cranial compartments (cerebrospinal fluid, blood and vasculature, brain parenchyma, or calvarium) shows increased volume. Megalencephaly, defined by true brain overgrowth exceeding 2 SD, must be distinguished from macrocephaly and is most often genetic in origin. Both syndromic and isolated nonsyndromic forms occur, with congenital onset through infancy and early childhood and serial OFC assessment guiding evaluation.

The estimated prevalence is up to approximately 2-5% of the paediatric population (OFC >2 SD); values above 3 SD are regarded as clinically relevant. The proportion attributable to genetic causes is not consistently reported.

A large number of genes have been associated with macrocephaly. The genetic forms include PI3K-AKT-mTOR pathway overgrowth, chromatin-modifier syndromes, , and . Frequently identified causes include (PTEN,
germline tumour-suppressor loss with congenital macrocephaly), (NSD1, de novo histone-methyltransferase overgrowth with macrocephaly), and (NF1, neurocutaneous Ras/MAPK disorder with macrocephaly in 35-45%).

, also known as , confers a predisposition to basal cell carcinomas and commonly presents with macrocephaly and coarse facial features. Mutations in the PTCH1 gene cause this autosomal dominant disorder.

Cowden syndrome also predisposes affected individuals to certain malignancies, including thyroid and breast cancers, and may present with macrocephaly. Mutations in the PTEN gene underlie this autosomal dominant condition. Many patients with macrocephaly harbor pathogenic genetic mutations, including those in the PPP2R5D gene. Genetic disorders often demonstrate variable penetrance and expressivity, resulting in a broad spectrum of clinical manifestations.

Metabolic megalencephaly involves enlargement of the brain parenchyma due to the accumulation of metabolic products within neural tissue. Conditions include leukodystrophies, e.g., Alexander disease, lysosomal storage disorders, e.g., , and organic acid disorders. Affected patients often present with a normal head circumference at birth followed by growth that exceeds the expected trajectory.

The genetic conditions associated with macrocephaly follow heterogeneous inheritance patterns. Autosomal dominant, autosomal recessive, X-linked, somatic mosaic, and imprinting-related forms are all represented across the spectrum, with germline overgrowth syndromes distinguished from segmental overgrowth that most often reflects somatic variants in the PI3K-AKT-mTOR pathway.

• Where macrocephaly is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.