Neurogenetics and Congenital Malformations
What to know
Malformations follow the embryologic timeline. Neurulation (days 18–28) produces neural tube defects - anencephaly, encephalocele, myelomeningocele - prevented by periconceptional folic acid. Proliferation defects give microcephaly or megalencephaly; migration defects give lissencephaly, heterotopia, polymicrogyria, and schizencephaly.
Classic lissencephaly (agyria-pachygyria) is caused by LIS1 deletion at 17p13.3 (Miller-Dieker syndrome when the contiguous deletion includes facial dysmorphism) or by X-linked DCX: hemizygous males have severe lissencephaly, heterozygous females have subcortical band heterotopia ("double cortex"). Cobblestone lissencephaly accompanies dystroglycanopathies such as Walker-Warburg and muscle-eye-brain disease.
Holoprosencephaly ranges from alobar to the mild "single central incisor" spectrum; SHH, ZIC2, SIX3, and TGIF are classic genes, and endocrine deficits such as diabetes insipidus are common. Posterior fossa: Chiari I is tonsillar herniation beyond 5 mm with cough headache and syrinx; Chiari II accompanies myelomeningocele; Dandy-Walker combines vermian hypoplasia with a cystic fourth ventricle; Joubert shows the molar-tooth sign with apnea and ataxia.
Phakomatoses: NF1 (17q11, café-au-lait macules, axillary freckling, Lisch nodules, optic glioma); tuberous sclerosis (TSC1/TSC2, cortical tubers, subependymal giant cell astrocytoma, infantile spasms, hypomelanotic macules); Sturge-Weber (GNAQ, facial port-wine stain, leptomeningeal angioma, glaucoma).
Traps
Do not assume a point mutation when a contiguous gene deletion is the mechanism - Miller-Dieker requires deletion testing. Remember the sex difference in DCX. Midline facial defects predict midline brain defects.
Rule of thumb
A child with a V1-distribution facial vascular malformation, seizures, and hemiparesis has Sturge-Weber until disproven; obtain contrast MRI and ophthalmologic evaluation.