Which metabolic disorder includes a severe form that presents with microcephaly, lethal cardiac and brain anomalies, and ambiguous genitalia?

• A. Congenital lactic acidosis
• B. Urea cycle disorder
• C. Menkes disease
• D. Smith-Lemli-Opitz syndrome

Answer: (D)

Smith-Lemli-Opitz syndrome is the metabolic disorder that fits this presentation. It results from a defect in cholesterol synthesis (DHCR7 deficiency), which disrupts essential developmental signals that depend on cholesterol, leading to midline and genital anomalies. In severe cases, this can manifest as microcephaly with significant brain and cardiac malformations and ambiguous genitalia due to impaired steroid hormone production during development. Cholesterol’s role in embryogenesis, particularly for signaling pathways like sonic hedgehog, explains why midline defects and genital ambiguity occur together in this condition.

The other disorders described don’t typically present with this combination. Congenital lactic acidosis is a mitochondrial/energy-production issue with metabolic acidosis and lactic elevation rather than characteristic structural malformations or genital ambiguity. Urea cycle disorders cause hyperammonemia and encephalopathy without the distinctive midline and genital anomalies. Menkes disease involves copper transport failure with neurodegeneration and hair/skin findings rather than the congenital, midline morphologic defects seen in severe Smith-Lemli-Opitz syndrome.