Context: The cholesterol side-chain cleavage enzyme catalyzes the conversion of cholesterol to pregnanalone in the first step of steroidogenic pathways. Defective enzyme activity leads to the deficiency of all steroid hormones, including progesterone, which is essential to sustain term pregnancy.
Results: We report a homozygous point mutation in the CYP11A1 gene in a 46, XY phenotypic female born at term to healthy heterozygous parents, presenting relatively late at the age of 1 yr 9 months with life-threatening adrenal insufficiency and complete sex reversal. She was found to have complete agenesis of corpus callosum. The mutation resulted in a single amino acid substitution: valine for alanine at position 359. The functional analysis of the mutant enzyme revealed markedly reduced enzyme activity, but about 11% residual activity was demonstrated. We explained the completion of pregnancy to term and the late presentation by a possible difference in the mutant enzyme activity in vivo and in vitro or by the residual mutant activity, which would have been enough to maintain pregnancy and viability of the patient. The clinical findings of nearly undetectable levels of steroid hormones at presentation are explained by the total disruption of steroidogenic cells later on, with recurrent ACTH stimulation leading to intramitochondrial cholesterol accumulation and cell death (a two-hit mechanism).
Conclusion: This report of a homozygous mutation in CYP11A1 gene in a child with agenesis of corpus callosum shows that homozygous mutations in CYP11A1 gene can be compatible with term pregnancy and delayed presentation.