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Image Description: Dominant negative mechanism. The allele of the STAR gene with a c.65-2 A>G or A>C mutation is in the dark color on the left. The wild-type allele is light and on the right. Both alleles result in translation of a stable protein but the allele with one of these specific mutations does not have a full MTS and is not trafficked into the mitochondria. The protein is not functional outside of the mitochondria and also inhibits the function of the STAR protein expressed from the wild-type allele, accounting for the dominant negative action and the occurrence of a clinical phenotype in individuals with only a heterozygous mutation (and not biallelic mutations). Created using BioRender.com. Case Description: Lipoid congenital adrenal hyperplasia (LCAH) is typically inherited as an autosomal recessive condition. There are 3 reports of individuals with a dominantly acting heterozygous variant leading to a clinically significant phenotype. We report a 46,XY child with a novel heterozygous intronic variant in STAR resulting in LCAH with an attenuated genital phenotype. The patient presented with neonatal hypoglycemia and had descended testes with a fused scrotum and small phallus. Evaluation revealed primary adrenal insufficiency with deficiencies of cortisol, aldosterone, and androgens. He was found to have a de novo heterozygous novel variant in STAR: c.65-2A>C. We report a case of a novel variant and review of other dominant mutations at the same position in the literature. Clinicians should be aware of the possibility of attenuated genital phenotypes of LCAH and the contribution of de novo variants in STAR at c.65-2 to the pathogenesis of that phenotype.
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