A Novel Intronic Splice-Site Mutation of the CYP11A1 Gene Linked to Adrenal Insufficiency with 46,XY Disorder of Sex Development

Abstract

A novel CYP11A1: c.1236 + 5G > A was identified, expanding the mutation spectrum of the congenital adrenal insufficiency with 46,XY sex reversal. In a now 17-year-old girl delivered full-term (G2P2, parents unrelated), adrenal failure was diagnosed in the first year of life based on clinical picture of acute adrenal crisis with vomiting, dehydration, weight loss, hypotension, and electrolyte disturbances. At the time, hormonal tests revealed primary adrenocortical insufficiency and steroid profiles showed lack of products of steroidogenesis, and since then the patient has been treated with substitution doses of hydrocortisone and fludrocortisone. At the age of 14, considering the absence of puberty symptoms, extended diagnostic tests revealed elevated LH levels (26.5 mIU/mL) with pre-puberty FSH levels (4.9 mIU/mL), low estradiol (28 pmol/L), testosterone (<2.5 ng/mL), and extremely high levels of ACTH (4961 pg/mL). A cytogenetic study revealed a 46 XY karyotype. A molecular examination confirmed the missense mutation and a novel splice-site mutation of CYP11A1 gene. Compound heterozygosity for the CYP11A1 gene with a known pathogenic variant in one allele and a novel splice site mutation in the second allele is most probably responsible for congenital adrenal insufficiency with 46,XY sex reversal. We discuss the necessity of cytogenetic test in the case of early onset of adrenal failure in the absence of steroidogenesis metabolites in the steroid profile.

Keywords: CYP11A1 gene; congenital adrenal hyperplasia (CAH); disorder of sex development (DSD); novel mutation.

Figure 1

Two initial steps of steroidogenesis related to the StAR and p450scc activity.

Figure 2

Magnetic resonance imaging (MRI) of abdomen and pelvis minor showing presence of gonads (right (A), left (B)) with the absence of the structures derived from the Müllerian ducts.

Figure 3

Results of automated DNA sequencing for CYP11A1 splice site mutation NM_000781.2 c.1236 + 5G > A (upper chromatogram) and missense mutation NM_000781.2 c.566C > T; p.(Ala189Val) (bottom chromatogram).

Figure 4

Expected CYP11A1: c.1236 + 5G > A mutation effect on splicing. (A) Splicing mutation within the canonical splice sites leading to whole exon skipping; (B) splicing mutation resulting in the usage of the cryptic exonic or intronic splice site that leads to the inclusion of an intron fragment or exon fragment skipping.