Non-classical 11β-hydroxylase deficiency caused by a novel heterozygous mutation: a case report and review of the literature.

PURPOSE: 11β-hydroxylase deficiency (11β-OHD) constitutes a rare form of congenital adrenal hyperplasia (CAH), typically accounting for ~5-8% of CAH cases. Non-classical 11β-OHD is reported even more rarely and frequently results in misdiagnosis or underdiagnosis due to its mild clinical symptoms.

METHODS: A clinical, biochemical, radiological, and genetic study was conducted on a 9-year-old girl presenting with mild breast development, axillary hair growth, and advanced bone age. Additionally, a comprehensive review and synthesis of the literature concerning 11β-OHD were conducted.

RESULTS: The patient presented with breast enlargement, axillary hair development, and accelerated growth over the past year. Laboratory tests revealed levels of cortisol, luteinizing hormone, testosterone, and progesterone that were below normal. A gonadotropin-releasing hormone (GnRH) stimulation test suggested the possibility of central precocious puberty. Radiologic examination revealed a 2-year advance in bone age, while bilateral adrenal ultrasonography showed no abnormalities. Her mother exhibited hirsutism, while her father's physical examination revealed no abnormalities. Whole-exon genetic testing of the child and her parents indicated a heterozygous mutation of c.905_907delinsTT in exon 5 of the 11β-hydroxylase gene (CYP11B1) in the child and her mother. This mutation resulted in a substitution of aspartic acid with valine at amino acid position 302 of the coding protein. This frameshift resulted in a sequence of 23 amino acids, culminating in a premature stop codon (p.Asp302ValfsTer23). A review of the previous literature revealed that the majority of heterozygous mutations in 11β-OHD were missense mutations, occurring primarily in exons 2, 6, 7, and 8. The most common mutation among 11β-OHD patients was the change of Arg-448 to His (R448H) in CYP11B1. Furthermore, bioinformatics analyses revealed that heterozygous mutation of c.905_907delinsTT had deleterious effects on the function of CYP11B1 and affected the stability of the protein, presumably leading to a partial impairment of enzyme activity. The results of the in vitro functional study demonstrated that the missense mutant (p.Asp302ValfsTer23) exhibited partial enzymatic activity.

CONCLUSIONS: We report a novel heterozygous mutation of CYP11B1 (c.905_907delinsTT), enriching the spectrum of genetic variants of CYP11B1. This finding provides a valuable case reference for early diagnosis of non-classical patients with 11β-OHD.