Pitfalls in the diagnosis of 11β-hydroxylase deficiency new insights from three patients carrying novel CYP11B1 mutations

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 596-621-Pediatric Endocrinology /Steroids and Puberty
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-604
Silvia Parajes*1, Roxana Marino2, Ian T Rose1, Angela E Taylor1, Natalia Perez Garrido2, Mercedes Maceiras2, Pablo Ramirez2, Diana Warman2, Marco A Rivarola2, Wiebke Arlt1, Alicia Belgorosky2 and Nils Krone1
1University of Birmingham, Birmingham, United Kingdom, 2Hospital de Pediatria Garrahan, Buenos Aires, Argentina
Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) represents the second most common form of congenital adrenal hyperplasia (CAH) (5-8%). In most populations, 11OHD affects 1:100,000 individuals and is associated with adrenal insufficiency, hypertension, and with disorders of sex development in 46,XX patients. Mild 11OHD is rare and patients present later in life with signs of hyperandrogenism indistinguishable from nonclassic 21-hydroxylase (CYP21A2) deficiency (21OHD). Herein we describe three patients with clinical and biochemical features indicative of 11OHD, carrying three novel CYP11B1 mutations.

Patient 1 (P1) was a 46,XX baby born with ambiguous genitalia (Prader stage IV). Patient 2 (P2) had a 46,XY karyotype and manifested with sings of androgen excess, including pubic hair, penile growth and stimulation, and advanced bone age at 3 yrs of age. Patient 3 (P3a) was a 46,XY boy consulting for gynecomastia at 7.7 yrs of age. Clinical and biochemical investigations were indicative of 21OHD. However, no CYP21A2 mutations were found, and at 11.3 yrs, elevated serum 11-deoxycortisol (S) concentrations were measured. Advanced bone age and genital skin hyperpigmentation were noted in his younger brother (P3b) at 3.3 yrs. Biochemical investigations showed typically elevated concentrations of 17-hydroxyprogesterone, S and androgens in all patients.

CYP11B1 genetic analyses revealed compound heterozygosity in all patients: the novel p.R453W mutation and a CYP11B2/CYP11B1 chimeric gene (P1), p.R374Q and the novel p.R453W (P2), and the novel p.R138C and p.L407F mutations (P3a and P3b). The ability of the novel CYP11B1 mutations to convert S to cortisol was assessed in COS7 cells co-overexpressing wild-type or mutant CYP11B1 and adrenodoxin cDNAs. Functional analyses demonstrated that the novel p.R453W and p.L407F mutations completely abolished CYP11B1 enzyme activity, and p.R138C only retained 9.8% of wild-type activity. These findings were compatible with the patients' phenotype.

Herein, we described a broad phenotypic spectrum associated with 11OHD. Functional analysis confirmed the pathogenicity of the three novel mutations found in the patients. Similarly to 21OHD, 5-10% residual CYP11B1 activities may result in an intermediate phenotype. Overall, our study emphasizes that 46,XY patients with 11OHD may be at risk of delayed diagnosis or misdiagnosis of 21OHD.

Nothing to Disclose: SP, RM, ITR, AET, NP, MM, PR, DW, MAR, WA, AB, NK

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