Session: SAT 596-621-Pediatric Endocrinology /Steroids and Puberty
Poster Board SAT-604
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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