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Objective: P450 side‐chain cleavage deficiency (SCCD) patients present with primary adrenal insufficiency (PAI) with or without undervirilized external genitalia. The distinction between classic and nonclassic steroidogenic acute regulatory protein deficiency has been described, whereas in SCCD is unclear. The data on gonadal function and its correlation with SCCD genotype has not been studied. We describe our experience and perform a systematic review of genetically proven SCCD patients to determine the distinct phenotypic and genotypic characteristics of 46,XY SCCD patients with typical male external genitalia (SCCD‐TMG) and atypical (SCCD‐AG) external genitalia. Design, Patients and Measurements: Retrospective review of three genetically proven SCCD patients from our centre and per‐patient data analysis from a systematic review of 52 probands was performed. SCCD‐TMG (n = 19) was defined as external genitalia of Sinnecker score 1 with 46,XY karyotype; the rest (Sinnecker 2–5) were classified as SCCD‐AG (n = 15). Results: We report two new Indian cases of SCCD with three novel likely pathogenic variants and pubertal follow‐up of a previously reported patient. In systematic review, age at diagnosis of PAI and elevated renin were not different between 46,XY SCCD‐TMG (n = 19) and SCCD‐AG (n = 15), whereas spontaneous puberty (9/9 vs. 0/3, p =.0045), normal prepubertal (5/5 vs. 6/6, p =.002), pubertal gonadotropins (2/9 vs. 0/3, p = 1) and normal pubertal testosterone (9/11 vs. 0/3, p =.027) were more common in SCCD‐TMG. Testicular adrenal rest tumours were exclusive to SCCD‐TMG (n = 4). SCCD‐TMG was associated with four particular genotypes [monoallelic p.Glu314Lys with another deleterious variant on the second allele (p.Glu314Lys/X‐CHS: X‐compound heterozygous state), biallelic p.Arg451Trp, p.Phe215Ser/p.Arg232Ter and monoallelic p.Val79Ile]. 46,XX SCCD patients with p.Glu314Lys/X‐CHS also had normal gonadotropins with spontaneous puberty. Conclusion: SCCD‐TMG is associated with four specific genotypes and distinct gonadal characteristics from SCCD‐AG with overlapping features of PAI. [ABSTRACT FROM AUTHOR]

Objective: To report clinical, hormonal and structural effects of CYP11B1 pathogenic variations in Indian patients with 11β‐hydroxylase deficiency (11βOHD) and find hormonal criteria that accurately distinguish 11βOHD from 21α‐hydroxylase deficiency (21OHD). Design: Retrospective record review of genetically diagnosed patients with 11βOHD. Patients and Measurements: Clinical features, hormonal parameters at diagnosis (by immunoassay) and recent follow‐up of 13 genetically proven 11βOHD patients managed at our centre were retrospectively reviewed. ACTH‐stimulated serum adrenal steroids (measured by LC‐MS/MS) of 11βOHD were compared with those of simple virilizing and non‐classic 21OHD. Structural analysis of the observed pathogenic variations was performed by computational modelling. Results: Nine (four females) and four (all females) patients had classic and non‐classic disease, respectively. All 11βOHD patients had elevated ACTH‐stimulated serum 11‐deoxycortisol (26.5–342.7 nmol/L) whereas none had elevated serum 17‐hydroxyprogesterone (4.2–21.2 nmol/L); both hormonal parameters distinguished 11βOHD from 21OHD with 100% accuracy. ACTH‐stimulated serum cortisol, but not 11‐deoxycortisol, clearly distinguished classic (<70 nmol/L) from non‐classic (>160 nmol/L) disease. Thirteen (eight novel, two recurrent) pathogenic variants were observed. Only missense mutations were observed among patients with non‐classic disease. Computational modelling predicted the possible affection of enzyme structure and function for all the observed missense mutations. Conclusions: This first Indian study describes 13 11βOHD patients, including four with the rarer non‐classic variant. A total of eight novel pathogenic variants were identified in our study, highlighting regional genetic heterogeneity. Measurement of ACTH‐stimulated adrenal steroids by LC‐MS/MS will help avoid the misdiagnosis of 11βOHD as 21OHD and has potential to distinguish classic from non‐classic 11βOHD. [ABSTRACT FROM AUTHOR]