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.
Keywords: gonadal function; novel mutation; side-chain cleavage enzyme deficiency; testicular adrenal rest tumours.
© 2022 John Wiley & Sons Ltd.