Abstract 159: Side-Chain Cleavage Enzyme Deficiency: Systematic Review and Case Series

Background: side-chain cleavage deficiency (SCCD) patients present with primary adrenal insufficiency (PAI) with or without under virilized external genitalia. Distinction between classic and nonclassicalsteroidogenic acute regulatory protein (StAR) deficiency has been described, whereas in SCCD is unclear. The data on gonadal function and its correlation with SCCD genotype has not been studied. Objectives: We describe our experience and perform a systematic review of genetically-proven SCCD patients to determine the distinct phenotypic and genotypic characteristics of 46XY SCCD patients with typical male external genitalia (SCCD-TMG) and atypical (SCCD-AG) external genitalia. Methods: Retrospective review of three genetically proven SCCD patients from our center 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 46XY 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 primary adrenal insufficiency (PAI), and elevated renin were not different between 46XY SCCD-TMG (n = 19) and SCCD-AG (n = 15) whereas spontaneous puberty (9/9 vs 0/3, p = 0.0045), normal prepubertal (5/5 vs 6/6, p = 0.002), pubertal gonadotropins (2/9 vs 0/3, p = 1), and normal pubertal testosterone (9/11 vs 0/3, p = 0.027) were more common in SCCD-TMG. Testicular adrenal rest tumors 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]. 46XX 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.