Side‐chain cleavage enzyme deficiency: Systematic review and case series

Abstract

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.

Steroidogenic acute regulatory protein (STAR) deficiency: Our experience and systematic review for phenotype–genotype correlation

“…5 Akin to SCCD, LCAH patients with TMG (Group C) had normal or compensated (with higher gonadotropin) pubertal Leydig cell function. 7 These observations indicate better preservation of gonadal function in Group C, also reflected by complete antenatal virilization. Recently, preserved spermatogenesis, including normozoospermia, has also been reported in a few adult NCLCAH males.…”

“…It is well-described that the age at PAI diagnosis may depend on factors other than underlying disease severity. 7,8 At diagnosis, the hormonal parameters of PAI were similar among the three subgroups except for a lower frequency of mineralocorticoid deficiency in Group C versus Group A patients.…”

“…4 In contrast to SCCD, T A B L E 2 (Continued) | 437 gonadotropin levels were normal in most 46,XX patients, even with severe STAR deficiency. 7 Adrenal enlargement was observed only in ~60% of LCAH in infancy, thus the possibility of SCCD is a differential in the remainder. 21 Furthermore, higher proportion of 46,XY in Group A had hyperplastic adrenals as compared to Group B/C, which may indicate a role for disease severity in adrenal hyperplasia.…”

“…[3][4][5][6] Unlike side chain cleavage enzyme deficiency (SCCD), a lower frequency of NCLCAH than that of CLCAH was reported from Japan but such an information across the globe is unavailable. 7,8 46,XY NCLCAH individuals have typical male external genitalia (TMG) though may rarely have hypospadias. 6 They typically manifest with PAI, most often after infancy and may have a gradual decline in testicular function postpuberty.…”

“…Some STAR mutations code for STAR protein with retained partial function, broadening its clinical spectrum to nonclassic LCAH (NCLCAH) 3–6 . Unlike side chain cleavage enzyme deficiency (SCCD), a lower frequency of NCLCAH than that of CLCAH was reported from Japan but such an information across the globe is unavailable 7,8 . 46,XY NCLCAH individuals have typical male external genitalia (TMG) though may rarely have hypospadias 6 .…”