Department of Endocrinology, Seth G S Medical College & KEM Hospital, Mumbai, India.
Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, India.
Clin Endocrinol (Oxf). 2023 Mar;98(3):351-362. doi: 10.1111/cen.14848. Epub 2022 Nov 17.
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).
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.
SCCD-TMG is associated with four specific genotypes and distinct gonadal characteristics from SCCD-AG with overlapping features of PAI.
P450 侧链裂解缺陷（SCCD）患者表现为原发性肾上腺功能不全（PAI），伴有或不伴有未发育的外生殖器。已经描述了经典和非经典类固醇急性调节蛋白缺陷之间的区别，而 SCCD 中的区别尚不清楚。关于性腺功能及其与 SCCD 基因型的关系的数据尚未研究。我们描述了我们的经验，并对经过基因证实的 SCCD 患者进行了系统回顾，以确定具有典型男性外生殖器（SCCD-TMG）和非典型（SCCD-AG）外生殖器的 46,XY SCCD 患者的独特表型和基因型特征。
设计、患者和测量：对来自我们中心的三名经基因证实的 SCCD 患者进行回顾性分析，并对系统回顾中 52 名先证者的每位患者进行数据分析。SCCD-TMG（n=19）定义为具有 46,XY 核型的 Sinnecker 评分 1 的外生殖器；其余（Sinnecker 2-5）被归类为 SCCD-AG（n=15）。
我们报告了两例新的印度 SCCD 病例，伴有三种新的可能致病变异，并对先前报道的患者进行了青春期随访。在系统回顾中，46,XY SCCD-TMG（n=19）和 SCCD-AG（n=15）之间的 PAI 诊断年龄和升高的肾素没有差异，而自发性青春期（9/9 与 0/3，p=0.0045）、正常青春期前（5/5 与 6/6，p=0.002）、青春期促性腺激素（2/9 与 0/3，p=1）和正常青春期睾酮（9/11 与 0/3，p=0.027）在 SCCD-TMG 中更为常见。睾丸肾上腺残余肿瘤仅见于 SCCD-TMG（n=4）。SCCD-TMG 与四种特定基因型相关[单等位基因 p.Glu314Lys 与第二个等位基因上的另一种有害变异（p.Glu314Lys/X-CHS：X 复合杂合状态），双等位基因 p.Arg451Trp，p.Phe215Ser/p.Arg232Ter 和单等位基因 p.Val79Ile]。具有 p.Glu314Lys/X-CHS 的 46,XX SCCD 患者也具有正常的促性腺激素和自发性青春期。
SCCD-TMG 与四种特定基因型相关，与 SCCD-AG 具有不同的性腺特征，与重叠的 PAI 特征相关。
