Department of Paediatrics, Centre Hospitalo-Universitaire Bab El Oued, Algiers, Algeria.
Section of Child Health, School of Medicine, Queen Elizabeth University Hospital, Glasgow, United Kingdom.
Front Endocrinol (Lausanne). 2022 Jun 10;13:867073. doi: 10.3389/fendo.2022.867073. eCollection 2022.
3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world literature and few data on outcomes.
We report a mixed longitudinal and cross-sectional study from a single Algerian center between 2007 and 2021. Virilization and under-masculinization were assessed using Prader staging and the external masculinization score (EMS), pubertal development staged according to the system of Tanner. Adrenal steroids were measured using mass spectrophotometry (LC-MS/MS). A genetic analysis of was performed using Sanger sequencing.
A 3βHSD2 defect was confirmed in 6 males and 8 females from 10 families (8 consanguineous), with p.Pro222Gln mutation in all but two siblings with a novel deletion: c.453_464del or p.(Thr152_Pro155del). Probable 3βHSD2 deficiency was diagnosed retrospectively in a further 6 siblings who died, and in two patients from two other centers. In the genetically confirmed patients, the median (range) age at presentation was 20 (0-390) days, with salt-wasting (n = 14) and genital anomaly (n = 10). The Prader stage for female patients was 2 (1-2) with no posterior fusion of the labia. The EMS for males was 6 (3-9). Median (range) values at diagnosis for 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxypregnenolone (17OHPreg) were elevated: 73.7 (0.37-164.3) nmol/L; 501.2(9.4-5441.3) nmol/L, and 139.7 (10.9-1500) nmol/l (NB >90 nmol/L diagnostic of 3βHSD2 defect). Premature pubarche was observed in four patients (3F:1M). Six patients (5F:1M) entered puberty spontaneously, aged 11 (5-13) years in 5 girls and 11.5 years in one boy. Testicular adrenal rest tumors were found in three boys. Four girls reached menarche at 14.3 (11-14.5) years, with three developing adrenal masses (surgically excised in two) and polycystic ovary syndrome (PCOS), with radiological evidence of ovarian adrenal rest tumor in one. The median IQ was 90 (43-105), >100 in only two patients and <70 in three.
The prevalence of 3βHSD2 deficiency in Algeria appears high, with p.Pro222Gln being the most frequent mutation. Mortality is also high, with significant morbidity from adrenal tumors and PCOS in adolescence and an increased risk of learning disability. The finding of adrenal tumors in older patients with 3βHSD2 indicates under-replacement, requiring effective hydrocortisone and fludrocortisone treatment rather than surgical removal.
3β-羟类固醇脱氢酶 2（3βHSD2）缺乏症是一种罕见的先天性肾上腺增生症（CAH）形式，全世界文献报道的病例少于 200 例，关于结局的数据很少。
我们报告了 2007 年至 2021 年期间，一家阿尔及利亚中心进行的一项混合纵向和横断面研究。使用 Prader 分期和外部男性化评分（EMS）评估男性的男性化和女性的未男性化，根据 Tanner 系统对青春期发育进行分期。使用质谱法（LC-MS/MS）测量肾上腺类固醇。使用 Sanger 测序对 进行基因分析。
在 10 个家庭（8 个近亲）的 6 名男性和 8 名女性中证实存在 3βHSD2 缺陷，除了 2 个兄弟姐妹有新的缺失（c.453_464del 或 p.(Thr152_Pro155del) 外，所有患者均存在 p.Pro222Gln 突变。在另外 6 名死亡的同胞和来自其他 2 个中心的 2 名患者中，回顾性诊断出可能存在 3βHSD2 缺乏症。在基因确认的患者中，就诊时的中位（范围）年龄为 20（0-390）天，伴有盐耗竭（n=14）和生殖器异常（n=10）。女性患者的 Prader 分期为 2（1-2），阴唇后部无融合。男性患者的 EMS 为 6（3-9）。17-羟孕酮（17-OHP）、脱氢表雄酮硫酸酯（DHEA-S）和 17-羟孕烯醇酮（17OHPreg）的诊断中位（范围）值升高：73.7（0.37-164.3）nmol/L；501.2（9.4-5441.3）nmol/L，和 139.7（10.9-1500）nmol/L（NB >90 nmol/L 诊断为 3βHSD2 缺陷）。4 名患者（3 名女性：1 名男性）出现早熟性阴毛。6 名患者（5 名女性：1 名男性）自发性进入青春期，5 名女孩年龄为 11（5-13）岁，1 名男孩为 11.5 岁。3 名男孩发现睾丸肾上腺残余肿瘤。4 名女孩 14.3（11-14.5）岁初潮，其中 3 人发生肾上腺肿块（2 人手术切除）和多囊卵巢综合征（PCOS），1 人有卵巢肾上腺残余肿瘤的放射学证据。中位数智商为 90（43-105），只有 2 名患者智商>100，3 名患者智商<70。
阿尔及利亚 3βHSD2 缺乏症的患病率似乎很高，p.Pro222Gln 是最常见的突变。死亡率也很高，青春期肾上腺肿瘤和 PCOS 导致显著发病率，学习障碍风险增加。3βHSD2 患者年龄较大时出现肾上腺肿瘤表明替代不足，需要有效的氢化可的松和氟氢可的松治疗，而不是手术切除。
