Genotype, Mortality, Morbidity, and Outcomes of 3β-Hydroxysteroid Dehydrogenase Deficiency in Algeria

Abstract

Background3β-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.Patients and MethodsWe 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 HSD3B2 was performed using Sanger sequencing.ResultsA 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.ConclusionsThe 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.

Approach of Heterogeneous Spectrum Involving 3beta-Hydroxysteroid Dehydrogenase 2 Deficiency

“…We synthetized the studies published according to the mentioned methodology in Table 1 [ 5 , 22 , 25 , 26 , 27 , 31 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ].…”

“…Most articles introduce cases with SW forms, which seem like a common presentation due to its severity. The majority of patients were diagnosed after a SW crisis (vomiting, diarrhoea, hyponatremia, hyperkaliaemia, and hypoglycaemia) early during childhood or soon after birth [ 22 , 25 , 26 , 31 , 38 , 40 , 41 , 43 , 44 , 47 , 50 , 53 , 55 , 57 , 58 ]. Other signs and symptoms that are described under these circumstances are a lack of sweating, malnutrition, and developmental delay [ 31 , 50 ].…”

“…Some patients with SW associated DSD with males (mostly 46,XY males and mild virilisation in some 46,XX females; these generally are less affected concerning the spectrum of DSDs). Most cases of ambiguous genitalia were found in male patients who were affected by undermasculinization and presented with hypospadias, embedded penis, micropenis, scrotum bifidum, cryptorchidism, and vaginal introitus [ 22 , 25 , 26 , 31 , 38 , 39 , 40 , 43 , 44 , 46 , 47 , 48 , 49 , 53 , 56 , 57 , 58 , 59 ]. Female patients had either normal genitalia or were mildly virilised (for instance, clitoromegaly) [ 22 , 25 , 26 , 31 , 38 , 40 , 43 , 44 , 46 , 47 , 48 , 49 , 53 , 56 , 57 , 58 , 59 , 61 ].…”

“…Most cases of ambiguous genitalia were found in male patients who were affected by undermasculinization and presented with hypospadias, embedded penis, micropenis, scrotum bifidum, cryptorchidism, and vaginal introitus [ 22 , 25 , 26 , 31 , 38 , 39 , 40 , 43 , 44 , 46 , 47 , 48 , 49 , 53 , 56 , 57 , 58 , 59 ]. Female patients had either normal genitalia or were mildly virilised (for instance, clitoromegaly) [ 22 , 25 , 26 , 31 , 38 , 40 , 43 , 44 , 46 , 47 , 48 , 49 , 53 , 56 , 57 , 58 , 59 , 61 ]. Other elements of clinical spectrum include: premature pubarche, gynecomastia, obesity, intellectual and developmental delay, and neurological sequelae (irritability, convulsions, etc.…”

“…Other elements of clinical spectrum include: premature pubarche, gynecomastia, obesity, intellectual and developmental delay, and neurological sequelae (irritability, convulsions, etc. [ 22 , 31 , 38 , 46 , 47 , 51 , 57 , 61 ]. We mention the study of Ladjouze A. et al, in 14 Algerian patients with SW type who associated a median Prader stage of 2 for females (N = 8/14) at median age of 20 days without posterior labial fusion, while males had a median external masculinization score of 6 (N = 6/14).…”