1. Revisiting Classical 3β-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases
- Author
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Bon Chu Chung, Goncagül Haklar, Serap Turan, Cengiz Kara, Jamala Mamadova, Tulay Guran, Melek Yildiz, Ahmet Anık, Eda Celebi Bitkin, Jen-Chieh Lin, Zeynep Atay, Teoman Akcay, Gönül Çatlı, Birgül Kirel, Hasan Önal, Azad Akbarzade, Onder Sirikci, Abdullah Bereket, Mehmet Keskin, Karl-Heinz Storbeck, Ayla Guven, Gülay Can Yılmaz, Tugba Baris, Filiz Tutunculer, Lise Barnard, İstinye Üniversitesi, Hastane, Akcay, Teoman, and Ondokuz Mayıs Üniversitesi
- Subjects
Male ,Turkey ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Physiology ,Puberty, Precocious ,Biochemistry ,Endocrinology ,HSD3B2 ,Chlorocebus aethiops ,Missense mutation ,3 beta HSD2 deficiency ,Child ,Children ,Sanger sequencing ,Hsd3b2 ,CAH ,Cah ,Homozygote ,Polycystic ovary ,Child, Preschool ,COS Cells ,symbols ,Metabolome ,Female ,adrenal insufficiency ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Pediatric endocrinology ,Mutation, Missense ,Context (language use) ,symbols.namesake ,children ,Internal medicine ,medicine ,Adrenal insufficiency ,Animals ,Humans ,Genetic Testing ,Genetic Association Studies ,Adrenal Hyperplasia, Congenital ,business.industry ,Progesterone Reductase ,Biochemistry (medical) ,Infant ,medicine.disease ,3 Beta Hsd2 Deficiency ,Cross-Sectional Studies ,Mineralocorticoid ,business ,Adrenal Insufficiency - Abstract
Context The clinical effects of classical 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency are insufficiently defined due to a limited number of published cases. Objective To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3βHSD2 deficiency. Design Multicenter, cross-sectional study. Setting Nine tertiary pediatric endocrinology clinics across Turkey. Patients Children with clinical diagnosis of 3βHSD2 deficiency. Main Outcome Measures Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3βHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. Results Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ± 5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3βHSD2 activity in vitro had a non-salt–losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. Conclusions Genetically-documented 3βHSD2 deficiency includes salt-losing and non-salt–losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3βHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3βHSD2 deficiency.
- Published
- 2019