Clinical and Genetic Characteristics of Patients with Common and Rare Types of Congenital Adrenal Hyperplasia: Novel Variants in STAR and CYP17A1

Objectives: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases characterized by salt wasting or virilization. 21 hydroxylase deficiency (21-OHD) accounts for 90–95% of all cases of CAH and caused by the genetic defects of CYP21A2. Other forms include 3-β-hydroxysteroid dehydrogenase deficiency, 11-β-hydroxylase deficiency (11β-OHD) (%5-8), 17-α-hydroxylase deficiency (17α-OHD), and steroidogenic acute regulatory protein (STAR) defects (congenital lipoid adrenal hyperplasia) with mutations in HSD3B2, CYP11B1, CYP17A1, and STAR, respectively. Objectives: Herein, we aimed to present the clinical and genetic features of 64 patients with various types of CAH.
Methods: Sixty-four patients with CAH, monitored in the Izmir Dr. Behcet Uz Children Hospital Division of Pediatric Endocrinology, were retrospectively analyzed for the clinical, laboratory, and genetic data.
Results: Fifty-six patients (87.5%) had 21-OHD and four patients (6.3%) had 17α-OHD, three patients (4.7%) had 11β-OHD, and one patient (1.5%) had STAR defect. The most common presenting features in 21-OHD were ambiguous genitalia. Patients with 21-OHD were diagnosed earlier than the rare groups. Disease-causing variants of CYP21A2 were identified in 46 patients. The most common mutations were IVS2, Q318X, I172N, and large deletions. Three patients with 11β-OHD were presented with enlargement of penis and early pubic hair at the median presenting age of 26 months. 17α-OHD deficiency was detected in 4 cases. Genetic analysis revealed two different homozygous CYP17A1 variants. The patient with STAR defect was presented with dehydration and cholestasis in 44 days of the life. Genetic analysis of patient with STAR deficiency revealed a novel homozygous variant.
Conclusion: The current study reported a genotype-phenotype correlation consistent with literature data in CAH cases with 21-OHD. This study also reported novel homozygous variants in STAR and CYP17A1 genes that lead to rare types of CAH.

Konjenital Adrenal Hiperplazili Olgularýmýzýn Klinik ve Genetik Özellikleri: STAR ve CYP17A1 Geninde Saptanan Yeni Mutasyonlar

Giriþ: Konjenital adrenal hiperplazi (KAH), tuz kaybý ve virilizasyon ile karakterize, otozomal resesif kalýtýlan bir hastalýktýr. CYP21A2 genindeki mutasyonlardan kaynaklanan 21 hidroksilaz eksikliði KAH’lý hastalarýn %90-95’ini oluþturur. Diðer daha nadir formlar ise 3-β-hidroksisteroid dehidrogenaz eksikliði (3β-HSD), 11-β-hidroksilaz eksikliði (11β-OHD) (%5-8), 17-α-hidroksilaz eksikliði (17α-OHD) ve STAR defektleridir (Konjenital lipoid adrenal hiperplazi).
Bu çalýþmamaýzda, kliniðimizde izlenen 64 KAH hastasýnýn klinik ve laboratuar verileri sunulmuþtur.
Material-metod: Ýzmir Dr. Behçet Uz Çocuk Hastanesi Çocuk Endokrinoloji kliniðinde izlenmekte olan 64 KAH tanýlý hastanýn klinik, laboratuar ve genetik özellikleri retrospektif olarak incelenmiþtir.
Bulgular: Hastalarýn ellialtýsý (%87,5) 21-OHD, 4’ü (%6,3) 17α-OHD, 3’ü (%4,7) 11β-OHD ve biri (%1,5) STAR defekti tanýsý almýþtý. 21-OHD tanýlý olgularýn en sýk baþvuru nedeni belirsiz dýþ genital yapý idi. 21-OHD tanýlý olgular diðer nadir KAH nedenli olgulardan daha erken taný almýþlardý. 21-OHD tanýlý olgularýn 46’sýnda CYP21A2 geninde mutasyon tanýmlandý; en sýk mutasyonlar IVS2, Q318X, I172N ve büyük delesyonlar idi. 11β-OHD tanýlý üç olgu makropenis ve erken pubik kýllanma ile baþvurmuþtu (median baþvuru yaþý: 26 ay idi). 17α-OHD tanýlý dört olgu mevcuttu ve bu olgularda CYP17A1 geninde iki farklý mutasyon tanýmlandý; bu mutasyonlardan biri daha önce literatürde tanýmlanmamýþtý. STAR defekti tanýlý olgu, yaþamýnýn 44. Gününde dehidratasyon ve kolestaz tablosunda baþvurmuþtu. Genetik analizinde STAR geninde daha önce tanýmlanmamýþ novel bir varyant saptandý.
Sonuç: Sonuç olarak, çalýþmamýzda 21-OHD’li KAH olgularýnda literatür ile uyumlu fenotip-genotip korelasyonu izlendi. Ayný zamanda çalýþmamýzda KAH’ýn nadir tiplerine neden olan STAR ve CYP17A1 genlerinde daha önce tanýmlanmamýþ novel mutasyonlar saptandý. (SETB-2021-06-177)