J Clin Res Pediatr Endocrinol. 2022; 14(2): 153-171 | DOI: 10.4274/jcrpe.galenos.2022.2021-9-19

Mutations in AR or SRD5A2 Genes: Clinical Findings, Endocrine Pitfalls, and Genetic Features of Children with 46,XY DSD

Neþe Akcan¹, Oya Uyguner³, Firdevs Baþ⁴, Umut Altunoðlu², Güven Toksoy³, Birsen Karaman³, Þahin Avcý², Zehra Yavaþ Abalý⁴, Þükran Poyrazoðlu⁴, Agharza Aghayev³, Volkan Karaman³, Rüveyde Bundak⁶, Seher Baþaran³, Feyza Darendeliler^4
1Near East University Faculty of Medicine, Department of Pediatric Endocrinology, Nicosia, Cyprus
²Ýstanbul University, Ýstanbul Faculty of Medicine, Department of Medical Genetics, Ýstanbul, Turkey and Koç University Faculty of Medicine, Department of Medical Genetics, Ýstanbul, Turkey
³Ýstanbul University, Ýstanbul Faculty of Medicine, Department of Medical Genetics, Ýstanbul, Turkey
⁴Ýstanbul University, Ýstanbul Faculty of Medicine, Department of Pediatric Endocrinology, Ýstanbul, Turkey
⁵Koç University Faculty of Medicine, Department of Medical Genetics, Ýstanbul, Turkey
⁶University of Kyrenia, Faculty of Medicine, Department of Pediatric Endocrinology, Kyrenia, Cyprus

INTRODUCTION: Objective: Androgen insensivity syndrome (AIS) and 5α-reductase deficiency (5α-RD) present with indistinguishable phenotypes
among the 46,XY disorders of sexual development (DSD) that usually necessitate molecular analyses for the definitive diagnosis in the
prepubertal period. The aim was to evaluate the clinical, hormonal and genetic findings of 46,XY DSD patients who were diagnosed as
AIS or 5α-RD.
METHODS: Methods: Patients diagnosed as AIS or 5α-RD according to clinical and hormonal evaluations were investigated. Sequence variants of
steroid 5-α-reductase type 2 were analyzed in cases with testosterone/dihydrotestosterone (T/DHT) ratio of ≥20, whereas the androgen
receptor (AR) gene was screened when the ratio was <20. Stepwise analysis of other associated genes were screened in cases with
no causative variant found in initial analysis. For statistical comparisons, the group was divided into three main groups and subgroups
according to their genetic diagnosis and T/DHT ratios.
RESULTS: Results: A total of 128 DSD patients from 125 non-related families were enrolled. Birth weight SDS and gestational weeks were significantly higher in 5α-RD group than in AIS and undiagnosed groups. Completely female phenotype was higher in all subgroups of both AIS and 5α-RD patients than in the undiagnosed subgroups. In those patients with stimulated T/DHT <20 in the prepubertal period, stimulated T/DHT ratio was significantly lower in AIS than in the undiagnosed group, and higher in 5α-RD. Phenotype associated variants were detected in 24% (n=18 AIS, n=14 5α-RD) of the patients, revealing four novel AR variants (c.94G>T, p.Glu32*, c.330G>C, p.Leu110=; c.2084C>T, p.Pro695Leu, c.2585_2592delAGCTCCTG, p.(Lys862Argfs*16), of these c.330G>C with silent status remained undefined in terms of its causative effects.
DISCUSSION AND CONCLUSION: Conclusion: T/DHT ratio is an important hormonal criterion, but in some cases, T/DHT ratio may lead to diagnostic confusion. Molecular
diagnosis is important for the robust diagnosis of 46,XY DSD patients. Four novel AR variants were identified in our study.

Keywords: 46, XY disorders of sex development, 5α, -reductase deficiency, androgen insensitivity syndrome, androgen receptor gene mutations, SRD5A2 gene mutations

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