Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children

Abstract

ABSTRACT. We performed an exploratory study by analyzing the correlation of 46, XY disorders of sex development (46, XY DSD) with androgen receptor (AR) and steroid 5α-reductase-2 (SRD5A2) gene mutations and a safety analysis of dihydrotestosterone (DHT) gel treatment for pediatric micropenis. We collected samples from 76 pediatric patients with 46, XY DSD and 50 healthy adult men with normal fertility as the control group. The pediatric patients were treated with DHT gel (0.1-0.3 mg/kg/day) for three to six months. The extended penis length, testicular volume, and multiple blood parameters were collected before treatment and one, three, and six months after treatment. Of the 76 cases with 46, XY DSD, 31.58% had hypospadias with micropenis and 6.58% had male pseudohermaphroditism. Through AR gene screening, it was found that 14 patients had AR point mutations and 22 patients had SRD5A2 mutations. After treatment with DHT, the penis length of the patients significantly improved after one, three, and six months of treatment, with longer treatment times resulting in greater improvement. Before treatment with DHT, the average serum DHT value of patients with 46, XY DSD was 24.29 pg/mL. After one, three, and six months of treatment, this value increased to 430.71, 328.9, and 323.6 pg/mL, respectively. We conclude that for pediatric patients who have male hermaphroditism or hypospadias with micropenis, AR and SRD5A2 gene mutation detection should be performed. Local application of DHT gel can promote penis growth effectively without systemic adverse reactions.

Polymorphisms of <b><i>MAMLD1, SRD5A2,</i></b> and <b><i>AR</i></b> Candidate Genes in Seven Dogs (78,XY; <b><i>SRY</i></b>-Positive) Affected by Hypospadias or Cryptorchidism

“…In particular, frameshift deletions, nonsense substitutions, and missense substitutions have been found in hypospadic patients [Di Marco et al, 2013;Yuan et al, 2017]. Fu et al [2016] identified mutations or polymorphisms in the AR and SRD5A2 genes in a cohort of 76 patients (XY DSD), which included 46 boys diagnosed with hypospadias and micropenis, and found 6 SNPs in AR and 5 polymorphisms (5 SNPs and 1 indel) in SRD5A2 . Among hypospadic patients with micropenis, genetic variation of AR and SRD5A2 was observed in 24 cases, and 1 missense mutation in SRD5A2 was identified as a hotspot mutation for hypospadias.…”

Molecular investigation of mutations in androgen receptor and 5‐alpha‐reductase‐2 genes in 46,XY Disorders of Sex Development with normal testicular development

“…This gene encodes the steroid 5‐alpha‐reductase two enzymes involved in male sexual development by converting the hormone testosterone to DHT in males (Berra et al, ; Boudon et al, ). Previous studies have indicated AR and SRD5A2 gene mutations as culprits behind 46,XY DSDs for the most part (Fu, Zhang, & Qu, ; Mendonca, Domenice, Arnhold, & Costa, ). Thus, we focused on these two genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre.…”

5-Alpha-Reductase 2 Deficiency in Newborns: A Review

“…The diagnosis and care for patients with DSD involves a holistic approach and discussion among endocrinologists, surgeons, psychologists, social workers and family members. The degree of patients' masculinity and penis size, response to androgens and treatments, social culture and norms, and quality of life are considered in the care (1,2) . to before century, made by the Greek historian Diodorus Siculus.…”

“…The condition is autosomal recessive and often found in males born in consanguineous parents in areas with high rates of inbreeding (7) . The major gene mutations in 5AR2D occur in the androgen receptor (AR) and steroid-5-alpha-reductase 2, (SRD5A2) genes (1) . Type 1 isoenzyme is encoded by the SRD5A1 gene located on chromosome 5p15, and expressed mainly in the liver and non-genital skin (6) .…”