Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Abstract

Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. Design and methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9TOA, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)_(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function. Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

“…Progressive androgen production and virilization in adolescence has been observed in several XY patients with NR5A1 mutations, in contrast to the severe undervirilized external genitalia found in most patients (Cools et al, 2012; Gabriel Ribeiro de Andrade et al, 2014; Tantawy et al, 2014; Fabbri et al, 2016). The almost normal testosterone levels after hCG stimulation or at pubertal age suggest that NR5A1 action may be less implicated in pubertal steroidogenesis than during fetal life.…”

Novel Heterozygous Mutations of <b><i>NR5A1</i></b> and Their Functional Characteristics in Patients with 46,XY Disorders of Sex Development without Adrenal Insufficiency

“…Subjects with mutations in NR5A1 have a risk for the development of hypogonadotropic hypogonadism. However, spontaneous virilization was observed in some cases with 46,XY females with NR5A1 mutations at a pubertal age [29,30]. Gender identity in subjects with NR5A1 mutations is not necessarily concordant with the degree of virilization of the external genitalia at birth [30].…”

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

“…Case Report M-A Burckhardt and others Histology of HSD3B2 deficiency 173:5 K8 Table 4 (8,9,12,13,14,16,23,24,25,26,27,28,29,30,31,32,33,34,35,36). For spermatogenesis and thus fertility, the few data available suggest that it varies between different androgen biosynthetic defects as well as between individuals carrying defects in the same gene.…”