Genetic Analysis of <b><i>NR0B1</i></b> in Congenital Adrenal Hypoplasia Patients: Identification of a Rare Regulatory Variant Resulting in Congenital Adrenal Hypoplasia and Hypogonadal Hypogonadism without Testicular Carcinoma in situ

Abstract

deletion of a direct repeat, c.857_862delTGGTGC predicting p.(Leu286_Val287del); pedigree 4 (English Caucasian), c.1168+1G 1 A, a regulatory variant within the NR0B1 splice donor site. This last male patient, aged 30 years, presented with evidence of HH but incomplete gonadotrophin deficiency, following an earlier diagnosis of Addison's disease at 3 years. Hormonal therapy induced virilisation. Testicular biopsy was performed. The c.1168+1G 1 A variant abrogated normal splicing of testicular mRNA. Histological examination showed poorly organised testicular architecture and absence of spermatozoa. Morphological analyses and the absence of immunohistochemical staining for OCT3/4 excluded the presence of malignant germ cell cancer and its precursor lesion, CIS. These studies add to the knowledge of the types and ethnic diversity of NR0B1 mutations and their associated phenotypes, and provide insight into the assessment and interpretation of testicular histology in AHC and HH. AbstractThere have been few testicular histology reports of adult patients with congenital adrenal hypoplasia/hypogonadal hypogonadism (AHC/HH), but Leydig cell hyperplasia has been observed, an indicator of the possibility of malignant transformation. We aimed to define the basis of AHC/HH in 4 pedigrees of different ethnic backgrounds. One patient was elected to have testicular biopsy which was examined for evidence of carcinoma in situ (CIS). NR0B1 mutation analysis was performed by sequence analysis. NR0B1 expression was investigated by RT-PCR. Testicular biopsy sections were stained with HE or immunostained for OCT3/4, an established marker of CIS. We identified NR0B1 variants in the 4

Combined in vitro and in silico analyses of FGFR1 variants: genotype‐phenotype study in idiopathic hypogonadotropic hypogonadism

“…Associated nonreproductive phenotypes occur with variable frequency, such as cleft lip/palate, syndactyly, oligodactyly, renal agenesis or hypoplasia, hearing loss, dental agenesis, mandibular hypoplasia, butterfly vertebrae and scoliosis 2,3 . Currently, at least 31 genes have been reported to underlie IHH, acting alone or in combination 4‐9 …”

Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism

“…Currently, at least 31 genes have reported associations with IHH. These include ANOS1, FGFR1/FGF8, and PROK2/PROKR2 (4)(5)(6)(7)(8). However, only approximately 40% of IHH patients have mutations in these genes (9), indicating that many genes underlying the pathogenesis of IHH remain to be discovered.…”