Centre for Cardiovascular Genetics, BHF Laboratories, UCL Institute of Cardiovascular Science, University College London, 5 University Street, London, UK.
Sex Dev. 2012;6(6):284-91. doi: 10.1159/000342295. Epub 2012 Sep 27.
There 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 AHC pedigrees: pedigree 1 (United Arab Emirates), c.1130A>G predicting p.(Glu377Gly); pedigree 2 (English Caucasian), c.327C>A predicting p.(Cys109*); pedigree 3 (Oman), a 6-bp deletion of a direct repeat, c.857_862delTGGTGC predicting p.(Leu286_Val287del); pedigree 4 (English Caucasian), c.1168+1G>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>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.
先天性肾上腺发育不全/低促性腺激素性性腺功能减退症（AHC/HH）患者的睾丸组织学报告很少，但已经观察到睾丸间质细胞增生，这是恶性转化的可能性的一个指标。我们旨在确定 4 个不同种族背景的家系中 AHC/HH 的基础。选择一名患者进行睾丸活检，检查是否存在原位癌（CIS）。通过序列分析进行 NR0B1 突变分析。通过 RT-PCR 研究 NR0B1 的表达。睾丸活检切片用 HE 染色或免疫组化染色，免疫组化标志物为 OCT3/4，是 CIS 的既定标志物。我们在 4 个 AHC 家系中发现了 NR0B1 变异：家系 1（阿拉伯联合酋长国），c.1130A>G 预测 p.(Glu377Gly)；家系 2（英国白种人），c.327C>A 预测 p.(Cys109*)；家系 3（阿曼），一个直接重复的 6 个碱基对缺失，c.857_862delTGGTGC 预测 p.(Leu286_Val287del)；家系 4（英国白种人），c.1168+1G>A，NR0B1 剪接供体位点内的调节变异。最后一位 30 岁的男性患者，表现为 HH，但促性腺激素缺乏不完全，3 岁时曾被诊断为 Addison 病。激素治疗诱导了男性化。进行了睾丸活检。c.1168+1G>A 变异阻止了睾丸 mRNA 的正常剪接。组织学检查显示睾丸组织结构不良，没有精子。形态学分析和 OCT3/4 的免疫组化染色缺失排除了恶性生殖细胞癌及其前体病变 CIS 的存在。这些研究增加了对 NR0B1 突变类型和种族多样性及其相关表型的认识，并深入了解 AHC 和 HH 中睾丸组织学的评估和解释。
