Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature
Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature
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DOI：
10.1530/eje-15-0599
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发表时间：
2015-11-01
影响因子：
5.8
通讯作者：
Flueck, Christa E.
中科院分区：
文献类型：
--
作者：
Burckhardt, Marie-Anne;Udhane, Sameer S.;Flueck, Christa E.
背景：3β-羟基类固醇脱氢酶缺乏症(3β-HSD)是一种罕见的性发育和类固醇激素生成障碍。3βHSD有两种同工酶：HSD3B1和HSD3B2。人类已知HSD3B2基因突变，该基因在性腺和肾上腺中表达。目的：描述HSD3B2基因突变的分子遗传学、类固醇生物化学、免疫组织化学和临床意义。方法：对人类生物材料进行生化、遗传学和免疫组织化学研究。结果：1例46，XY男婴出生时外生殖器严重男性化。类固醇分析显示，盐皮质激素、糖皮质激素和性激素的类固醇产量较低，具有典型的HSD3B2缺乏症的前体代谢物。对HSD3B2基因的遗传分析显示为c.687del27纯合缺失。在青春期，他表现出外生殖器的一些男性化，一些性类固醇代谢物似乎是通过睾丸分泌的前体和周围组织中未受影响的HSD3B1转化而产生的。然而，他也通过在外围产生雌激素而形成了丰满的乳房。在青春期晚期，睾丸组织学主要表现为仅支持细胞模式，仅有少量小管，精子发生受阻，间质中有少量间质细胞，但无肿瘤性改变。结论：c.687del27缺失所致HSD3B2缺陷的睾丸不表达该缺陷蛋白。这名患者不太可能生育，他患性腺恶性肿瘤的风险很低。对于含有雄激素生物合成缺陷的性腺的恶性风险，还需要进一步的研究。
Context: 3 beta-hydroxysteroid dehydrogenase deficiency (3 beta HSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3 beta HSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk.Objective: To describe the molecular genetics, the steroid biochemistry, the (immuno-) histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation.Methods: Biochemical, genetic and immunohistochemical investigations on human biomaterials.Results: A 46, XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c. 687del27 deletion. At pubertal age, he showed some virilization of the external genitalia and some sex steroid metabolites appeared likely through conversion of precursors secreted by the testis and converted by unaffected HSD3B1 in peripheral tissues. However, he also developed enlarged breasts through production of estrogens in the periphery. Testis histology in late puberty revealed primarily a Sertoli-cell-only pattern and only few tubules with arrested spermatogenesis, presence of few Leydig cells in stroma, but no neoplastic changes.Conclusions: The testis with HSD3B2 deficiency due to the c. 687del27 deletion does not express the defective protein. This patient is unlikely to be fertile and his risk for gonadal malignancy is low. Further studies are needed to obtain firm knowledge on malignancy risk for gonads harboring defects of androgen biosynthesis.