Section of Paediatric Endocrinology, Vall d'Hebron University Hospital, Barcelona, Spain.
CIBER of Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Front Endocrinol (Lausanne). 2022 Jun 28;13:884107. doi: 10.3389/fendo.2022.884107. eCollection 2022.
(X chromosome) is one of the recognized genes related to different sex development. It is expressed in testis and ovaries and seems to be involved in fetal sex development and in adult reproductive function, including testosterone biosynthesis. However, its exact role remains unclear. Over 40 genetic variants have been described, mainly in male individuals and mostly associated with hypospadias. Although MAMLD1 has been shown to regulate the expression of the steroidogenic pathway, patients with variants mostly show normal gonadal function and normal testosterone levels. Here we describe a patient (46,XY) with hypospadias and microphallus, with low testosterone and dihydrotestosterone (DHT) levels, and with inappropriately low values of luteinizing hormone (LH) during minipuberty. This hormonal pattern was suggestive of partial hypogonadotropic hypogonadism. A stimulation test with hCG (4 months) showed no significant increase in both testosterone and dihydrotestosterone concentrations. At 5 months of age, he was treated with intramuscular testosterone, and the penis length increased to 3.5 cm. The treatment was stopped at 6 months of age. Our gonadal function massive-sequencing panel detected a previously unreported nonsense variant in the gene (c.1738C>T:p.Gln580Ter), which was classified as pathogenic. This variant, predicting a truncated protein, could explain his genital phenotype. His hormonal profile (low testosterone, dihydrotestosterone, and LH concentrations) together with no significant increase of testosterone and DHT plasma concentrations (hCG test) highlight the potential role of this gene in the biosynthesis of testosterone during the fetal stage and minipuberty of the infant. Besides this, the LH values may suggest an involvement of MAMLD1 in the LH axis or a possible oligogenesis. It is the first time that a decrease in DHT has been described in a patient with an abnormal .
(X 染色体)是与不同性别发育相关的公认基因之一。它在睾丸和卵巢中表达，似乎参与胎儿性别发育和成人生殖功能，包括睾酮生物合成。然而，其确切作用仍不清楚。已经描述了超过 40 种遗传变异，主要在男性个体中发现，并且主要与尿道下裂有关。尽管已经表明 MAMLD1 可以调节类固醇生成途径的表达，但携带 变异的患者大多表现出正常的性腺功能和正常的睾酮水平。在这里，我们描述了一位患有尿道下裂和小阴茎的患者（46,XY），其睾酮和二氢睾酮（DHT）水平较低，在小青春期期间黄体生成素（LH）值过低。这种激素模式提示部分促性腺激素低下性性腺功能减退症。用 hCG（4 个月）进行刺激试验显示，睾酮和二氢睾酮浓度均无明显增加。在 5 个月大时，他接受了肌肉内睾酮治疗，阴茎长度增加到 3.5 厘米。6 个月大时停止治疗。我们的性腺功能大规模测序小组在 基因中检测到一个以前未报道的无意义变异（c.1738C>T:p.Gln580Ter），该变异被归类为致病性的。这种 变异，预测一种截断的蛋白质，可解释他的生殖器表型。他的激素谱（低睾酮、二氢睾酮和 LH 浓度）以及睾酮和 DHT 血浆浓度（hCG 试验）无明显增加，突出了该基因在胎儿期和婴儿小青春期期间睾酮生物合成中的潜在作用。除此之外，LH 值可能表明该基因在 LH 轴或可能的寡基因发生中起作用。这是第一次在异常 患者中描述 DHT 降低。
