Alhamoudi Kheloud M, Alghamdi Balgees, Aljomaiah Abeer, Alswailem Meshael, Al-Hindi Hindi, Alzahrani Ali S
Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Front Genet. 2022 Jul 5;13:885589. doi: 10.3389/fgene.2022.885589. eCollection 2022.
Mutations in the nuclear receptor subfamily 5 group A member 1 () are the underlying cause of 10-20% of 46,XY disorders of sex development (DSDs). We describe a young girl with 46,XY DSD due to a unique novel mutation of the gene. An 11-year-old subject, raised as a female, was noticed to have clitromegly. She looked otherwise normal. However, her evaluation revealed a 46,XY karyotype, moderate clitromegly but otherwise normal female external genitalia, undescended atrophied testes, rudimentary uterus, no ovaries, and lack of breast development. Serum testosterone and estradiol were low, and gonadotropins were elevated. Adrenocortical function was normal. DNA was isolated from the peripheral leucocytes and used for whole exome sequencing. The results were confirmed by Sanger sequencing. We identified a novel mutation in changing the second nucleotide of the translation initiation codon (ATG>ACG) and resulting in a change of the first amino acid, methionine to threonine (p.Met1The). This led to severe gonadal dysgenesis with deficiency of testosterone and anti-Müllerian hormone (AMH) secretion. Lack of the former led to the development of female external genitalia, and lack of the latter allowed the Müllerian duct to develop into the uterus and the upper vagina. The patient has a female gender identity. Bilateral orchidectomy was performed and showed severely atrophic testes. Estrogen/progesterone therapy was initiated with excellent breast development and normal cyclical menses. In summary, we describe a severely affected case of 46,XY DSD due to a novel mutation involving the initiation codon that fully explains the clinical phenotype in this subject.
核受体亚家族5组A成员1（）基因突变是46，XY性发育障碍（DSD）中10%-20%病例的根本原因。我们描述了一名因该基因独特的新突变而患有46，XY DSD的年轻女孩。一名11岁的受试者，自幼被当作女性抚养，被发现阴蒂增大。除此之外她看起来正常。然而，她的检查显示核型为46，XY，阴蒂中度增大但其他方面女性外生殖器正常，睾丸未降且萎缩，子宫发育不全，无卵巢，且乳房未发育。血清睾酮和雌二醇水平低，促性腺激素升高。肾上腺皮质功能正常。从外周血白细胞中分离DNA并用于全外显子测序。结果通过桑格测序得到证实。我们在中鉴定出一个新突变，该突变改变了翻译起始密码子的第二个核苷酸（ATG>ACG），导致第一个氨基酸由甲硫氨酸变为苏氨酸（p.Met1Thr）。这导致严重的性腺发育不全，睾酮和抗苗勒管激素（AMH）分泌不足。前者缺乏导致女性外生殖器发育，后者缺乏使苗勒管发育为子宫和上阴道。该患者具有女性性别认同。进行了双侧睾丸切除术，显示睾丸严重萎缩。开始进行雌激素/孕激素治疗，乳房发育良好且月经周期正常。总之，我们描述了一例因涉及起始密码子的新突变而导致的严重46，XY DSD病例，该突变充分解释了该受试者的临床表型。
