Department of Pediatric Endocrinology and Diabetes, Gaafar Ibn Auf Pediatric Tertiary Hospital, Khartoum 11114, Sudan.
Sudan Childhood Diabetes Center, Khartoum 11111, Sudan.
Genes (Basel). 2022 Apr 8;13(4):657. doi: 10.3390/genes13040657.
Pathogenic variants within the gene encoding the pituitary-specific transcription factor, POU class 1 homeobox 1 (), are associated with combined pituitary hormone deficiency (CPHD), including growth hormone, prolactin, and thyrotropin stimulating hormone deficiencies. The aim of the study was to identify genetic aetiology in 10 subjects with CPHD from four consanguineous Sudanese families. Medical history, as well as hormonal and radiological information, was obtained from participants' medical records. Targeted genetic analysis of the gene was performed in two pedigrees with a typical combination of pituitary deficiencies, using Sanger sequencing, and whole-exome sequencing was performed in the other two pedigrees, where hypocortisolism and additional neurologic phenotypes were also initially diagnosed. In gene (NM_001122757.2) a novel homozygous splice-site deletion-namely, c.744-5_749del-was identified in all 10 tested affected family members as a cause of CPHD. Apart from typical pituitary hormonal deficiencies, most patients had delayed but spontaneous puberty; however, one female had precocious puberty. Severe post-meningitis neurologic impairment was observed in three patients, of whom two siblings had Dyke-Davidoff-Masson syndrome, and an additional distantly related patient suffered from cerebral infarction. Our report adds to the previously reported gene variants causing CPHD and emphasises the importance of genetic testing in countries with high rates of consanguineous marriage such as Sudan. Genetic diagnostics elucidated that the aetiologies of hypopituitarism and brain abnormalities, identified in a subset of affected members, were separate. Additionally, as central hypocortisolism is not characteristic of POU1F1 deficiency, hydrocortisone replacement therapy could be discontinued. Elucidation of a genetic cause, therefore, contributed to the more rational clinical management of hypopituitarism in affected family members.
该基因编码的垂体特异性转录因子，POU 类 1 同源框 1 (), 的致病变体与联合垂体激素缺乏症 (CPHD) 有关，包括生长激素、催乳素和促甲状腺激素刺激激素缺乏症。本研究的目的是在来自四个苏丹近亲家庭的 10 名 CPHD 受试者中确定遗传病因。从参与者的病历中获得了病史以及激素和影像学信息。在两个具有典型垂体缺乏症组合的家系中，使用 Sanger 测序对 基因进行了靶向基因分析，在另外两个家系中也进行了全外显子组测序，最初还诊断出这些家系存在低皮质醇血症和其他神经表型。在 基因 (NM_001122757.2) 中，在所有 10 名受影响的家族成员中均发现了一种新的纯合剪接位点缺失，即 c.744-5_749del-，这是 CPHD 的原因。除了典型的垂体激素缺乏症外，大多数患者的青春期延迟但自发；然而，有一名女性患有性早熟。三名患者出现严重的脑膜炎后神经损伤，其中两名兄弟姐妹患有 Dyke-Davidoff-Masson 综合征，另一名远亲患者患有脑梗死。我们的报告增加了先前报道的 基因变异导致 CPHD 的内容，并强调了在像苏丹这样近亲结婚率高的国家进行基因检测的重要性。遗传诊断阐明了在受影响成员的一部分中确定的垂体功能减退和脑异常的病因是分开的。此外，由于中枢性皮质醇缺乏症不是 POU1F1 缺乏症的特征，因此可以停止氢化可的松替代治疗。因此，明确遗传病因有助于更合理地管理受影响家庭成员的垂体功能减退症。
