Department of Pediatric Endocrinology and Diabetes, Marmara University School of Medicine, Ustkaynarca/Pendik, Istanbul, Turkey.
Department of Medical Genetics, Marmara University School of Medicine, Ustkaynarca/Pendik, Istanbul, Turkey.
J Clin Endocrinol Metab. 2021 Sep 27;106(10):e4142-e4154. doi: 10.1210/clinem/dgab352.
Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extrapituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut, and pancreatic development.
This work aims to characterize 2 patients with syndromic hypopituitarism due to FOXA2 gene defects.
We report a novel heterozygous nonsense c.616C > T(p.Q206X) variant that leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the glucose transporter type 2 (GLUT2)-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 Mb deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment.
Our 2 cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.
导致先天性垂体功能减退的垂体发育障碍可分为孤立性或与垂体外异常相关（综合征性垂体功能减退）。大量综合征性垂体功能减退病例与转录因子的突变有关。叉头框 A2（FOXA2）是一种转录因子，在中枢神经系统、前肠和胰腺发育中起关键作用。
本研究旨在对 2 例因 FOXA2 基因突变导致的综合征性垂体功能减退患者进行特征分析。
我们报告了一种新的杂合性无义突变 c.616C>T（p.Q206X），导致截短蛋白缺失 FOXA2 的部分 DNA 结合域，从而削弱葡萄糖转运蛋白 2（GLUT2）-荧光素酶报告基因的转录激活。该患者是文献中描述的第 6 例 FOXA2 突变患者，也是首例表现为胰腺发育不良的患者。我们还报告了第 2 例新的散发性 20p11.2 缺失 8.53Mb 的患者，该缺失包括 FOXA2，患者发生了对磺脲类药物治疗有反应的糖尿病。
我们的 2 个病例扩大了 FOXA2 相关疾病的分子和临床谱，报道了首例无义突变和首例胰腺发育不良病例。
