背景:染色体域解旋酶DNA结合蛋白7(CHD7)基因中的杂合功能丧失突变可引起CHARGE综合征,其特征是各种先天性异常。大多数CHARGE综合征患者表现为先天性促性腺激素低性腺功能减退症(HH),和联合垂体激素缺乏症(CPHD)也可以存在。而CHD7突变已在一些分离的HH患者中发现,而没有CHARGE综合征的诊断,目前尚不清楚在不符合CHARGE综合征标准的CPHD患者中是否能发现CHD7突变.
方法:我院收治一名33岁女性。她患有原发性闭经,阴毛和乳房发育均处于Tanner阶段2。她被诊断出患有CPHD(HH,生长激素缺乏,和中枢甲状腺功能减退症),和一个杂合的罕见错义突变(c.6745G>A,鉴定了CHD7基因中的p.Asp2249Asn)。我们的保守性分析和大量的计算机模拟分析表明,这种突变具有致病潜力。她有轻微的智力障碍,CHARGE综合征的一个次要特征,但不符合CHARGE综合征的标准。
结论:我们报告了一例CHD7突变但无CHARGE综合征的CPHD罕见病例。这个案例为CHD7突变引起的表型提供了有价值的见解。根据垂体功能减退症的严重程度和CHARGE特征,CHD7突变可以具有连续的表型谱。因此,我们想提出CHD7相关综合征的新概念。
BACKGROUND: Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (
CHD7) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas
CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome.
METHODS: A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome.
CONCLUSIONS: We report a rare
case of CPHD harboring
CHD7 mutation without CHARGE syndrome. This
case provides valuable insights into phenotypes caused by
CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of
CHD7-associated syndrome.