Pediatric Endocrinology Unit, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia.
J Clin Endocrinol Metab. 2019 Jul 1;104(7):2925-2930. doi: 10.1210/jc.2018-02316.
The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare.
We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity.
Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.
转录因子 RAX 是一种配对型同源蛋白，在脊椎动物物种的眼睛和前脑发育中起着关键作用。RAX 敲除小鼠表现出无眼症、腭裂和异常下丘脑，并显示围产期致死性。在人类中，已报道纯合子或复合杂合 RAX 突变会导致双侧小眼症或无眼症，但没有一致的相关特征。先天性垂体功能减退症可与各种眼部或颅面异常相关；然而，先天性垂体功能减退症、无眼症、腭裂和尿崩症同时发生非常罕见。
我们报告了一例患有无眼症、先天性垂体功能减退症、尿崩症和双侧唇裂和腭裂的儿童，该儿童在 RAX 基因的外显子 1 中存在纯合移码截断突变 c.266delC（p.Pro89Argfs*114）。Rax 敲除小鼠显示出前脑腹侧结构、垂体和 basosphenoid 骨以及腭裂和沿口腔顶部错位的前垂体的缺失。
我们患者的表型比其他患者报道的更严重。虽然大多数先前报道的 RAX 突变患者在其至少一个 RAX 等位基因中显示错义或一些不太严重的突变，但我们的患者是截短突变的纯合子，这将产生严重的、无效的蛋白表型。遗传缺陷的严重程度、敲除小鼠与患者内分泌表型之间的精确匹配以及 RAX 在眼睛和垂体发育以及间脑模式形成中的突出作用表明，RAX 缺失突变可以完全解释观察到的表型。
