Abstract
Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency, and 2 presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2–/– mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4–/– and Dchs1–/– mouse mutants, but all animal models displayed normal commitment to anterior pituitary cell types. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.
Highlights
Developmental pituitary defects affect 0.5 in 100,000 live births and may lead to varying degrees of pituitary hormone deficiency [1, 2]
We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption
We studied 28 patients with congenital pituitary abnormalities of ectopic posterior pituitary (EPP) and/or PSIS with whole-exome sequencing (WES), focusing on all 4 FAT genes, as well as DCHS1 and DCHS2
Summary
Developmental pituitary defects affect 0.5 in 100,000 live births and may lead to varying degrees of pituitary hormone deficiency [1, 2]. A region of the ventral diencephalon of the hypothalamus termed the infundibulum, and a region of the oral epithelium termed Rathke’s pouch (RP), evaginate toward each other to form the pituitary gland. These actions are mediated by an array of developmental signals as well as the action of the surrounding mesenchyme The vast majority of cases with pituitary developmental defects are sporadic and of unknown cause; few cases appear to be familial, and they are often attributed to germline biallelic mutations in transcription factors involved in the development of the infundibulum [5,6,7]. A whole-exome sequencing (WES) screen of patients with such defects identified compound defects in DCHS1 among other gene variants, indicating that protocadherins could be involved in pituitary development [8]
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