Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family protocadherins that have high functional redundancy. identified seven variants, four which putatively damaging, FAT2 DCHS2 six recruited through a cohort mostly ectopic posterior gland and/or interruption. All had growth two presented multiple deficiencies small glands. were strongly expressed mesenchyme surrounding normal developing human pituitary. analyzed Dchs2-/- mouse mutants anterior hypoplasia partially penetrant infundibular defects. Overlapping abnormalities distinct morphogenesis observed Fat4-/- Dchs1-/- but all animal models displayed commitment cell type. Together our data implicate hypothalamic-pituitary development identify as candidates underlying such