A novel POU1F1 mutation (p.Thr168IlefsX7) associated with an early and severe form of combined pituitary hormone deficiency: functional analysis and follow-up from infancy to adulthood

Context POU1F1 encodes a pituitary-specific homeodomain transcription factor that is crucial for development and differentiation of anterior pituitary cell types producing GH, TSH and PRL. Although the first mutations in humans were reported in 1992, to date, less than 25 different mutations of POU1F1 have been identified worldwide. Objectives To describe the long-term follow-up of a 22-year-old male of Israeli Arab Muslim origin, born to a consanguineous union, with congenital hypothyroidism, who presented with life-threatening hypoglycaemic episodes and severe growth retardation from infancy. To identify the molecular basis of this severe disease. Main Outcome Measures Endocrine investigations, neuroimaging, sequencing of POU1F1 and assessment of the identified mutated POU1F1's ability to transactivate three specific targets (POU1F1, TSH beta and PRL). Results Central hypothyroidism was diagnosed at the age of 2 months and GH and PRL deficiencies were documented at 9 months. MRI at 14 years revealed a hypoplastic adenohypophysis. The patient underwent spontaneous but delayed puberty. A novel disease-causing mutation (c.502insT) was identified in the homozygous state in exon 4 of POU1F1. This insertion results in a frameshift introducing an early termination codon at position 174 (p.Thr168IlefsX7), leading to a severely truncated protein lacking the entire homeodomain. This mutation abolishes POU1F1's transactivation properties on three target promoters. Conclusion This study, which identifies a novel loss-of-function mutation in POU1F1, describes the phenotype of a rare condition in a patient followed from the first weeks of life to adulthood. The severity of the central hypothyroidism should alert clinicians to assess other pituitary axes, in particular GH and prolactin.