Endocrine Abstracts

Background: Mutations in POU1F1/PIT1 gene, a pituitary-specific transcription factor, affect the development and function of the anterior pituitary and lead to combined pituitary hormone deficiency (CPHD).

Objective: The clinical and genetic analysis of the twin patients presenting with mild form of CPHD and functional characterization of identified mutation.

Cases: Five-year-old identical twin brothers were referred to determine the etiology of their short stature in 1993. They were the first children of unrelated Japanese parents, born small for gestational age by caesarean section at term. Their heights were both less than −2.5 S.D. with delayed bone ages. Both parents were healthy, normal height father and rather small mother (−1.9 S.D.). Based on the clinical and endocrinological findings, they were diagnosed as having partial CPHD, with mild GH and PRL deficiencies and borderline TSH deficiency. It was decided that medical therapy, including GH and levothyroxine administration, was not necessary. Their growth chart showed similar growth curves throughout the entire period of growth, and indicated lack of pubertal growth spurt. Their adult heights were −1.8S.D. and −1.9S.D..

Results: A novel heterozygous splice site mutation (Ex2+1G>T; c.214+1G>T) was detected. This mutation was also present in their undiagnosed mother, but not in any of the controls. In vitro splicing studies suggested this mutation to result in an in-frame skipping of exon2. Heterologous expression studies of the mutated POU1F1 protein showed only modest reductions in its transactivation activities in HEK293T cells, while acting as a dominant-negative inhibitor of the endogenous activities of POU1F1 in pituitary GH3 cells.

Conclusions: This is the first report of a mutation at the exon2 donor splice site of POU1F1. The addition of this mutation to the growing list of pathological POU1F1 mutations may provide deeper insights into clinical heterogeneity and better understanding of the structure-function relationships of POU1F1.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.