ESPE Abstracts (2018) 89 FC9.1

aDepartment of Paediatric Endocrinology, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; bDepartment of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA; cUnit of Developmental Endocrinology, Laboratory of Hormones and Molecular Genetics, University of São Paulo, São Paulo, Brazil; dInstitute of Human Genetics, University Hospital Leipzig, Leipzig, Germany; eDivision of Genetics Endocrinology, Cellular and Molecular Endocrinology Laboratory LIM25, Discipline of Endocrinology, Medicine College of University of São Paulo, São Paulo, Brazil; fDivision of Endocrinology, Boston Children’s Hospital and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA; gDivision of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; hDepartment of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA

Background: Hypopituitarism is characterized by deficiency of one or more anterior pituitary hormones. POU1F1 mutations are the second most frequent known cause of combined pituitary hormone deficiency (CPHD). Patients are typically deficient in GH, TSH, and prolactin, although two unrelated cases were reported with isolated GH deficiency (IGHD). To date, all POU1F1 mutations have been reported for the predominantly expressed alpha isoform, which is a transcriptional activator.

Objective: We identified two heterozygous missense variants in a minor, alternative isoform of POU1F1 (POU1F1 beta), which segregated with CPHD or IGHD in two unrelated families. We report the clinical characteristics of these patients and probable mechanism of action.

Results: A German index case presented with secondary hypothyroidism one week after birth. During infancy, she developed severe GH deficiency (height SDS −5.42). Her daughter (birth length −3.45 SDS) was born with severe congenital hypothyroidism due to TSH deficiency (TSH 0.28 mU/l, fT4 5.4 pmol/l). GH therapy was started 6 months after birth because of GH deficiency (height SDS −4.93, GH <0.55 ng/ml, IGF-1 -2.62 SDS, IGFBP-3 -3.77 SDS). Prolactin was very low in both family members. MRI of the pituitaries were normal. Exome sequencing revealed heterozygous variants in POU1F1 beta (c.157T>G, p.S53A) in the index case and her daughter. In a Brazilian family, the index case and her brother (birth length −3.96 SDS) presented with severe short stature (height SDS −4.6 and −4.0) at age 2 years. Both were diagnosed with GH deficiency (GH peak 0.9 and 0.8 ng/ml; GH peak 0.5 ng/ml). Thyroid hormone levels were in the low normal range. The index cases father has short stature (adult height −3.7 SDS) with a low normal IGF-1 (84 μg/l, NR 84–277 μg/l), and a GH peak of 7.6 ng/ml in the insulin tolerance test. GH deficiency was also diagnosed in the index patient’s daughter. Genetic analyses identified heterozygous variants in POU1F1 beta (c.152T>G, p.I51S) in the index case, her brother, father, and daughter. Functional testing revealed that both variants ablate splicing at the acceptor site necessary for producing the alpha isoform, resulting in predominance of the beta isoform, which can act as a repressor.

Conclusion: Variants in the POU1F1 beta coding region interfere with splicing necessary to produce POU1F1 alpha, and are associated with hypopituitarism, ranging from IGHD to CPHD including GH, TSH and prolactin deficiencies.

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