Precocious or early puberty in patients with combined pituitary hormone deficiency due to POU1F1 gene mutation: case report and review of possible mechanisms.

Abstract

Central precocious puberty (CPP) or early puberty (EP) is a rare entity in combined pituitary hormone deficiency (CPHD), the latter caused by mutations in pituitary transcription factor genes. The early onset of puberty in two patients with CPHD with POU1F1 gene mutation was evaluated. A 3-month-old boy was diagnosed with central hypothyroidism, and l-thyroxine was commenced. He was referred for the evaluation of short stature at 20months of age. Anthropometric evaluation revealed severe short stature (-6.1 SDS), and growth hormone (GH) and prolactin deficiencies were diagnosed. Homozygous POU1F1 gene mutation (c.731T>G, p. I244S) was also detected. Testicular enlargement and high luteinizing hormone (LH) levels were observed at 7years and 9months of age while he was on GH and l-thyroxine treatment. Due to rapid progression of puberty, gonadotropin-releasing hormone analogue (GnRHa) was initiated at 11.3years of age. This patient recently turned 19.2years old, and his final height was -2.3 SDS. The second patient, a 6-month-old boy, was also referred for growth retardation. His height was -2.7 SDS, and GH and thyroid-stimulating hormone (TSH) deficiencies were diagnosed. He also had homozygous (c.10C>T, p.Q4*) POU1F1 gene mutation. Onset of puberty was relatively early, at 10years, with advanced bone age. He was on GnRHa treatment between 11.5 and 12.5years of age. Recent evaluation of the patient was at 13.6years of age, and he is still on levothyroxine and GH treatment. The relationship between the POU1F1 genotype and CPP or EP has not as yet been firmly established in humans. Animal studies have revealed that the Pou1f1 gene has a major effect on regulation of GnRH receptor function and the Gata2 gene. It has also been demonstrated that this gene controls gonadotrope evolution and prevents excess gonadotropin levels. Further studies are, however, needed to elucidate the relation between POU1F1 function and CPP.