Clinical and Molecular Characterization of a Brazilian Patient with Pit-1 Deficiency

Abstract

We studied a 14 year-old girl with extreme short stature (-9.5 SDS), normal psychomotor development and signs of progressive hypothyroidism. Basal IGF-I and T4 were low. Serum GH was low after insulin-induced hypoglycemia and GH-releasing hormone administration. Both TSH and prolactin were low and did not rise after TRH administration. Gonadotropins were normal and cortisol levels were elevated. In contrast, DHEA-S levels were low and she did not develop pubic hair until 26 years of age, compatible with deficiency of a putative pituitary adrenal androgen stimulating hormone. Pituitary size was reduced on magnetic resonance imaging. Sequencing of the Pit-1 gene revealed a heterozygous C to T transition in codon 271 resulting in substitution of tryptophane for a highly conserved arginine. Her parents were homozygous normal for this locus indicating a de novo mutation with dominant expression. Genetic and phenotypic heterogeneity of patients with Pit-1 gene mutations, particularly the R271W mutation, may reveal further information about the nature of genetic silencing, imprinting, and epigenetic inheritance. The relationship of Pit-1 deficiency to abnormal adrenal secretion remains to be elucidated.

Absent or Delayed Adrenarche in Pit-1/POU1F1 Deficiency

“…Arnhold et al [22] previously reported subnormal adrenarche and delayed pubarche (until age 26 years) in a Brazilian female with Arg271Trp mutation in POU1F1 . The consistent findings in these 9 patients, each of whom had normal ACTH-cortisol secretion, point to a role of POU1F1 in the development of adrenarche and female pubarche.…”

Bases Genéticas dos Distúrbios de Crescimento

“…Pacientes com pan-hipopituitarismo por mutação no PIT-1 foram descritos por diversos grupos em 1992 (30)(31)(32)(33). Várias mutações no PIT-1 têm sido reconhecidas em casos esporádicos e em famílias afetadas com pan-hipopituitarismo (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). A herança pode ser autossômica recessiva, causada por mutações em homozigose ou heterozigose composta, que produzem vários graus de perda de ligação ao DNA ou perda da ativação da transcrição (31,32,(34)(35)(36)40,45).…”

“…A herança pode ser autossômica recessiva, causada por mutações em homozigose ou heterozigose composta, que produzem vários graus de perda de ligação ao DNA ou perda da ativação da transcrição (31,32,(34)(35)(36)40,45). A herança também pode ser autossômica dominante, causada por mutações em heterozigose, porque a proteína mutante tem uma afinidade aumentada pelos sítios promotores de GH e PRL, causando um efeito dominante negativo sobre a proteína normal (33,38,41,46,47). A mutação R271W em heterozigose é de longe a mais freqüente e ocorre em um dinucleotídeo CpG, provável motivo da freqüente recorrência.…”

Longitudinal Hormonal and Pituitary Imaging Changes in Two Females with Combined Pituitary Hormone Deficiency due to Deletion of A301,G302 in the PROP1 Gene1

“…(1). The human POU domain, class I, transcription factor gene (POU1F1), also termed Pit-1, was the first to be recognized and is the most extensively studied (2)(3)(4)(5)(6)(7). Mutations in the Pit-1 gene account for a form of combined pituitary hormone deficiency (CPHD) of GH, PRL, and TSH.…”