Familial Combined Pituitary Hormone Deficiency due to a Novel Mutation R99Q in the Hot Spot Region of Prophet of Pit-1 Presenting as Constitutional Growth Delay

Abstract

Combined pituitary hormone deficiency (CPHD) is characterized by impaired production of GH and one or more of the other anterior pituitary hormones. Prophet of Pit-1 (PROP-1), one of the pituitary specific homeodomain transcription factors, is involved in the differentiation of the anterior pituitary cells (somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs), and PROP-1 gene mutations may interfere with the development of these cells, resulting in CPHD. We performed molecular analyses of the PROP-1 gene in two siblings, born to consanguineous parents, who presented with short stature. The index patient, a boy, was initially diagnosed with constitutional growth delay based on familial short stature, low parental target height, normal GH secretion, and imaging of the pituitary gland. On follow-up, auxological data and pubertal delay prompted a thorough reevaluation, which documented GH, TSH, and gonadotropin deficiencies. Direct sequencing of the PROP-1 gene revealed a novel homozygous transition 296G-->A in exon 2 in the two affected siblings. The mutation substitutes a highly conserved arginine by a glutamine at codon 99 (R99Q) in the second helix of the DNA-binding domain of the PROP-1 protein. Compared with wild-type PROP-1, R99Q displays a significant decrease in DNA binding on a paired box response element (PRDQ9) and trans-activation of a luciferase reporter gene. The findings emphasize the importance of repeated evaluations and illustrate that patients with CPHD associated with PROP-1 mutations present with a phenotypic spectrum, suggesting that the consequences of distinct PROP-1 mutations may be diverse and/or that additional factors, such as modifier genes, may have an impact on their expressivity.

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

“…The same happened with his older sister who looked for medical attention only at the age of 15 years for lack of puberty, while her stature was compatible with her target height and she had no symptoms of other pituitary hormone deficiencies (table 3). The phenotype of these siblings is also compatible with a mild PROP1 deficiency (32).…”

“…The mutation 296G>A predicts an amino acid change at codon 99 replacing a highly conserved arginine by a glutamine (R99Q) in the second helix of the paired DNA-binding homeodomain of PROP1. The mutant protein presents a weak binding to its target DNA sequence but still preserves some functional activity (32).…”

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

“…CPHD has been documented in patients with mutations in several transcription factors involved in pituitary development and hormone expression, specifically POU1F1 (PIT1), PROP1, LHX3, LHX4, and HESX1 (for review: (27)). Among these defects, PROP1 mutations are by far the most common and they have been reported in several Brazilian families (28)(29)(30)(31)(32).…”

Terapia de reposição hormonal no hipopituitarismo

“…Na infância, tumores como craniofaringeomas e germinomas supra-selares, a granulomatose de células de Langerhans (Histiocitose X), a anóxia perinatal, o traumatismo crânio-encefálico, as infecções do sistema nervoso central, assim como a neurocirurgia e a radioterapia craniana podem causar DGH. Entre os defeitos genéticos conhecidos estão as mutações em genes de expressão hipofisária (genes do GH, do receptor do GHRH, e dos fatores de transcrição hipofisários: Pit-1, PROP-1, Rpx, Lhx3, e Lhx4) (1)(2)(3)(4)(5)(6)(7)(8), as alterações congênitas da linha média e a agenesia hipofisária, cujas bases moleculares ainda são desconhecidas.…”