title: 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.
authors.affiliation: Division of Endocrinology, Department of Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Vieira
authors.forename: Magnus R
authors.initials: MR
authors.lastname: Dias da Silva
authors.forename: Janete M
authors.initials: JM
authors.lastname: Cerutti
authors.forename: Elisa
authors.initials: E
authors.lastname: Brunner
authors.forename: Mariana
authors.initials: M
authors.lastname: Borges
authors.forename: Liliane T
authors.initials: LT
authors.lastname: Arnaldi
authors.forename: Peter
authors.initials: P
authors.lastname: Kopp
authors.forename: Julio
authors.initials: J
authors.lastname: Abucham
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D002648:Child; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D006130:Growth Disorders / Q000209:etiology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010907:Pituitary Hormones / Q000172:deficiency*; D017434:Protein Structure, Tertiary / Q000235:genetics*; D014162:Transfection
chemical_list: D018398:Homeodomain Proteins; D010907:Pituitary Hormones; C102134:Prophet of Pit-1 protein; D004247:DNA