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

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Vieira, Teresa C. [UNIFESP] ; Dias-da-Silva, Magnus Régios [UNIFESP] ; Cerutti, Janete Maria [UNIFESP] ; Brunner, Elisa [UNIFESP] ; Borges, M. [UNIFESP] ; Arnaldi, Liliane Aparecida Teixeira [UNIFESP] ; Kopp, P. ; Abucham, Julio [UNIFESP] (2003)

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.
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