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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

Division of Endocrinology, Department of Medicine, Universidade Federal de Sao Paulo (T.C.V., M.R.D.d.S., J.M.C., E.B., M.B., L.T.A., J.A.), Sao Paulo, Brazil; and Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University (P.K.), Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Julio Abucham, M.D., Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo 910, Sao Paulo SP 04039-002, Brazil. E-mail: julioabucham{at}nw.com.br.

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 296GA 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.

Footnotes

This work was supported by Grant 97/14182–9 from Fundação de Amparo à Pesquisa do Estado de São Paulo (to T.C.V. and J.A.) and the Premio Dr. Ettore Balli (to P.K.).

Abbreviations: CPHD, Combined pituitary hormone deficiency; CT, computed tomography; GFP, green fluorescent protein; hGH, human GH; MRI, magnetic resonance imaging; PROP-1, Prophet of Pit-1.

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