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A Familial Form of Congenital Hypopituitarism Due to a PROP1 Mutation in a Large Kindred: Phenotypic and in Vitro Functional Studies

Laboratoire des Interactions Cellulaires Neuro-Endocriniennes (R.R., S.V.-K., A.B., I.P.-B., A.E., T.B.), Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique, Université de la Méditerranée, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine Nord, 13926 Marseille, France; Department of Endocrinology, Diabetology, Farhat Hached Hospital (M.C.-C., L.C.), University of Sousse, Sousse, Tunisia 4000; and Departments of Pediatrics (R.R., J.S.) and Endocrinology (S.V.-K., T.B.), Centre Hospitalo-Universitaire Timone, and Laboratoire de Biochimie et Biologie Moleculaire (A.B., A.E.), Hôpital de la Conception, 13385 Marseille, France

Address all correspondence and requests for reprints to: Thierry Brue, M.D., Ph.D., Hôpital de la Timone, 264 rue St. Pierre, 13385 Marseille Cedex 5, France. E-mail: Thierry.Brue{at}mail.ap-hm.fr.

We report the natural history of a hypopituitarism in a large Tunisian kindred including 29 subjects from the same consanguineous family. The index case was a 9-yr-old girl with severe growth retardation due to complete GH deficiency and partial corticotroph, lactotroph, and thyrotroph deficiencies. Magnetic resonance imaging showed a hyperplastic anterior pituitary. Thirteen of the 28 relatives examined (10 female subjects) had hypopituitarism. In the 14 patients, previously untreated (aged 6–53 yr), height was –5.7 ± 1.7 SD score, and puberty was spontaneously initiated in only two females. Complete GH deficiency was found in all 12 patients investigated, of whom 11 had thyrotroph and eight of 10 had corticotroph deficiency. A homozygous R73C mutation of PROP1 was present in all 10 patients studied, and a heterozygous mutation was found in six unaffected parents or siblings. In vitro the mutant had 11.5% of the transactivation capacity of the wild type and was unable to bind to a high-affinity DNA sequence. This report showed the deleterious effect of the recessive R73C mutation that affects a hot spot of the PROP1 gene and was associated with severe dwarfism, a lack of spontaneous puberty, and a high incidence of early onset of corticotroph deficiency.

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