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PROP1 Gene Screening in Patients with Multiple Pituitary Hormone Deficiency Reveals Two Sites of Hypermutability and a High Incidence of Corticotroph Deficiency

Department of Endocrinology (S.V.-K., P.J., T.B.), Centre Hospitalier Universitaire (CHU) Timone, Marseille, France 13385; Laboratoire ICNE (S.V.-K., A.B., A.D., M.M., I.P.-B., P.J., A.E., T.B.), CNRS UMR 6544, IFR Jean Roche, Marseille, France; Department of Endocrinology (C.T., J.L.C.), Hôpital Saint Vincent de Paul, 75014 Paris, France; Department of Endocrinology (F.B.), Hôpital de l’Antiquaille, 69005 Lyon, France; Department of Endocrinology (P.B.), Hôpital Saint Antoine, 75012 Paris, France; and Department of Endocrinology (R.B.), Hôpital Necker-Enfants Malades, 75015 Paris, France

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

Abstract

Alterations of the gene encoding the pituitary transcription factor PROP1 were associated with congenital forms of multiple pituitary hormone deficiencies in several families. Among 23 patients with multiple pituitary hormone deficiencies screened for a PROP1 gene abnormality, nine belonging to eight unrelated families had homozygous PROP1 gene defects. All mutations were located in exon 2 and affected only two different sites: a homozygous AG deletion at codons 99/100/101 (n = 5); homozygous point mutations affecting codon 73: R73C (n = 2) or R73H (n = 1), and a R73C/R99X double-heterozygous mutation (n = 1). R73H and R99X were never described. All patients were born to unaffected parents, and consanguinity was documented in two patients. They had complete GH, LH-FSH, and TSH deficiencies and normal basal levels of PRL. Delayed ACTH deficiency was diagnosed in four of nine patients. At magnetic resonance imaging the anterior pituitary was hypoplastic in seven patients and hyperplastic in two. This study found two novel mutations (R73H and R99X) and underlines the high incidence of PROP1 gene alterations in patients with multiple pituitary hormone deficiencies. A corticotroph deficiency was frequently observed in association with GH, TSH, and gonadotropin deficiencies and should be carefully sought during follow-up.

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