Detection of genetic hypopituitarism in an adult population of idiopathic pituitary insufficiency patients with growth hormone deficiency Helena Filipsson Nystro ¨m • Alexandru Saveanu • Edna J. L. Barbosa • Anne Barlier • Alain Enjalbert • Camilla Glad • Jenny Palming • Gudmundur Johannsson • Thierry Brue Published online: 5 December 2010 Ó Springer Science+Business Media, LLC 2010 Abstract Idiopathic pituitary insufficiency (IPI) is diag- nosed in 10% of all hypopituitary patients. There are sev- eral known and unknown aetiologies within the IPI group. The aim of this study was to investigate an adult IPI population for genetic cause according a screening sche- dule. From files of 373 GH deficient (GHD) patients on GH replacement 50 cases with IPI were identified. Of the 39 patients that approved to the study, 25 patients were selected for genetic investigation according to phenotype and 14 patients were not further tested, as sporadic isolated GHD (n = 9) and GHD with diabetes insipidus (n = 5) have low probability for a known genetic cause. Geno- typing of all coding exons of HESX1, LHX4, PROP1, POU1F1 and GH1 genes were performed according to a diagnostic algorithm based on clinical, hormonal and neuroradiological phenotype. Among the 25 patients, an overall rate of 8% of mutations was found, and a 50% rate in familial cases. Among two sibling pairs, one pair that presented with complete anterior pituitary insufficiency, had a compound heterozygous PROP1 gene mutation (codons 117 and 120: exon 3 p Phe 117 Ile (c349 T [ A) and p Arg 120 Cys (c358 C [ T)) with a phenotype of very late onset ACTH-insufficiency. In the other sibling pair and in the sporadic cases no mutation was identified. This study suggests that currently known genetic causes are rare in sporadic adult IPI patients, and that systematic genetic screening is not needed in adult-onset sporadic cases of IPI. Conversely, familial cases are highly suspect for genetic causes. Keywords Genetics Á PROP1 Á Adult hypopituitarism Á Idiopathic pituitary insufficiency Á GHD Introduction Hypopituitarism is a common feature in pituitary diseases and is most commonly caused by pituitary tumours [1, 2]. However, a small group of patients, in whom no obvious lesion is detected, is qualified as idiopathic pituitary insufficiency (IPI). In recent years, several genetic muta- tions have been discovered in human [3], which may explain some of the IPI cases. A cascade of signalling molecules and transcription factors are required for the development of the pituitary and its hormonal production [4, 5]. In humans, alterations of genes encoding several of these factors have been identified to cause hypopituitarism; both isolated GH deficiency (IGHD) and combined pituitary hormone defi- ciencies (CPHD) [3, 5]. Most cases of IGHD are idiopathic, but syndromic cases have been identified [6]. The most commonly identified genetic cause in CPHD patients is a H. F. Nystro ¨m (&) Á E. J. L. Barbosa Á C. Glad Á J. Palming Á G. Johannsson Department of Endocrinology, Sahlgrenska Academy, University of Gothenburg, Gro ¨na Stra ˚ket 8, 41345 Gothenburg, Sweden e-mail: helena.filipsson@telia.com A. Saveanu Á A. Barlier Á T. Brue Department of Endocrinology, Centre Hospitalo-Universitaire Timone, Marseille, France A. Saveanu Á A. Barlier Á A. Enjalbert Laboratory of Biochemistry and Molecular Biology, Centre Hospitalo-Universitaire Conception, Marseille, France A. Saveanu Á A. Barlier Á A. Enjalbert Á T. Brue Laboratory CNRS—UMR 6231, Centre de Recherche en Neurobiologie—Neurophysiologie de Marseille—CRN2M, Universite ´ de la Me ´diterrane ´e—Universite ´ Paul Ce ´zanne-CNRS, Marseille, France 123 Pituitary (2011) 14:208–216 DOI 10.1007/s11102-010-0278-8