CLINICAL STUDY Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features Elisabetta Ferretti 1 , Marie-Lise Jaffrain Rea 1 , Carmela Asteria 2 , Domenica Di Stefano 5 , Vincenzo Esposito 4 , Luigi Ferrante 4 , Pantaleo Daniele 1 , Claudio Tiberti 3 , Massimo Gallucci 1 , Cesare Bosman 5 , Edoardo Alesse 1 , Alberto Gulino 5 , Paolo Beck-Peccoz 2 and Guido Tamburrano 3 1 Department of Experimental Medicine, University of L'Aquila, Italy, 2 Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, Italy, 3 Department of Clinical Sciences, 4 Department of Neurological Sciences and 5 Department of Experimental Medicine and Pathology, University of Rome `La Sapienza', Italy (Correspondence should be addressed to E Ferretti, Dipartimento di Medicina Sperimentale, Universita Á degli Studi di L'Aquila, Via Vetoio-Coppito 2, 67100 L'Aquila, Italy; Email: eliferretti@tin.it) Abstract Objective: Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain. Materials and methods: In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course. Results: Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values. Conclusion: To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease. European Journal of Endocrinology 144 227±235 Introduction Pituitary adenomas are usually sporadic tumours. Most of them are monoclonal proliferations, with some well- recognised abnormalities of oncogene or tumour sup- pressor gene structure or expression, and endogenous and exogenous factors such as growth factors, neuro- peptides and steroids contributing to their progression (1, 2). In about 4% of cases, pituitary tumours are part of multiple endocrine neoplasia type 1 (MEN-1), with a higher incidence in patients with prolactinomas (3). A familial susceptibility, mainly based on inherited muta- tions of tumour suppressor genes, has been well recognised in some human cancers (4). Similarly, a small number of pituitary tumours occur in McCune± Albright disease or with a familial aggregation, as a component of MEN-1 syndrome or Carney complex, but some of them may present as apparently isolated familial pituitary adenomas (2). Until now, 72 cases of familial growth hormone (GH)-secreting pituitary adenomas have been reported in 25 families (5±18). In addition, seven cases of prolactinomas in four families (19, 20) and two cases of familial non-functioning pituitary adenoma in a family (21) have been described. To our knowledge, no familial gonadotroph, thyrotroph, corticotroph or clinically silent GH-secreting adenomas have been reported yet. Recently, six families with GH-secreting pituitary adenomas have been negatively screened for genetic abnormalities of the MEN-1 gene, three for loss of heterozygosity and six for mutations (11±18), suggest- ing that familial acromegaly is a distinct entity. Although a linkage to chromosome 11q13.1 and a potential second locus at chromosome 2p16-12 have been recently proposed (22), the pathogenesis of familial pituitary adenomas remains largely unknown. In particular, no somatic point mutation in the Gsa gene, ISSN 0804-4643 European Journal of Endocrinology (2001) 144 227±235 q 2001 Society of the European Journal of Endocrinology Online version via http://www.eje.org