Familial pheochromocytomas and paragangliomas: Stories from the sign-out room
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Stories From the Sign-Out Room
Familial Pheochromocytomas and Paragangliomas: Stories From the Sign-Out Room Aurel Perren1 and Paul Komminoth2 Abstract In this overview we present five patients with apparently sporadic pheochromocytomas or paragangliomas which turned out to be associated with an inheritable familial disease. For each patient a family history together with clinical, morphological, as well as molecular data are reported. The identified syndromes include multiple endocrine neoplasia type 2 (MEN2), von Hippel–Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), and familial pheochromocytoma/paraganglioma syndrome (SDHx). A brief summary of phenotypes, the genes involved, and typical mutations in these syndromes is provided. Key Words: Pheochromocytoma; paraganglioma; MEN2; VHL; NF1; SDH.
Introduction
1
Institute of Surgical Pathology, University Hospital Zürich, Switzerland and 2Institute of Pathology, Kantonsspital Baden, Switzerland. Address correspondence to Dr. Paul Komminoth, Institute of Pathology, Kantonsspital Baden, Switzerland. E-mail: paul. [email protected] Endocrine Pathology, vol. 17, no. 4, 337–344, Winter 2006 © Copyright 2006 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046-3976/1559-0097 (Online)/ 06/17:337–344/$30.00
Pheochromocytomas (PCC) and paragangliomas (PGL) are neural crest–derived neuroendocrine tumors. They arise in the adrenal medulla and in paraganglia, respectively. Tumors of the adrenal medulla and of sympathetic paraganglia may produce cathecholamines and cause accompanying clinical symptoms, whereas paraganglia arising in cranial and thoracic branches of the glossopharyngeal and vagus nerve become clinically apparent by local symptoms. Ten to 20% of PCCs and PGLs occur in a familial setting and are due to a germline mutation of the Ret, VHL, NF1, SDHB, SDHC, or SDHD gene. In this overview, a patient history is reported for each syndrome and clinical, morphological, as well as genetic features are briefly summarized. To illustrate the clinical context of the syndromes and make pathologists more aware, the following patients were presented at the companion meeting of the “Endocrine Pathology Society” at the 2006 Annual Meeting of the United States & Canadian Academy of Pathology.
All patients gave informed consent for germline analysis. Patient 1: RET A 28-yr-old women was diagnosed and operated on for an adrenal pheochromocytoma (PCC). The family history was negative and therefore genetic testing was not performed. Five years later our patient developed a metastasizing medullary thyroid carcinoma (MTC) and a multiple endocrine neoplasia type 2a (MEN2a) syndrome was now suspected. Mutation analysis of the RET protooncogene on chromosome 10q11.2 using blood DNA revealed an activating germ-line point mutation in a cystein codon of exon 11 (C634R), which is typical for a MEN2a syndrome. This clinical presentation of a MEN2a syndrome is unusual. Owing to the high penetrance of MTC in disease gene carriers, the family history is usually pos
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