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Submitted on December 21, 2006
Accepted on April 3, 2007
Department of Nephrology, University Medical Center Freiburg, Germany; Institute for Human Genetics and Anthropology, University of Freiburg, Germany; Center of Human Genetics, Freiburg, Germany; Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany; Department of Laboratory Medicine, University Medical Center Freiburg, Germany; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; Istituto Oncologico Veneto IRCCS, Padova, Italy; Department of Hypertension, Institute of Cardiology, Warsaw, Poland; Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy; Department of Dermatology, University of Rome La Sapienza, Rome, Italy ; Department of Endocrinology, Azienda Ospedaliero-Universitaria. Ospedali Riuniti di Ancona, Italy; Medical Clinic I, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Germany; Department of Endocrinology, Ludwig-Maximilians-University of Munich, Germany; Department of Pathology, University of Padova, Italy; Department of of Digestive and Endocrine Surgery University Hospital Nancy, University of Nancy, France; Institute of Nuclear Medicine, Division of Endocrinology, University of Basel, Switzerland; Department of Clinical Pathophysiology, Endocrine Unit, University of Florence, Florence, Italy; Blood Pressure Unit, Department of Cardiovascular Sciences, St George's University, London, Great Britain; Endocrine Surgery Unit, Hammersmith Hospital, London, Great Britain; Centro de Investigaciones Endocrinologicas - CONICET, Buenos Aires, Argentina; Department of Surgery, Kliniken Essen-Mitte, Essen, Germany; Department of Pediatrics, University of Essen, Germany; Department of Endocrinology, Medizinische Hochschule, Hannover, Germany; Department of Pediatrics, University of Leipzig, Germany; Dept. of Internal Medicine I - Endocrine and Diabetes, University of Wuerzburg; Department of Surgery, Hospital of the German Red Cross, Berlin, Germany; Department of Nephrology and Hypertension, University of Berne, Switzerland; Department of Visceral Surgery, University of Halle, Germany; Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie; Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland; Genomic Medicine Institute, Cleveland Clinic Foundation, and Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
* To whom correspondence should be addressed. E-mail: neumann{at}med1.ukl.uni-freiburg.de.
Background: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma who also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.
Materials and Methods: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing high performance liquid chromatography for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity (LOH) analysis using markers in and around NF1 was performed.
Results: There were 37 eligible subjects (ages 14 to 70). Among 21 patients with corresponding tumor available 67% showed somatic loss of the non-mutated allele at the NF1 locus versus 0/12 sporadic tumors (P=0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35%, but RAS-GAP domain (RGD) in only 13%. There did not appear to be an association between any clinical features, in particular pheochromocytoma presentation and severity, and NF1 mutation genotype.
Conclusion: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RGD suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. LOH of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.
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  A. Karagiannis, D. P Mikhailidis, V. G Athyros, and F. Harsoulis Pheochromocytoma: an update on genetics and management Endocr. Relat. Cancer, December 1, 2007; 14(4): 935 - 956. [Abstract] [Full Text] [PDF]
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