title: Familial nonsyndromic pheochromocytoma.
abstract: Judging from recent data, heritable forms account for 30-40% of pheochromocytomas. The molecular basis for the familial pheochromocytoma has been largely elucidated and the role of germline mutation of the VHL, RET, SDHB, and SDHD genes has been established. However, on genotyping a group of 172 sporadic or familial pheochromocytomas, we characterized four unrelated probands with familial pheochromocytomas without any sequence variants of RET (exons 8, 10, 11, 13, 14, 15, and 16) or the entire coding sequence of VHL, SDHB, SDHC, SDHD, and EGLN3 (exon-intron boundaries included). The proband of family 1 is a man who had a bilateral pheochromocytoma at the age of 32 and a local recurrence at the age of 48 years. His brother died of malignant pheochromocytoma and his nephew died suddenly of an undiagnosed pheochromocytoma. The proband of family 2 is a female who had a 5-cm benign adrenal pheochromocytoma at the age of 34 years, while her cousin (maternal branch) had a monolateral pheochromocytoma at the age of 42 years. No other tumors had been reported in either family. The proband of family 3 is a female who had a bilateral pheochromocytoma at the age of 66 years. Her sister had a bilateral pheochromocytoma and breast cancer at the age of 54 years. Several other tumors were recorded in this family, including laryngeal cancer, leukemia, and a case of medullary thyroid carcinoma (MTC) in one brother. MTC was naturally ruled out in the proband and her sister. In family 4, the proband was a female who had a bilateral pheochromocytoma at the age of 46 years and a local recurrence a few years later, with liver metastases from the pheochromocytoma. Her brother had a monolateral benign pheochromocytoma. The proband also had a melanoma and bilateral renal cysts. This case revealed a VHL sequence variant IVS2+43 A>G, which was also found in one other unrelated sporadic pheochromocytoma. VHL mRNA integrity is currently being evaluated. The proband had no cerebellar or spinal NMR findings or retinal alterations. In family 5, the proband was a female who had a right adrenal pheochromocytoma at the age of 50 years and a breast cancer at 49 years of age. Her mother had had a right adrenal pheochromocytoma at 61 years of age. Although other molecular mechanisms, such as particular variants in untranslated regions or partial gene deletions, cannot be ruled out, we think finding families with nonsyndromic pheochromocytoma without any RET, VHL, SDHB, SDHC, SDHD, or EGLN3 mutation may argue in favor of the presence of other pheochromocytoma susceptibility genes.
authors.affiliation: Endocrinology Unit, Department of Medical and Surgical Sciences, University Hospital of Padova, Padova, Italy. giuseppe.opocher@nipd.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Iacobone
authors.forename: Antonio
authors.initials: A
authors.lastname: Toniato
authors.forename: Sabina
authors.initials: S
authors.lastname: Sattarova
authors.forename: Zoran
authors.initials: Z
authors.lastname: Erlic
authors.forename: Maddalena
authors.initials: M
authors.lastname: Martella
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
authors.forename: Isabella
authors.initials: I
authors.lastname: Merante Boschin
authors.forename: Laura
authors.initials: L
authors.lastname: Zambonin
authors.forename: Paola
authors.initials: P
authors.lastname: De Lazzari
authors.forename: Alessandra
authors.initials: A
authors.lastname: Murgia
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Pelizzo
authors.forename: Gennaro
authors.initials: G
authors.lastname: Favia
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D010673:Pheochromocytoma / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C497446:VHL protein, human