A Decade (2001-2010) of Genetic Testing for Pheochromocytoma and Paraganglioma

Abstract

The identification of 9 susceptibility genes for paraganglioma/pheochromocytoma between 2001 and 2010 has led to the development of routine genetic tests. To study the evolution in genetic screening for paraganglioma/pheochromocytoma over the past decade, we carried out a retrospective study on the tests performed in our laboratory from January 2001 to December 2010. A genetic test for paraganglioma/pheochromocytoma was assessed for 2 499 subjects, 1 620 index cases, and 879 presymptomatic familial genetic tests. A germline mutation in a PGL/PCC susceptibility gene was identified in 363 index cases (22.4%): 269 in SDHx genes (137 in SDHB, 100 in SDHD, 30 in SDHC, 2 in SDHA), 64 in VHL, 23 in RET, and 7 in TMEM127. A presymptomatic paraganglioma/pheochromocytoma test was positive in 427 subjects. Advances in molecular screening techniques led to an increase in the total number of mutation-carriers diagnosed each year. Overall, during the last decade, our laboratory identified a germline mutation in 44.7% of patients with a suspect hereditary PGL/PCC and in 8% of patients with an apparently sporadic PGL/PCC. During the past decade, the discoveries of new paraganglioma/pheochromocytoma susceptibility genes and the subsequent progress of molecular screening techniques have enabled us to diagnose a hereditary paraganglioma/pheochromocytoma in about 22% of patients tested in routine practice. This genetic testing is of major importance for the follow-up of affected patients and for the genetic counselling of their families.

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…This analysis should not only include sequence evaluation of coding regions and exon-intron boundaries of target genes, but also large indels or gene rearrangements. These grosser defects, which have been reported in the VHL, SDH and MAX genes [39][40][41][42] , might not be identifiable by WES performed at average depth of coverage. Instead, other…”

DIAGNOSIS OF ENDOCRINE DISEASE: Biochemical diagnosis of phaeochromocytoma and paraganglioma

“…Until now, germline mutations in ten genes have been identified to be responsible for genetic PPGL syndromes including von Hippel-Lindau (VHL), multiple endocrine neoplasia type 2 (RET), neurofibromatosis type 1 (NF1), succinate dehydrogenase subunits A, B, C and D (SDHA/B/C/D), succinate dehydrogenase complex assembly factor 2 (SDHAF2) and the more recently reported transmembrane protein 127 (TMEM127) and MYC associated factor X (MAX) (6,7,8). The presence of these germline mutations identifies patients who are at risk for syndromic presentation, multifocal PPGL (SDHx, RET, TMEM127), recurrent disease (all mutations) or malignancy (SDHB mutation) (9). Furthermore, the detection of somatic mutations in NF1, VHL, RET, MAX, HIF2a and SDHx in at least 17% of sporadic tumours has brought the proportion of all patients with PPGL due to a genetic abnormality to w50% (6,10,11,12).…”

ENDOCRINOLOGY IN PREGNANCY: Pheochromocytoma in pregnancy: case series and review of literature

“…After the diagnosis, pheochromocytoma has been confirmed, genetic counseling should be considered during follow-up, as disease-causing mutations can be found in up to 20-30% of all patients (16,19,20). Also in a series of patients diagnosed with pheochromocytoma during pregnancy, a disease-causing mutation was found in around 30% of patients (5).…”