Penetrance and clinical consequences of a gross SDHB deletion in a large family

Abstract

Mutations in the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) are inherited in an autosomal dominant manner and are associated with hereditary paraganglioma (PGL) and pheochromocytoma. The phenotype of patients with SDHB point mutations has been previously described. However, the phenotype and penetrance of gross SDHB deletions have not been well characterized as they are rarely described. The objective was to describe the phenotype and estimate the penetrance of an exon 1 large SDHB deletion in one kindred. A retrospective and prospective study of 41 relatives across five generations was carried out. The main outcome measures were genetic testing, clinical presentations, plasma catecholamines and their O-methylated metabolites. Of the 41 mutation carriers identified, 11 were diagnosed with PGL, 12 were found to be healthy carriers after evaluation, and 18 were reportedly healthy based on family history accounts. The penetrance of PGL related to the exon 1 large SDHB deletion in this family was estimated to be 35% by age 40. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion was observed, including low penetrance, diverse primary PGL tumor locations, and malignant potential.

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…73,74 In addition, some research suggests that germ-line and somatic interactions could account for the clinical variability observed among carriers of an identical SDH germ-line mutation, including those within the same family. 46,[75][76][77] In this context, the occurrence of SDH-related tumors is extremely rare in the absence of a germ-line mutation. Indeed, only a few cases have been reported: one extra-adrenal PGL harboring a somatic SDHB mutation (c.299C>T, p.Ser100Phe) and a somatic SDHD mutation in a PCC (c.242C>T, p.Pro81Leu), both displaying LOH; one PA harboring two somatic SDHA mutations (c.725_736del; c.989_990insTA); and tumors from four patients with the Carney triad showing a DNA hypermethylation of SDHC.…”

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

“…Several other neoplasms have been reported in SDHx mutation carriers including papillary thyroid carcinoma (PTC), medullary thyroid carcinoma, pancreatic neuroendocrine tumor, adrenal cortical adenoma, neuroblastoma (NBL), ganglioneuroma (GN), adenomatoid tumor of the adrenal gland, melanoma, lung cancer, breast carcinoma, oesophageal cancer, rectal and ovarian carcinomas, uterine adenocarcinoma, uterine leiomyoma, testicular seminoma, bladder cancer, meningioma, oligodendroglioma, cecal polyps, and hematolymphoid malignancies (7,8,9,10,11,12,13,14,15,16,17,18,19).…”

A Large Deletion in the Succinate Dehydrogenase B Gene (SDHB) in a Japanese Patient with Abdominal Paraganglioma and Concomitant Metastasis

“…while the majority of patients undergoing SDHB mutation analysis have missense and nonsense mutations, some mutation negative patients have been reported to carry either large partial or total deletions of the SDHB gene [10][11][12][13][14][15][16][17][18]. to investigate this possibility, we carried out MLPA and identified a heterozygous SDHB gene deletion encompassing sequences corresponding to the promoter region, exon 1 and exon 2 ( Fig.…”

“…Given that only a small number of SDHB deletion cases have been described [10][11][12][13][14][15][16][17][18], it is difficult to meaningfully compare the phenotypes and penegest to us that these tests capable of detecting such large deletions, such as MLPA, should be made routine. Conceivably, MLPA could be used to screen for large deletions in all three SDHx genes in a single test.…”

“…Since large deletions are rare and are undetectable using this method, neither the frequency nor the clinical manifestation associated with large SDHB deletions is well known. recently, in addition to these mutations, the use of methods such as multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex PCR of short fluorescent fragments (QmPSF) have resulted in increased reports of large SDHB deletions [10][11][12][13][14][15][16][17][18].…”