Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma

Abstract

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.

Figure 1

Family 1, with documented RCC, cardiac PGL, and the germline SDHB R27X mutation. A, Pedigree of family 1. Generation numbers are represented by Roman numerals. Individual numbers are in Arabic numerals. The index patient (proband) is III-1, indicated by the arrow. “Mut+” indicates mutation-positive individuals. B, Sequencing chromatogram representing part of SDHB exon 2. The sequences around codon 27 from a normal control is shown at the top (“Normal”). The germline of the proband showed a heterozygous R27X mutation with a wild-type C and a mutant T (N8168). The tumor DNA shows loss of the wild-type C allele, leaving only the mutant T (T8168). The proband’s mother’s germline (N8104) showed the heterozygous R27X mutation, whereas her tumor (T8104) showed loss of the remaining wild-type allele. (Note that, although the right panel was obtained in reverse sequence, the reverse complement chromatogram, which represents a computer-generated forward sequence, is shown for ease of viewing.)

Figure 2

Family 2, with documented PGL and RCC and germline heterozygous SDHB c.847-50delTCTC mutation. A, Pedigree of family 2. The mutation-positive individuals are indicated by “Mut+.” The index patient is II-2 (5792), indicated by the arrow. B, Sequencing chromatogram in the region of nucleotides 845–855 of SDHB. The wild-type sequence from a normal control is in the top panel (“Normal”). The bar below the TCTC denotes the region of deletion. The germline DNA from both the index patient and her brother showed the heterozygous c.847-50delTCTC microdeletion mutation. Note that, because of the nature of the repeats, we cannot ascertain whether the microdeletion is c.847-50delTCTC or c.848-51delCTCT. When the mutant allele is present heterozygously with the wild type (“5842 germline” and “5792 germline”), the reading frame is shifted at the point of microdeletion. When the wild-type allele is lost, as in all three tumors (“5842 RCC,” “5792 RCC,” and “5792 PGL”), the mutant allele remains.