Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations

Abstract

Background: The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations.

Methods: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis.

Results: We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm.

Conclusions: Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life.

Figure 1

Patient 1 – pedigree and immunohistochemistry. a) An arrow indicates the proband. Filled boxes indicate paraganglioma and plus or minus the SDHD mutation status. NT = not tested. b) Chromosome 11 haplotypes of family members. Microsatellite markers are shown with genomic location (marker D11S4177 is close to the telomere of the p arm. Marker D11S4098 is close to the telomere of the q arm), and the position of SDHD is indicated. Alleles in bright yellow blocks represent the probable disease haplotype, present in the proband, mother and maternal grandmother. Other colors represent probable additional haplotypes in the family and possible recombinations; nd = not determined. ci) SDHB immunohistochemistry of the pheochromocytoma, 25×. Inset, adrenal cortex positive for SDHB, 25×. cii) Detail of adrenal medulla, 200×, with inset of positive cortex, 200×.

Figure 2

Patient 1 – tumor analysis. a) Sanger sequencing of SDHD in normal (ai) and tumor (aii) DNA. Arrows indicate the relevant nucleotides in the heterozygous patient. b) Typical profiles of microsatellite marker alleles showing loss of heterozygosity. Arrows indicate the allele lost. c) Table indicating loss of microsatellite marker alleles and parental origin, with approximate positions indicated on an ideogram of chromosome 11.

Figure 3

Patient 2 – pedigree, DNA and tumor analysis. a) MRI of the skull base in patient 2, showing a probable vagal body tumor (white arrow). b) Pedigree of family 2 - arrow indicates the proband, filled boxes indicate paraganglioma, and plus or minus the SDHD mutation status. NT = not tested. c) Chromosome 11 haplotypes of family members. Alleles in bright yellow blocks represent the likely disease haplotype, present in all mutation carriers. Other colors represent probable additional haplotypes in the family and possible recombinations. The proband and siblings all carry the disease haplotype. d) Histochemistry and immunohistochemistry: d1) HE staining of adrenal tumor, 25×, with inset 200×. d2) SDHB immunohistochemistry of adrenal tumor, 25×. Inset, chromogranin A staining, 25×. e) Sanger sequencing of SDHD in normal and tumor DNA. f) Typical profiles of microsatellite marker alleles showing no loss of heterozygosity.

Figure 4

Patient 4 – pedigree, DNA and tumor analysis. a) Arrow indicates the proband, filled boxes indicate paraganglioma, plus or minus the SDHD mutation status, and question marks indicate suspicious but unconfirmed phenotypes. b) Chromosome 11 haplotypes of immediate family. Microsatellite markers are shown with genomic location. Alleles in yellow blocks represent the probable disease haplotype. c) Histochemistry and immunohistochemistry: c1) HE staining of JT PGL, 25×. c2) SDHB immunohistochemistry, 25×. d) Sanger sequencing of SDHD in normal (e1) and tumor (e2) DNA. e) Typical profiles of microsatellite marker alleles showing no loss of heterozygosity.