Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation.
BACKGROUND
Inactivating mutations of SDHD, which is mapped to 11q23 and encodes the cybS subunit of succinate dehydrogenase, predispose to hereditary paraganglioma (PGL) and/or pheochromocytoma. So far no disease was shown to occur in case of maternal transmission of a SDHD mutation, suggesting the existence of genomic imprinting. A hypothetic model, involving the loss of the maternal copy of a tumor suppressor gene mapped to 11p15 in the tumoral tissue, has been proposed to explain this mode of inheritance.


OBJECTIVE
Our objective was to investigate the possibility of maternal transmission of SDHD-linked PGL.


METHODS
A three-generation family carrying the SDHD W43X mutation was studied at the clinical, pathological, and genetical levels.


RESULTS
The germline's mutation was probably inherited from the grandfather. In the second generation, three carriers (two females and one male), who had the same at risk 11q13-q23 haplotype, developed multiple cervical PGLs. In the third generation, one boy received the mutation from his mother and developed a glomus tympanicum PGL at 11 yr. He shared only the 11q23 haplotype with the other affected members of the family. Methylation analysis of the differentially methylated region upstream of the maternally expressed H19 gene, mapped to 11p15, showed that the seventh CTCF binding site is hypermethylated in the germline of the affected boy suggesting a gain of imprinting.


CONCLUSIONS
Our data show that maternal transmission of a SDHD-linked PGL, even if a rare event, can occur. Therefore, we propose that children who inherited a pathogenic mutation from their mother should be considered as at risk of PGL.
Pigny
Pascal
P
Laboratoire de Biochimie et Hormonologie, Centre de Biologie et Pathologie, Centre Hospitalier Régional & Universitaire, Lille cedex, France. p-pigny@chru-lille.fr
Vincent
Audrey
A
Cardot Bauters
Catherine
C
Bertrand
Monelle
M
de Montpreville
Vincent Thomas
VT
Crepin
Michel
M
Porchet
Nicole
N
Caron
Philippe
P
D000328:Adult; D000368:Aged; D019175:DNA Methylation; D005260:Female; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*
C491545:SDHD protein, human; D013385:Succinate Dehydrogenase