Alternative titles; symbols
ORPHA: 29072; DO: 0050773;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q12.2 | Pheochromocytoma/paraganglioma syndrome 2 | 601650 | Autosomal dominant | 3 | SDHAF2 | 613019 |
A number sign (#) is used with this entry because of evidence that pheochromocytoma/paraganglioma syndrome-2 (PPGL2) is caused by heterozygous mutation in the SDHAF2 gene (613019), which encodes a protein necessary for flavination of SDHA (600857), on chromosome 11q12.
Pheochromocytoma/paraganglioma syndrome-2 (PPGL2) is an autosomal dominant disorder characterized by the development of neuroendocrine tumors, usually in adulthood. Paragangliomas are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PPGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (Baysal, 2002; Neumann et al., 2004).
For a discussion of genetic heterogeneity of pheochromocytoma/paraganglioma syndrome, see PPGL1 (168000).
Van Baars (1980) and van Baars et al. (1981, 1981, 1982) reported a large Dutch family in which 26 persons had nonchromaffin paragangliomas of the head and neck. The disorder was inherited in an autosomal pattern spanning 6 generations, with increased penetrance with age. There was a fairly equal distribution of different locations in the head and neck, with the most common location at the carotid body, and a tendency toward tumor multiplicity.
By linkage analysis and haplotyping of the large Dutch family reported by van Baars et al. (1981), Mariman et al. (1993) found linkage to a region on chromosome 11q14-q21 proximal to the tyrosinase locus (TYR; 606933) (maximum lod score of 5.4 at theta = 0.0 between FGF3 164950 on 11q13.3 and D11S527 on 11q13.5). The pattern of inheritance was consistent with maternal genomic imprinting. In the same family, Mariman et al. (1995) refined the putative disease locus to a 5-cM region on 11q13.1 between D11S956 and PYGM (608455). A maximum lod score of 7.62 at theta = 0.0 was obtained for D11S480. The interval did not overlap with the PGL1 locus for glomus tumors at 11q22.3-q23.3.
The transmission pattern of PPGL2 in the family reported by van Baars et al. (1982) and Hao et al. (2009) was consistent with autosomal dominant inheritance.
In the large Dutch family with hereditary paragangliomas described by van Baars et al. (1982), Hao et al. (2009) found a heterozygous missense mutation in the SDH5 gene on chromosome 11q13.1 encoding a change of a glycine at position 78 to an arginine (G78R; 613019.0001). This mutation was not detected in 400 unaffected control individuals. Within the family, the mutation was found to cosegregate with the disease haplotype in all 45 individuals who inherited this haplotype, and was not detected in 44 unaffected members without this haplotype. Thirty-three individuals with the mutation had developed the disease, but not 7 individuals (median age 74 years) who inherited the mutation from their mothers. This suggested an SDHD (602690)-like parent of origin-specific inheritance pattern. Only 5 individuals with a paternal mutation (median age 42 years) had not developed overt paragangliomas. Because penetrance of this disease increases with age, Hao et al. (2009) suggested that these individuals may develop tumors, or that tumors were already present but undetected.
Hensen et al. (2012) determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (87.1%), followed by SDHAF2 (6.7%), SDHB (185470) (5.9%), and SDHC (602413) (0.3%). Almost 70% of all carriers had the founder mutation D92Y (602690.0004) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The founder G78R mutation in SDHAF2 (613019.0001) was identified in 46 cases from 4 families. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere.
Baysal, B. E. Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet. 39: 617-622, 2002. [PubMed: 12205103] [Full Text: https://doi.org/10.1136/jmg.39.9.617]
Hao, H.-X., Khalimonchuk, O., Schraders, M., Dephoure, N., Bayley, J.-P., Kunst, H., Devilee, P., Cremers, C. W. R. J., Schiffman, J. D., Bentz, B. G., Gygi, S. P., Winge, D. R., Kremer H., Rutter, J. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325: 1139-1142, 2009. [PubMed: 19628817] [Full Text: https://doi.org/10.1126/science.1175689]
Hensen, E. F., van Duinen, N., Jansen, J. C., Corssmit, E. P. M., Tops, C. M. J., Romijn, J. A., Vriends, A. H. J. T., van der Mey, A. G. L., Cornelisse, C. J., Devilee, P., Bayley, J. P. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin. Genet. 81: 284-288, 2012. [PubMed: 21348866] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01653.x]
Mariman, E. C. M., van Beersum, S. E. C., Cremers, C. W. R. J., Struycken, P. M., Ropers, H. H. Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity. Hum. Genet. 95: 56-62, 1995. [PubMed: 7814027] [Full Text: https://doi.org/10.1007/BF00225075]
Mariman, E. C. M., van Beersum, S. E. C., Cremers, C. W. R. J., van Baars, F. M., Ropers, H. H. Analysis of a second family with hereditary non-chromaffin paragangliomas locates the underlying gene at the proximal region of chromosome 11q. Hum. Genet. 91: 357-361, 1993. [PubMed: 8388849] [Full Text: https://doi.org/10.1007/BF00217356]
Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng. C. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292: 943-951, 2004. Note: Erratum: JAMA 292: 1686 only, 2004. [PubMed: 15328326] [Full Text: https://doi.org/10.1001/jama.292.8.943]
van Baars, F., Cremers, C., van den Broek, P., Geerts, S., Veldman, J. Genetic aspects of nonchromaffin paraganglioma. Hum. Genet. 60: 305-309, 1982. [PubMed: 6286462] [Full Text: https://doi.org/10.1007/BF00569208]
van Baars, F. M., Cremers, C. W. R. J., van den Broek, P., Veldman, J. E. Familial non-chromaffinic paragangliomas (glomus tumors): clinical and genetic aspects. Acta Otolaryng. 91: 589-593, 1981. [PubMed: 6267872] [Full Text: https://doi.org/10.3109/00016488109138545]
van Baars, F. M. Glomustumoren et herediteit. Thesis: Catholic Univ. of Nijmegen (pub.) 1980.
van Baars, F., van den Broek, P., Cremers, C., Veldman, J. Familial non-chromaffinic paragangliomas (glomus tumors): clinical aspects. Laryngoscope 91: 988-996, 1981. [PubMed: 6264239]