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Department of Nephrology, Section of Preventive Medicine, Albert-Ludwigs-University, D 79106 Freiburg, Germany
Address all correspondence and requests for reprints to: Hartmut P. H. Neumann, M.D., Medizinische Universitätsklinik, Abteilung Innere Medizin 4, Hugstetter Strasse 55, D 79106 Freiburg, Germany. E-mail: hartmut.neumann{at}uniklinik-freiburg.de.
Paraganglioma syndrome (PGL) has been known as an inherited disorder for decades. However, it was not until the year 2000, when Bora Baysal identified the SDHD gene, the gene encoding the succinate dehydrogenase (SDH) subunit D, as the susceptibility gene for a subset of these families (1). Subsequently, germline mutations of genes encoding other subunits of SDH, the SDHC gene and the SDHB gene, have been identified in other families with PGL. The molecular classification differentiates familial paraganglioma into four types: PGL1 is associated with SDHD mutations; PGL3 is associated with SDHC mutations; PGL4 is associated with SDHB mutations; and, for PGL2, the susceptibility gene remains to be identified (1, 2, 3, 4). SDHA is not a susceptibility gene for paraganglioma syndromes.
Clinical presentations of paraganglioma syndromes include head and neck paraganglioma; adrenal and extraadrenal retroperitoneal abdominal, pelvic, and thoracic pheochromocytom, and in some subtypes, gastrointestinal stromal tumors and clear cell renal carcinoma (5, 6, 7, 8, 9). The phenotypes overlap, and the unique differences are multiple tumors predominantly in PGL1, malignant paraganglial tumors mainly in PGL4, and prevalence of head and neck paragangliomas in PGL3 (5, 9, 10, 11).
High prevalence of germline mutations in apparently nonsyndromic patients with paraganglial tumors (e.g. head and neck paragangliomas as well as adrenal and extraadrenal pheochromocytomas) justifies mutation screening, which has became the crucial tool to identify syndromic cases and thus help in the assessment of the patient’s and eventually of her/his relatives’ risk profiles. Accordingly, patients carrying a germline mutation, as well as asymptomatic carriers in their family, undergo complete clinical screening in 1- to 2-yr intervals to timely identify new tumor manifestations, which helps in the management and therapy of the patients (11, 12).
The inheritance of paraganglioma syndromes is of special interest and was autosomal dominant in all cases of PGL3 and PGL4, affecting both genders equally. In contrast, families with PGL1 and PGL2 showed paraganglial tumors only in mutation carriers who inherited the mutation from the father (4, 13). This observation has not been violated in the literature to date (5, 9, 13, 14, 15). Consequently, maternal imprinting has been assumed. Maternal imprinting means that a gene inherited from the mother is imprinted and not expressed in the offspring. This means that for correct functioning of the protein, the expression of only one allele is needed. If the mutated SDHD allele is inherited from the mother, it could play no role in the tumor pathogenesis, and the offspring could be considered not at risk. The classical definition of maternal imprinting, however, is inactivation usually due to methylation of the gene or its promoter, and this has so far not been observed in the SDHD gene, leaving the molecular/genetic mechanism of the parent-of-origin-dependent transmission in PGL1 open to be clarified (1, 16).
For the first time, Pigny et al. (17), in this issue of the Journal, describe a family that does not follow the observed rule of inheritance. The index case is an 11-yr-old male patient. He and his mother were both diagnosed with head and neck paraganglioma. They shared the identical germline mutation SDHD c.129 G
A, which causes truncation of the encoded protein by a stop codon (Trp43X). This report has potentially enormous consequences for both the clinical management of SDHD mutation carriers and the understanding of inheritance of PGL1. Therefore, critical reconsideration of three major points is essential: the clinical diagnosis, the impact on clinical counseling, and the molecular understanding.
The Diagnosis of Head and Neck Paraganglioma in the Index Case
A major surprise is incoherence of symptoms, the initial finding, and the radiological diagnosis in this case report. Recurrent epistaxis and a palpable pulsatile right cervical mass are unlikely to be explained by a left jugulotympanic paraganglioma, the diagnosis made by the authors based on angiography. Obviously, the finding discovered by angiography is an incidentaloma. However, the fundamental concern is that the patient has not been operated on this lesion. There is no histology and therefore no proof that the tumor is a paraganglioma. The treatment was embolization, and 16 yr after this intervention, there are no remnants seen by magnetic resonance imaging, which is astonishing. The young age of the index case at presentation of this rare tumor argues against a sporadic manifestation and is therefore to be considered as part of a syndrome.
Potential Consequences for Counseling and Management
Regarding genetic counseling and clinical management, the report of Pigny et al. (17), if the doubts in the above paragraphs can be sufficiently excluded, demonstrates that potentially all subjects with SDHD mutations who are offspring of female mutation carriers need clinical screening investigations for paraganglial tumors. In this context, it is important to consider that no report exists demonstrating that a symptomatic tumor manifestation has been observed in carriers who inherited the mutation from the mother. Furthermore, as far as performed, clinical screening of these mutation carriers has not identified any tumor manifestations (5, 9, 13, 14). Therefore, very large clinical studies would be necessary to calculate the penetrance and behavior of tumor manifestations in this particular subgroup of mutation carriers.
The Molecular/Genetic Mechanism
Hensen and colleagues (16) have hypothesized that different parental methylation of the chromosomal region 11p15 might be responsible for the parent-of-origin-dependent inheritance of paraganglial tumors in PGL1. In fact, Pigny et al. (17) repropose the Hensen model of inheritance. Briefly, Hensen and colleagues hypothesized that a second target gene, a paternally imprinted gene, localized on chromosome 11 (11p15) is involved in the tumor formation of SDHD mutation-related tumors. Interestingly, a parent-of-origin-dependent inheritance has been described in the Beckwith-Wiedemann syndrome and focal hyperplasia of Langerhans islets causing congenital hyperinsulinism. For these diseases, the susceptibility genes are located in the nonmethylated region of chromosome 11 and are therefore not imprinted. It has been demonstrated that genes that undergo imprinting in the 11p15 region are responsible for the peculiar inheritance in these two diseases (18, 19, 20). According to the Hensen model, the loss of both, the nonmutated (paternal) active SDHD gene and the active nonmethylated 11p15 region (maternal), are necessary for the tumor formation in case of maternal inheritance of the SDHD mutation.
Pigny et al. (17) analyzed the methylation status of germline DNA of the 11p15 region, in particular the differentially methylated region (DMR) of the H19 gene. The results showed a hypermethylation of this region in the index case but not in other subjects of the family. The authors hypothesize that the usually active H19 gene (of maternal origin) in the index case was also inactivated (due to incomplete loss of imprinting in the oogenesis), and therefore, tumor formation was possible. Based on their observations, the authors conclude that H19 is the gene located in the region 11p15 responsible for the peculiar inheritance of PGL1 and that its germline inactivation was the reason for the tumor formation, which is in accordance with the Hensen model.
Missing are important additional arguments in the reported case. Even if probable, the loss of the paternal active SDHD gene was not molecularly confirmed, because no tumor material was available.
Additional studies are needed. The inactivation of both the H19 and SDHD genes in a larger cohort of SDHD mutation-associated tumors should be confirmed. Furthermore, in asymptomatic SDHD mutation-carrying offspring who inherited the mutation from the mother, the germline methylation status should be analyzed. If these studies confirm the postulated events, an easy tool will be available to differentiate at-risk-for-disease from not-at-risk SDHD mutation carriers, who inherited their mutation from the mother.
In summary, the analyses of Pigny et al. (17) contribute with interesting clinical observations and molecular/genetic findings that add arguments for the Henson model, which may indeed be relevant for the inheritance of PGL1. Doubts remain in both fields, the clinical and the molecular/genetic observations. Most importantly, additional PGL1 families showing paraganglial tumors in offspring who inherited the SDHD mutation from the mother need to be identified with histological confirmation of the diagnosis. In addition, molecular/genetic analyses presented thus far are confined to constitutional DNA and must be extended to tumor tissue.
Footnotes
Abbreviation: PGL, Paraganglioma syndrome; SDH, succinate dehydrogenase.
Received March 10, 2008.
Accepted March 12, 2008.
References
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