Maternal Transmission of Symptomatic Disease withSDHDMutation: Fact or Fiction?

Abstract

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 (1–4). 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 (5–9). 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, 9–11). 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 1to 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, 13–15). 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 G3A, 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.