International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers

Abstract

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.

Exploring the Leukemogenic Potential of GATA-1S, the Shorter Isoform of GATA-1: Novel Insights into Mechanisms Hampering Respiratory Chain Complex II Activity and Limiting Oxidative Phosphorylation Efficiency

“…In this context, a growing body of research has focused on the role of SDH as a tumor suppressor factor and the relationship between complex II dysregulation and tumorigenesis consequent to chronic ROS elevation and impaired regulation of apoptosis [18,20,21]. Accordingly, germline mutations in SDH genes resulting in impaired SDH activity have been found in several tumor types including pheochromocytoma, paraganglioma, gastrointestinal carcinoma, renal cell carcinoma, thyroid carcinoma, neuroblastoma, and breast cancer along with altered SDH epigenetic and post-translational mechanisms of regulation [22,23,[27][28][29]. Furthermore, the oncogenic activity of these mutations has been associated with a high production of O 2 − that may be responsible for the genomic instability of cancer cells.…”

“…An example is represented by hereditary pheochromocytoma, paraganglioma, renal cell carcinoma and gastrointestinal stromal tumors characterized by mutations in SDH subunits leading to the functional loss of complex II activity and, consequently, succinate accumulation, increased ROS generation, and decreased ATP production through OXPHOS. However, in this context, it is noteworthy that mutations occurring in different SDH genes lead to remarkable differences in clinical phenotype [22,23].…”

New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications

“…However, there are no established guidelines on how to screen and then follow up asymptomatic mutation carriers. A recent consensus algorithm was established for initial screening and follow-up of SDHx mutation carriers by an international panel of 29 experts from 12 countries in 2020, using the Delphi method [21] (Table 2). The penetrance of SDHx-related PPGL is not firmly established.…”

“…In this review, we summarize recent advances in the discovery of new genes during the past five years. Additionally, we summarize the latest guidelines by Amar et al for the diagnosis and surveillance of asymptomatic SDHx mutation carriers [21].…”

Perioperative Management of Pheochromocytomas and Sympathetic Paragangliomas

“…High-risk patients (young patients and those with a genetic disease [mainly those with SDHB mutations], > 5 cm pheochromocytoma, and/or a paraganglioma of any size) should have lifelong annual follow-up [ 6 ]. Patients with syndromic disease require a personalized approach according to specific affected genes based on the association with other tumors and the risk of multifocal or metastatic lesions ( Table 4 ) [ 8 , 70 , 71 ]. The screening recommendations for asymptomatic mutation carriers are beyond the scope of this article.…”