Clinical progression and metachronous paragangliomas in a large cohort of SDHD germline variant carriers

Abstract

Although it is well established that paternally transmitted germline variants in SDHD are associated with multifocal paragangliomas and lifelong follow-up is generally advised, the risk of metachronous lesions is presently unknown. In a large Dutch cohort of SDHD variant carriers, we studied the development of new paragangliomas, and the evolution of symptoms and cranial nerve impairment. Recurrent event analysis and the Kaplan-Meier product limit estimator were used to study the risk of new lesions. The relation between several predictors and development of new symptoms was assessed using logistic regression. Of the 222 SDHD variant carriers included, 65% presented with symptoms and 11% with cranial nerve dysfunction. Over a median period of 8 years, 42% reported new symptoms, and new cranial nerve impairment was observed in 11% of subjects. The estimated fraction of subjects that developed new HNPGL increased to 73% (95% CI: 52-85%) after 22 years of follow-up. Males were more likely to develop new HNPGL compared to females (HR: 1.63, 95% CI: 1.10-2.40), as were subjects that presented with symptoms, compared to subjects that were asymptomatic at baseline (HR: 1.61, 95% CI: 1.01-2.55). In addition, the risk of new lesions decreased with number of HNPGL present at first diagnosis (HR: 0.68 and 95% CI: 0.56-0.82). Carriers of a paternally inherited SDHD variant face a considerable risk for new HNPGL. In addition, nearly 50% of subjects reported new symptoms. However, new cranial nerve deficits were observed in only 11%, which is less than reported in surgical series. These risks should be taken into account when considering treatment strategies and counseling.

Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma–paraganglioma

“…In accordance with the Dutch law, approval of an institutional ethics committee was not required because all data were collected for routine patient care. This dataset has been described previously 19. Details of this patient dataset, differentiated by SDH gene and variant type, can be found in online supplementary table 4.…”

“…Molecular genetic analysis of SDH variants in the DE dataset was carried out using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis (SALSA MLPA Kit P226; MRC-Holland, Amsterdam, The Netherlands), and in the other datasets as described 13 18 19. Genotype–phenotype correlations were analysed in individuals with pathogenic or probable pathogenic variants and likely VUS were excluded from the analysis.…”

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

“…Therefore, one initial screening is not sufficient and these individuals should be followed up. Although people who do not have PPGL at initial screening have a reduced risk of developing new tumours during follow-up, they are still at risk of developing these tumours during their lifetime 49 . This risk has led experts to consider that follow-up is mandatory in asymptomatic carriers of an SDHx mutation.…”

“…After a certain age, a carrier of an SDHx mutation who has not developed a PPGL by initial screening or during follow-up has a considerably reduced risk of developing new tumours 49 .…”

Tumor multifocality with vagus nerve involvement as a phenotypic marker of SDHD mutation in patients with head and neck paragangliomas: A 18F‐FDOPA PET/CT study

“…The optimal follow‐up algorithm has not yet been validated in nonproband SDHx ‐PPGLs but most likely requires a more frequent and complete imaging workup than for their sporadic counterparts. The aim is to detect tumors at early stages of development, thereby minimizing tumor extension, and cranial nerve impairment as for example, published for SDHD ‐related HNPGLs, facilitating curative treatment, and potentially reducing the occurrence of local and distant metastatic spread, especially in more aggressive genotypes (eg, SDHB ). At initial staging, the use of PET imaging should provide an adequate sensitivity and specificity at WB scale with limited radiation exposure.…”