Clinical Information

Succinate dehydrogenase (SDH) is a mitochondrial membrane-bound enzyme complex consisting of 4 subunits: SDHA, SDHB, SDHC, and SDHD. SDH is an oxidoreductase that catalyzes the oxidation of succinate to fumarate (tricarboxylic acid cycle function) and the reduction of ubiquinone to ubiquinol (respiratory chain function).

Heterozygous pathogenic variants of SDHB, SDHC, or SDHD result in an autosomal dominant tumor syndrome with variable lifetime penetrance. Patients have only 1 functioning germline copy of the affected SDH subunit gene. When the second, intact copy is somatically lost or mutated in target tissues, tumors develop. Tumorigenesis is believed to be mediated through the hypoxia-inducible factor (HIF) pathway, which gets activated as a consequence of the loss of function of the enzyme complex. Sympathetic and parasympathetic ganglia are preferentially affected, resulting in development of paragangliomas (PGLs) or pheochromocytomas (PCCs).

PGLs might include parasympathetic ganglia (neck and skull-base) or sympathetic ganglia (paravertebral sympathetic chain from neck to pelvis). PCCs can involve 1 or both adrenal glands. Almost all PCCs overproduce catecholamines, resulting in hypertension with a predilection for hypertensive crises. About 20% of PGL, mostly intra-abdominal, also secrete catecholamines. PGLs in the neck usually do not produce catecholamines. SDH-associated PGLs and PCCs are typically not malignant; however, malignancy has been described in a minority of patients (especially in patients with pathogenic SDHB variants). In addition, because of the germline presence of the pathogenic variant, new primary tumors might occur over time in the various target tissues.

SDHB is most strongly associated with PGL (usually functioning), but adrenal PCCs also occur, as do occasional gastrointestinal stromal tumors (GIST) and renal cell carcinomas (RCC). The lifetime penetrance of SDHB-related PGL/PCC is relatively low (25%-40%), but approximately half of the clinically affected patients will experience metastatic disease.

SDHD shows a disease spectrum similar to SDHB, except head and neck PGLs are more frequent than in SDHB, while functioning or malignant PGLs/PCCs and GISTs are less common. RCCs have thus far not been observed. The lifetime penetrance of paternally transmitted pathogenic SDHD variants is essentially 100%, while maternal transmission of a dysfunctional SDHD copy rarely leads to disease.

SDHC has, thus far, been mainly associated with PGLs of skull base and neck. Abdominal and functioning PGLs or PCCs are uncommon, and GISTs are very rare. RCCs have thus far not been observed. However, there is limited certainty about the SDHC genotype-phenotype correlations, as the reported case numbers are low. For the same reason there are no reliable estimates about the lifetime penetrance of SDHC-related PGL/PCC.

Collectively, heterozygous germline pathogenic variants of SDHB, SDHC, or SDHD are found in 30% to 50% of apparently sporadic PGL cases, and can be confirmed in approximately 90% of clinically hereditary cases. The corresponding figures are 1% to 25% and 20% to 30% for outwardly sporadic PCC and seemingly inherited PCC, respectively. The prevalence of pathogenic SDHB variants is higher than that of SDHD, which in turn exceeds the numbers for SDHC. SDHB and SDHC show classical autosomal dominant inheritance, while SDHD shows a modified autosomal dominant inheritance with chiefly paternal transmission, suggesting maternal imprinting, the exact molecular correlate of which remains unknown; however, recent evidence suggests tissue-specific distant imprinting that leads to long-range regulation of SDHD expression.

A minority of individuals with familial PGL will have pathogenic variants in other genes: SDHAF2 (also known as SDH5), TMEM127, and MAX.

Other genes have been described, but need additional study to confirm their clinical relevance and the utility of genetic testing: (i) SDHA variants have been described in familial PCC/PGL; however, all SDHA variants described thus far have been found in patients with seemingly sporadic PCC/PGL, not in familial cases, Moreover, the available data suggests that SDHA variants may have low penetrance and thus clinical utility of genetic testing is difficult to determine. (ii) EGLN1/PHD2, HIF2 alpha, IDH1, and KIF1 beta have also been proposed to predispose to PCC or PGL, but have thus far not been confirmed to do so, or, only do so very rarely.

Screening for pathogenic variants in SDH genes is not currently advocated for sporadic PCC, but is gaining in popularity, often alongside tests for mutations of other predisposing genes: SDHAF2, TMEM127, MAX, RET (multiple endocrine neoplasia type 2: MEN2), VHL (von Hippel-Lindau syndrome), NF1 (neurofibromatosis type 1). However, seemingly familial PCC cases that do not have an established diagnosis of a defined familial tumor syndrome, may benefit from SDH gene testing, along with screening of the other predisposing genes previously listed.

In order to minimize the cost of genetic testing, the clinical pattern of lesions in PGL and PCC patients may be used to determine the order in which the various predisposing genes listed above should be tested. The latest Endocrine Society Clinical Practice Guideline for pheochromocytoma and paraganglioma (2014) provides the current favored targeted testing approach. Genetic diagnosis of index cases allows targeted presymptomatic testing of relatives.