The SDHA gene is located at human chromosome 5p15.33 [26] and codes for the largest subunit of the SDH complex. The gene consists of 15 exons and produces a 2,286 nucleotide transcript, which encodes a 644 amino acid polypeptide of 70 kDa. SDHA is a flavoprotein, which forms the SDH catalytic domain in complex with SDHB, an iron-sulfur protein. Disease-related mutations in the SDHA gene were first identified in Leigh syndrome patients with mitochondrial respiratory chain complex II deficiency [27], which is inherited in an autosomal recessive fashion. In 2010, the first case of an SDHA mutation associated PGL/PCC syndrome was reported in a patient with an extra-adrenal PGL [7], which is also categorized as paraganglioma syndrome type 5 (PGL5, OMIM #600857). The mutation was a germline heterozygous missense mutation, c.1765C>T (p.R589W), identified in the patient’s blood sample. However, in the patient’s tumor tissue, the mutant molecules were found to be predominant (much greater than 50 %), suggesting LOH, which was confirmed by array comparative genomic hybridization (aCGH) analysis. The predisposition to PGL/PCC tumors due to an SDHA germline mutation is inherited as an autosomal dominant trait at the pedigree level, but recessive at the cellular level, requiring a second mutation to lead to tumorigenesis.

Twenty-eight (28) point mutations in the SDHA gene have been reported in Human Genome Mutation Database (HGMD) (as of November 2014). Five mutations are associated with PGL/PCC. The remaining mutations are associated with Leigh syndrome, optic atrophy, ataxia, and myopathy [27–32]. The germline mutations were found in sporadic cases of PGL/PCC with negative SDHA immunostaining and LOH in their tumor tissues. The penetrance of SDHA mutations may be low. For example, the p.R31* and p.R585W mutations were found at a frequency of 0.3 % and 0.1 %, respectively, in the general population who are not affected with PGL/PCC, suggesting a low penetrance [33].

The SDHB gene is located at chromosome 1p36.13 and consists of eight exons encoding a 30 kDa protein of 280 amino acids. The SDHB protein is an iron-sulfur protein forming part of the SDH complex catalytic domain with the SDHA subunit. SDHB is the most commonly mutated gene in PGL/PCC (PGL4, OMIM #185470). Currently, 195 SDHB mutations associated with PGL/PCC have been recorded in the HGMD, in contrast to the number of mutations in the other SDH genes (5 in SDHA, 44 in SDHC, 144 in SDHD, and 2 in SDHAF2) (Table 30.2). SDHB mutations are more frequently found in secreting PGL and malignant tumors [8, 34]. However, the penetrance of SDHB mutations is low (approximately 18 % at age 60) [35], which may explain why SDHB mutations are more common in sporadic PGLs/PCCs. Since the survival rate for patients with SDHB-immunonegative tumors is lower than for patients with SDHB-immunopositive tumors, SDHB germline mutation may serve as a prognostic marker for patients with PGL/PCC [36].

The SDHC gene is located at chromosome 1q23.3 and has at least four alternatively spliced isoforms, although the functional significance of the isoforms is not well understood. The longest isoform (NM_003001.3) consists of six exons. The SDHC protein is located in the mitochondrial inner membrane and together with SDHD forms an anchor domain for the mitochondria respiratory chain complex II. SDHC was the second SDH gene associated with PCC/PGL [8]. Mutations in SDHC have been found in paraganglioma syndrome type 3 (PGL3, OMIM #602413) but are much less frequent than those in SDHB or SDHD (Table 30.1). SDHC mutations are mostly found in head and neck PGL, although PGLs/PCCs in other loci caused by SDHC mutations have been reported [37, 38]. Germline deletion of exon 3 of the SDHC gene has been identified in a patient in a study of 190 patients affected with PGL/PCC. The patient had germline deletion of SDHC exon 3, but LOH was not found in the tumor. Instead, there was a gain of the entire 1q harboring the mutated SDHC gene with exon 3 deletion in the tumor tissue, suggesting that the mutant allele was duplicated [10].

SDHD is the smallest subunit in the SDH complex and was the first protein subunit in the SDH complex identified to cause paraganglioma syndrome type 1 (PGL1, OMIM #168000) [5]. The SDHD gene is located at chromosome 11q23.1 and has four exons encoding a 159-amino-acid polypeptide. SDHD mutations are predominantly found in head and neck PGL [34, 39]. Although PGL/PCC with an SDHD mutation is transmitted in an autosomal dominant mode, inheritance is almost exclusively through paternal transmission, which suggests maternal imprinting (inactivation) even though the SDHD gene itself is not imprinted [5]. Hensen and colleagues studied 23 SDHD-linked tumors and found all had lost the entire maternal chromosome 11. Thus, they hypothesized that PGL/PCC caused by SDHD mutations might require three hits: an SDHD germline mutation, the loss of or a somatic mutation in the wild-type SDHD gene in the tumor, and defects in another paternally imprinted tumor suppressor gene on chromosome 11, most likely 11p15 where the only imprinted gene cluster on chromosome 11 is located [40]. However, one definitive adrenal PCC case had maternal transmission of the SDHD mutation. Molecular studies on tumor and blood demonstrated a germline mutation, a loss of the wild-type paternal SDHD, and a loss of the maternal 11p region. Although lacking the typical paternal transmission, this case also supports a 3-hit hypothesis [41].

SDHAF2 (SDH5) is the latest SDH complex gene found to be involved in the tumorigenesis of PGL/PCC. SDHAF2 (SDH5) is located at chromosome 11q12.2, about 50 Mb away from the SDHD gene, and consists of four exons encoding a 166-amino-acid polypeptide. SDHAF2 interacts with SDHA and is required for the flavination of SDHA. Thus, mutations in SDHAF2 destroy SDH activity, reduce the stability of the SDH complex, and result in paraganglioma syndrome type 2 (PGL2, OMIM #601650) [4]. Inheritance of the risk for PGL/PCC due to an SDHAF2 mutation is also via an autosomal dominant mechanism but shows parent-of-origin effects. Similar to SDHD mutations, SDHAF2 mutations are paternally inherited for tumor susceptibility, and maternally transmitted mutations do not result in tumors [4]. By studying a large family with an SDHAF2 mutation, Kunst et al. found that 12 of 16 carriers who inherited the mutation from their fathers were affected. Twenty-four tumors were found in 11 affected family members (one patient’s clinical information was unavailable) and 10 of the 11 patients had at least two tumors. All tumors were found in the head and neck with the majority in the carotid body (17/24 or 71 %) [42]. Currently, two mutations have been reported. One mutation, c.232G>A (p.G78R), was identified in a large Dutch family and a Spanish family [4, 42, 43]. A study of 443 sporadic PGL/PCC patients who had no mutations identified in the SDHB, SDHC, or SDHD genes did not identify any germline mutations or gross deletions in the SDHAF2 gene, suggesting a very low incidence [43]. The other mutation, c.358dupT, was reported in a sporadic patient with head and neck paraganglioma in the right carotid body [44].