gms | German Medical Science

Head and neck paragangliomas are highly vascularized, slow-growing tumors that arise from parasympathetic ganglia. The yearly estimated incidence of these tumors, also known as glomus tumors or chemodectomas is about 1 in 30.000 [Ref. 1]. The most common tumor sites are the carotid body, the glomus jugulare, vagale and tympanicum [Ref. 2]. Paragangliomas of the head and neck commonly presents in the fourth or fifth decade as an asymptomatic tumor mass or with symptoms due to compression and damage of surrounding structures. Different cranial nerve deficits, bradycardia, hoarsness of voice and hearing loss are typical symptoms patients report on. Head and neck paragangliomas are usually benign. A progression to malignancy is observed in 2% to 10% of the cases [Ref. 3]. Malignant tumors, defined as neoplasms with distant metastases particularly spread to bones and lungs.

Although paragangliomas occur sporadically, 10% to 50% are considered familial in nature [Ref. 4]. Hereditary head and neck paragangliomas are associated with 4 different cancer syndromes, paraganglioma syndrome type 1 (PGL 1), type 2 (PGL 2), type 3 (PGL 3) and paraganglioma syndrome type 4 (PGL 4), respectively (Table 1 [Tab. 1]) [Ref. 5], [Ref. 6], [Ref. 7], [Ref. 8], [Ref. 9], [Ref. 10], [Ref. 11], [Ref. 12]. The moleculargenetic basis are mutations of the succinate dehydrogenase (SDH), an important enzymatic complex in both the Krebs cycle and the respiratory chain. Four nuclear genes encode the four different subunits of the succinate dehydrogenase: two hydrophilic proteins, a flavoprotein (SDHA) and an iron-sulfur protein (SDHB) forming the enzymatic core and two hydrophobic integral membrane proteins the larger SDHC and the smaller SDHD anchoring the complex in the inner mitochondrial membrane. Whereas mutations of the SDHA gene are linked to optic atrophy, ataxia, myopathia and Leigh syndrome, as classic mitochondrial disorders, mutations of the SDHB gene, the SDHC gene and the SDHD gene cause three of the four paraganglioma syndrome entities [Ref. 5], [Ref. 6], [Ref. 7], [Ref. 8], [Ref. 9], [Ref. 10], [Ref. 11], [Ref. 12], [Ref. 13].

Mutations of the SDHD gene are due to paraganglioma syndrome type 1. The SDHD gene, mapping to chromosome 11q23, comprises four exons and encodes a 159-amino acid protein [Ref. 14]. To date more than 30 different mutations are described. Mutations were distributed throughout all 4 exons of the gene. The spectra of mutations included all different types such as missense, nonesenes and splice site mutations as well as small insertions and deletions. Recently a large deletion of the SDHD gene of about 96 kb was identified in a paraganglioma familiy [Ref. 15]. Patients with paraganglioma syndrome type 1 are not only at risk for head and neck paraganglioma. An association of SDHD gene mutations with the development of adrenal or extra-adrenal pheochromocytoma was first described 2001 [Ref. 7]. A large population-based study of patients with head and neck paraganglioma and adrenal or extra-adrenal pheochromocytoma was performed 2004 to evaluate gene specific clinical features, demographics and penetrance of SDHD and SDHB gene mutation positive persons [Ref. 16]. Mean age at diagnosis of the PGL 1 patients was 32 years. Patients are preferentially at risk for head and neck paraganglioma as well as pheochromocytomas of the adrenal glands with 79% and 53% respectively (Figure 1 [Fig. 1]). Multiple tumors were observed in 74% of the neoplasms. No malignant tumor, defined as a tumor with distant metastases was found in patients with paraganglioma syndrome type 1. Age-related penetrance was 50% by the age of 31 years and increases to 86% by 50 years. PGL 1 is inherited in an autosomal-dominant fashion with incomplete penetrance when transmitted through fathers, whereas no disease phenotype occurs when transmitted maternally [Ref. 17]. This inheritance pattern is consistent with genomic imprinting. The mechanism is still unclear. A selective loss of one or more imprinted genes in the 11p15 region of the maternal chromosome is presumed to be responsible for this effect [Ref. 18].

Only one publication showed by linkage analysis and haplotyping of a large parganglioma familiy the association of these type of tumors with a still unidentified gene on chromosome 11q13 [Ref. 9].

Little is known about paraganglioma syndrome type 3. Mutations of the SDHC gene that maps to chromosome 1q21 are responsible for the disease. The gene encodes a small peptide of 15.5 kDa and has six exons [Ref. 19]. Three intragenic mutations, one splice site defect and two missense mutations, and one large deletion of 8.372 bp spanning exon 6 of the SDHC gene were identified so far [Ref. 10], [Ref. 11], [Ref. 20], [Ref. 21], [Ref. 22]. All mutation carriers had head and neck paraganglioma. None of the mutation positive patients were found to have an adrenal or extra-adrenal pheochromocytoma. All tumors were begnin.

Mutations of the SDHB gene cause paraganglioma syndrome type 4. The gene was mapped to chromosome 1p36.1. The entire transcript is encoded by eight exons within approximately 40kb [Ref. 23]. The mutation spectra is similar to those of the SDHD gene comprising all different types of mutation. One large deletion, involving the 5'end of SDHB, was described in a familiy with extra-adrenal pheochromocytoma [Ref. 15]. Mean age at diagnosis was 31 years. Extra-adrenal pheochromocytoma are a typical clinical feature of paraganglioma syndrome type 4. Only 31% of these patients present with head and neck paraganglioma. Dysfunctions of the SDHB gene have an apparently aggressive nature: more than 30% of the tumors found in these patients were malignant and 4 patients were identified to have renal cell carcinoma only or associated with a pheochromocytoma [Ref. 24]. 50% of SDHB mutation carriers were estimated to develop at least one tumor by 35 years. Age-related penetrance increases to 77% by the age of 50 years [Ref. 16]. In comparison to the inheritance pattern of SDHD gene mutations pedigree analysis of SDHB positive families showed an autosomal dominant fashion without any sign of genomic imprinting [Ref. 6], [Ref. 8], [Ref. 15].

Familial paraganglioma has been a known entity for decades but has been classified due to a moleculargenetic background only in the last few years. Mutations of the succinate dehydrogenase subunits B, C and D predispose to head and neck paraganglioma and adrenal or extra-adrenal pheochromocytoma. Prevalence of germline mutations of the SDHB and the SDHD gene is 5% to 20% in patients with apparently sporadic head and neck paraganglioma and approximately 100 % in patients with familial tumors [Ref. 6], [Ref. 8], [Ref. 16], [Ref. 21], [Ref. 25], [Ref. 26]. Severe clinical morbidities such as vocal paralysis, dysphagie and facial palsy can be a result of the continuous, slow growth of these tumors. Furthermore patients are at risk for a malignant progression and the development of extra-paraganglial malignancy. Early treatment of these tumors results in a significant decrease in morbidity and mortality [Ref. 2]. To support and focus clinical screening and to estimate riskprofiles of the disease routine analysis for mutations in one of these genes should be considered as a clinical standard of care. Genetic testing should be time and cost effective. The knowledge of gene specific prevalence as well as typical clinical features is of utmost importance. The diagnosis of head and neck paraganglioma only or of head and neck paraganglioma and adrenal pheochromocytoma clearly suggests starting the molecular genetic analysis with SDHD. Multiple, benign tumors are a typtical feature in SDHD positive patients. Extra-adrenal pheochromocytomas are frequently observed in SDHB mutations. Malignant tumors are most often associated with SDHB which makes them the first target of mutational analysis. Furthermore SDHB mutations predispose to renal cell carcinoma. Mutations of the SDHC gene seems to be extremely rare and only due to the development of benign head and neck paraganglioma.