15 YEARS OF PARAGANGLIOMA: Clinical manifestations of paraganglioma syndromes types 1-5

Abstract

The paraganglioma (PGL) syndromes types 1-5 are autosomal dominant disorders characterized by familial predisposition to PGLs, phaeochromocytomas (PCs), renal cell cancers, gastrointestinal stromal tumours and, rarely, pituitary adenomas. Each syndrome is associated with mutation in a gene encoding a particular subunit (or assembly factor) of succinate dehydrogenase (SDHx). The clinical manifestations of these syndromes are protean: patients may present with features of catecholamine excess (including the classic triad of headache, sweating and palpitations), or with symptoms from local tumour mass, or increasingly as an incidental finding on imaging performed for some other purpose. As genetic testing for these syndromes becomes more widespread, presymptomatic diagnosis is also possible, although penetrance of disease in these syndromes is highly variable and tumour development does not clearly follow a predetermined pattern. PGL1 syndrome (SDHD) and PGL2 syndrome (SDHAF2) are notable for high frequency of multifocal tumour development and for parent-of-origin inheritance: disease is almost only ever manifest in subjects inheriting the defective allele from their father. PGL4 syndrome (SDHB) is notable for an increased risk of malignant PGL or PC. PGL3 syndrome (SDHC) and PGL5 syndrome (SDHA) are less common and appear to be associated with lower penetrance of tumour development. Although these syndromes are all associated with SDH deficiency, few genotype-phenotype relationships have yet been established, and indeed it is remarkable that such divergent phenotypes can arise from disruption of a common molecular pathway. This article reviews the clinical presentations of these syndromes, including their component tumours and underlying genetic basis.

Keywords: gastrointestinal stromal tumour; paraganglioma; phaeochromocytoma; renal cancer; succinate dehydrogenase.

Figure 1

Tumour types associated with paraganglioma syndromes 1–5. In each panel the tumour is arrowed and is: (A) a left-sided carotid body paraganglioma (the scar from previous surgery for a right carotid body PGL is faintly visible); (B) a left-sided phaeochromocytoma; (C) abdominal PGL (not shown); (D) a pituitary macroadenoma; (E) renal cell carcinoma (not shown), and (F) a gastrointestinal stromal tumour.

Figure 2

PGL1 due to mutations in SDHD. Genotypes associated with paraganglioma syndromes. Mutations are not represented by standard nomenclature; abbreviations are used for representation purposes only. Not all mutations identified worldwide have been included. M1^∧, mutation in initiator methionine indicating loss of transcript; *, represent stop codons; □□, represent a large deletion/insertion/duplication and the number indicates the number of different mutations at that site. Data from http://chromium.lovd.nl/lovd_sdh, Bayley et al. (2005), McWhinney et al. (2004).

Figure 3

PGL3 due to SDHC mutations. Genotypes associated with paraganglioma syndromes. Mutations are not represented by standard nomenclature; abbreviations are used for representation purposes only. Not all mutations identified worldwide have been included. M1^∧, mutation in initiator methionine indicating loss of transcript; *, represent stop codons; □□, represent a large deletion/insertion/duplication and the number indicates the number of different mutations at that site. Data from http://chromium.lovd.nl/lovd_sdh, Bayley et al. (2005).

Figure 4

PGL4 due to SDHB mutations. Genotypes associated with paraganglioma syndromes. Mutations are not represented by standard nomenclature; abbreviations are used for representation purposes only. Not all mutations identified worldwide have been included. M1^∧, mutation in initiator methionine indicating loss of transcript; *, represent stop codons; □□, represent a large deletion/insertion/duplication and the number indicates the number of different mutations at that site. Data from http://chromium.lovd.nl/lovd_sdh, McWhinney et al. (2004), Bayley et al. (2005), Cascón et al. (2006).

Figure 5

PGL5 due to SDHA mutations. Genotypes associated with paraganglioma syndromes. Mutations are not represented by standard nomenclature; abbreviations are used for representation purposes only. Not all mutations identified worldwide have been included. M1^∧, mutation in initiator methionine indicating loss of transcript; *, represent stop codons; □□, represent a large deletion/insertion/duplication and the number indicates the number of different mutations at that site. Data from http://chromium.lovd.nl/lovd_sdh, Bayley et al. (2005).

Figure 6

A representative clinical vignette of PGL syndrome type 1.