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British Medical Bulletin 2006 79-80(1):141-151; doi:10.1093/bmb/ldl002
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© The Author 2006. Published by Oxford University Press. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Genetics of phaeochromocytoma

Eamonn R. Maher*

Section of Medical and Molecular Genetics, University of Birmingham School of Medicine and West Midlands Regional Genetics Service, Birmingham, UK

* Correspondence to: Prof. E. R. Maher, Section of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham, B15 2TT, UK. Tel.: +44 121 627 2741; fax: +44 121 414 2538; e-mail: e.r.maher{at}bham.ac.uk


   Abstract
Top
 Abstract
Introduction
 Clinical and molecular genetics...
 Frequency of Germline Mutations...
 Mechanisms of Tumourigenesis in...
 Acknowledgements
 References
 
Recent advances in determining the molecular basis for phaeochromocytoma susceptibility have revealed a much larger inherited contribution to the pathogenesis of phaeochromocytoma than had been generally recognized. The identification of individuals with phaeochromocytoma susceptibility disorders (e.g. von Hippel-Lindau disease, succinate dehydrogenase subunit mutations, multiple endocrine neoplasia type 2 and neurofibromatosis type 1) is important because of the opportunity to reduce morbidity and mortality from phaeochromocytoma and other relevant tumours in affected individuals and their at-risk relatives. Recent studies have also provided clues to the molecular pathogenesis of phaeochromocytoma development in familial cases and suggest that this differs from that seen in sporadic non-inherited cases.

Keywords: genetics • inherited • phaechromocytoma


   Introduction
Top
 Abstract
 Introduction
Clinical and molecular genetics...
 Frequency of Germline Mutations...
 Mechanisms of Tumourigenesis in...
 Acknowledgements
 References
 
Phaeochromocytomas are catecholamine-producing tumours that usually arise within the adrenal medulla but are extra-adrenal in about 10% of cases. Phaeochromocytomas arise from the adrenal medulla or when extra-adrenal from sympathetic paraganglia. Although extra-adrenal phaeochromocytomas are sometimes referred to as ‘paragangliomas’, this term is also used to describe carotid body chemodectomas and glomus jugulare tumours (herein described as head and neck paragangliomas (HNPGL)) that are derived from parasympathetic paraganglia and do not usually secrete catecholamines [1]. The presenting features of phaeochromocytoma are variable, but hypertension is the most common clinical feature and cardiovascular disease is the leading cause of death.

Phaeochromocytoma was first described in patients with Neurofibromatosis type 1 (NF1, von Recklinghausen disease) in 1910 [2] and in 1953 phaeochromocytoma was recognized as a feature of von Hippel-Lindau (VHL) disease [3]. In 1961 Sipple [4] reported an association between bilateral phaeochromocytomas with carcinoma of the thyroid, a condition later delineated as Multiple Endocrine Neoplasia Type 2 (MEN 2, Sipple disease), At the end of the 20th century, inherited phaeochromocytoma was generally considered to account for ~10% of all cases. However the identification of germline mutations in succinate dehydrogenase subunit genes (SDHB and SDHD) in patients with familial and sporadic phaeochromocytoma has significantly increased estimates of the frequency of inherited phaeochromocytoma [5–11]. Furthermore investigations of the molecular mechanisms of inherited phaeochromocytoma have suggested that Mendelian disorders predisposing to phaeochromocytoma share a common defect in programmed cell death during normal development [12].


   Clinical and molecular genetics of familial phaeochromocytoma susceptibility syndromes
Top
 Abstract
 Introduction
 Clinical and molecular genetics...
Frequency of Germline Mutations...
 Mechanisms of Tumourigenesis in...
 Acknowledgements
 References
 
Succinate Dehydrogenase SDHB and SDHD Subunit Mutations

Following the mapping of a locus for HNPGL to 11q23, germline mutations in the SDHD gene were identified in a subset of familial HNPGL kindreds [13]. Germline SDHD mutations are associated with an unusual pattern of inheritance such that tumours only develop when an individual inherits the mutation from their father (Fig. 1) [14, 15]. This parent of origin effect is classically seen with imprinted genes (i.e. those genes for which allelic expression depends on parental origin), but so far no conclusive evidence for imprinting and allele-specific expression of SDHD has been found.


Figure 1
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  		Fig. 1 Autosomal dominant inheritance with parent-of-origin effects as seen with a germline SDHD mutation. Clinically affected individuals are shown by filled symbols (square = male and circle = female). Clinical disease only occurs in individuals who have inherited an SDHD mutation from their father.

 
Phaeochromocytoma occurs in about 5% of HNPGL, suggesting SDHD as a candidate phaeochromocytoma susceptibility gene and germline SDHD mutations were identified in a familial phaeochromocytoma kindred and in isolated cases of phaeochromocytoma [5, 6]. Subsequently germline SDHB mutations were identified in kindreds with familial phaeochromocytoma with or without HNPGL [6]. Germline mutations in SDHB cause a dominantly inherited susceptibility to phaeochromocytoma and/or HNPGL but, unlike SDHD mutations, there is no evidence of parent-of-origin effects on expression. Germline SDHB or SDHD mutations may be found in ~40% of patients with familial or bilateral phaeochromocytoma and 5–10% of isolated cases. Unsurprisingly a personal or family history of HNPGL increases the likelihood of detecting a SDHB or SDHD mutation. Among patients presenting with phaeochromocytoma, SDHB mutations are more frequent than SDHD mutations, but the reverse is true for patients presenting with HNPGL [7–11, 16–19]. In addition the risk of malignant phaeochromocytoma appears to be higher with SDHB mutations than for other forms of familial and sporadic phaeochromocytoma [9, 11]. The most common SDHD mutation detected in familial HNPGL patients, P81L, appears to be associated with a low risk of phaeochromocytoma.

SDHB and SDHD encode two subunits of the succinate dehydrogenase enzyme (mitochondrial complex II, succinate:ubiquinone oxydoreductase) which has a key role in the Krebs tricarboxylic acid cycle and participates in aerobic electron transport [20]. SDHA and SDHB are the enzymatic subunits and SDHC and SDHD anchor the heterotetrameric complex to the mitochondrial membrane. Germline mutations in SDHC appear to cause HNPGL but not phaeochromocytoma [21, 22]. Although germline SDHA mutations have not been described in phaeochromocytoma or HNPGL cases, homozygous germline SDHA mutations causes an autosomal recessive form of infantile encephalopathy (Leigh syndrome) (Table 1) [23, 24].


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  		Table 1 Human disease phenotypes associated with germline mutations in succinate dehydrogenase (SDH) subunit genes (see text for further details)

 
Von Hippel-Lindau disease

VHL disease is a dominantly inherited familial cancer syndrome characterised by susceptibility to haemangioblastomas of the retina and central nervous system, clear cell renal cell carcinoma (RCC), phaeochromocytoma, pancreatic islet cell tumours and endolymphatic sac tumours. In addition, renal, pancreatic and epididymal cysts are common [25, 26]. VHL disease has an approximate incidence of 1/36 000 live-births [27] and germline VHL mutations are found in ~40% of familial or bilateral phaeochromocytoma and 5–10% of sporadic cases [8, 9, 28–30]. Different VHL mutations are associated with varying clinical features and hence prognosis. Thus the identification of germline VHL mutations in patients presenting with apparently isolated familial or sporadic phaeochromocytoma is important as in many such individuals the VHL mutation will also carry a high risk for developing retinal or central nervous system haemangioblastoma and RCC (Type 2B VHL disease). However, in some cases, a VHL mutation (e.g. p.Tyr98His) may predispose to retinal and central nervous system haemangioblastomas and phaeochromocytoma, but not, or rarely, RCC (Type 2A VHL disease) [31]. Intriguingly in rare cases a germline VHL mutation may appear to predispose to phaeochromocytoma but not haemangioblastomas or RCC (Type 2C) [29, 30].

The VHL gene product encodes two proteins, a full length 213 amino acid product (30 kDa, pVHL30) and a shorter product lacking the first 53 amino acids (pVHL19). No pathogenic mutations have been reported in the first 53 amino acids and pVHL19 and pVHL30 appear to possess equivalent tumour suppressor activity in in vitro studies [32–37]. The nature of the germline VHL mutation determines phaeochromocytoma risk in VHL disease families. Thus families without phaeochromocytoma (Type 1 phenotype) usually have a germline deletion, truncating mutations or a missense mutation that disrupts the structural integrity of the VHL protein. In contrast, missense mutations at protein surface residues are associated with a high risk of phaeochromocytoma (Type 2A, 2B and 2C phenotypes) [32–36]. These observations suggested that pVHL has multiple tissue-specific functions and that either total loss of pVHL function is non-permissive for phaeochromocytoma development (tumours from VHL patients show loss of the wild-type allele [38, 39]) and/or that phaeochromocytoma associated VHL missense mutations have a "gain of function effect". Functional studies have demonstrated that pVHL has multiple functions including regulation of the cell cycle, apoptosis, mRNA stability, extracellular fibronectin matrix assembly, microtubule function and regulation of atypical protein kinase C [40–43]. However, the best-studied function of pVHL is the targeting of the {alpha} subunits of the HIF-1 and HIF-2 transcription factors for ubiquitylation and proteolytic degradation [44–47]. Thus pVHL is part of an E3 ubiquitin ligase complex in which pVHL binds the target proteins [44–50]. The ability of pVHL to bind to the HIF-{alpha} subunits depends on the hydroxylation status of two proline residues [51, 52]. Hydroxylation of these residues by PHD (or EglN) enzymes is dependent on the availability of oxygen and in hypoxic conditions the lack of prolyl hydroxylation renders the {alpha} subunits resistant to pVHL binding. Under normoxic conditions, HIF {alpha} subunits are rapidly ubiquitylated and destroyed so that the heterodimeric HIF-1 and HIF-2 transcription factors cannot be assembled. However, in hypoxia and in cells with VHL tumour suppressor gene inactivation (e.g. in tumours from individuals with VHL disease and in many sporadic clear cell renal cell carcinomas and haemangioblastomas) stabilization of the {alpha} subunits (and heterodimer formation) enables HIF-1 and HIF-2 to activate hypoxia inducible target genes (including angiogenic growth factors such as VEGF) which promote angiogenesis and regulate glucose metabolism, apoptosis and matrix metabolism. Recent data suggests that HIF-1 and HIF-2 regulate overlapping, but differing, repertoires of target genes and that they may have different biological effects, with HIF-2, but not HIF-1, being oncogenic per se [53, 54].

Multiple endocrine neoplasia type 2

Phaeochromocytoma features in two of the three clinical variants of MEN 2. Thus MEN 2A and MEN 2B are both characterised by a predisposition to medullary thyroid carcinoma and phaeochromocytoma, but MEN 2B is distinguished by an earlier age of tumour diagnosis and characteristic dysmorphic and skeletal features (e.g. multiple mucosal neuromas, intestinal ganglioneuromatosis and Marfanoid habitus) [55]. Phaeochromocytoma develops in about 50% of individuals with MEN 2 and in MEN 2A occurs, on average, about 8 years after medullary thyroid carcinoma (mean age at diagnosis of 37 years) [55]. In contrast to SDHB and SDHD mutations, extra-adrenal tumours are infrequent in MEN 2A and MEN 2B. All three clinical variants of MEN 2 result from germline mutations in the RET proto-oncogene, but there are clear genotype–phenotype correlations. RET is a transmembrane receptor tyrosine kinase [56–58]. Germline mutations associated with MEN 2A are usually missense mutations in highly conserved cystines in the extracellular domain of the receptor (most mutations are in exons 10 and 11). Detailed analysis of genotype–phenotype relationships revealed that codon 634 mutations were associated with a high risk of phaeochromocytoma and hyperparathyroidism [58]. Almost 95% of MEN 2B cases have a methionine to threonine substitution at codon 918. Missense RET mutations have also been described in the third variant, familial medullary thyroid carcinoma, but the mutation pattern is different, with a lower proportion of codon 634 mutations and some mutations have been specifically associated with familial medullary thyroid carcinoma (e.g. mutations at codons 768 and 804) [58].

Neurofibromatosis Type 1 (NF1, von Recklinghausen disease)

This is the fourth, and most common (prevalence ~1 per 3000 persons), autosomal dominantly inherited disorder to be associated with phaeochromocytoma susceptibility. Approximately 50% of cases represent new mutations. The clinical features of NF1 are variable, but characteristic features include café-au-lait lesions, cutaneous and plexiform neurofibroma, axillary or inguinal freckling and Lisch nodules. A clinical diagnosis of NF1 can usually be made by the age of 10 and although mutation analysis is possible, the NF1 gene is very large and molecular analysis is not usually required for diagnosis. The frequency of phaeochromocytoma in individuals with NF1 is small (~3%), most tumours are solitary and adrenal and mean age at diagnosis is 42 years [59].


   Frequency of Germline Mutations in Predisposing Genes in Phaeochromocytoma
Top
 Abstract
 Introduction
 Clinical and molecular genetics...
 Frequency of Germline Mutations...
Mechanisms of Tumourigenesis in...
 Acknowledgements
 References
 
Traditionally it has been estimated that 10% of phaeochromocytoma patients have genetic susceptibility. However in a population-based analysis of 271 non-syndromic sporadic phaeochromocytoma cases, germline mutations in VHL, RET, SDHB or SDHD were detected in 24% (total 66 patients, VHL=30 cases, RET=13, SDHB=12 and SDHD=11] of sporadic cases [8]. This finding prompted suggestions that all patients with phaeochromocytoma might be offered genetic analysis irrespective of clinical features. However, whilst this series represents the largest population-based study, in other series the overall frequency of germline mutations has been less (e.g. 15–20%) ([9], unpublished observations) and it seems that the detection rate of molecular analysis depends on the extent of investigations to uncover a family history of phaeochromocytoma and subclinical evidence of a syndromic cause. Comprehensive mutation analysis of VHL, SDHD, SDHB and RET is not readily available to all centres, and under such circumstances a combination of detailed clinical, biochemical and radiological work up (e.g. careful pedigree analysis, examination for neurofibromas and café-au-lait spots, retinal examination for angiomas, plasma calcitonin and calcium levels, and abdominal scanning for renal and pancreatic tumours and cysts) and targeted molecular analysis may be the most appropriate strategy. Individuals might be prioritized for molecular genetic analysis according to the presence or absence of features of a specific phaeochromocytoma susceptibility syndrome, positive family history, tumour site and age at diagnosis. Thus in sporadic cases without evidence of an underlying syndromic cause, extra-adrenal tumours have an increased frequency of SDH subunit mutations and malignant tumours are preferentially associated with SDHB mutations. Age at diagnosis is an important risk factor for a germline mutation, as in the series reported by Neumann et al. [8], the overall frequency of mutations was 24% but only ~1% in those aged >50 years. For centres where universal testing is not available, after careful clinical evaluation and laboratory investigations for evidence of a syndromic cause of phaeochromocytoma, VHL, SDHB, SDHD and RET mutation analysis should be offered to familial and bilateral phaeochromocytoma cases, VHL, SDHB and SDHD analysis to extra-adrenal phaeochromocytoma and SDHB testing to patients with malignant phaeochromocytoma. Apparently sporadic adrenal phaeochromocytoma patients aged under 30 years should be offered VHL, SDHB, SDHD and RET mutation analysis and, if resources allow, VHL, SDHB and SDHD to those aged 30–40 years.


   Mechanisms of Tumourigenesis in Inherited Phaeochromocytoma
Top
 Abstract
 Introduction
 Clinical and molecular genetics...
 Frequency of Germline Mutations...
 Mechanisms of Tumourigenesis in...
Acknowledgements
 References
 
VHL, SDHB and SDHD inactivation have all been linked with HIF-dysregulation. Thus the ability to regulate HIF {alpha}-subunit stability is a well-defined function of pVHL and is disrupted by mutations associated with Type 2A and 2B VHL disease (and Type 1) [44, 60, 61]. In addition, phaeochromocytomas from patients with germline SDHB and SDHD mutations demonstrate increased expression of HIF-1 and HIF-2 and hypoxia inducible target genes [62–65]. However, reports that Type 2C (phaeochromocytoma only) pVHL mutants retained the ability to ubiquitylate HIF-1{alpha} subunits suggested that HIF dysregulation did not provide a complete explanation for phaeochromocytoma development [60, 61]. Accordingly it was suggested that, in view of the role of mitochondria in apoptosis, inactivation of SDH might lead to failure of apoptosis in neuroendocrine progenitor cells predisposing to the development of phaeochromocytoma and paraganglioma [1, 7]. Lee et al. [12] have provided experimental evidence for this concept and, furthermore, suggested that all four inherited phaeochromocytoma syndromes share a common mechanism of tumourigenesis due to impaired developmental culling of sympathetic neuronal precursor cells (Fig. 2). Thus, normally, many such cells undergo c-Jun-dependent apoptosis during normal development as nerve growth factor levels become limiting. The c-Jun-dependent apoptosis pathway is antagonized by JunB and RET and VHL mutations linked with phaeochromocytoma susceptibility were found to be associated with increased JunB expression. The prolyl hydroxylase, EglN3 (PHD3) acts downstream of c-Jun and is pro-apoptotic. VHL mutations linked with phaeochromocytoma were associated with reduced EglN3 expression and SDH inactivation inhibited EG1N3 proapoptotic activity [12]. As mutations in the NF1 gene product were known to promote survival after NGF withdrawal, these studies implicated a failure of developmental apoptosis in all four inherited phaeochromocytoma disorders. Furthermore, the "developmental culling" hypothesis of Lee et al. [12] is also consistent with the observation that somatic mutations of SDHB, SDHD, RET and VHL are rare in sporadic phaeochromocytoma [8, 66–68].


Figure 2
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  		Fig. 2 Inherited phaeochromocytoma susceptibility genes and neuronal developmental apoptosis pathways. Germline inactivating mutations in NF1, SDHB, SDHD and VHL, and activating RET mutations, impair apoptosis associated with NGF withdrawal (adapted from Lee et al. [12]).

 


   Acknowledgements
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 Abstract
 Introduction
 Clinical and molecular genetics...
 Frequency of Germline Mutations...
 Mechanisms of Tumourigenesis in...
 Acknowledgements
References
 
I apologize to the many authors and investigators whose work I was unable to cite because of space constraints. With thanks to Cancer Research UK and the British Heart Foundation for research support.

Accepted for publication May 18, 2006.


   References
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 Abstract
 Introduction
 Clinical and molecular genetics...
 Frequency of Germline Mutations...
 Mechanisms of Tumourigenesis in...
 Acknowledgements
 References
 

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