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Annales d'Endocrinologie
Vol 66, N° 3  - juin 2005
pp. 178-185
Doi : AE-06-2005-66-3-0003-4266-101019-200502452
Genetic Testing for Pheochromocytoma-associated Syndromes

Chr. Pawlu [1], B. Bausch [1], N. Reisch [2], H.P.H. Neumann [1]
[1] Department of Nephrology and Hypertension, Albert-Ludwigs-Universität, Freiburg, Germany,
[2] Department of Endocrinology, Medizinische Klinik Innenstadt, Ludwig-Maximilians- Universität, München, Germany.

Tirés à part : H.P.H. Neumann

[3] , address above.


Les phéochromocytomes et paragangliomes correspondent à des tumeurs du système nerveux autonome. Différents syndromes sont associés à la présence de phéochromocytomes et de paragangliomes : les néoplasies endocriniennes multiples de type 2 (NEM2, gène de susceptibilité : RET), la maladie de von Hippel-Lindau (VHL, gène de susceptibilité : VHL), le neurofibromatose 1 (NF1), et les syndromes paraganglionnaires de type 1, 3, et 4 (gènes de susceptibilité : SDH gènes des sous unités D, C et B de la succinate déshydrogénase). La prévalence et la présentation clinique des phéochromocytomes et des paraganglionomes sont différentes pour chacun de ces syndromes. L’analyse des mutations des gènes de susceptibilité de ces syndromes chez les patients ayant une phéochromocytome ou une paragangliome peut contribuer à l’évaluation du risque de tumeurs multiples et de l’apparition d’une phéochromocytome maligne ou d’une autre tumeur maligne. Nous présentons une revue des progrès de caractérisation clinique et de tests génétiques pour ces syndromes. À partir des caractéritiques des tumeurs et des données de prévalence, nous précisons les tests génétiques recommandés chez les patients ayant une phéochromocytome ou une paragangliome.


Pheochromocytoma and paraganglioma are tumors of the autonomic nervous system. Various syndromes have been found to be associated with the development of pheochromocytomas and paragangliomas: multiple endocrine neoplasia type 2 (MEN 2, susceptibility gene: RET), von Hippel-Lindau disease (VHL, susceptibility gene: VHL), neurofibromatosis 1 (NF 1), and paraganglioma syndromes type 1, 3, and 4 (susceptibility genes: succinate dehydrogenase gene, SDH, subunits D, C and B, respectively). Prevalence and clinical features of pheochromocytomas and paragangliomas are different for each of these syndromes. Mutational analysis of the susceptibility genes of these syndromes in patients presenting with pheochromocytoma or paraganglioma may help to judge the risks of multifocality of the tumor as well as development of malignant pheochromocytoma or of other malignant tumors. Here we review the recent progress in clinical characterization and genetic testing for these syndromes. Based on tumor characteristics and prevalence data we give recommendations for an efficient genetic testing procedure in patients presenting with pheochromocytomas and paragangliomas.

Mots clés : Phéochromocytomes , paragangliomes , maladie de von Hippel-Lindau , néoplasies endocriniennes multiples , neurofibromatose , gènes de la succinate déshydrogénase , syndromes PGL

Keywords: Pheochromocytoma , paraganglioma , von Hippel-Lindau disease , multiple endocrine neoplasia , neurofibromatosis , succinate deshydrogenase gene , PGL syndromes


In recent years we and others have provided with details of pheochromocytoma patients and their possible risks for other tumors forming syndromes of genetic origin [1], [2], [3], [4], [5]. This has challenged the long established view that sporadic pheochromocytoma and paraganglioma reach a fraction of up to 90 per cent of these diseases. Today we know that likely at least each fourth case is associated with hereditable mutations in one out of just a few genes. Among these the best known syndrome is multiple endocrine neoplasia type 2 (MEN 2). In the past decade von Hippel-Lindau disease (VHL) has attracted much interest. For neurofibromatosis type 1 (NF 1) associated pheochromocytoma only a few reports exist. In recent years families with paraganglioma of the head and neck area have been subjected to genetic studies and form the complex of paraganglioma syndromes (PGL) with several subtypes. In this review we present a condensed description of all these syndromes and their genetic causes.

Definition of pheochromocytoma and paraganglioma

Pheochromocytoma and paraganglioma are tumors of the autonomic nervous system with an estimated yearly incidence of 1:300000 [3], [6]. Tumors originating from the autonomous nervous system are named pheochromocytoma and paraganglioma. Although the terminology is divergent, for clinical purposes we and others use the terms as follows: pheochromocytoma refers to tumor location in the adrenal glands as well as in extraadrenal abdominal and in thoracic locations. The term paraganglioma refers to tumors in the head and neck area. Following this definition, most pheochromocytomas are endocrinologically active, whereas head and neck paragangliomas (HNPs) tend to be non-functioning.

To date it is still difficult to predict the clinical behavior of pheochromocytomas and paragangliomas. For the patient, however, it is of utmost importance whether at some stage of the disease malignancy has to be expected or not, whether multifocal tumors have to be taken into account or not and whether functioning or non-functioning neoplasias are likely.

A major progress in the characterization of these diseases and in the differentiation between distinct syndromes was the introduction of molecular-biological methods as standard diagnostic procedure in these patients. By now, based on a number of studies, predictions of the further progress of the disease are possible even in individual cases in which the syndrome is genetically clearly identified.

Given the costs of a detailed investigation of the candidate genes that may cause hereditary pheochromocytoma or paraganglioma, mutation analysis should start with the genes that are more likely affected than others in the respective patient. Therefore it may be valuable to define a diagnostic pathway based on tumor location and clinical features.

Men 2 and RET gene

Two syndromes caused by mutations in two different gene loci are referred to as multiple endocrine neoplasias (MEN) [7]. MEN 1 is caused by mutations in the MEN 1 gene (11q13) and characterized clinically by tumors of the parathyroid, by entero-pancreatic tumors, and pituitary tumors. Whereas the adrenal cortex is also affected in up to 20 per cent of the cases, pheochromocytomas are extremely rare in MEN 1 patients (≪1 per cent) [8]. MEN 2, on the other hand, is characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors. In up to 25 per cent of the cases, pheochromocytoma is diagnosed before medullary thyroid carcinoma is apparent [9]. MEN 2 is caused by mutations in the RET-protooncogene on chromosome 10q11.2, which encodes a transmembrane receptor tyrosine-kinase. There is good evidence for phenotype-genotype correlations in MEN 2 syndrome, i.e. the location of the mutation defines which of three subtypes develops: MEN 2A, MEN 2B, or familiar medullary thyroid carcinoma (FMTC). MEN 2A seems to be associated preferentially with mutations in the cysteine-rich extracellular domain of the RET protein, which allow the formation of pathological dimers. Codon 634 is affected in 85 per cent of the cases. Mutations in the intracellular tyrosin-kinase domain of RET (most often M918T), however, are found in MEN 2B [8], [10]. Pheochromocytomas have been found in both MEN 2A and MEN 2B patients. The vast majority are adrenal pheochromocytomas, other locations and head and neck paragangliomas are very rare (table I). Codon 634 mutations seem to favor early development of pheochromocytomas. No pheochromocytomas, however, have been described so far in MEN 2 patients with mutations in the codons 609, 768, V804M, and 891 [8], which are usually found in patients with FMTC. Patients who present with pheochromocytoma as first symptom will thus benefit from early diagnosis of MEN 2 by DNA-based testing and subsequent total thyroidectomy even before expressing medullary thyroid carcinoma. As a standard procedure mutational analysis of c-ret is performed to dectect mutations in the codons 609, 611, 618, 620, 634, 768, 804, and 918 [11].

VHL and VHL gene

Patients with von-Hippel-Lindau disease (VHL) are at risk for retinal angiomas, hemangioblastomas of the brain and of the spinal cord, pheochromocytomas, renal cysts, renal clear cell carcinomas, pancreatic cysts, islet cell carcinomas, epididymal cystadenomas, and endolymphatic sac tumors of the inner ear. VHL is an autosomal dominant syndrome with an incidence of one in 39000 births per year [5], [12]. Clinically one can distinguish VHL patients from families with low risk (type 1) and with high risk of pheochromocytoma (type 2). In the second case, occurrence of renal cancer then defines a type 2A, other than type 2B. Sometimes a type 2C, defined by isolated pheochromocytoma, is defined as a distinct subtype [13]. These subtypes are based on substantial genotype-phenotype correlations [12], [14]. More than 400 different VHL mutations are known so far. Approximately 43 per cent of the VHL type 2 families have a mutation in codon 167 of the VHL gene. In general, missense mutations in the VHL gene seem to favor type 2 of the disease [15]. Mutations of the codons 595 and 695 seem to be associated with a young age of onset in pheochromocytomas [15].

The VHL gene contains three exons and is located on chromosome 3p25. VHL is a tumor suppressor gene that encodes a protein expressed in most tissues. It is involved in the regulation of hypoxia-inducible genes and inhibits the accumulation of hypoxia-induced proteins, mediated by binding to hypoxia-inducible factor α (HIF-α), but also participates in the regulation of the cell-cycle and mRNA stability [13]. The exact mechanism of tumorigenesis is not understood so far, but some aspects can be explained with an increased vulnerability of certain tissues by hypoxia.

Neurofibromatosis 1 (von Recklinghausen’s disease) and NF 1 gene

The term neurofibromatosis summarizes a set of genetic disorders which are associated with tumor growth in various neuroectodermal tissue, from a clinical view neurofibromatosis has been divided into cases without (NF 1) and with (NF 2) acoustic neuromas. NF 1, also known as peripheral neurofibromatosis or von Recklinghausen’s disease, accounts for more than 90% of all neurofibromatosis cases. A clinical diagnosis of NF 1 is made, if 2 or more of the following signs are positive: ≥6 café au lait spots, ≥2 neurofibromas or 1 plexiform neurofibroma, inguinal or axillary freckling, optic glioma, ≥2 iris hamartomas (Lisch nodules), osseous lesions. Only one of these signs suffices for the diagnosis if a first degree relative has neurofibromatosis according to at least two of these criteria. Almost one-hundred years ago an association of pheochromocytomas with von Recklinghausen’s disease has been described for the first time [16]. The prevalence of pheochromocytoma in NF 1 ranges between 0.1 and 5.7% [17] and thus is lower than in the other familiar syndromes that are summarized here. No increased risk has been found in NF 2.

The NF 1 gene is very large and contains a total number of 60 exons. It is located on chromosome 17q11.2 and encodes for the neurofibromin protein, which most likely acts as a tumor suppressor. NF 1 is an autosomal-dominant syndrome that reaches almost 100 per cent penetrance in adulthood. The NF 1 mutation rate is extremely high and affects preferentially the paternal chromosome. Accordingly about 50 per cent of the NF 1 cases are caused by new mutations and no frequently returning mutation is known.

More than 90 per cent of the pheochromocytomas in NF 1 affect the adrenals. About 90% are unilateral (table I). Whereas a low incidence of malignancy in pheochromocytoma is usually assumed to be a typical feature of hereditary familiar pheochromocytoma-associated syndromes, a malignancy rate of 11.5% for pheochromocytomas in NF1 patients appears quite high [17] in comparison.

Paraganglioma syndromes (PGL) and SDH genes

In recent years convincing evidence has come up that the majority of cases of familial paragangliomas and also a significant fraction of the non-familial tumors are associated with gene mutations in three subunits of the succinate dehydrogenase (SDH) [6]. As a complex of the mitochondrial electron transport chain, the SDH protein is a major link between two important biochemical mechanisms, Krebs cycle and oxidative phosphorylation. This enzyme, coded completely in nuclear DNA, consists of four protein subunits, which are referred to as SDHA, SDHB, SDHC, and SDHD, respectively.

SDHA is part of the catalytic part of the enzyme, and defects in this subunit cause ataxia, optic atrophy, and Leigh syndrome, a necrotizing encephalomyelopathy [18]. These metabolic disorders indicate that SDHA defects cause a metabolic disorder of the Krebs cycle.

SDHB, SDHC, and SDHD, however, are the susceptibility genes for three forms of paragangliomas syndromes (PGL4, PGL3, and PGL1, respectively). Pathophysiologically, an impaired ability of intracellular oxygen sensing might be involved in tumorigenesis, resulting in constant signaling of hypoxia in the cell. The expression of hypoxic-angiogenic responsive genes was found in SDH mutations [19], [20], and may indicate a pathophysiology related to the models of VHL disease.

The SDHB gene, encoding for the iron-sulfur protein in mitochondrial complex II, consists of 8 exons and is located on chromosome 1p35-36. The SDHC gene encodes for the large subunit of cytochrome c, consists of 6 exons and is located on chromosome 1q21. The SDHD gene encodes for the small subunit of cytochrome b, consists of 4 exons and is located on chromosome 11q23. Interestingly, SDHD mutation carriers only develop a phenotype if the defect allele was inherited from the patient’s father. Table II gives an overview of the known mutations in the SDHB gene. To date, missense and nonsense mutations of the exons 1, 2, 3, 4, 6, and 7 are known, as well as mutations in three of the introns. Table III contains parallel information on mutations of the SDHC gene, and table IV for SDHD.

The clinical manifestations of these syndromes are different. In PGL 1, tumors are preferentially located in head and neck paraganglia and in the adrenal glands. On the other hand, extraadrenal pheochromocytoma was observed more often. So far there is no report about malignant pheochromocytoma or paraganglioma in PGL 1, whereas more than 30 per cent of tumors found in patients with PGL 4 were malignant (table I). Therefore these patients might especially benefit from early genetic testing.

Only few reports on paranganglioma associated with SDHC mutations have been published so far (table III) and thus not a lot is known yet on the specifics of SDHC-mutation related paragangliomas. Nevertheless, given the dichotomy between the clinical features of SDHB- and SDHD-mutation-related pheochromocytoma and paragangliomas, it appears likely that carriers of SDHC mutations may have a different pathologic, clinical, and demographic profile compared to carriers of SDHB and of SDHD mutations, too. Thus genetic testing is also relevant for these patients to exclude other syndromes and to learn about the clinical aspects from an increasing number of SDHC mutation cases.

Discussion and recommendations

We conclude from personal experience and the literature that early recognition of a possible genetic nature of pheochromocytomas and paragangliomas is mandatory. This is relevant for the patient and possibly affected relatives who may carry the given mutation. It includes prevention not only for pheochromocytoma but also for associated tumors and provides with facilities for early and probably definitive cure of carcinomas such as medullary thyroid cancer in MEN 2.

In patients presenting with pheochromocytoma or paragangliomas, we suggest using a combined clinical and molecular genetic approach, since some clinical tests are easy to perform, but age-dependent penetrance and a broad spectrum of phenotypes suggest genetic analyses in addition.

Personal and family history in high penetrance genetic disorders may indicate whether a patient’s disease fits into a familial pattern or may later be diagnosed as sporadic occurrence. Furthermore other family members may have shown symptoms that are not yet present in the patient, but point towards a distinct syndrome.

Specific clinical investigation of the disease should always include a review of the already existing CT and MRI scans of the abdomen with special respect to the number of pheochromocytomas and pancreas or kidney lesions. Evaluation of calcitonin, calcium, and PTH levels as well as retinoscopy are obligate, and MRI of the brain and the spinal cord as well as of neck and chest may be added. A review of MIBG scintigraphy may sometimes reveal information on multifocality of the disease.

Eventually, mutational analysis will uncover or exclude one of the genetic syndromes discussed here. Given that actually one out of four apparently sporadic pheochromocytomas is an inherited tumor and considering the chance of predicting other lesions, once a specific syndrome has been diagnosed, a search for germline mutations is mandatory. In many cases this may well affect medical management, e.g. by dealing with an increased risk for other cancers, additional pheochromocytomas and counseling of family members [12]. Whenever from additional signs or from the family history there is no clear hypothesis which syndrome might underlie the pheochromocytomas or paragangliomas, the order of gene tests should be chosen according to the clinical features of the disease in the respective patient. This will help to save time and money. Overall it helps to keep in mind that about 25-30% of these tumors can be attributed to one of the syndromes reviewed here, and of those 70% of the familial pheochromocytoma cases are associated with RET mutations, 14% with VHL, 5% with NF1 and roughly 4% with mutations in the SDH genes, whereas the SDH related syndromes account for almost all of the familial paraganglioma cases [21]. The cases that are most relevant clinically are discussed here, and we give suggestions which genes should be investigated first.

Extraadrenal pheochromocytomas are frequently observed in SDHB and SDHD mutations, which makes them the first targets of mutational analysis. VHL and NF 1 are also known to yield extraadrenal pheochromocytomas and thus should be tested next. In the low number of SDHC patients who have been described so far, only paragangliomas were found. According to present data an association with MEN 2 is also very unlikely.

The diagnosis of pheochromocytoma and paragangliomas in the same patient clearly suggests starting with SDHD, then SDHB and SDHC testing. Only very rarely head and neck paragangliomas have been observed as an inherited condition in VHL patients [21] and in MEN 2 [22]. Therefore mutational analysis of the VHL, RET, and NF 1 genes does not have high priority in these cases.

Renal cell carcinomas are found in roughly 25% of patients with VHL. In patients presenting with pheochromocytoma and renal tumors the most likely genetic alteration is therefore a mutation in the VHL gene. Interestingly clear renal cell carcinoma was also found in members of one family with an SDHB mutation [3], which may mean to investigate the SDHB gene if no mutation could be found in VHL. Similarly, diagnosis of pheochromocytoma in childhood and youth points to VHL.

A rate of malignancy of 35% was found in SDHB-related pheochromocytomas and paragangliomas [3], roughly 10% in NF 1-associated cases [17]. If the patient presents with malignant pheochromocytoma, testing should begin with SDHB, then the NF 1 gene, and, if nothing has been found until then, continue with VHL, RET, and SDHC and SDHD.

Multifocal tumors, e.g. bilateral pheochromocytoma, are found in all of the syndromes discussed here, with a relatively low but still substantial rate in NF 1 and in SDHB related disease. If multifocality is the only clue for the decision on the procedure in genetic testing, the overall high probability of RET mutations should guide the clinician to screen this gene first and to proceed with VHL, NF 1, SDHD, SDHB, and SDHC.

The recent progress in the characterization of these tumors and associated syndromes yields a differentiated view on the genetic background and the pathophysiology and thus may support diagnosis, treatment and counseling of pheochromocytoma and paraganglioma.


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