, Volume 12, Issue 3, pp 175–181

Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC)


    • Institut für HumangenetikJustus-Liebig-Universität, Gießen, and bio.logis, Zentrum für Humangenetik, Frankfurt a.M.

DOI: 10.1007/s10048-011-0280-y

Cite this article as:
Müller, U. Neurogenetics (2011) 12: 175. doi:10.1007/s10048-011-0280-y


Paragangliomas/pheochromocytomas (PGL/PCC) are tumors of the paraganglia. They can occur sporadically, as one sign in a hereditary (tumor) syndrome or as the only manifestation in hereditary PGL/PCC. To date, five forms of hereditary PGL/PCC have been described. They are inherited as autosomal dominant traits and are caused by mutations in genes required for structure and function of complex II of the respiratory chain (succinate-ubiquinone oxidoreductase, succinate dehydrogenase, SDH). Mutations in genes encoding the small subunits of SDH, i.e., SDHD and SDHC, cause PGL1 and PGL3. Mutations in the large subunit genes SDHB, SDHA (currently only one case), and in SDHAF2 cause PGL4, 5, and 2, respectively. This article gives an overview of PGL/PCC in the context of the anatomy and function of paraganglia. It describes SDH, the genes encoding SDH, and provides information on genetic mechanisms in hereditary PGL/PCC. A model is proposed to explain exclusive paternal inheritance and loss of the maternal (putatively imprinted) allele as a prerequisite for tumor formation in PGLs 1 and 2.


Hereditary paraganglioma/pheochromocytomaMaternal imprintingTumorigenesisCellular hypoxiaSDHASDHBSDHCSDHDSDHAF2Succinate-ubiquinone oxidoreductaseComplex IIPartial imprinting

Paragangliomas (PGLs) are highly vascularized, usually benign tumors of the paraganglia. Paraganglia derive from the neuroectoderm and can be divided into non-chromaffin and chromaffin forms. Non-chromaffin paraganglia and the PGLs derived from them are associated with the parasympathetic nervous system and chromaffin paraganglia as well as chromaffin PGLs are components of the sympathetic nervous system.

Parasympathetic paraganglia (Fig. 1)

Parasympathetic paraganglia are primarily found in the head and neck. They include the
  • paraganglion (glomus) caroticum at the bifurcation of the carotis,

  • paraganglion (glomus) tympanicum,

  • paraganglion (glomus) jugulare at the jugular vein,

  • superior and inferior paraganglion (glomus) laryngeum. The former is adjacent to thyroid cartilage in close proximity to superior laryngeal artery and nerve, the latter in close proximity and superior to the glottis.
    Fig. 1

    Location of paraganglia (from Lips et al. [40]). For details, see text

Of these paraganglia, the role of the carotid body (glomus caroticum) is best understood. It functions as oxygen and, to a lesser extent, as carbon dioxide sensor and regulates the oxygen supply in the body. Its receptors are activated by hypoxia, pH, and temperature [1]. The carotid body is composed of two cell types, glomus type I (“chief”) cells and glomus type II (sustentacular) cells. PGLs originate from “chief” cells.

Sympathetic paraganglia (Fig. 1)

Sympathetic paraganglia are chromaffin tissues and frequently secrete catecholamines. The adrenal medulla is the most important sympathetic paraganglion during postnatal life. Via secretion of catecholamines, mainly epinephrine (adrenaline) and norepinephrine (noradrenaline), the adrenal medulla regulates blood pressure, heart rate, blood glucose level, and plays an important role in stress situations. During embryonic life, the organ of Zuckerkandl (paraganglion aorticum abdominale) fulfills these roles. The paraganglion aorticum abdominale is located at the bifurcation of the inferior mesenteric artery at the abdominal aorta. While this tissue is well-differentiated and functional during prenatal life, it degenerates towards birth. Its functions are then taken over by the adrenal medulla and other sympathetic paraganglia of thorax and abdomen.


Tumors arising from paraganglia can be clinically divided into neuroendocrine and non-endocrine tumors. Neuroendocrine tumors primarily originate from sympathetic paraganglia, mainly the adrenal medulla, and are referred to as pheochromocytomas (PCCs) [2]. The term pheochromocytoma is usually used to describe all chromaffin, endocrinologically active PGLs. However, some authors only classify chromaffin catecholamine-secreting adrenal tumors as “pheochromocytomas” and refer to other chromaffin, catecholamine-secreting tumors as “secreting paragangliomas” [3]. According to the recommendations of the National Cancer Institute (, only adrenal PGLs are referred to as PCCs. All other paraganglia-derived tumors are called either PGLs, glomus tumors, or chemodectomas. Non-endocrine PGLs are most frequently derived from parasympathetic paraganglia of the head and neck. They can be clinically further subdivided based on their location and include carotid body PGLs, tympanic and jugular PGLs, laryngeal PGLs, nasopharyngeal, and orbital PGLs. Clinically, tympanic and jugular PGLs are sometimes hard to differentiate and therefore are referred to as temporal PGLs. In rare instances, secretory parasympathetic PGLs have been observed.

Paragangliomas/pheochromocytomas can arise sporadically, occur as one of several signs within a hereditary (tumor-) syndrome or may be transmitted as the only trait in families (hereditary PGLs). Sporadic PGLs can be caused by low oxygen concentrations in the tidal air. Thus, the prevalence of PGLs is significantly increased in people living at high altitudes such as the Andes as compared to persons living at sea level [4]. Syndromic occurrence of PGLs/PCCs is found in neurofibromatosis 1, von Hippel–Lindau syndrome, and multiple endocrine neoplasia 2 [5, 6]. The hereditary PGLs/PCCs are a genetically heterogeneous group of tumor syndromes that present with PGL and/or PCC as the only sign.

Hereditary PGL/PCC and succinate ubiquinone-oxidoreductase

Hereditary PGLs are inherited as autosomal dominant traits. To date, five types of hereditary PGL/PCC are known. They are caused by mutations in genes coding for components of mitochondrial complex II (succinate ubiquinone-oxidoreductase, succinate dehydrogenase, SDH) of the respiratory chain (Fig. 2).
Fig. 2

Schematic of mitochondrial complex II (succinate-ubiquinone-oxidoreductase, succinate dehydrogenase, SDH) within mitochondrial membrane and enlarged. Subunits SDHA, B, C, and D and the succinate dehydrogenease complex assembly factor 2 (SDHF2) are given. (Figure modified from [41])

Succinate–ubiquinone (succinate-coenzyme Q) oxidoreductase is composed of four subunits, SDHA, SDHB, SDHC, and SDHD (Fig. 2). Subunits SDHA (flavoprotein subunit) and SDHB (iron-sulfur protein subunit) have catalytic function. They are anchored in the inner mitochondrial membrane by the smaller subunits SDHC and SDHD. An additional protein, SDHAF2 (SDH5) is required for flavination of SDHA. SDHA is the largest subunit of succinate-ubiquinone oxidoreductase (72.692 kDa). It consists of 664 amino acids. SDHB is a polypeptide of 31.63 KDa and 280 amino acids. The smaller subunits SDHC and SDHD are polypeptides of 18.61 kDa (169 amino acids) and of 17.043 kDa (159 amino acids), respectively. SDHAF2 (succinate dehydrogenase complex assembly factor 2) is a polypeptide of 19.599 kDa, composed of 166 amino acids.

SDHA catalyzes the conversion of succinate to fumarate within the citric acid cycle (succinate + ubiquinone = fumarate + ubiquinol). This reaction also generates FADH2 from FAD. As part of the respiratory chain electrons from FADH2 are transferred to the SDHB subunit and finally to ubiquinone via the SDHC/SDHD subunits. Interaction of SDHA with SDHAF2 is required for FAD attachment.

The gene SDHA is located on chromosome 5 (5p15.33) and composed of 15 exons. SDHB is on chromosome 1 (1p36.13) and comprises eight exons. SDHC (six exons) and SDHD (four exons) are on chromosome 1 (1q23.3), and on chromosome 11 (11q23.1), respectively. SDHAF2 (SDH5) consists of four exons in 11q12.2 (for genes, their products and location see:

Paragangliomas, type 1 (PGL1) are caused by mutations in the SDHD gene [7] and account for up to 50% of cases with hereditary PGL/PCC [8, 9]. However, the frequency of SDHD mutations varies considerably between populations. For example, it is up to 94% in Dutch families [10]. SDHD mutations are mainly found in non-secreting PGLs of the head and neck. In several cases of hereditary PGL/PCC, SDHD mutations were also found in thoracic and pelvic locations, in malignant PGL [11], and in PCCs (catecholamine-secreting PGLs) [1214]. Risk for malignant transformation, however, is generally low in PGL1. PGLs caused by mutations in SDHB [15] are the second most common form and are referred to as PGL4. Frequency of PGL4 is about 20% of PGL/PCC cases. Again, frequency varies among populations and was only found in 6% of Dutch PGL/PCC families [10] and in 9% of 11 Australian families studied [16]. SDHB mutations are also found in PGL/PCC of the head and neck. In addition, thoracic and abdominal locations are common. Sympathetic paraganglia are more frequently affected, and secreting PGLs (PCC) are more common in PGL4 than in PGL1. Furthermore, the risk for malignant transformation is relatively high in SDHB-PGL/PCC [17]. PGL/PCC caused by mutations in SDHB were also found associated with neuroblastoma [18]. Mutations in SDHC [19] are rare and make up only about 4% of hereditary PGL/PCC cases. SDHC-related PGLs are referred to as PGL3. They are most commonly non-secreting and benign and occur in the head and neck. As in PGLs caused by SDHD and SDHB mutations [13, 2023], malignant and secreting tumors have also been found in PGLs caused by SDHC mutations [24]. Mutations in SDHAF2 (SDH5) [25] are exceedingly rare. Identical mutations, c.232 G > A in exon 2 of SDHAF2, which result in a Gly78Arg change were found in one large Dutch and in one Spanish pedigree [26]. In addition, this same mutation is relatively common in the Netherlands owing to a common founder [27]. Mutations in SDHA have been thought not to occur in PGL and were considered specific for Leigh syndrome, a neurodegenerative disorder. Recently, however, one case with PGL and a mutation in SDHA was detected [28].

Mechanisms of tumorigenesis in hereditary PGL/PCC

Tumorigenesis is triggered by loss of heterozygosity (LOH), i.e., loss of the wild-type allele in tumors in all five forms of autosomal dominant PGL/PCC [9]. Thus, all hereditary PGL/PCC follow Knudson's classic two-hit model of tumorigenesis. LOH results in severe reduction or loss of the respective components of SDH, i.e., SDHA in one case of hereditary PCC/PGL described so far, SDHB in PGL4, SDHC in PGL3, SDHD in PGL1, and SDHAF2 in PGL2. This reduction/loss of SDH activity interferes with normal function of both the citric acid cycle and the respiratory chain. Succinate and reactive oxygen species (ROS) accumulate [29, 30]. Succinate is an important “oxygen sensor” and stabilizes the hypoxia-dependent subunit of hypoxia inducible factor 1α (HIF1α). This is accomplished by inhibition of HIF-prolyl-hydroxylase (PHD, HPH or EgIN) that is necessary for degradation of HIF1α [31, 32]. As a result, HIF1α is not sufficiently degraded and hypoxia-dependent pathways are activated. Similarly, ROS enables these pathways.

One important hypoxia-inducible gene is vascular endothelial growth factor (VEGF). VEGF induces angiogenesis [33], a finding consistent with the high degree of vascularization of PGLs. An additional factor contributing to the development of PGL/PCC may include inhibition of apoptosis of neuronal cells. Succinate-mediated inhibition of PHD/HPH/EgIN3 results in loss of the proapoptotic function of this enzyme. Provided inhibition of apoptosis plays a role in tumorigenesis, this inhibition should mainly affect the chief cells (type1 cells) of paraganglia as this cell type is transformed in tumors. Furthermore, the well-established ROS-induced genetic damage could contribute to tumorigenesis. This might occur by damaging DNA repair genes and/or genes that encode proteins involved in regulation of ROS thus accelerating ROS-induced damage [34, 35].

Paternal transmission of PGL1 and PGL2

While PGLs 3,4, and probably 5 (caused by SDHA mutation) arise independent of the parental origin of the germ line mutation, PGL 1, and 2 only occur if the germ line mutation derives from the father. This phenomenon suggests maternal imprinting (inactivation) of the respective genes, i.e., SDHD and SDHAF2. The hypothesis of maternal imprinting is complicated by several findings:
  • There is biallelic expression of SDHD in various organs including brain, kidney, and lymphoblastoid cells [7]. To date, no convincing data are available on the expression pattern of SDHD in paraganglia. No findings are presently available for SDHAF2.

  • The regions of the long arm of chromosome 11 where SDHD (11q23) and SDHAF2 (11q12.2) are located are not genetically imprinted.

  • The SDHD promoter is neither methylated in the normal adrenal medulla nor in PCCs and breast tumors [36, 37]. Thus, at least, DNA methylation does not appear to be the underlying mechanism causing inactivation of maternally derived SDHD. No findings have been reported on SDHAF2.

  • Despite exclusive paternal transmission, loss of the maternal allele is a prerequisite for tumor formation. However, if the maternal allele was completely inactivated, tumors should arise even in the absence of LOH. This is clearly not the case.

In order to account for these findings, Hensen et al. [38] speculated that rather than SDHD, a hypothetical tumor suppressor gene is inactivated in the imprinted region of the short arm of chromosome 11 (11p15). This hypothetical tumor suppressor would be active if derived from the mother but would be inactive if paternally derived. By loss of the entire maternal chromosome 11 in tumors, both the non-imprinted wild-type SDHD allele and the hypothetical active tumor suppressor would be lost. As a result, a tumor arises (Fig. 3a). Conversely, if the mutation was transmitted maternally and the paternal chromosome 11 was lost, the tumor suppressor would stay active. Tumorigenesis would not be initiated (Fig. 3b). In order for maternal transmission of a mutation to result in tumorigenesis, two events would be required. First, recombination needs to occur between the long arms of maternal and paternal chromosome 11 and secondly, non-disjunction needs to arise of the recombinant chromosome 11, which would then harbor both an inactivated (paternally imprinted) hypothetical tumor suppressor gene and the maternally derived mutation in 11q. Likelihood for both events to occur is rather low (Fig. 3c).
Fig. 3

Tumor formation in PGL1 according to the model of Hensen et al. (2004) [38]. This model assumes a hypothetical paternally imprinted tumor suppressor gene in distal 11p and non-imprinting of SDHD. Maternally derived chromosome 11 is red and the paternally derived one is blue. Paternal transmission of the SDHD mutation and loss of the maternal copy results in tumor formation (a). Tumor formation does not occur upon maternal transmission and loss of the paternal copy, since the hypothetical tumor suppressor is active (b). Only several events including recombination between the homologous long arms of chromosome 11 would lead to tumor formation upon maternal transmission of the SDHD mutation (c). (Figure modified from [38])

This hypothesis is not entirely convincing. First, there is no evidence for a paternally imprinted tumor suppressor gene in 11p. Second, this tumor suppressor might also need to be deleted in PGLs 3,4,5. Yet this appears not to be the case, and was excluded in PGL3 [19 and unpublished results]. In PGLs 3,4,5 LOH occurs of the homologous regions of the mutated genes, i.e., SDHC, SDHB, and SDHA, respectively.

Here, I propose another model, which explains why tumors only arise in PGL1 and PGL2 if the respective mutations in SDHD and SDHAF2 derive from the father but not from the mother. This model assumes partial inactivation of the maternally derived genes (SDHD or SDHAF2). The mechanism of partial imprinting is currently not known. Given that there is no increased DNA-methylation in the promoter region of at least SDHD, a mechanism other than DNA-methylation is thought to operate. As a result of partial inactivation, some residual activity of SDH is present in cells with a paternally derived mutation (Fig. 4b). This residual activity suffices for normal function of paraganglia cells over a considerable length of time. Yet, ROS and increased levels of succinate accumulate over time. The cells are chronically hypoxic, which favors non-disjunction. The maternal chromosome 11 or parts of it get lost, no sufficient amounts of SDH are left and tumorigenesis is triggered (see above “Mechanisms of tumorigenesis in hereditary PGL/PCC”). This mechanism is consistent with the adult-onset of hereditary PGLs. Conversely, if the mutation is maternally derived, there will be enough SDH activity (encoded by the paternally derived wild type allele of SDHD) in the cell to allow normal function (Fig. 4c). SDH activity is close to that of the wild type (Fig. 4a). In this scenario, non-disjunction and thus loss of the wild-type allele are not favored. This model also allows for exceptions to the rule of paternal transmission of PGL1 and PGL2. In the only case of PGL1 which was found to be maternally transmitted [39], LOH was probably a random event that was not favored by hypoxia.
Fig. 4

Development of PGL/PCC in maternally but not paternally transmitted SDHD mutations. The model is based on partial imprinting (inactivation) of the maternally derived copy of SDHD. In wild-type cells, “full” paternal and “reduced” maternal expression of SDHD (owing to incomplete maternal imprinting) guarantee high SDH activity and low levels of succinate, HIF1a, and ROS. No tumor arises (a). If the mutation is derived from the father, increased levels of succinate, HIF1a, and ROS arise owing to significantly reduced levels of SDHD and thus of SDH activity. This chronic cellular hypoxia is above a critical threshold (marked) where non-disjunction and tumor induction eventually occur (b). If the SDHD mutation is maternally derived “full” paternal expression of SDHD guarantees sufficient SDH activity to keep succinate, HIF1a, and ROS levels below the critical threshold (c). No tumor arises. This model also applies to paragangliomas caused by SDHAF2 mutations

In conclusion, the five known forms of hereditary PGL/PCC are caused by germ line mutations in the genes encoding various components of succinate-ubiquinone oxidoreductase and LOH of the respective regions in tumors. The increasing levels of succinate and the resulting cellular hypoxia lead to tumor formation. Given increased occurrence of sporadic PGLs at low oxygen pressure, cellular hypoxia, and thus, similar mechanisms might operate in tumor formation in sporadic as in hereditary PGL/PCC. This knowledge will facilitate the development of conservative treatments for PGL/PCC, which interfere with one or several of the various events leading to and resulting from cellular hypoxia.


I thank Ms Silke Reichmann for preparation of the manuscript.

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© Springer-Verlag 2011