Paragangliomas 1

A number sign (#) is used with this entry because of evidence that familial paragangliomas-1 (PGL1) is caused by heterozygous mutation in the SDHD gene (602690), which encodes the small subunit of cytochrome B in succinate-ubiquinone oxidoreductase, on chromosome 11q23.

Description

Paragangliomas, also referred to as 'glomus body tumors,' are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors (hence, the tumor name 'chemodectomas') and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (Baysal, 2002; Neumann et al., 2004).

The triad of gastric leiomyosarcoma, pulmonary chondroma, and extraadrenal paraganglioma constitutes a syndrome that occurs mainly in young women and is known as the Carney triad (604287). This triad is not to be confused with the other Carney syndrome of myxoma, spotty pigmentation, and endocrinopathy (160980).

Baysal (2008) provided a review of the molecular pathogenesis of hereditary paraganglioma.

Genetic Heterogeneity of Paragangliomas

See also PGL4 (115310), caused by mutation in the SDHB gene (185470) on chromosome 1p36; PGL3 (605373), caused by mutation in the SDHC gene (602413) on chromosome 1q21; PGL2 (601650), caused by mutation in the SDHAF2 gene (613019) on chromosome 11q13; PGL5 (614165), caused by mutation in the SDHA gene (600857) on chromosome 5p15; PGL6 (618464), caused by mutation in the SLC25A11 gene (604165) on chromosome 17p13; and PGL7 (618475), caused by mutation in the DLST gene (126063) on chromosome 14q24.

Clinical Features

Kroll et al. (1964) found carotid body tumors in 12 members of a family in an autosomal dominant pattern of inheritance. Resler et al. (1966) reported a patient with bilateral carotid body tumors and a glomus jugulare tumor. The authors noted that familial carotid body tumors tended to be multiple. Familial glomus jugulare tumors were likely described in 3 affected sisters reported in 1937 by Goekoop (cited by Rosen, 1952). Also see Ladenheim and Sachs (1961). Bartels (1949) identified carotid body tumors in members of 3 successive generations of a family.

Wilson (1970) reviewed familial reports of carotid body tumors and described a family with male-to-male transmission and a skipped generation. Pratt (1973) reviewed the literature and reported 8 new cases of either unilateral or bilateral carotid body tumors in 4 generations of a kindred. In 1 generation of this family, 4 sisters had bilateral tumors and 1 brother had unilateral tumors. None of the 8 tumors reported were malignant. Chedid and Jao (1974) identified carotid body tumors in 6 members of 2 consecutive generations of a family. Four also had chronic obstructive pulmonary disease with persistently high arterial pCO(2) and low pO(2). The authors theorized that the tumors started as hyperplasia secondary to the stimulus of these altered blood gases. Nissenblatt (1978) reported a young woman with hypoplastic right heart syndrome who developed a carotid body tumor at age 28 years. He suggested a connection between low-oxygen situations such as high altitude living, emphysema, and cyanotic congenital heart disease, and the development of carotid body tumors.

Grufferman et al. (1980) reported 2 sisters with carotid body tumors and reviewed reports of 88 familial and 835 nonfamilial CBT cases. Familial cases had an equal sex ratio and followed autosomal dominant inheritance. Bilateral disease occurred in 31.8% of familial cases and 4.4% of sporadic cases. Six percent of all patients developed second primary tumors, mostly other paragangliomas. Parry et al. (1982) reviewed the records of 222 histologically diagnosed cases of carotid body tumors, including 146 females and 76 males. The mean age at tumor development was 44.7 years. In 16 patients who had other extraadrenal paragangliomas, suggesting a multiple primary tumor syndrome, the diagnosis occurred earlier (mean, 35.4 years; p less than 0.01). Five patients also developed thyroid cancer. Familial cases were more often bilateral and diagnosed slightly earlier.

Van Baars et al. (1982) provided a review of the literature of familial nonchromaffin paragangliomas. Carotid body tumors were the most common, followed by glomus jugulare, glomus vagale, and glomus tympanicum.

Parkin (1981) reported 2 unrelated families with a hereditary syndrome of pheochromocytoma associated with multiple glomus tumors of the head and neck. DeAngelis et al. (1987) reported the occurrence of pheochromocytoma and multiple paragangliomas in a patient with neurofibromatosis (162200). Karasov et al. (1982) described a sporadic case of a girl with a record number of 21 paragangliomas removed between the ages of 13 and 17 years, with evidence of remaining tumors. The tumors were catecholamine-producing. Khafagi et al. (1987) reported 2 unrelated adults, both of whom had a positive family history of paraganglioma. Both had malignant nonfunctional paragangliomas detected by uptake of iodine-131 metaiodobenzylguanidine; this agent proved to be of therapeutic value in the management of unresectable metastases.

Van Schothorst et al. (1998) reported 10 families with head and neck paragangliomas who originated from the same geographic region in the Netherlands. The carotid bifurcation was the most frequently affected site (57% of all head and neck tumors), and multiple paragangliomas occurred in 66% of patients. Three patients from different families developed a pheochromocytoma. No affected offspring of female carriers was observed, and all affected family members received the disease gene from their father.

Prontera et al. (2008) reported an Italian family with PGL1. The proband was a 49-year-old man who presented with throat pain, dysphonia, dyspnea, and mild hypertension, and was found to have bilateral carotid chemodectomas with multiple highly vascularized laryngeal and carotid paragangliomas. Family history revealed that the father, who died at age 71 of lung cancer, was diagnosed at age 66 with bilateral paragangliomas in the pericarotid region. The 55-year-old sister of the proband developed multiple laryngeal and carotid paragangliomas at age 52. The proband and his sister both carried a heterozygous truncating mutation in the SDHD gene.

Hensen et al. (2010) used the Kaplan-Meier method to calculate the age-specific penetrance of paragangliomas in 243 members of a large 7-generation Dutch family (Oosterwijk et al., 1996) with PGL1 caused by a founder mutation in the SDHD gene (D92Y; 602690.0004). The age at onset of symptoms ranged from 14 to 47 years. By clinical signs and symptoms alone, the penetrance reached a maximum of 57% by age 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated at 54% by age 40, 68% by age 60, and 87% by age 70. Multiple tumors were found in 65%, and 8% of paraganglioma patients had pheochromocytomas. One (3%) patient developed a malignant paraganglioma. None of 11 instances of maternal transmission of the mutation resulted in the development of paragangliomas. The findings indicated that the majority of mutation carriers will eventually develop head and neck paragangliomas, although Hensen et al. (2010) stated that the penetrance in this study was lower than some previous estimates. Hensen et al. (2010) emphasized the importance of including clinically unaffected mutation carriers in estimates of penetrance.

Among 47 asymptomatic carriers of SDHD mutations screened by physical examination or MRI, Heesterman et al. (2013) found that 28 (59.6%) carried a total of 57 tumors, including 38 carotid body tumors, 17 vagal body tumors, and 2 jugulotympanic tumors. Multiple tumors were seen in 34% of patients. Two patients (4.3%) had a sympathetic paraganglioma. The report indicated that a high percentage of asymptomatic SDHD mutation carriers have occult head and neck paragangliomas.

Inheritance

Maternal Imprinting

From a study of 15 pedigrees, van der Mey et al. (1989) concluded that familial paragangliomas, which they referred to as hereditary glomus tumors, were inherited almost exclusively through the paternal line, a finding inconsistent with simple autosomal dominant transmission. They suggested a role for genomic imprinting, in which the maternally derived gene is inactivated during female oogenesis and can be reactivated only during spermatogenesis. Heutink et al. (1992) stated that all individuals with hereditary paragangliomas had inherited the disease gene from their father; expression of the phenotype was not observed in the offspring of an affected female until subsequent transmission of the gene through a male carrier. The observations strongly suggested genomic imprinting.

Baysal et al. (1997) noted that the age of onset of symptoms was significantly different between fathers and children: affected children had an earlier age of onset in 39 of 57 father-child pairs.

Maternal Inheritance

Pigny et al. (2008) reported what they believed to be the first description of a paraganglioma kindred with maternal transmission of the mutated SDHD (602690) allele. A boy received the W43X mutation (602690.0023) from his mother and developed a glomus tympanicum paraganglioma at 11 years of age. He shared only the 11q23 haplotype with the other affected members of the family. Pigny et al. (2008) concluded that maternal transmission of a SDHD-linked paraganglioma, even if a rare event, can occur.

Mapping

In a large Dutch pedigree with hereditary paragangliomas, Heutink et al. (1992) found linkage with marker D11S147 located at chromosome 11q23-qter (maximum lod score of 6.0 at theta = 0.0 ). Likelihood calculations yielded a very high odds ratio in favor of genomic imprinting versus absence of genomic imprinting. Devilee et al. (1992) performed haplotyping in this large Dutch family using 15 markers in the region 11q13-q23. Two recombination events placed the PGL locus distal to STMY (185260) and proximal to D11S836, thus excluding the oncogenes INT2 (164950) and ETS1 (164720) as the site of the mutation. In an affected PGL family that showed imprinting, Mariman et al. (1995) found linkage to the locus on distal 11q.

In patients with familial nonchromaffin paragangliomas, Devilee et al. (1994) found loss of heterozygosity (LOH) only on chromosome 11, with a marked clustering on the distal half of the long arm. In all 8 cases in which they could determine the parental origin, the allele undergoing loss was maternally derived. However, LOH in all tumors was only partial, and it was not clear whether this represented an allelic imbalance or cellular heterogeneity. In a later study, van Schothorst et al. (1998) performed LOH analysis for the 11q22-q23 region on DNA-aneuploid tumor cells, enriched by flow sorting, and on purified chief cell fractions obtained by single-cell microdissection. Complete LOH was found in both types of cells, indicating that the chief cells were clonal proliferated tumor cells.

Oosterwijk et al. (1996) gave the location of the PGL1 gene as 11q22.3-q23. They offered genetic counseling on the basis of DNA linkage diagnosis in an extended Dutch pedigree. Presymptomatic testing of the paternal allele was performed in 16 cases; 4 of these appeared to have the at-risk haplotype and in 2 of the 4 a glomus tumor was subsequently detected on MRI. In 1 case linkage results were inconclusive because of recombination and 1 person did not want to learn his test result. The maternal allele was tested for carrier status in 4 cases of which 1 appeared to be a carrier.

Baysal et al. (1997) reported linkage of paraganglioma to chromosome 11q23 in 3 of 6 North American families. Recombinants narrowed the critical region to a 4.5-Mb interval flanked by the markers D11S1647 and D11S622. Partial allelic loss of strictly maternal origin was detected in 5 of 19 tumors. Milunsky et al. (1997) confirmed linkage to 11q23 in studies of 3 affected families. The inheritance pattern was consistent with genetic imprinting; the disorder was transmitted only by males.

Another 10 families with hereditary head and neck paragangliomas were ascertained by van Schothorst et al. (1998) from the same geographic region as that from which the large PGL1-linked Dutch family originated (Heutink et al., 1992). They determined the disease-linked haplotype, as defined by 13 markers encompassing a large interval on 11q21-q23, in these families and showed that alleles were identical for 6 contiguous markers spanning a genetic distance of 6 cM and containing PGL1. Despite this strong indication of a common ancestor, no kinship between the families could be demonstrated through genealogic surveys going back to 1800. Baysal et al. (1999) reevaluated the haplotype data of the multigenerational Dutch PGL1-linked family, using 2 additional single tandem repeat polymorphisms (STRPs) contained within the PGL1 critical interval proposed by van Schothorst et al. (1998). They excluded this interval, and instead predicted a nonoverlapping, more proximal 2-Mb critical interval between markers D11S1647 and D11S897. Analysis of 4 new American PGL families defined the telomeric border of the critical region as D11S1347. Among 3 unrelated American PGL families, significant haplotype sharing within this new interval was observed, strongly suggesting that they originated from a common ancestor. In sum, the authors refined the PGL1 locus to a 1.5-Mb region between D11S1986 and D11S1347.

Molecular Genetics

Astrom et al. (2003) stated that a large number of PGL1 families had been reported from the Netherlands and that there may be Dutch founder mutations.

In affected members of families with hereditary paraganglioma, Baysal et al. (2000) identified mutations in the SDHD gene (602690.0001-602690.0005), including the Dutch founder mutation (602690.0004).

Gimm et al. (2000) identified several mutations in the SDHD gene in unrelated patients. One patient had a pheochromocytoma and a carotid body paraganglioma (see 602690.0010); 2 unrelated patients, 1 with an extraadrenal intraabdominal pheochromocytoma with involvement of the jugular fossa, suggesting malignancy, and 1 with an isolated intestinal lipoma, had the same mutation (602690.0011); and a 33-year-old woman had 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic (see 602690.0002). Finally, the authors identified a somatic SDHD mutation in a pheochromocytoma (602690.0003).

In 7 families with familial paragangliomas, Milunsky et al. (2001) identified mutations in the SDHD gene (602690.0006-602690.0009). Three unrelated families had the same mutation (602690.0003), suggesting a founder effect. A restriction enzyme assay was developed for initial screening for the common mutation.

Paragangliomas of the central nervous system are rare, occur almost exclusively in the cauda equina of the spinal cord, and are considered nonfamilial. In a spinal paraganglioma and similar cerebellar tumors that developed 22 years later in the same patient, Masuoka et al. (2001) identified a mutation in the SDHD gene (602690.0011). There was no family history of paragangliomas, but DNA from white blood cells of this patient showed the same sequence alterations, indicating the presence of a germline mutation.

Cascon et al. (2002) performed mutation analysis of the SDHD gene in 25 consecutive, unrelated patients with pheochromocytoma and/or paraganglioma, with or without family history. There were 18 patients with pheochromocytoma, 4 with paraganglioma alone, and 3 with both, who had tested negative for germline mutations in the VHL (608537) and RET (164761) genes. Two novel truncating mutations were detected, a 4-bp deletion (602690.0022) in an apparently sporadic case of paraganglioma and pheochromocytoma, and a nonsense mutation (602690.0023) in a patient with paraganglioma with a family history of pheochromocytoma.

In a patient of German descent with sporadic bilateral carotid body paragangliomata, Leube et al. (2004) identified a frameshift mutation in the SDHD gene (602690.0020).

Mhatre et al. (2004) performed a mutation screen of the SDHB, SDHC, and SDHD genes in blood and tumor samples of 14 sporadic and 3 familial cases of head and neck paragangliomas. Germline mutations in SDHB and SDHD were identified in 2 of the 3 affected individuals with familial PGL, whereas no germline or somatic mutations were identified in the 14 sporadic cases. The presence of mutations within SDHB and SDHD in 2 of the 3 samples of familial PGL and absence of mutations in sporadic cases is consistent with a significant contribution of these genes to familial but not sporadic PGL.

Heterogeneity

Carotid Body Paragangliomas with Sensorineural Hearing Loss

Badenhop et al. (2001) studied 4 families with familial carotid body paragangliomas, 2 of which exhibited coinheritance of PGL and sensorineural hearing loss or tinnitus. Sequence analysis identified mutations in exon 1 and exon 3 of the SDHD gene, including a novel 2-bp deletion in exon 3 creating a premature stop codon at position 67 (602690.0013); a novel 3-bp deletion in exon 3 resulting in the loss of tyr93 (602690.0014); a missense mutation in exon 3 resulting in a pro81-to-leu substitution (602690.0003); and a novel G-to-C substitution in exon 1 resulting in a met1-to-val substitution (602690.0015). The PGL1 region contains another gene, DPP2/TIMM8B (606659), a homolog of the X-linked TIMM8A gene (300356), mutations in which cause dystonia and deafness seen in Mohr-Tranebjaerg syndrome (304700). The authors found no base changes in the TIMM8B gene; thus, it would seem that the association of paraganglioma with sensorineural hearing loss cannot be explained by the proximity of the TIMM8B and SDHD genes.

Genotype/Phenotype Correlations

In a review of several studies, Baysal et al. (2002) found that 83 cases of paragangliomas-1 in 'unrelated' families and patients were attributable to 3 founder populations in the Netherlands, in stark contrast to 25 distinct SDHD mutations reported among 43 independent familial and nonfamilial cases in other parts of the world. Astrom et al. (2003) interpreted this finding as suggesting that low altitudes in the Netherlands reduce penetrance and relax the natural selection on SDHD mutations. They studied the influence of altitude on the phenotype of PGL1 in 58 patients from 23 families. Patients who were diagnosed with single tumors at their first clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumors (p less than 0.012). Nonsense/splicing mutation carriers developed symptoms 8.5 years earlier than missense mutation carriers (p less than 0.012). Pheochromocytomas developed in 6 patients, 5 of whom had nonsense mutations. Patients with pheochromocytomas also lived at higher average altitudes and were exposed to higher altitude-years than those without them. Astrom et al. (2003) concluded that collectively, these data suggested that higher altitudes and nonsense/splicing mutations are associated with increased severity in PGL1 and supported the hypothesis that SDHD mutations impair oxygen sensing.

In a population-based genetic study of 334 unrelated patients with adrenal or extraadrenal pheochromocytomas and 83 patients with head and neck paragangliomas, Neumann et al. (2004) found that 12% of patients had a mutation in either the SDHB or SDHD gene, with equal distribution between the 2 genes (25 and 24 patients with mutations in the SDHB and SDHD genes, respectively). Mean age at diagnosis was similar between the 2 groups (approximately 30 years). Inheritance of SDHD mutations was consistent with maternal imprinting. Examination of relatives yielded a total of 32 and 34 manifesting carriers of SDHB and SDHD mutations, respectively. Multiple tumors occurred in 28% of SDHB carriers and 74% of SDHD carriers; adrenal pheochromocytomas occurred in 28% of SDHB carriers and 53% of SDHD carriers, whereas extraadrenal pheochromocytomas were identified in 48% of SDHB carriers and 21% of SDHD carriers; head and neck paragangliomas occurred in 31% of SDHB carriers and 79% of SDHD carriers; and malignancy occurred in 34% of SDHB carriers but no SDHD carriers. Two related SDHB carriers had renal cell carcinoma, and 1 SDHB and 1 SDHD carrier each had papillary thyroid carcinoma. Age-related penetrance for carriers of the 2 mutations was similar: SDHB and SDHD carriers showed 77% and 86% penetrance by age 50 years, respectively.

Benn et al. (2006) determined genotype/phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs 28 years, respectively; p = 0.3). However, when all 112 mutation carriers were included, the estimated age-related penetrance was different for SDHB versus SDHD mutation carriers (p = 0.008).

Population Genetics

Hensen et al. (2012) determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (87.1%), followed by SDHAF2 (6.7%), SDHB (5.9%), and SDHC (0.3%). Almost 70% of all carriers had the founder mutation D92Y (602690.0004) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere.

Nomenclature

Strauchen (2002) noted that the interchangeable use of 'paraganglioma' and 'glomus tumor' was a 'common point of confusion.' He emphasized that the glomus tumor is a tumor of modified perivascular smooth muscle, which frequently presents as a painful subungual mass, and is unrelated to tumors of the adrenal and extraadrenal paraganglia. Jugulotympanic paraganglioma is often referred to as a 'glomus jugulare tumor.' This tumor arises from minute, anatomically dispersed paraganglia located at the base of the skull and temporal bone and is closely related to similar tumors of the carotid body and other extraadrenal paraganglia. It is unrelated to the much more common glomus tumor of skin and soft tissue. See 138000 for an inherited form of smooth muscle tissue glomus tumors.

History

The glomus jugulare was first discovered by Stacy R. Guild at Johns Hopkins in 1941 (Guild (1941, 1953)).