Pheochromocytomas are catecholamine-secreting tumors that usually arise within the adrenal medulla. Approximately 10% arise in extraadrenal sympathetic ganglia, and are referred to as 'paragangliomas.' Approximately 10% are malignant, and approximately 10% are hereditary (Maher and Eng, 2002; Dluhy, ... Pheochromocytomas are catecholamine-secreting tumors that usually arise within the adrenal medulla. Approximately 10% arise in extraadrenal sympathetic ganglia, and are referred to as 'paragangliomas.' Approximately 10% are malignant, and approximately 10% are hereditary (Maher and Eng, 2002; Dluhy, 2002). Bolande (1974) introduced the concept and designation of the neurocristopathies, and identified 'simple,' including pheochromocytoma and medullary carcinoma of the thyroid, and 'complex' neurocristopathies and neurocristopathic syndromes, including NF1 and MEN2. Knudson and Strong (1972) applied Knudson's 2-mutation theory to pheochromocytoma (see discussion in 180200) and concluded that it fits. Maher and Eng (2002) reviewed the clinical entities and genes associated with pheochromocytoma.
Familial pheochromocytoma was first reported by Calkins and Howard (1947).
Hadorn (1963) reported a German family in which 3 sibs had adrenal tumors consistent with pheochromocytomas. A brother and sister suffered from tachycardia, sweating, hypertension, and ... Familial pheochromocytoma was first reported by Calkins and Howard (1947). Hadorn (1963) reported a German family in which 3 sibs had adrenal tumors consistent with pheochromocytomas. A brother and sister suffered from tachycardia, sweating, hypertension, and albuminuria. The sister had advanced hypertensive retinopathy and the brother had congestive heart failure. At autopsy, the sister showed cerebral hemorrhage and bilateral adrenocortical tumors. A surviving sib developed similar symptoms. The Regitine test was strongly positive, the urine contained large amounts of norepinephrine, and pneumoperitoneum demonstrated an enlarged right adrenal which contained adrenal and paraganglion tissue. Engelman et al. (1968) noted that familial pheochromocytoma is usually bilateral and the patients are likely to show resistance to the vasopressor effects of tyramine. Swinton et al. (1972) reported a family in which 4 members, including a father and son, had pheochromocytomas. They pointed out that associated hypercalcemia may be due to secretion of a calcitonin-like substance; hypercalcemia could be corrected by adrenalectomy. Kaufman and Franklin (1979) reported a family with 7 documented and other possible cases of pheochromocytoma. Ohno et al. (1982) observed pheochromocytoma in 2 sisters whose father also had pheochromocytoma. One of the sisters had aniridia and her pheochromocytoma was malignant.
Neumann et al. (2001) stated that germline mutations in the VHL gene and in the SDHD gene together account for 15 to 20% of all nonfamilial presentations of pheochromocytoma. Neumann et al. (2002) identified germline mutations in 66 ... Neumann et al. (2001) stated that germline mutations in the VHL gene and in the SDHD gene together account for 15 to 20% of all nonfamilial presentations of pheochromocytoma. Neumann et al. (2002) identified germline mutations in 66 (24%) of 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of disease. Eleven patients (4%) had 7 different germline mutations in the SDHD gene (see, e.g., 602690.0002; 602690.0004; 602690.0025; 602690.0026). Twelve patients (4%) had 9 different germline mutations in the SDHB gene (see, e.g., 185470.0004-185470.0006; 185470.0008; 185470.0009). Thirteen patients (5%) had 7 different germline mutations in the RET gene (see, e.g., 164761.0003-164761.0006; 164761.0011; 164761.0012; 164761.0034). Thirty patients (11%) had 22 different mutations in the VHL gene (see, e.g., 608537.0010; 608537.0011; 608537.0014; 608537.0026). Clinically, the presence of a germline mutation was associated with younger age, multifocal tumors, and extraadrenal tumors. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. In 23 (35%), the tumor presented after the age of 30 years, and in 17 (8%) after the age of 40. Neumann et al. (2002) concluded that since almost one-fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations, routine analysis for mutations in the 4 genes studied is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed. Sixty-one (92%) of the 66 patients had no associated signs and symptoms of a syndrome at the time of presentation. - Mutation in the VHL Gene In affected members of 2 unrelated kindreds with pheochromocytoma with no clinical evidence of VHL disease, Crossey et al. (1995) identified 2 missense mutations in the VHL gene (V84L; 608537.0025 and R238W; 608537.0003). In 4 of 48 sporadic pheochromocytomas, Eng et al. (1995) identified mutations in the VHL gene. Two mutations were somatic and 2 were germline. Woodward et al. (1997) identified germline missense mutations in the VHL gene in 3 of 8 kindreds with familial pheochromocytoma. A germline VHL mutation was also characterized in 1 of 2 patients with bilateral pheochromocytoma. No mutations were identified in the VHL or RET genes in 6 patients with multiple extraadrenal pheochromocytoma or adrenal pheochromocytoma with a family history of neuroectodermal tumors. Brauch et al. (1997) found VHL mutations in 2 (3%) of 62 German patients with pheochromocytoma without a history of hereditary disease; No mutations were detected in the RET gene. Bar et al. (1997) found that 1 of 27 sporadic patients with pheochromocytoma had a VHL germline mutation; none had a RET mutation. Both groups concluded that sporadic pheochromocytomas are rarely associated with germline mutations in either of these genes. Van der Harst et al. (1998) identified a mutation in the VHL gene (R64P; 608537.0015) in an uncle and his nephew with pheochromocytoma. Mutations in the VHL gene were identified in 4 other unrelated patients with pheochromocytomas (see, e.g., L63P, 608537.0016). In total, 6 (8.8%) of 68 patients with pheochromocytomas had germline mutations in the VHL gene. Using comparative genomic hybridization, Hering et al. (2006) found that 10 (72%) of 14 pediatric pheochromocytoma tumors had a combinatorial loss of chromatin from chromosome 3p and 11p, resulting from either a total loss of chromosomes 3 and 11 (6 patients) or confined deletions of the 3p and 11p arms (4 patients). All of these patients had mutations in the VHL gene. The findings suggested that mutations in the VHL gene select for combinatorial deletions of 3p and 11p. Of the 4 remaining patients, 2 had familial syndromes (NF1 and PGL1, respectively) and 2 had unknown etiology. Hering et al. (2006) concluded that true sporadic pheochromocytoma is rare in childhood and that affected children should be screened for a predisposing gene. - Mutation in the RET Gene In 5 of 48 apparently sporadic pheochromocytomas, Eng et al. (1995) identified mutations in the RET gene. Of these, 1 was a germline mutation (C634G; 164761.0003) and another was a somatic mutation (M918T; 164761.0013). - Mutation in the SDHD Gene In tumor tissue from a patient with sporadic pheochromocytoma, Gimm et al. (2000) identified a mutation in the SDHD gene (P81L; 602690.0003). Flanking markers also showed loss of heterozygosity. - Mutation in the KIF1B Gene In a pheochromocytoma tumor sample and in germline DNA from the corresponding patient, Schlisio et al. (2008) identified a mutation in the KIF1B gene (S1481N; 605995.0005). The proband was a 28-year-old female who presented at 17 months of age with a neuroblastoma and in adulthood developed a mature ganglioneuroma and bilateral pheochromocytoma. Her paternal grandfather harbored the mutant S1481N allele and also developed bilateral pheochromocytoma. Functional studies in primary rat sympathetic neurons revealed that induction of apoptosis was impaired with the S1481N KIF1B variant compared to wildtype. - Mutation in the TMEM127 Gene Qin et al. (2010) identified 7 different heterozygous mutations in the TMEM127 gene (see, e.g., 613403.0001-613403.0004) in 7 unrelated probands with pheochromocytoma. Six of the mutations were truncating mutations, consistent with a loss of function. All tumors examined showed loss of heterozygosity at the TMEM127 locus, suggesting a classic mechanism of the 2-hit model of tumor suppressor inactivation. Four of the probands had a family history of pheochromocytoma. The average age of onset was 45.3 years, all tumors arose from the adrenal medulla, and they were bilateral in about half of cases. Overall, mutations were found in about 30% of familial cases and 3% of sporadic cases. Microarray-based expression profiling showed that the transcription signature of TMEM127-mutant tumors was increased in kinase receptor signals, similar to pheochromocytomas due to NF1 (162200) and RET (164761) mutations. This was in contrast to the expression profiles of pheochromocytomas with mutations in the VHL (608537), SDHB (185470) or SDHD (602690) genes, which were uniquely enriched in transcripts involved in response to hypoxia. - Mutation in the MAX Gene Using exome sequencing in 3 unrelated families with bilateral pheochromocytoma, Comino-Mendez et al. (2011) identified 3 different heterozygous germline mutations in the MAX gene (154950.0001-154950.0003) that segregated with the disease. A follow-up study of 59 patients with pheochromocytoma identified 5 additional mutations (see, e.g., 154950.0004-154950.0005). Studies of tumor tissue showed a lack of full-length MAX protein and loss of heterozygosity (LOH) of the MAX allele, which resulted from paternal uniparental disomy (UPD) and loss of the maternal allele. This LOH constituted the somatic second-hit of the Knudson hypothesis. The paternal origin of the mutated allele detected in 6 families suggested preferential paternal transmission of the disease (p = 0.031). In addition, 2 children who inherited the mutation from their mother and 2 obligate carriers from another family did not develop tumors, further supporting this theory. Eight of 12 cases had bilateral tumors, and 3 of 8 probands had metastases at diagnosis. Overall, the findings indicated that MAX acts as a classic tumor suppressor gene. - Somatic Mutations Using genomewide copy number analysis to study several genes known to be associated with pheochromocytomas, Welander et al. (2012) found that 35 (83%) of 42 samples had an altered copy number of at least 1 of the genes involved in familial pheochromocytoma. Eleven (26%) of the tumors had loss of 1 copy of NF1, and sequencing showed that 10 of the 11 carried a somatic truncating mutation in the NF1 gene. Loss of NF1 was associated with low mRNA expression in the tumors. Most tumors displayed loss of the normal allele, but in 2 cases there was no sign of loss of heterozygosity, although mRNA expression was clearly reduced. Frequent copy number variation in sporadic tumors was also observed for the VHL, SDHD, SDHAF2, and KIF1B genes. The findings suggested that the NF1 gene constitutes a common target of somatic mutations in sporadic pheochromocytomas. By direct sequencing of the NF1 gene, Burnichon et al. (2012) identified a somatic inactivating NF1 mutation in 25 (41%) of 61 pheochromocytomas, which was associated with loss of the wildtype allele in 21 (84%) of the 25 cases. Gene expression signature of NF1-related tumors highlighted the downregulation of NF1 and the major overexpression of SOX9 (608160). Among a second set of 11 tumors, 2 sporadic tumors carried somatic mutations in NF1 as well as in another susceptibility gene. These findings suggested that NF1 loss of function is a frequent event in the tumorigenesis of sporadic pheochromocytoma. - Modifier Genes In 1 of 28 sporadic pheochromocytomas, Woodward et al. (1997) identified a mutation in the glial cell line-derived neurotrophic factor gene (GDNF; R93W; 600837.0001), which is a natural ligand for RET. The mutation was present in both germline and tumor tissue. The findings suggested that variation at the GDNF locus may modify pheochromocytoma susceptibility.