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Pheochromocytoma in genetic disorders
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: May 8, 2012.

INTRODUCTION — Pheochromocytoma is a rare neoplasm, probably occurring in less than 0.2 percent of patients with hypertension [1,2]. Pheochromocytoma in genetic disorders will be reviewed here. The diagnosis and treatment of pheochromocytoma are discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Treatment of pheochromocytoma in adults".)

PHEOCHROMOCYTOMA IN GENETIC DISORDERS — Most catecholamine-secreting tumors are sporadic. However, some patients (15 to 20 percent) have the disease as part of a familial disorder; in these patients, the catecholamine-secreting tumors are more likely to be bilateral adrenal pheochromocytomas or paragangliomas.

Hereditary catecholamine-secreting tumors typically present at a younger age than sporadic neoplasms [3]. Sporadic pheochromocytoma is usually diagnosed on the basis of symptoms or an incidental discovery on computed imaging, whereas syndromic pheochromocytoma is frequently diagnosed earlier in the course of disease because of biochemical surveillance or genetic testing [4].

Familial pheochromocytoma — There are several familial disorders associated with pheochromocytoma, all of which have autosomal dominant inheritance: von Hippel-Lindau (VHL) syndrome, MEN2, and less commonly, neurofibromatosis type 1.

The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in MEN2, and 0.1 to 5.7 percent with neurofibromatosis type 1 [5,6]. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Neurofibromatosis type 1 (von Recklinghausen's disease)".)

VHL syndrome — The VHL phenotype includes pheochromocytoma (frequently bilateral), paraganglioma (mediastinal, abdominal, pelvic), hemangioblastoma (involving the cerebellum, spinal cord, or brain stem), retinal angioma, clear cell renal cell carcinoma, pancreatic neuroendocrine tumors, endolymphatic sac tumors of the middle ear, serous cystadenomas of the pancreas, and papillary cystadenomas of the epididymis and broad ligament.

The VHL tumor suppressor gene, located on chromosome 3p25-26, encodes a protein that regulates hypoxia-induced proteins. More than 300 germline VHL mutations have been identified that lead to loss of function of the VHL protein.

Patients with VHL syndrome may be divided into two groups: type I and type II. Patients from kindreds with type I syndrome do not develop pheochromocytoma, whereas patients with kindreds with type II syndrome are at high risk for developing pheochromocytoma. In addition, kindreds with type II VHL syndrome are subdivided into type IIA (low risk for renal cell carcinoma), type IIB (high risk for renal cell carcinoma), and type IIC (pheochromocytomas only). Genotype-phenotype correlations have been documented for this disorder and specific mutations are associated with particular patterns of tumor formation. In up to 98 percent of cases, pheochromocytoma is associated with missense mutations (rather than truncating or null mutations) in the VHL gene. Certain missense mutations appear to be associated with the type IIC presentation of VHL (pheochromocytomas only). (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

MEN2 — MEN 2A is characterized by medullary thyroid cancer (MTC) in all patients, pheochromocytoma in 50 percent, primary hyperparathyroidism in 20 percent, and cutaneous lichen amyloidosis in 5 percent [7-10].

Most mutations in MEN 2A kindreds (93 to 98 percent) involved one of six cysteine residues in the cysteine-rich region of the RET protein’s extracellular domain encoded in RET exons 10 (codons 609, 611, 618, and 620) or 11 (codons 630 or 634). Eighty-five percent of individuals with MEN 2A have a mutation in codon 634, particularly p.Cys634Arg. Aganglionic megacolon (Hirschsprung’s disease) can occur in families with mutations of codons 618 and 620 in exon 10. (See "Classification and genetics of multiple endocrine neoplasia type 2".)

MEN type 2B represents approximately 5 percent of all MEN2 cases and the phenotype is characterized by MTC in all patients, pheochromocytoma in 50 percent, mucocutaneous neuromas (typically involving the tongue, lips, and eyelids) in most patients, skeletal deformities (eg, kyphoscoliosis or lordosis), joint laxity, myelinated corneal nerves, and intestinal ganglioneuromas (hyperganglionic megacolon).

MEN 2B-associated tumors are caused by mutations in the RET protein’s intracellular domain. A single methionine to threonine missense mutation in exon 16 (p.Met918Thr) is responsible for more than 95 percent of MEN 2B cases. Another mutation, alanine to phenylalanine at codon 883 in exon 15, has been found in 4 percent of MEN 2B kindreds. (See "Classification and genetics of multiple endocrine neoplasia type 2".)

Phenotype of MEN2 versus VHL syndrome — The clinical and biochemical characteristics of pheochromocytomas in MEN2 versus the VHL syndrome were investigated in a study of 19 and 30 patients with these disorders, respectively; the following findings were noted [11]:

  • MEN2 patients were more symptomatic with a higher incidence of hypertension (primarily paroxysmal).
  • MEN2 patients all had elevated serum concentrations of metanephrine (the epinephrine metabolite), while all VHL patients had elevated serum normetanephrine concentrations (the norepinephrine metabolite).
  • Compared to MEN2 tumors, VHL tumors had lower total tissue contents of catecholamines and expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. They also had much lower expression of phenylethanolamine N-methyltransferase (PNMT, the enzyme that converts norepinephrine to epinephrine) and tissue stores of epinephrine.

Thus, the difference in clinical phenotype (MEN2 patients are more symptomatic) can be explained by the differences in biochemical phenotype (MEN2 patients, due to the higher PNMT and TH expression, have an adrenergic phenotype with higher rates of catecholamine biosynthesis).

Neurofibromatosis type 1 — There is also an association with neurofibromatosis type 1 (NF1) [5], an autosomal dominant disorder characterized by neurofibromas, multiple cafe au lait spots, axillary and inguinal freckling, iris hamartomas (Lisch nodules), bony abnormalities, central nervous system gliomas, pheochromocytoma and paraganglioma, macrocephaly, and cognitive deficits. The expression of these features is variable. Approximately 2 percent of patients with NF1 develop catecholamine-secreting tumors. In these patients, the catecholamine-secreting tumor is usually a solitary benign adrenal pheochromocytoma, occasionally bilateral adrenal pheochromocytoma, and rarely a peri adrenal abdominal paraganglioma.

Genetic testing for NF1 is available but is not routinely performed, as the diagnosis is made based upon clinical phenotype. (See "Neurofibromatosis type 1 (von Recklinghausen's disease)".)

Other mutations — More genetic causes of pheochromocytoma and paraganglioma are yet to be discovered. For example, in 2010, loss of function mutations in the FP/TMEM127 gene were identified in patients with familial and sporadic pheochromocytoma, but not paraganglioma. TMEM127 is a negative regulator of mammalian target of rapamycin (mTOR) effector proteins. In a study of 990 individuals with pheochromocytoma or paraganglioma, germline mutations in FP/TMEM127 were identified in 20 individuals with adrenal tumors, five of whom had a family history of pheochromocytoma [12]. Among 547 patients who presented with sporadic pheochromocytoma (unilateral adrenal tumor with negative family history), 11 (2 percent) had FP/TMEM127 mutations.

In 2011, loss of function mutations in the MAX gene were identified in patients with familial pheochromocytoma [13]. In an initial study of three individuals with familial pheochromocytoma (who did not have mutations in any of the nine previously described susceptibility genes), MAX germline mutations were found. MAX is a component of the MYC-MAX-MXD1 transcription factors that regulate cell proliferation, differentiation, and apoptosis. In an extension of this study, MAX mutations were found in 5 of 59 patients (8.5 percent) with suspected familial pheochromocytoma (based on age of onset <30 years, bilateral pheochromocytoma, or positive family history) [13].

Familial paraganglioma — Familial paraganglioma is an autosomal dominant disorder characterized by paragangliomas that are located most often in the head and neck but also in the thorax, abdomen, pelvis, and urinary bladder.

The occurrence of catecholamine hypersecretion in a patient with familial paraganglioma depends upon tumor location; approximately 5 percent of head and neck paragangliomas and more than 50 percent of abdominal paragangliomas produce hormones [14]. (See "Paragangliomas of the head and neck".)

Most cases of familial paraganglioma are caused by mutations in the succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD, SDHAF2, SDHA), which compose portions of mitochondrial complex II [15-21]. Mitochondrial complex II is a tumor suppressor gene involved in the electron transport chain and the tricarboxylic-acid (TCA) cycle.

  • Most germline mutations in SDHD, SDHAF2, and SDHC have been identified in multi-generational families with biochemically silent head and neck paragangliomas [22,23]. (See "Paragangliomas of the head and neck".) In patients with SDHD and SDHAF2 mutations, penetrance depends on the mutation's parent of origin [18,19,22]. Hence, the disease is not manifested when the mutation is inherited from the mother but is highly penetrant when inherited from the father. This phenomenon is known as maternal imprinting.
  • The SDH gene mutation detection rate for individuals with familial paraganglioma is currently unknown.
  • SDHB mutations have been associated with families that have abdominal, pelvic, and thoracic catecholamine-secreting familial paraganglioma.
  • SDHB mutation carriers develop disease early (mean age at diagnosis was 34 years, with a range of 10 to 62 years in one report) [24], and are more likely to develop malignant paragangliomas and additional neoplasms (eg, renal cell carcinoma) [22,25].
  • SDHD, SDHC, SDHAF2, and SDHB germline mutation screening are commercially available and staged testing (eg, starting with SDHD, SDHC, and SDHAF2 mutation analysis in patients with head and neck paragangliomas and SDHB and SDHC mutation analysis in patients with paragangliomas below the neck) should be considered in all patients with paraganglioma [21]. (See 'Genetic screening' below.)

Sporadic pheochromocytoma

Frequency of genetic abnormalities — A separate issue is the frequency of the above genetic abnormalities in patients with sporadic and nonsyndromic pheochromocytoma. Data have been conflicting, with frequency estimates ranging from 13 to 24 percent [3,25,26]. In one series of 271 patients with apparent sporadic pheochromocytoma from population-based registries in Germany and Poland who were tested for germline mutations in the four genes described above that have been associated with pheochromocytoma (VHL, RET, SDHD, and SDHB [3]), the following findings were noted:

  • A mutation was identified in 66 (24 percent) — 30 VHL (11 percent of patients overall), 13 RET (4.8 percent), 12 SDHB (4.4 percent), and 11 SDHD (4 percent). All but four of the patients had no signs or symptoms of the diseases associated with the specific mutation. Possible explanations for sporadic and frequently localized disease in these patients include spontaneous mutation, decreased penetrance, maternal imprinting, and gene-gene or gene-environment interactions.
  • Although all had a negative family history at entry, the family history became positive at last follow-up in 12 of 30 with a VHL mutation, 6 of 13 with a RET mutation, and none of 23 with a SDH complex mutation.

In contrast to the relatively high frequency of mutations noted in this report [3], other studies have reported a lower frequency. As an example, in a subsequent study based upon a larger group of patients with apparently sporadic pheochromocytoma (n = 545), the frequency of mutations was considerably lower (12.7 percent; 69 of 545 patients) [26].

Other series have also reported a lower frequency of VHL, RET, and SDHD mutations when compared with the study described above [3]:

  • Only 11 of 337 had a VHL mutation (3.3 percent) in three studies [25,27,28].
  • Only 1 of 414 patients (0.2 percent) had a RET mutation [25,27-30].
  • In one series, only 2 of 102 (2 percent) of patients with apparently sporadic pheochromocytoma had a SDHD mutation [31].

These markedly discrepant findings could be due in part to differences in the populations studied and perhaps to ascertainment bias toward inherited disease in registry-based cases. For example, although the overall frequency of a genetic mutation in one series was 24 percent [3], only 31 of the 66 patients with a gene mutation (11.4 percent of the study population) had a unilateral adrenal tumor [3]. The remaining patients had multifocal and/or extraadrenal tumors, and therefore should not have been categorized at baseline as having “apparently sporadic pheochromocytoma” [3].

Implications for genetic screening — Based upon the above data, it appears that the yield of routine genetic testing in patients with apparently sporadic adrenal pheochromocytoma (defined by unilateral disease, a negative family history, and no syndromic signs of symptoms) is very low, particularly for MEN2. Nevertheless, clinicians should have an increased index of suspicion for a hereditary syndrome.

All patients should be monitored for findings of a genetic syndrome, some of which can be detected on physical examination [6,32], including:

  • Retinal angiomas in VHL syndrome
  • A thyroid mass in MEN2
  • Cafe au lait spots, axillary and inguinal freckling, and subcutaneous neurofibromas in neurofibromatosis type 1
  • A neck mass in paraganglioma syndromes

Evaluation and monitoring of first-degree relatives is also important, since each of these disorders is transmitted as an autosomal dominant trait.

GENETIC SCREENING — Genetic testing should be considered if a patient has one or more of the following:

  • Paraganglioma
  • Bilateral adrenal pheochromocytoma
  • Unilateral adrenal pheochromocytoma and a family history of pheochromocytoma/paraganglioma
  • Unilateral adrenal pheochromocytoma onset at a young age (eg, <45 years), or
  • Other clinical findings suggestive of one of the previously discussed syndromic disorders

An asymptomatic person at risk for disease on the basis of family history of pheochromocytoma/paraganglioma should have genetic testing only if an affected family member has a known mutation.

Genetic testing can be complex; testing one family member has implications for related individuals. Genetic counseling is recommended to help families understand the implications of genetic test results, to coordinate testing of at-risk individuals, and to help families work through the psychosocial issues that may arise before, during, or after the testing process.

Suggested approach — Given the considerable cost of genetic testing, using a stepwise approach based on each patient's clinical scenario is prudent. The clinician may obtain a list of clinically approved molecular genetic diagnostic laboratories at GeneTests; genetic screening for mutations in RET, VHL, NF-1, TMEM127, SDHD, SDHC, SDHB, and SDHAF2 is currently available.

Bilateral adrenal pheochromocytoma — If a patient presents with bilateral adrenal pheochromocytoma but without a history of MTC or goiter, tests for mutations in the following genes should be ordered sequentially: VHL, RET, SDHD, SDHB, TMEM127. The biochemical phenotype (eg, adrenergic [MEN 2] or noradrenergic [VHL]) can also be used to guide genetic testing. If a mutation is identified at any point in the testing algorithm, no further testing should be performed.

Young age at presentation — If a patient 45 years [33] of age or less presents with apparent sporadic unilateral adrenal pheochromocytoma, tests for mutations in the following genes should be ordered sequentially: VHL, RET, SDHB, SDHD, TMEM127. If a mutation is identified at any point in the testing algorithm, no further testing should be performed.

Abdominal paraganglioma — If a patient has a catecholamine-secreting abdominal paraganglioma, tests for mutations in the following genes should be ordered sequentially: SDHB, SDHD, VHL. If a mutation is identified at any point in the testing algorithm, no further testing should be performed.

Skull-base or neck paraganglioma — If a patient has a skull-base or neck paraganglioma, tests for mutations in the following genes should be ordered sequentially: SDHD, SDHC, SDHAF2, SDHB. In some clinical laboratories it may be less expensive to order an analysis of all SDH mutations as a package. If kindred show a typical maternal imprinting inheritance pattern, then SDHD and SDHAF2 should be ordered. If a mutation is identified at any point in the testing algorithm, no further testing should be performed.

Known mutation — Additional evaluation for patients with an identified mutation or syndrome (VHL syndrome, MEN2, neurofibromatosis type 1) is discussed separately. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Neurofibromatosis type 1 (von Recklinghausen's disease)".)

SUMMARY AND RECOMMENDATIONS

Most catecholamine-secreting tumors are sporadic. However, some patients (15 to 20 percent) have the disease as part of a familial disorder; in these patients the catecholamine-secreting tumors are more likely to be bilateral adrenal pheochromocytomas or paragangliomas.

There are several familial disorders associated with pheochromocytoma, all of which have autosomal dominant inheritance:

  • Von Hippel-Lindau syndrome, associated with mutations in the VHL tumor suppressor gene (see 'VHL syndrome' above).
  • Multiple endocrine neoplasia type 2, which is associated with mutations in the RET-proto-oncogene (see 'MEN2' above).
  • Pheochromocytoma is also seen, albeit rarely, with neurofibromatosis type 1, due to mutations in the NF1 gene (see 'Neurofibromatosis type 1' above).
  • The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in MEN2, and 0.1 to 5.7 percent with neurofibromatosis type 1.

Most cases of familial paraganglioma are caused by mutations in the succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD, SDHAF2, SDHA). (See 'Familial paraganglioma' above.)

Genetic testing should be considered if a patient has one or more of the following (see 'Genetic screening' above):

  • Paraganglioma
  • Bilateral adrenal pheochromocytoma
  • Unilateral adrenal pheochromocytoma and a family history of pheochromocytoma/paraganglioma
  • Unilateral adrenal pheochromocytoma onset at a young age (eg, <45 years), or
  • Other clinical findings suggestive of one of the previously discussed syndromic disorders (see 'Genetic screening' above)

An asymptomatic person at risk for disease on the basis of family history of pheochromocytoma/paraganglioma should have genetic testing only if an affected family member has a known mutation.

The specific genetic tests ordered should be based upon the patient presentation. (See 'Suggested approach' above.)

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