Pheochromocytoma in genetic disorders

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, approximately 40 percent of patients have the disease as part of a familial disorder [3,4].

Hereditary catecholamine-secreting tumors typically present at a younger age than sporadic neoplasms [4,5]. 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 [6]. Familial pheochromocytoma is also diagnosed at a younger age because of much earlier symptomatic tumor development [4].

Familial pheochromocytoma — There are several familial syndromic disorders associated with adrenal pheochromocytoma, all of which have autosomal dominant inheritance: von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2) and, less commonly, neurofibromatosis type 1 (NF1).

The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in MEN2, and 3 percent with NF1 [7-9]. (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 (NF1): Pathogenesis, clinical features, and diagnosis".)

VHL syndrome — The von Hippel-Lindau (VHL) phenotype includes pheochromocytoma (frequently bilateral), paraganglioma (mediastinal, abdominal, pelvic, neck, and skull base), hemangioblastoma (involving the cerebellum, spinal cord, or brainstem), 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 pathogenic variants 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 pathogenic variants are associated with particular patterns of tumor formation. In up to 98 percent of cases, pheochromocytoma is associated with missense pathogenic variants (rather than truncating or null pathogenic variants) in the VHL gene. Certain missense pathogenic variants appear to be associated with the type IIC presentation of VHL (pheochromocytomas only). (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Pheochromocytomas'.)

MEN2 — Multiple endocrine neoplasia type 2A (MEN2A) 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 [10-13].

Most pathogenic variants in MEN2A kindreds (93 to 98 percent) involve 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 MEN2A have a pathogenic variant in codon 634, particularly p.Cys634Arg. Aganglionic megacolon (Hirschsprung disease) may occur in families with MEN2A who have a "Janus" pathogenic variant (a pathogenic variant that acts simultaneously as both a gain-in-function and a loss-of-function pathogenic variant) in the RET proto-oncogene (exon 10: codons 609, 611, 618, 620). (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).

MEN2B-associated tumors are caused by pathogenic variants in the RET protein's intracellular domain. A single methionine to threonine missense pathogenic variant in exon 16 (p.Met918Thr) is responsible for more than 95 percent of MEN2B cases. Another pathogenic variant, alanine to phenylalanine at codon 883 in exon 15, has been found in 4 percent of MEN2B 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 multiple endocrine neoplasia type 2 (MEN2) versus the von Hippel-Lindau (VHL) syndrome were investigated in a study of 19 and 30 patients with these disorders, respectively; the following findings were noted [14]:

●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 with 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 NF1 [7], 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 3 percent of patients with NF1 develop catecholamine-secreting tumors [9]. 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 it is not routinely performed, as the diagnosis is made based upon clinical phenotype. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Other pathogenic variants — Since 1990, at least 20 different pheochromocytoma/paraganglioma susceptibility genes have been reported [4,15]. Susceptibility (or driver) genes where genetic variants predispose to pheochromocytoma and paraganglioma have three general transcription signatures: cluster 1, genes encoding proteins that function in the cellular response to hypoxia; cluster 2, genes encoding proteins that activate kinase signaling; and cluster 3, genes encoding proteins that are involved in Wnt signaling (table 1). Cluster 1 tumors are mostly extra-adrenal paragangliomas (except in VHL where most tumors are localized to the adrenal), and nearly all have a noradrenergic biochemical phenotype, whereas cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype. Cluster 3 tumors can have a noradrenergic or adrenergic biochemical phenotype. Cluster 1 germline driver genes include: SDHD, SDHC, SDHB, SDHAF2, SDHA, VHL, HIF2A (EPAS1), FH gene encoding fumarate hydratase, EGLN1 (PHD2), EGLN2 (PHD1), KIF1B, SLC25A11, IDH1, MDH2, DLST, and DNMT3A. Cluster 2 germline driver genes include: RET, NF1, MAX, and TMEM127 (table 1) [16-20]. Cluster 3 germline driver genes include: CSDE1, MAML3, and UBTF::MAML3 fusions.

Familial paraganglioma — Familial paraganglioma is an autosomal dominant disorder characterized by paragangliomas that are located most often in the skull base and neck but also in the mediastinum, abdomen, pelvis, and urinary bladder [16].

The occurrence of catecholamine hypersecretion in a patient with familial paraganglioma depends upon tumor location; approximately 5 percent of skull base and neck paragangliomas and more than 50 percent of abdominal paragangliomas hypersecrete catecholamines and metanephrines [21]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)

Most cases of familial paraganglioma are caused by pathogenic variants in the succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD, SDHAF2, SDHA), which compose portions of mitochondrial complex II [22-28]. Mitochondrial complex II is a tumor suppressor gene involved in the electron transport chain and the tricarboxylic-acid (TCA) cycle. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH pathogenic variants'.)

●Most germline pathogenic variants in SDHD, SDHAF2, and SDHC have been identified in multigenerational families with biochemically silent skull base and neck paragangliomas [29,30]. In patients with SDHD and SDHAF2 pathogenic variants, penetrance depends on the pathogenic variant's parent of origin [25,26,29]. Hence, the disease is not manifested when the pathogenic variant is inherited from the mother but is highly penetrant when inherited from the father. This phenomenon is known as maternal imprinting.

●In a prospective study, 445 patients with skull base and neck and/or thoracic-abdominal or pelvic paragangliomas were recruited over 5 years in 20 referral centers [31]. SDH germline pathogenic variants were found 242 patients (54.4 percent): 130 in SDHD, 96 in SDHB, and 16 in SDHC. A skull base and neck paraganglioma was present in 97.7 percent of the SDHD and 87.5 percent of the SDHC pathogenic variant carriers, but in only 42.7 percent of the SDHB carriers. A thoracic-abdominal or pelvic location was present in 63.5 percent of the SDHB, 16.1 percent of the SDHD, and in 12.5 percent of the SDHC pathogenic variant carriers. Multiple paragangliomas were diagnosed in 66.9 percent of the SDHD pathogenic variant carriers. A malignant paraganglioma was documented in 37.5 percent of the SDHB, 3.1 percent of the SDHD, and none of the SDHC pathogenic variant carriers.

●SDHD, SDHC, SDHAF2, SDHA, and SDHB germline pathogenic variant screening is commercially available and staged testing (eg, starting with SDHD, SDHC, and SDHAF2 pathogenic variant analysis in patients with skull base and neck paragangliomas and SDHB pathogenic variant analysis in patients with paragangliomas below the neck) should be considered in all patients with paraganglioma [28]. (See 'Genetic screening' below.)

Sporadic pheochromocytoma

Frequency of genetic abnormalities — In an early series of 271 patients with apparent sporadic pheochromocytoma from population-based registries in Germany and Poland who were tested for germline pathogenic variants in the four genes described above that have been associated with pheochromocytoma (VHL, RET, SDHD, and SDHB [5]), the following findings were noted:

●A pathogenic variant was identified in 66 patients (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 pathogenic variant. Possible explanations for sporadic and frequently localized disease in these patients include spontaneous pathogenic variant, 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 pathogenic variant, 6 of 13 with a RET pathogenic variant, and none of 23 with a SDH complex pathogenic variants.

A retrospective study from France reported on molecular genetic testing over a decade (2001 to 2010) [32]. A genetic test for paraganglioma/pheochromocytoma was assessed for 2499 subjects, of which 1620 were index cases. Germline pathogenic variants were found in 363 index cases (22.4 percent): 269 in SDHx genes (137 in SDHB, 100 in SDHD, 30 in SDHC, 2 in SDHA), 64 in VHL, 23 in RET, and 7 in TMEM127. Overall, a germline pathogenic variant was identified in 44.7 percent of patients with a suspected hereditary pheochromocytoma/paraganglioma and in 8 percent of patients with an apparently sporadic paraganglioma/pheochromocytoma.

More recently, a prospective observational study from the United Kingdom National Health Service included a total of 501 probands with pheochromocytoma/paraganglioma: 31 percent of patients had a pathogenic variant in SDHB, SDHD, or VHL [33]. Pathogenic variant detection rates were highest in those with a positive family history (62 percent), malignancy (53 percent), multiple tumors (33 percent), or paraganglioma (44 percent). Twenty-eight percent of individuals with a single sporadic adrenal pheochromocytoma had a disease-causing pathogenic variant.

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) ranges from 8 to 28 percent.

All patients should be monitored for findings of a genetic syndrome, some of which can be detected on physical examination [8,34], including:

●Retinal angiomas in VHL syndrome

●A thyroid mass in MEN2

●Cafe au lait spots, axillary and inguinal freckling, Lisch nodules on the iris, and subcutaneous neurofibromas in NF1

●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 in all patients with documented pheochromocytoma or paraganglioma [4]. 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.

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 disease-causing pathogenic variant.

Suggested approach — The clinician may obtain a list of clinically approved molecular genetic diagnostic laboratories at Genetic Testing Registry. The field of genetic testing is rapidly evolving, and at many clinical laboratories, sequential genetic testing is no longer done, as it is less expensive to utilize next-generation sequencing technology for all clinically available mutations as a package. However, in those patients with neck and skull base paragangliomas, a case can be made for obtaining an SDHx panel.

Genetic testing for neurofibromatosis type 1 (NF1) is available but is not routinely performed, as the diagnosis is made based upon clinical phenotype.

Bilateral adrenal pheochromocytoma — If a patient presents with bilateral adrenal pheochromocytoma, it will always be caused by germline pathogenic variant, primarily in RET or VHL [35]. However, approximately 7 percent of patients will have germline pathogenic variants in TMEM127, NF1, SDHx, or MAX [35]. The biochemical phenotype (eg, adrenergic [multiple endocrine neoplasia type 2 (MEN2)] or noradrenergic [von Hippel-Lindau (VHL) syndrome]) can also be used to predict the results of genetic testing.

Known pathogenic variant — Additional evaluation for patients with an identified pathogenic variant or syndrome (VHL syndrome, MEN2, NF1) 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 (NF1): Pathogenesis, clinical features, and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pheochromocytoma and paraganglioma".)

SUMMARY AND RECOMMENDATIONS

●Familial pheochromocytoma – Most catecholamine-secreting tumors are sporadic. However, some patients (approximately 40 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. Several familial syndromic disorders are associated with pheochromocytoma, all of which have autosomal dominant inheritance:

•Von Hippel-Lindau (VHL) syndrome, associated with pathogenic variants in the VHL tumor suppressor gene. (See 'VHL syndrome' above.)

•Multiple endocrine neoplasia type 2 (MEN2), which is associated with pathogenic variants in the RET proto-oncogene. (See 'MEN2' above.)

•Pheochromocytoma is also seen, albeit infrequently, with neurofibromatosis type 1 (NF1), due to pathogenic variants 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 3 percent with NF1.

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

●Genetic testing – Genetic testing should be considered in all patients with pheochromocytoma or paraganglioma. (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 disease-causing pathogenic variant. (See 'Suggested approach' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic review.