Rare Nephrology News

Disease Profile

Hereditary paraganglioma-pheochromocytoma

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Childhood

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ICD-10

C74.1 C75.5 D35.0 D35.6

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hereditary pheochromocytoma-paraganglioma; Familial pheochromocytoma-paraganglioma; SDHx-related paraganglioma-pheochromocytoma

Categories

Blood Diseases; Congenital and Genetic Diseases; Endocrine Diseases;

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 29072

Definition
Hereditary paraganglioma-pheochromocytomas (PGL/PCC) are rare neuroendocrine tumors represented by paragangliomas (occurring in any paraganglia from the skull base to the pelvic floor) and pheochromocytomas (adrenal medullary paragangliomas; see this term).

Epidemiology
Hereditary PGL/PCCs represent 30% of all PGL/PCC, for which prevalence is around 1/500,000 for PCC and 1/1,000,000 for PGL.

Clinical description
PGL can be either hypersecreting (catecholamines) or non-secreting and PCCs usually secrete catecholamines. Secreting (sympathetic) PGLs are predominantly found in the thoracic, abdominal and pelvic areas. Hypersecretion manifests as sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor and apprehension or anxiety. Urinary bladder PGL may be revealed by painless hematuria and blood pressure increase after micturition. Non-secreting (parasympathetic) PGLs are predominantly located in the head and neck and present as enlarging masses that may be asymptomatic or may be associated with unilateral hearing loss, pulsatile tinnitus, cough, hoarseness of voice, pharyngeal fullness, swallowing difficulty, pain and/or problems with tongue motion. There are no validated markers of malignancy (rate around 15%); the only criterion is the presence of metastases. Gastric stromal tumors and renal cancers are rarely associated.

Etiology
Up to 10% of genetically determined PCC/PGLs are due to a SDHx germline mutation. Hereditary PCC/PGLs are caused by mutations in the SDHD, SDHC, SDHB, SDHA and SDHAF2 (or SDH5) genes (11q23, 1q21, 1p36.1-p35, 5p15 and 11q31.1 respectively). Transmission is autosomal dominant but associated with maternal genomic imprinting for SDHD and SDHAF2 and expressed when the mutation is inherited from the father. Penetrance depends on the gene, age and tumor sites. Tumors in patients with SDHB mutations are more likely to become malignant than those in patients with other SDHx mutations.

Diagnostic methods
Diagnosis is based on clinical examination and family history. Young age at onset, presence of bilateral, extra-adrenal or multiple tumors, or malignancy suggest an inherited disorder. Imaging studies (MRI, CT) are used to detect tumors and may include functional imaging (scintigraphy, PET). Biochemical testing includes plasma free metanephrines and/or 24 hour-urinary fractionated metanephrines. Molecular genetic testing confirms the diagnosis.

Differential diagnosis
Differential diagnoses include non-hereditary PCC/PGL (although hereditary PCC/PGL tends to present at younger ages, to be multi-focal, bilateral, and recurrent, or to have multiple synchronous neoplasms), PCC/PGL associated with other hereditary conditions (neurofibromatosis type 1, von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2, Carney triad and Carney-Stratakis syndrome; see these terms) and familial PCC due to TMEM127 mutation.

Antenatal diagnosis
Prenatal testing is not recommended. Presymptomatic testing is proposed in at-risk children from 6 years of age.

Management and treatment
Treatment for secreting tumors involves blood pressure control with alpha-blockers followed by surgery by specialized teams. If the tumors have not metastasized, surgical resection can be curative. Follow-up is required due to the risk of recurrence and malignancy in particular for SDHB mutationcarriers. For head and neck PGL, external radiotherapy can be proposed. When metastases have occurred, other treatment options including chemotherapy and targeted radiotherapy should be proposed.

Prognosis
The disease may be fatal, but some have lived with malignant PCC/PGL for 20 years or more.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Adrenal pheochromocytoma
0006748
Extraadrenal pheochromocytoma
0006737
30%-79% of people have these symptoms
Cerebral hemorrhage
Bleeding in brain
0001342
Chest pain
0100749
Dysphonia
Inability to produce voice sounds
0001618
Elevated urinary dopamine
0011979
Elevated urinary epinephrine
0003639
Elevated urinary norepinephrine
0003345
Episodic abdominal pain
0002574
Episodic hyperhidrosis
Sporadic excessive sweating
0001069
Episodic paroxysmal anxiety
0000740
Fatigue
Tired
Tiredness

[ more ]

0012378
Flushing
0031284
Glomerular sclerosis
0000096
Hypercalcemia
High blood calcium levels
Increased calcium in blood

[ more ]

0003072
Hypertensive retinopathy
0001095
Nausea
0002018
Palpitations
Missed heart beat
Skipped heart beat

[ more ]

0001962
Paraganglioma of head and neck
0002864
Paroxysmal vertigo
0010532
Positive regitine blocking test
0003574
Proteinuria
High urine protein levels
Protein in urine

[ more ]

0000093
Pulsatile tinnitus
0008629
Recurrent paroxysmal headache
0002331
Sinus tachycardia
0011703
Weight loss
0001824
5%-29% of people have these symptoms
Arachnoid hemangiomatosis
0012222
Conductive hearing impairment
Conductive deafness
Conductive hearing loss

[ more ]

0000405
Congestive heart failure
Cardiac failure
Cardiac failures
Heart failure

[ more ]

0001635
Cranial nerve compression
0001293
Elevated calcitonin
0003528
Hematuria
Blood in urine
0000790
Pallor
0000980
Panic attack
0025269
Renal cell carcinoma
Cancer starting in small tubes in kidneys
0005584
Retinal capillary hemangioma
0009711
Tremor
0001337
Vocal cord paralysis
Inability to move vocal cords
0001605
1%-4% of people have these symptoms
Aniridia
Absent iris
0000526

Treatment

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

  • Iobenguane I 131(Brand name: Azedra) Manufactured by Progenics Pharmaceuticals, Inc.
    FDA-approved indication: July 2018, iobenguane I 131 (Azedra) was approved for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.
    National Library of Medicine Drug Information Portal

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • Genetics Home Reference (GHR) contains information on Hereditary paraganglioma-pheochromocytoma. This website is maintained by the National Library of Medicine.

      In-Depth Information

      • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Hereditary paraganglioma-pheochromocytoma. Click on the link to view a sample search on this topic.