Hereditary paraganglioma-pheochromocytoma

Other Names: Hereditary pheochromocytoma-paraganglioma; Familial pheochromocytoma-paraganglioma; SDHx-related paraganglioma-pheochromocytoma

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).

Types

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.

Cause

Mutations in at least four genes increase the risk of developing the different types of hereditary paraganglioma-pheochromocytoma. Mutations in the SDHD gene predispose an individual to hereditary paraganglioma-pheochromocytoma type 1; mutations in the SDHAF2 gene predispose to type 2; mutations in the SDHC gene predispose to type 3; and mutations in the SDHB gene predispose to type 4. The SDHB, SDHC, and SDHD genes provide instructions for making three of the four subunits of an enzyme called succinate dehydrogenase (SDH). In addition, the protein made by the SDHAF2 gene is required for the SDH enzyme to function. The SDH enzyme links two important cellular pathways called the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. These pathways are critical in converting the energy from food into a form that cells can use.

As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Succinate acts as an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia).

Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Hereditary paraganglioma-pheochromocytoma is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors. An additional mutation that deletes the normal copy of the gene is needed to cause the condition. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.

The risk of developing hereditary paraganglioma-pheochromocytoma types 1 and 2 is passed on only if the mutated copy of the gene is inherited from the father. The mechanism of this pattern of inheritance is unknown. The risk of developing types 3 and 4 can be inherited from the mother or the father.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Adrenal pheochromocytoma
• Extraadrenal pheochromocytoma
• 30%-79% of people have these symptoms
• Cerebral hemorrhage(Bleeding in brain)
• Chest pain
• Dysphonia(Inability to produce voice sounds)
• Elevated urinary dopamine
• Elevated urinary epinephrine
• Elevated urinary norepinephrine
• Episodic abdominal pain
• Episodic hyperhidrosis(Sporadic excessive sweating)
• Episodic paroxysmal anxiety
• Fatigue(Tired)
• Flushing
• Glomerulosclerosis
• Hypercalcemia(High blood calcium levels)
• Hypertensive retinopathy
• Nausea
• Palpitations(Missed heart beat)
• Paraganglioma of head and neck
• Paroxysmal vertigo
• Positive regitine blocking test
• Proteinuria(High urine protein levels)
• Pulsatile tinnitus
• Recurrent paroxysmal headache
• Sinus tachycardia
• Weight loss

5%-29% of people have these symptoms

• Arachnoid hemangiomatosis
• Conductive hearing impairment(Conductive deafness)
• Congestive heart failure(Cardiac failure)
• Cranial nerve compression
• Elevated calcitonin
• Hematuria(Blood in urine)
• Pallor
• Panic attack
• Renal cell carcinoma(Cancer starting in small tubes in kidneys)
• Retinal capillary hemangioma
• Tremor
• Vocal cord paralysisInability to move vocal cords

1%-4% of people have these symptoms

• Aniridia(Absent iris)

Diagnosis

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.

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 mutation-carriers.

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

• Iobenguane I 131 (Brand name: Azedra) 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.

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.

Prognosis

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

NIH genetic and rare disease info

• NIH info on Hereditary paraganglioma-pheochromocytoma

Hereditary paraganglioma-pheochromocytoma is a rare disease.

Hereditary paraganglioma-pheochromocytoma Resources
Latest articles Most recent articles Ongoing trials	Wikipedia