Hereditary Pheochromocytoma/ Paraganglioma Syndromes – Definition
Hereditary pheochromocytoma/paraganglioma (HPP) syndromes are genetic diseases based on heterozygous pathogenic variants in an SDH gene, the MAX gene, or the TMEM127 gene. They are characterized by typically benign tumors originating in the neural crest. Extra-adrenal parasympathetic paragangliomas are frequently located in the area of the brain base, neck, and upper mediastinum and are generally not secretory. In contrast, sympathetic paragangliomas are usually located in the area of the lower mediastinum, abdomen, and pelvis and are hormone-producing. In addition, there is an association with gastrointestinal stromal tumors, renal cell tumors, and papillary thyroid adenomas.
Synonyms:
Familiar glomus tumors, familiar non-chromaffinic paragangliomas
Genes:
SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2)
MAX
TMEM127
Gene products:
SDH (succinate dehydrogenase) with subunits A-D, SDHAF2
MAX (MYC-associated factor X)
TMEM127 (transmembrane protein)
Function:
Tumorsuppressoren
Erbgang:
Autosomal dominant: SDHA, SDHB, SDHC, TMEM127
Paternal transmission: SDHD, SDHAF2, MAX
Around 65% of de novo mutations
Prevalence:
The incidence is around 1:300.000 per year.
Genotype-phenotype correlation:
SDHB:
- Higher level of morbidity and mortality than with other pathogenic SDHx variants
- Strong association with extra-adrenal, sympathetic paragangliomas
- Around 20% have pheochromocytomas Paragangliomas exhibit a considerable tendency towards metastasis
SDHD, SDHC, SDHAF2:
- Association with parasympathetic paragangliomas of the brain base and neck
- Patients with a pathogenic SDHD variant frequently have multiple tumors, while patients with a pathogenic SDHC variant tend to develop solitary tumors.
- Only tumors in the head and neck area – mainly carotid bifurcation tumors – have been reported so far in patients with a pathogenic SDHAF2 variant.
- SDHA: Most common pathogenic variant, which is associated with gastrointestinal stromal tumors (GIST)
Penetrance:
Pathogenic SDHD variants: 90%
Pathogenic SDHB variants: 30%-50%
Pathogenic SDHA, SDHC, SDHAF2, and TMEM127 variants: unclear to date
Hereditary Pheochromocytoma/ Paraganglioma Syndromes – Diagnosis
Suspected Diagnosis
The existence of HPP is suspected based on the following findings:
- Bilateral or multiple paragangliomas/pheochromocytomas
- Multifocal paragangliomas/pheochromocytomas, the occurrences of which are synchronous or metachronous
- Recurring paragangliomas/pheochromocytomas
- Early occurrence of paragangliomas/pheochromocytomas (< 45 years)
- Familiar presentation of paragangliomas/pheochromocytomas that are compatible with autosomal-dominant heredity
Genetic Diagnostics
The diagnosis of “hereditary paraganglioma/pheochromocytoma syndromes” is confirmed through evidence of a heterozygous pathogenic germline variant in one of the SDHx genes, the MAX gene, or the TMEM127 gene obtained through sequential, deletion, or duplication analysis. The use of panel studies involving multiple genes may be meaningful as well.
Differential Diagnoses
- Neurofibromatosis type 1 (NF1)
- Von Hippel-Lindau syndrome
- Multiple endocrine neoplasia type 2 (MEN2)
- Carney triad
- Carney-Stratakis syndrome
Clinical Presentation
Compared to sporadically occurring paragangliomas/pheochromocytomas (PGL/PHEO), tumors in the context of a pathogenic SDHx variant occur sooner, they are often multifocal or bilateral, and they tend to recur or occur as multiple synchronous neoplasias. Benign paragangliomas/pheochromocytomas grow slowly, while malignant tumors are typically more aggressive.
Paragangliomas in the Area of the Brain Base and Neck
Paragangliomas in these areas are generally associated with the parasympathetic nervous system. There does not tend to be hypersecretion of catecholamines with these paragangliomas. Clinical symptoms are typically caused by the space-occupying growth of these tumors, since they do not exhibit a tendency towards metastasis.
Carotid Bifurcation Tumors:
- Usually asymptomatic, laterally progressive space-occupying growth
- Symptoms caused by the tumor mass: compression of cranial nerves or the sympathetic trunk with resulting neuropathies
Vagal paragangliomas:
- Presentation as with carotid bifurcation tumors
- In addition, symptoms such as hoarseness, globus sensation, dysphagia, dysphonia, pain, cough, and aspirations may occur.
Jugulotympanic paragangliomas:
- Can cause pulsatile tinnitus, hearing loss, and other symptoms caused by compression of the deep cranial nerves
Paragangliomas in the Area of the Thorax, Abdomen, and Pelvis
Paragangliomas in these regions are generally associated with the sympathetic nervous system. Tumors in these areas typically exhibit hypersecretion of catecholamines.
Pheochromocytomas and Extra-Adrenal Sympathetic Paragangliomas
In the context of an HPP, these kinds of tumors have a presentation similar to that of sporadic occurrence. They are generally detected through one of the following scenarios:
- Signs and symptoms associated with hypersecretion of catecholamines, such as hypertension and tachycardia, headache, palpitations, extreme sweating, and anxiety. This kind of tumor may also trigger nausea, vomiting, lethargy, and weight loss.
- Signs and symptoms caused by the growth of the neoplasia
- Incidental finding from an MRI/CT
- Screening for family members with an increased risk
Extra-adrenal, sympathetic paragangliomas have an increased tendency toward becoming malignant. This tendency is much lower with pheochromocytomas.
Gastrointestinal Stromal Tumors (GIST)
These tumors can occur with mutations in all SDH subunits, most frequently with pathogenic SDHA variants. They are usually located in the stomach and originate in the submucosal cells of Cajal. Gastric bleeding may occur as a complication.
Clear Cell Renal Cell Carcinoma and Papillary Thyroid Carcinoma
These tumors are described in the context of pathogenic SDHB and SDHD variants.
Specific Features of Treatment
The treatment of hereditary paragangliomas and pheochromocytomas is not much different than that of sporadically occurring tumors. Contacting the GPOH study for endocrine tumors is recommended.
Hormone-Producing Tumors
- Pharmacological, adrenergic blocking for preventing a catecholamine excess
- Surgical resection for malignant tumors
Non-Hormone-Producing Paragangliomas of the Brain Base and Neck
- Early surgical therapy
- Carotid bifurcation and vagal paragangliomas
- Surgical resection is the therapy of choice. It is usually fully possible for this to be performed.
- In older patients or when multiple comorbidities exist, surgical therapy may be delayed with regular imaging examinations. Radiotherapy can also be considered for such patients.
- Jugulotympanic paragangliomas
- It is usually possible to surgically resect small tumors without any difficulty.
- For larger tumors, complications may occur due to surgical resection, such as CSF leakage, meningitis, stroke, hearing loss, and cranial nerve paralysis.
Pheochromocytomas
- Surgical resection – ideally by means of laparoscopy – is the therapy of choice.
- Before the operation, combined α and β-adrenergic blocking should be carried out with medication.
Patients with a pathogenic SDHB variant
- These patients should undergo surgical treatment as soon as possible after a tumor is diagnosed since tumors in the context of a pathogenic SDHB variant have a strong tendency toward metastasis.
Diagnosis of Hereditary Pheochromocytoma/ Paraganglioma Syndromes- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Hereditary Pheochromocytoma/ Paraganglioma Syndromes - What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
The risk of developing a tumour varies depending on the underlying genetic variant. The updated American Association of Cancer Research (AACR) recommendations have been adapted accordingly.
Paragangliomas/ Pheochromocytomas
- Blood pressure checks at every medical examination (at least once a year) from the age of 6-8 years
- Annual plasma methoxytyramin test from the age of 6-8 years
- Annual plasma-free metanephrines (PFM) test or fractionated metanephrines 24-hour urine test from the age of 6-8 years
- if PFM is ≥ 4x above the reference value: compatible with PGL/PHEO; imaging for localization should be performed
- if PFM is 2x-4x above the reference value: Repeat the examination in 2 months
- if PFM is marginally elevated: Repeat the examination in 6 months (or perform a clonidine suppression test to exclude false-positive values)
- Optional: Annual serum chromogranin A test from the age of 6-8 years
- MRI (base of skull to pelvis) depending on affected gene:
- SDHB: every 24 months from 6 years of age
- SDHA and MAX: every 24 months from 10 years of age
- SDHC and SDHD: every 36 months from 10 years of age
- SDHAF2 and TMEM127: every 24 months from 21 years of age
- In addition, neck MRI without contrast (+ post-contrast agent sequences depending on local practice)
Gastrointestinal Stromal Tumors (GIST)
- Annual complete blood count from 6-8 years of age
