What are hereditary pheochromocytoma / paraganglioma syndromes?

Hereditary pheochromocytoma / paraganglioma syndromes (HPP) are caused by mutations – or genetic changes – in the SDH, the MAX, or the TMEM127 gene. They are usually characterized by benign tumors that develop from precursor cells of the nerve cells of the involuntary nervous system. Referred to as pheochromocytomas and paragangliomas, these tumors can occur in regions of the brain, the neck, or the upper chest cavity, and they generally do not produce any hormones. If they occur in the lower chest cavity, the abdomen, or the pelvis, however, the tumors usually secrete hormones (e.g. adrenaline and/or noradrenaline). In addition, there is an increased risk of developing stomach, kidney, and thyroid tumors.

How is hereditary pheochromocytoma / paraganglioma syndrome diagnosed?

Suspected Diagnosis

HPP is suspected with the following presentations:

  • Multiple paragangliomas/pheochromocytomas or one extending to both sides

  • Paragangliomas/pheochromocytomas occurring at multiple locations, either at the same time or at differing times

  • Recurring paragangliomas/pheochromocytomas

  • Early occurrence of paragangliomas/pheochromocytomas (< 45 years)

  • Frequent incidence of paragangliomas/pheochromocytomas in the family

Genetic Diagnostics

The diagnosis of “hereditary pheochromocytoma / paraganglioma syndromes” is confirmed by detection of a mutation – or genetic change – in one of the SDHx genes (SDHA, SDHB, SDHC, SDH, or SDHAF2), in the MAX gene, or in the TMEM127 gene.

What is the risk of cancer?

Compared to sporadically occurring paragangliomas and pheochromocytomas (PGL/PHEO) the tumors associated with an SDHx mutation occur at an earlier point in time, are usually found in multiple locations, develop on both sides, and tend to recur. Benign paragangliomas and pheochromocytomas generally grow slowly, while malignant tumors are typically more aggressive.

The greatest risk of cancer is associated with mutations in the SDHB gene. Patients with this genetic alteration exhibit higher rates of mortality and have paragangliomas with a much stronger tendency to spread (metastasize) than patients with other SDH mutations.

Paragangliomas in the area of the brain base and neck

Paragangliomas in these regions are typically associated with the parasympathetic nervous system, which – along with the sympathetic nervous system – is part of the involuntary nervous system. These paragangliomas generally do not secrete hormones. Clinical symptoms are usually caused by the space-occupying growth of these tumors, since these types of tumors do not tend to spread (metastasize).
Different symptoms can occur depending on the location.

In the area of the carotid artery (carotid bifurcation tumors), these paragangliomas are usually asymptomatic unilateral space-occupying lesions, which only lead to complaints – such as sensation disorders or motor impairments in the neck, jaw, and facial regions – until the tumor grows larger.

Tumors located in the vagus nerve region (the tenth cranial nerve, which has a large number of motor and sensory properties) manifest the same way as the carotid bifurcation tumors described above. In addition, symptoms such as hoarseness, a foreign body sensation in the throat, swallowing disorders, pain, coughing, and aspiration (penetration of fluid or food into the airways) may occur.

Paragangliomas in the area of the ear may trigger tinnitus or loss of hearing.

Paragangliomas in the upper body, abdominal, and pelvic areas

Paragangliomas in these regions are typically associated with the sympathetic nervous system, which – along with the parasympathetic nervous system – is part of the involuntary nervous system. Tumors in these regions usually exhibit excessive hormone production (e.g. adrenaline and/or noradrenaline).

Pheochromocytomas and sympathetic paragangliomas outside of the adrenal glands

Pheochromocytomas are tumors that usually occur in the adrenal medulla and produce hormones such as adrenaline and noradrenaline (catecholamines). However, they can also occur outside of the adrenal glands, where they are called sympathetic paragangliomas. This type of tumor, when associated with HPP, manifests the same way as tumors that occur sporadically. They are usually discovered because of one of the following scenarios:

  • Signs and symptoms associated with the excess production of catecholamines (adrenaline, noradrenaline), such as high blood pressure and a rapid pulse, headaches, palpable skipped heartbeats, extreme sweating, and anxiety. Nausea, vomiting, fatigue, and weight loss can also be caused by this kind of tumor.

  • Signs and symptoms relating to growth of the tumor

  • An incidental finding with an MRI/CT

  • Screening relatives at increased risk

Sympathetic paragangliomas outside of the adrenal glands have an increased tendency towards malignant transformation. This tendency is much lower with pheochromocytomas.

Gastrointestinal stromal tumors (GIST)

These are malignant connective tissue tumors of the gastrointestinal tract – usually located in the stomach when associated with HPP. Stomach bleeding may occur as a complication. While these tumors can occur with mutations in all of the SDH genes, it is most common with mutations in the SDHA gene.

Clear-cell renal cell carcinoma and papillary thyroid carcinoma

These tumors have been associated with SDHB and SDHD mutations.

What causes hereditary pheochromocytoma / paraganglioma syndrome?

Hereditary pheochromocytoma / paraganglioma syndromes are caused by mutations – or genetic alterations – in the SDH genes, the MAX gene, or the TMEM127 gene. These genes encode for the corresponding SDH proteins and the MAX and TMEM127 proteins, all of which function as tumor suppressors; in other words, they control the proliferation of cells in our body. Now if one of these genes is altered, the corresponding protein will no longer be able to function correctly as a tumor suppressor, and result in the development of neoplasms and precursor cells of the involuntary nervous system.

HPP can be passed on by parents to their children. In these cases, it is inherited as an autosomal dominant disease. Genetic alterations in the SDHD, SDHAF2, and MAX genes are only inherited from the father.

Approximatly 65% of cases are due to a spontaneous or new mutation, called a de novo mutation.

Is there a treatment?

The treatment of hereditary paragangliomas and pheochromocytomas is not much different from that of sporadically occurring tumors. For children, it is recommended that you contact the GPOH study treatment team with regards to the endocrine tumors.

Hormone-producing tumors

  • Medicinal therapy to avoid the release of excessive hormone levels

  • Surgical removal of any malignant tumors

Paragangliomas which are located in the base of the brain and the neck region and which do not produce hormones

  • Early surgical treatment

  • Paragangliomas in the carotid artery and tenth cranial nerve region

    • Surgical removal is the treatment of choice. It is usually possible to remove paragangliomas completely.
    • In older patients or in the presence of other existing diseases, surgical treatment can be delayed if accompanied by regular imaging examinations. Radiotherapy may be worth considering for these patients.

  • Paragangliomas in the ear region

    • Small tumors can usually be surgically removed without difficulty.
    • For larger tumors, surgical removal may lead to complications, such as a spinal fluid leak, meningitis, stroke, loss of hearing, or cranial nerve paralysis.

Pheochromocytomas

  • Surgical removal, ideally by means of a laparoscopy, is the treatment of choice.

  • Antihormonal medicinal therapy should be carried out prior to the surgery.

Patients with an SDHB mutation

  • After a tumor is diagnosed, these patients should be operated on as quickly as possible, since tumors associated with an SDHB mutation have a strong tendency to metastasize.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Since tumors only rarely develop during the first ten years of life, the American Association of Cancer Research (AACR) currently recommends starting surveillance examinations for early detection at the age of 6-8. These are standard recommendations, independent of the genetic mutation present.

Paragangliomas / Pheochromocytomas

  • Blood pressure checks at every medical checkup from 6-8 years of age

  • Annual blood or urine test for adrenal gland hormones from 6-8 years of age

    • If there are any anomalies, an imaging examination or a repeat test should be conducted after 2 or 6 months depending on the values.

  • Full-body MRI (from the base of the skull to the pelvis) every two years from 6-8 years of age

  • Optional: MRI of the neck with/without contrast agent every two years

Gastrointestinal Stromal Tumors (GIST)

  • Annual complete blood count from 6-8 years of age

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as complaints such as high blood pressure and rapid pulse, headaches, palpable skipped heartbeats, extreme sweating, or anxiety occur. Nausea, vomiting, fatigue, and weight loss may also be signs of a hormone-producing tumor and should be checked by a doctor. Moreover, tinnitus or changes in hearing, swallowing or voice disorders, hoarseness, coughing, or a foreign body sensation in the throat should be noted and reported to a doctor as well. You should also see a doctor right away if you notice any other newly occurring anomalies or symptoms, such as abdominal pain, sensation disorders, or motor impairments.

Support Groups and Additional Information

Unfortunately, we are as yet unaware of any existing support groups for patients with hereditary pheochromocytoma / paraganglioma syndromes. We will add any new information in this regard We will add new information as it becomes available.