Compared to sporadic paragangliomas and pheochromocytomas (PGL/PHEO), the tumors associated with an SDHx mutation occur at an earlier stage, are more likely to be located in multiple sites, develop bilaterally, and are prone to recurrence. Benign paragangliomas and pheochromocytomas are usually slow-growing, whereas malignant tumors are typically more aggressive.

The most significant risk of cancer is associated with mutations in the SDHB gene. Patients with this genetic mutation have higher mortality rates and paragangliomas with a significantly greater tendency to spread (metastasize) than patients with other SDH mutations.

Paragangliomas in these regions are generally associated with the parasympathetic nervous system, which – along with the sympathetic nervous system – is part of the involuntary nervous system. There is usually no release of hormones in these paragangliomas. Clinical symptoms are typically caused by the space-occupying growth of these tumors, as there is no tendency for the tumors to spread (metastasize).
Depending on the location, various symptoms may occur.

In the area of the carotid artery (carotid bifurcation tumors), paragangliomas are usually asymptomatic, one-sided masses that only lead to symptoms such as sensory disturbances or motor impairments in the neck, jaw, and facial area as the tumor grows in size.

Tumors localized in the vagus nerve (the tenth cranial nerve, which has a variety of motor and sensory qualities) manifest themselves like the carotid bifurcation tumors described above. In addition, symptoms such as hoarseness, a foreign body sensation in the throat, difficulty swallowing, voice disorders, pain, coughing, and aspiration (penetration of liquid or food into the airways) can occur.
In the ear area, paragangliomas can cause tinnitus or hearing loss.

Paragangliomas in these regions are usually associated with the sympathetic nervous system, which – along with the parasympathetic nervous system – is part of the involuntary nervous system. Tumors in these areas usually show an overproduction of hormones (e.g., adrenaline and/or noradrenaline).

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 the adrenal glands as so-called sympathetic paragangliomas. This type of tumor presents in the same way as sporadic HPP. They usually present in one of the following scenarios:

• Signs and symptoms associated with an overproduction of catecholamines (adrenaline, noradrenaline) include high blood pressure and rapid pulse, headaches, noticeable heart palpitations, extreme sweating, and anxiety. Such a tumor can also trigger nausea, vomiting, fatigue, and weight loss.
• Signs and symptoms caused by the growth of the tumor
• Incidental finding with MRI/CT
• Screening for relatives at increased risk

Sympathetic paragangliomas outside the adrenal gland have an increased tendency to malignant degeneration. This tendency is significantly lower in pheochromocytomas.

These are malignant connective tissue tumors of the gastrointestinal tract, usually localized in the stomach in HPP. Gastric bleeding can occur as a complication. Mutations in all SDH genes can cause these tumors, but they are most common with mutations in the SDHA gene.

These tumors have been described in the context of SDHB and SDHD mutations.

Treating hereditary paragangliomas and pheochromocytomas is not significantly different from treating sporadically occurring tumors. Your treatment team should contact the GPOH study for endocrine tumors in children.

• Drug therapy to prevent excessive hormone release
• Surgical removal of malignant tumors

• Early surgical therapy
• Paragangliomas in the area of the carotid artery and the tenth cranial nerve
  • Surgical removal is the treatment of choice. This is usually possible in total.
    Surgical treatment can be delayed in older patients or those with other existing diseases, subject to regular imaging checks. Radiotherapy can also be considered for these patients.
• Paragangliomas in the ear area
  • Small tumors can usually be surgically removed without any problems.
  • Surgical removal of larger tumors can lead to complications such as leakage of cerebrospinal fluid, meningitis, stroke, hearing loss, and cranial nerve palsy.

• Surgical removal, ideally by laparoscopy, is the treatment of choice.
• Anti-hormonal drug therapy should be carried out before the operation.

These patients should be treated surgically as soon as possible after diagnosis of a tumor, as tumors with an SDHB mutation have a strong tendency to metastasize.

As tumors rarely develop in the first ten years of life, the American Association of Cancer Research (AACR) recommends screening at 6-8 years old. These recommendations are uniform and independent of the genetic mutation present.

• From 6 to 8 years of age, blood pressure is checked at every medical check-up (at least once a year).
• Annual blood or urine test for adrenal hormones from 6-8 years of age
  • If there are any abnormalities, imaging should be performed, or the examination should be repeated after 2 or 6 months, depending on the values.
• Whole-body MRI (skull base to pelvis) every two years from 6-8 years of age
• Optional: MRI neck with/without contrast agent every two years

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