Hereditary paraganglioma and pheochromocytoma (SDHB, SDHD, SDHC, SDHA)

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Hereditary paraganglioma and pheochromocytoma syndrome is an inherited condition that raises the risk of tumors developing from a specialized group of nerve-related cells. It is caused by a change in one of several genes that together build an enzyme called succinate dehydrogenase, usually shortened to SDH. The genes are SDHB, SDHD, SDHC, SDHA, and SDHAF2, referred to collectively as the SDHx genes.

The two main tumors are closely related. A pheochromocytoma develops in the adrenal gland, above the kidney. A paraganglioma is the same kind of tumor arising anywhere else along a chain of small nerve-associated structures that runs from the base of the skull down through the chest and abdomen to the pelvis. Together they are often abbreviated PPGL.

Three things about this condition shape everything below. Which gene is involved matters more here than in almost any other hereditary cancer syndrome, determining where tumors appear, how likely they are to spread, and in one case even which parent the change came from. Most of these tumors are not cancer, but a minority spread, and that minority is concentrated in one gene. And many of these tumors release hormones, so they cause symptoms and risks that have nothing to do with spreading.

This article is written for people who carry an SDHx change, whether or not a tumor has been found.

What do the SDH genes do?

Succinate dehydrogenase is an enzyme inside the mitochondria, the compartments where cells generate energy. It performs two jobs at once: it is a step in the chemical cycle that extracts energy from food, and it is part of the chain that produces that energy.

The enzyme is built from four subunits, each made by a separate gene, plus an assembly factor. When any one of them fails, the whole enzyme falls apart. Its chemical starting material, succinate, then builds up inside the cell, and at high levels succinate interferes with the machinery that senses oxygen. The cell behaves as though it were starved of oxygen even when it is not, and it grows and recruits new blood vessels.

This is the same final pathway that goes wrong in von Hippel-Lindau syndrome, by a different route, which is why the two conditions share pheochromocytoma as a feature.

The SDHx genes are tumor suppressor genes. A carrier is born with one working copy and one that does not work; if the working copy is lost in a susceptible cell, that cell loses the enzyme entirely. Because the whole enzyme collapses when any subunit is missing, a change in any of these genes produces the same detectable result in the tumor, which underlies the SDHB stain described below.

Tumors associated with SDH gene changes.

Paraganglioma of the head and neck

These arise along nerves in the neck and at the base of the skull, most often at the carotid artery in the neck, and are the characteristic tumor of SDHD and SDHC. They grow slowly, rarely spread, and usually do not release hormones. Problems come from local growth: a painless neck lump, hoarseness, difficulty swallowing, hearing loss, ringing in the ears, or dizziness. They are frequently multiple, particularly in SDHD carriers, where more than one tumor is present in the majority of cases.

Paraganglioma of the abdomen, chest, and pelvis

These arise along the chain of nerve structures running beside the spine, and are the characteristic tumor of SDHB. Unlike head and neck tumors, they commonly release hormones, and they carry a higher risk of spreading.

Pheochromocytoma

This is the same tumor type, but it arises in the adrenal gland. It nearly always releases hormones, causing episodes of high blood pressure, pounding headache, heavy sweating, palpitations, anxiety, and tremor, often coming in waves. Because the hormone surges can be dangerous during surgery or in pregnancy, an undiagnosed pheochromocytoma is a genuine risk in its own right, quite separate from any risk of spreading.

Kidney cancer

Succinate dehydrogenase deficient renal cell carcinoma is an uncommon kidney cancer that occurs almost exclusively in people carrying an SDHx change, most often SDHB. It affects roughly 5% to 14% of carriers and tends to occur younger than sporadic kidney cancer. Its appearance on a pathology report is itself a reason for genetic testing.

Gastrointestinal stromal tumor

SDH-deficient gastrointestinal stromal tumor is a distinct form of GIST that develops in the stomach, occurs in younger people, is often multiple, and behaves differently from ordinary GIST. It does not respond to imatinib the way ordinary GIST does. Most cases are linked to SDHA, and an SDH-deficient GIST prompts genetic testing regardless of family history.

Pituitary tumors

Uncommon, but pituitary tumors occur at slightly increased frequency and are recognized as part of the spectrum.

How lifetime risk is estimated and why the numbers vary

Risk in this condition is not one number. It differs so much between the genes that a figure quoted for “SDH carriers” describes nobody in particular.

As in every hereditary syndrome, the earliest estimates came from families identified because several members had tumors, and those figures were high. As testing widened and relatives without symptoms were tested, the estimates fell substantially. Studies that exclude the first person diagnosed in each family give the most realistic picture for someone found through family testing.

Using those figures, by around age 60 to 70:

SDHB — Roughly 25% to 50% develop a tumor. Tumors are typically in the abdomen, often release hormones, and carry a 25% to 30% risk of spreading, far higher than any other gene in this group. This gene drives most of the concern in this condition.
SDHD — Roughly 43% to 79% develop a tumor, the highest penetrance of the group. Still, tumors are usually in the head and neck, are frequently multiple, and carry a risk of spreading of under 5%. High chance of a tumor, low chance of a dangerous one.
SDHC — Lower penetrance, usually head and neck tumors, low risk of spreading.
SDHA — Penetrance appears very low, with estimates ranging from under 2% to about 10%. This gene is now found frequently on broad panels in people with no relevant history, and the finding often causes more alarm than the evidence supports.

Two points follow. First, a high chance of developing a tumor and a high chance of a dangerous tumor are different things, and the two most common genes sit at opposite corners: SDHD carriers are more likely to develop a tumor but far less likely to have one that spreads, while SDHB carriers face the reverse. Second, penetrance figures rise with imaging intensity, because scans find small tumors that would never have been counted before. Some of the apparent increase in risk over the years reflects better scanners rather than more disease.

Who should be tested?

Genetic testing is offered when:

A paraganglioma or pheochromocytoma is diagnosed at any age. Roughly 30% to 40% of these tumors are hereditary, one of the highest proportions of any tumor type, so testing is recommended for everyone diagnosed regardless of family history or age.
More than one such tumor is present, or a tumor occurs in childhood, or a tumor has spread.
An SDH-deficient gastrointestinal stromal tumor or SDH-deficient renal cell carcinoma is diagnosed.
A relative carries a known SDHx change.

Testing typically covers all SDHx genes, along with other genes that cause these tumors, including VHL, RET, NF1, MAX, TMEM127, and FH. Several distinct inherited conditions cause pheochromocytoma, and a panel can distinguish between them.

How the test is performed

Germline testing uses a blood or saliva sample to examine the DNA a person was born with, using next-generation sequencing along with a method that detects large deletions.

A useful preliminary step is available when a tumor has been removed. Because the whole succinate dehydrogenase enzyme collapses when any subunit is missing, an immunohistochemistry stain for the SDHB protein is lost in tumors caused by a change in any of the SDHx genes. Loss of SDHB staining therefore points strongly toward this group of conditions and tells the laboratory where to look, while retained staining makes an SDHx cause unlikely. This stain is performed on the tumor and does not replace germline testing, which is what establishes whether the change is inherited.

How results are reported

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to stop the gene working. This confirms the syndrome, and the report should name which gene.
Variant of uncertain significance — A change was found, but its effect is unknown. This is not a positive result. It is managed as though negative, with monitoring guided by personal and family history, and it is never a basis for preventive surgery or for starting lifelong imaging. Variants of uncertain significance are especially common in SDHB and SDHA, because both are frequently included on broad panels and many changes in them have not been characterized. Our article on variants of uncertain significance explains this result in detail.
Benign or likely benign variant — A harmless difference, usually not reported.
No variant identified — No change was found in the genes tested.

What the result means

A pathogenic or likely pathogenic variant confirms the syndrome. The gene determines where tumors are likely to appear, how closely they need monitoring, and the risk of spreading.

A negative result means two different things:

True negative — A specific change is already known in your family, and you tested negative for that exact change. You did not inherit it, you do not need surveillance, and your children cannot inherit it from you.
Uninformative negative — No change has been identified in anyone in the family. Because a substantial proportion of these tumors are hereditary and not all the responsible genes are known, a negative result in someone with a paraganglioma at a young age or with several tumors does not close the question, and surveillance may still be offered.

Germline versus somatic SDH changes

A germline change is present in the DNA a person was born with, exists in every cell, and can be passed to children. That is the syndrome.

A somatic change arises within a tumor during life, exists only in the tumor cells, and cannot be inherited.

Somatic SDHx changes do occur but are uncommon. The practical situation is the reverse of most genes in this section. When a paraganglioma or pheochromocytoma shows loss of SDHB staining, the change is usually inherited rather than confined to the tumor. That is why the stain leads directly to germline testing rather than being treated as a tumor finding on its own.

Inheritance from one parent only

SDHD and SDHAF2 behave in a way seen almost nowhere else in hereditary cancer, and it causes genuine confusion in families.

These genes are subject to imprinting, meaning the copy inherited from the mother is normally switched off in the tissues where these tumors form. A person who inherits the change from their father has only the father’s copy active, and loses it if that copy is damaged, so they are at risk. A person who inherits the identical change from their mother is very unlikely to develop tumors, because the copy at risk was already silent.

Three consequences follow:

A woman carrying an SDHD change is unlikely to develop tumors herself if she inherited it from her mother. However, each of her children still has a 50% chance of inheriting it, and her sons and daughters who receive it will pass it on with the risk switched on.
The condition can appear to skip generations entirely, which has historically led families to conclude that it had died out wrongly.
Surveillance recommendations for a carrier depend on which parent the change came from, so establishing that is part of the genetics assessment.

The other SDHx genes, including SDHB, do not behave this way and are inherited in the ordinary autosomal dominant pattern from either parent.

Surveillance and management

Surveillance in this condition is lifelong and combines blood or urine testing with whole-body imaging. Its purpose differs from most cancer screening: it is looking for tumors that are usually benign but that cause harm through hormone release or local growth, and, in the case of SDHB, for the minority that spread.

What surveillance involves

Blood or urine testing for the hormones these tumors release — Annually in adults, measuring substances called metanephrines. This detects hormone-producing tumors, though head and neck paragangliomas often produce nothing and are missed by it.
Whole-body MRI from the skull base to the pelvis — Every two to three years, and this is the part that finds the tumors blood tests cannot. MRI is used rather than CT because carriers are scanned repeatedly across a lifetime.
When to start — Around age 6 to 10 for SDHB carriers, where tumors occur earliest and carry the greatest risk, and around age 10 to 15 for SDHA, SDHC, and SDHD. Biochemical testing is generally done every two years through childhood and annually in adulthood.

Surveillance is a genuine burden sustained from childhood, and scans routinely find small findings that need follow-up and turn out to be nothing. Balanced against that, tumors found before they cause symptoms are considerably easier to treat, and for SDHB carriers early detection is the main defense against a tumor that has already spread.

Treatment

Surgery is the main treatment. For pheochromocytoma, this means removing the adrenal gland, with the surgeon aiming to preserve part of it where possible, since these tumors can affect both sides and losing both glands means lifelong steroid replacement. Before any operation on a hormone-producing tumor, medication is given for one to two weeks to block the hormone effects and prevent a dangerous rise in blood pressure during surgery. This preparation is essential and one reason these operations are done in experienced centers.

Head and neck paragangliomas sit close to nerves that control the voice, swallowing, and shoulder movement, so removing them carries a real risk of permanent damage. Because they grow slowly and rarely spread, monitoring is often the better option, particularly in older people or when the tumor is in a difficult position. Focused radiation is an alternative for tumors that are growing but difficult to remove.

Where a tumor has spread, treatment options include a targeted radioactive medication that seeks out these tumors, targeted drugs, and chemotherapy. Clinical trials are active in this area, and your team can tell you whether any are open to you.

Testing family members

Apart from SDHD and SDHAF2, these genes are inherited in an autosomal dominant pattern. Each child, sibling, and parent of a carrier has a 50% chance of carrying the same change. For SDHD and SDHAF2, the inheritance is the same, but whether the tumor risk is switched on depends on which parent the change came from, as described above.

Once a specific change is identified, relatives are tested for that exact change through cascade testing.

Children are tested in childhood rather than adulthood because surveillance begins early. For SDHB families, imaging and blood testing start between ages 6 and 10, so testing is generally offered in the preschool or early school years. A child who tests negative is spared all of it. For the other genes, testing is usually offered a few years later, matching the later start of surveillance.

Carriers planning a family sometimes ask whether they can avoid the change in their children. Preimplantation genetic testing, in which embryos created through IVF are tested before transfer, and prenatal testing are available in many places. A genetics service and a fertility specialist can work through these options together.

What happens next

For someone newly diagnosed with a paraganglioma or pheochromocytoma, genetic testing is arranged promptly, because the result determines how the rest of the body is watched and whether relatives need testing. Where the tumor produces hormones, medical preparation before surgery comes first.

For a carrier identified through family testing, the work is establishing a surveillance schedule appropriate to the gene and the age at which it starts, and arranging cascade testing for relatives.

Endocrinology usually coordinates care with surgery, radiology, and genetics. These tumors are uncommon enough that experience matters, particularly for the hormonal preparation before surgery and for head and neck operations, and referral to a center that manages them regularly is preferred.

Living with this diagnosis means decades of scans, often starting in childhood, frequently while carrying tumors that are being watched rather than removed. Experienced centers include psychological support, and patient organizations for paraganglioma and pheochromocytoma connect families facing the same long horizon.

Questions to ask your doctor

Which SDHx gene is involved, and what does that mean for where tumors are likely to appear?
Given my gene, what is my estimated risk of developing a tumor, and of a tumor that spreads?
If my change is in SDHD, did I inherit it from my father or my mother, and how does that affect my risk?
Did my tumor show loss of SDHB staining?
What surveillance do I need, and at what age does it start?
Will my imaging use MRI rather than CT, given how many scans I will have?
Do any of my tumors produce hormones, and have my levels been checked?
If I need surgery, will I have medication beforehand to block the hormone effects?
Is watching a tumor a reasonable option in my case rather than removing it?
Should I be seen at a center that manages these tumors regularly?
Which of my relatives should be tested, and at what age should my children be tested?
What reproductive options are available if I want to avoid passing this on?
Is psychological support or a patient organization available to my family?