Home Cancer Genetics and Molecular Tumor Testing SDHB Genetic Test: Paraganglioma, Pheochromocytoma, and Cancer Risk

SDHB Genetic Test: Paraganglioma, Pheochromocytoma, and Cancer Risk

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Understand what an SDHB genetic test shows, how results affect paraganglioma and pheochromocytoma surveillance, metastatic risk, and testing for relatives.

An SDHB genetic test looks for an inherited pathogenic variant in a gene that helps mitochondria process energy and restrain abnormal cell growth. A positive germline result confirms susceptibility to hereditary paraganglioma-pheochromocytoma syndrome. Carriers can develop paragangliomas outside the adrenal glands, adrenal pheochromocytomas, and, less often, other tumors such as renal cell carcinoma or gastrointestinal stromal tumor. SDHB-associated paragangliomas are clinically important because they have a higher average risk of metastatic behavior than tumors linked to several other susceptibility genes.

Testing usually uses blood or saliva and should include sequencing plus deletion-duplication analysis. Tumor studies, including loss of SDHB protein by immunohistochemistry, can support suspicion but do not replace germline confirmation. A positive result does not prove that a tumor is present or predict exactly when one will develop. It does support lifelong clinical, biochemical, and imaging surveillance, careful evaluation of symptoms, and targeted testing for relatives. Negative and uncertain results require interpretation in light of the tumor’s location, biochemical pattern, pathology, and family history.

  • A pathogenic SDHB variant raises the risk of paraganglioma and pheochromocytoma and warrants lifelong surveillance.
  • SDHB-associated tumors have a higher average metastatic risk, but no genetic result can label an individual tumor benign or malignant in advance.
  • A negative blood test does not exclude another hereditary PPGL gene or low-level mosaicism.
  • A variant of uncertain significance should not be used alone to diagnose the syndrome or test healthy relatives.
  • Plasma or urine metanephrines and periodic MRI are commonly used to screen carriers who have no symptoms.

Table of Contents

What SDHB Does

SDHB encodes one subunit of succinate dehydrogenase, an enzyme complex that participates in both the mitochondrial energy pathway and the electron transport chain. When the complex loses function, succinate accumulates. Excess succinate interferes with enzymes that normally help cells respond to oxygen and regulate gene activity. The resulting “pseudohypoxia” and epigenetic changes can promote tumor formation.

A person with an inherited SDHB pathogenic variant usually has one altered copy in every cell. Tumor development generally requires loss or inactivation of the remaining working copy in a susceptible cell. This two-hit process explains why the genetic variant creates risk rather than causing a tumor in every carrier.

SDHB belongs to the SDHx group, which includes SDHA, SDHB, SDHC, SDHD, and the assembly-factor gene SDHAF2. These genes overlap in the tumors they predispose to, but their typical locations, penetrance, and metastatic risk differ. SDHB is particularly associated with sympathetic paragangliomas in the abdomen, pelvis, or chest, although head and neck paragangliomas and adrenal pheochromocytomas can also occur.

A pheochromocytoma arises from adrenal medulla chromaffin cells. A paraganglioma arises from related cells outside the adrenal gland. Sympathetic paragangliomas often produce catecholamines. Parasympathetic head and neck tumors are frequently nonsecretory and instead cause symptoms from pressure on nerves and blood vessels.

The term metastatic is used when tumor is found in a site where normal paraganglial tissue does not occur, such as bone, liver, lung, or distant lymph nodes. Pathology under the microscope cannot always determine future behavior. An SDHB result is one risk factor among tumor size, location, biochemical profile, imaging, and clinical course; it is not a verdict that metastasis will occur.

Most disease-causing SDHB variants are germline and follow autosomal dominant inheritance. A tumor can also acquire somatic changes in SDH-related pathways. A finding on tumor-only genetic testing may therefore need confirmation in blood or another normal sample before it is treated as inherited.

Who May Need SDHB Testing

Genetic testing is recommended broadly for people with pheochromocytoma or paraganglioma because a substantial proportion have an identifiable hereditary cause, even without a strong family history. A multigene panel is often more efficient than testing SDHB alone because several genes produce overlapping presentations. Single-gene or targeted testing is most useful when a familial SDHB variant is already known or when tumor findings strongly point to the SDH complex.

Features that increase suspicion for an SDHB-related syndrome include:

  • A sympathetic paraganglioma in the abdomen, pelvis, or thorax.
  • Metastatic pheochromocytoma or paraganglioma.
  • A tumor diagnosed at a young age.
  • Multiple, bilateral, recurrent, or extra-adrenal tumors.
  • A family history of paraganglioma, pheochromocytoma, renal cancer, or SDH-deficient gastrointestinal stromal tumor.
  • Loss of SDHB staining in tumor cells on immunohistochemistry.
  • A tumor biochemical pattern that includes dopamine or its metabolite 3-methoxytyramine.
  • An SDH-deficient renal tumor or gastrointestinal stromal tumor without another explanation.

Loss of SDHB protein staining is a useful screening clue because dysfunction in several SDHx genes can destabilize the SDH complex. It does not identify which gene is altered and can occasionally be technically difficult to interpret. Abnormal immunostaining should lead to germline and, when needed, tumor molecular evaluation rather than a conclusion that SDHB is definitely the cause.

Testing is also offered to healthy relatives after a pathogenic familial variant is established. This is predictive testing: the person may have no tumor but can learn whether syndrome-specific surveillance is needed. Testing minors can be appropriate because surveillance begins in childhood or adolescence under many specialist protocols.

A person with metastatic disease may have both germline and tumor testing. Germline testing addresses inherited risk and family implications. Tumor profiling may identify somatic alterations, confirm SDH deficiency, or help with clinical-trial planning. These tests answer different questions and should not be substituted for one another.

Before testing, collect pathology reports, operative notes, tumor locations, biochemical results, and the exact laboratory report from any affected relative. A family history should include head and neck masses, adrenal tumors, unexplained hypertension episodes, kidney cancer, and GIST, not only cancers commonly listed on standard pedigrees.

How the Test Is Performed

Germline testing typically uses DNA from blood or saliva. No fasting is needed for the genetic sample, and medications do not change the DNA sequence. The laboratory should perform sequence analysis and deletion-duplication analysis because disease-causing changes can include single-letter substitutions, small insertions or deletions, splice variants, or larger missing segments.

A hereditary PPGL panel may include SDHB alongside SDHA, SDHC, SDHD, SDHAF2, VHL, RET, NF1, MAX, TMEM127, FH, and other validated genes. The panel’s exact content varies. A broader genetic panel test increases the chance of finding the cause but also increases the chance of an uncertain result.

The usual workflow is:

  1. Pretest counseling and consent. The clinician reviews possible positive, negative, uncertain, and incidental findings and discusses insurance and family implications.
  2. Sample collection. Blood is commonly preferred; saliva may be convenient but can require recollection if DNA quality is poor.
  3. Laboratory analysis. The assay reads SDHB and evaluates copy number using validated methods.
  4. Variant classification. The laboratory weighs population frequency, functional evidence, case data, segregation, computational evidence, and expert rules.
  5. Post-test interpretation. A genetics professional connects the result with the phenotype and creates a surveillance or family-testing plan.

Turnaround often ranges from two to six weeks, although urgent testing, insurance authorization, or complex follow-up studies can change that. Targeted testing for a known familial variant may be faster.

When blood testing is negative but the presentation is strongly suggestive, options can include review of assay coverage, a broader panel, deletion analysis if not already done, tumor sequencing, or testing another tissue for mosaicism. RNA studies can clarify some suspected splice variants. Repeating the same limited test without identifying its gap is less useful than selecting a method that addresses the unresolved possibility.

Tumor tissue may undergo SDHB and SDHA immunohistochemistry. Loss of SDHB with retained SDHA suggests dysfunction in SDHB, SDHC, SDHD, or another component affecting the complex. Loss of both SDHB and SDHA points more specifically toward SDHA deficiency. These patterns guide testing but do not replace the germline laboratory report.

Understanding SDHB Results

Clinical laboratories generally classify variants as pathogenic, likely pathogenic, uncertain significance, likely benign, or benign. The category describes evidence about the DNA change, not whether the person currently has cancer or how aggressive a known tumor will be.

Pathogenic or likely pathogenic

A positive germline result confirms SDHB-related hereditary paraganglioma-pheochromocytoma susceptibility. The person should receive a baseline evaluation and a long-term surveillance plan. If a tumor is already present, the result informs the extent of imaging, duration of follow-up, and assessment of relatives. It may also influence eligibility for research studies or genotype-focused trials.

“Likely pathogenic” generally means the evidence is strong enough for clinical management in the same way as pathogenic. The report should identify the exact variant using standard DNA and protein notation. Keep the original report because relatives need that exact change for focused testing.

A positive result does not establish the location or presence of a tumor. It also does not provide a reliable personal percentage for metastatic progression. Penetrance estimates come from groups and vary with study design, age, ascertainment, and surveillance intensity.

Negative

A negative result has different meanings depending on context. If the test was targeted to a known familial variant and that variant is absent, the person usually has not inherited the family’s SDHB risk and does not need SDHB-specific surveillance. This is a true negative.

If an affected person has negative full-gene or panel testing without a known family variant, the cause remains unexplained. The tumor may be sporadic, caused by another gene, due to a variant the assay cannot detect, or associated with mosaicism. Clinical follow-up may still be needed based on the tumor itself.

Variant of uncertain significance

A VUS means evidence is insufficient to call the variant disease-causing or harmless. It should not be used alone to diagnose the syndrome, intensify surgery, or test healthy relatives as though it were a known familial mutation. Management should rest on the person’s tumor history and established clinical guidance.

Uncertain variants may be reclassified. The laboratory may request family studies or tumor evidence, but such studies should be coordinated by genetics professionals. Patients should keep contact information current and periodically ask whether reinterpretation is available. General principles for VUS results are particularly important because SDHB missense variants can require detailed functional and case evidence.

Low-level or mosaic finding

A low variant allele fraction may reflect constitutional mosaicism, a technical artifact, sample contamination, or a blood-cell clone. Confirmation with a second specimen and laboratory consultation is necessary. Risk to other organs and to children depends on when the variant arose and whether reproductive cells carry it.

Tumor Risks and Symptoms

SDHB carriers have an increased risk of paraganglioma and pheochromocytoma, but many carriers never develop a recognized tumor. Published penetrance estimates vary substantially because older family studies often overrepresented affected people. Risk rises with age, yet first tumors can occur in childhood through late adulthood.

SDHB-associated tumors can occur from the skull base to the pelvis. Sympathetic tumors in the abdomen or pelvis are common and may secrete norepinephrine, normetanephrine, or dopamine-related metabolites. Head and neck paragangliomas often do not produce large catecholamine elevations and may present with a painless neck mass, pulsatile tinnitus, hearing change, hoarseness, swallowing difficulty, or cranial-nerve symptoms.

Catecholamine excess can cause:

  • Episodic or sustained high blood pressure.
  • Pounding headache, sweating, and palpitations.
  • Tremor, pallor, panic-like episodes, or chest discomfort.
  • Unexplained weight loss or high blood glucose.
  • Symptoms triggered by anesthesia, surgery, certain medications, exertion, or tumor pressure.

These symptoms are nonspecific and many people with them do not have PPGL. They deserve prompt evaluation in a known carrier because an untreated secretory tumor can cause arrhythmia, stroke, heart failure, or a hypertensive crisis. Severe headache with very high blood pressure, chest pain, fainting, new neurologic symptoms, or breathing difficulty requires urgent care.

SDHB is associated with a higher average probability of metastatic PPGL than several other susceptibility genes. Risk is influenced by primary tumor size, extra-adrenal location, biochemical phenotype, and disease duration. Metastases may appear years after removal of the primary tumor, which is why follow-up is long term even after apparently complete surgery.

Other reported SDHB-related tumors include renal cell carcinoma and SDH-deficient gastrointestinal stromal tumor. The absolute risks are lower than for PPGL, and surveillance protocols differ on how explicitly to screen for them. Periodic abdominal imaging used for PPGL surveillance can also visualize the kidneys. New blood in the urine, persistent flank pain, gastrointestinal bleeding, anemia, early satiety, or an abdominal mass should be evaluated rather than waiting for routine screening.

Pituitary tumors have been reported in SDHx families, but the strength of association and screening approach are less certain. Routine care should prioritize tumors supported by stronger evidence and investigate endocrine symptoms on their own merits.

Screening and Surveillance

Surveillance aims to find tumors before catecholamine complications, nerve damage, or metastatic spread. Protocols differ slightly across expert groups, but they generally combine clinical review, biochemical testing, and MRI from the skull base through the pelvis. The starting age is gene-specific and may be adjusted for the youngest diagnosis in the family.

A baseline evaluation for an asymptomatic carrier commonly includes:

  • A review of blood pressure, headaches, palpitations, sweating, neck symptoms, hearing changes, and prior anesthesia reactions.
  • Blood pressure measurement and physical examination.
  • Plasma free metanephrines or 24-hour urinary fractionated metanephrines; some centers add 3-methoxytyramine when available.
  • MRI of the head and neck, chest, abdomen, and pelvis using a protocol designed for PPGL surveillance.
  • Additional functional imaging when biochemical or anatomic findings are suspicious or when metastatic disease must be staged.

After a normal baseline, many consensus protocols use annual clinical review, periodic metanephrine testing, and MRI approximately every two to three years. Children may have biochemical tests less frequently under some guidance, and imaging intervals can be individualized. MRI is favored for repeated surveillance because it avoids cumulative ionizing radiation. CT remains useful for selected lesions, emergencies, surgical planning, or when MRI is unsuitable.

Biochemical preparation affects accuracy. The ordering team may advise resting before plasma collection and review caffeine, nicotine, exercise, stress, illness, and medications that can cause false-positive results. Mild elevations often require repeat testing under controlled conditions. Results several times above the upper reference limit are more concerning, but interpretation depends on the specific analyte and clinical context.

A biochemical-negative tumor is still possible, particularly in the head and neck or with small lesions. Imaging therefore remains part of surveillance. Conversely, an abnormal laboratory result should usually be confirmed and localized before treatment. Imaging should follow biochemical evidence unless symptoms or an incidental mass require immediate evaluation.

Pregnancy, surgery, and anesthesia require special planning. A known carrier should inform obstetric and surgical teams. Symptoms or biochemical evidence of PPGL should be evaluated before elective procedures because catecholamine release can create severe hemodynamic instability. Confirmed secretory tumors usually require expert preoperative alpha-adrenergic blockade, volume management, and an experienced multidisciplinary team.

Surveillance should continue after tumor removal. Follow-up includes postoperative biochemistry, periodic imaging, and assessment for recurrence or metastasis. The schedule is more intensive when a tumor was large, metastatic, biochemically active, incompletely resected, or associated with concerning features.

Family Testing and Inheritance

SDHB-related susceptibility is autosomal dominant. Each child of a carrier has a 50% chance of inheriting the variant, regardless of sex. Unlike SDHD, SDHB generally does not show a clinically important parent-of-origin effect. A variant inherited from either the mother or father can confer risk.

After a positive result, first-degree relatives are usually offered a focused familial variant test. Testing can then extend through the side of the family shown to carry the variant. A negative result for the known familial variant generally ends the need for SDHB-specific surveillance, although ordinary medical care and any separate personal risk still apply.

Testing children is considered because surveillance may start before adulthood. The timing should be discussed with a pediatric genetics or endocrine team. Age-appropriate education can help the child understand that the result signals a screening need, not a diagnosis of cancer.

If neither parent of an affected person carries the variant in blood, the change may be de novo. The chance for siblings is then usually low but not zero because a parent could have gonadal mosaicism. The affected person still has a 50% chance of transmitting the variant to each child.

Reproductive options include natural conception, prenatal diagnosis, and in vitro fertilization with preimplantation genetic testing for monogenic disease. Prenatal testing can determine whether the familial variant is present but cannot predict whether or when a tumor will develop. Nondirective counseling helps families weigh medical uncertainty, values, cost, and access.

Family letters should name the gene and exact variant, explain autosomal dominant inheritance, and state that surveillance can begin before symptoms. Vague wording such as “adrenal cancer gene” may cause relatives or clinicians to overlook head and neck and extra-adrenal tumors.

Limitations and Next Steps

Genetic testing cannot detect every disease mechanism. Deep intronic changes, complex rearrangements, promoter abnormalities, low-level mosaicism, and variants in genes not included on the panel may be missed. Laboratories also differ in coverage and classification. An unexplained SDH-deficient tumor deserves review by a genetics team even when an initial panel is negative.

Risk estimates are imperfect. Studies include different age groups, referral patterns, and definitions of metastatic disease. The same variant can produce different outcomes within a family. Surveillance recommendations should therefore follow current expert guidance rather than a single percentage found in an older paper.

A practical plan after a pathogenic result is:

  1. Confirm that the finding is germline and obtain the complete report.
  2. Meet with genetics and an endocrine or PPGL specialty team.
  3. Complete baseline metanephrine testing and recommended imaging.
  4. Create a written schedule for annual review and periodic MRI.
  5. Record symptoms that require prompt testing between scheduled visits.
  6. Alert clinicians before surgery, anesthesia, or pregnancy.
  7. Offer targeted testing to relatives and arrange pediatric care when needed.
  8. Keep tumor pathology, imaging, biochemical trends, and genetic results together.

When a tumor is found, care may involve endocrinology, surgical oncology, head and neck surgery, radiology, nuclear medicine, medical oncology, cardiology, genetics, and anesthesia. Treatment can include surgery, observation for selected head and neck tumors, radionuclide therapy, radiation, systemic therapy, or clinical trials. The genetic result helps frame risk, but treatment is determined by tumor location, secretion, spread, growth rate, and patient priorities.

Long-term coordination prevents two opposite errors: excessive repeated testing without a clear protocol and gaps in surveillance after care moves between specialists. One clinician or hereditary tumor program should maintain the overall schedule and update it as guidance and personal history change.

References

Disclaimer

An SDHB result should be interpreted by genetics and PPGL specialists using the exact variant, laboratory method, personal history, and current surveillance guidance. This article does not replace individualized medical care; severe blood-pressure symptoms, chest pain, fainting, or new neurologic symptoms require urgent assessment.

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