Home Cancer Genetics and Molecular Tumor Testing FH Genetic Test: Hereditary Leiomyomatosis, Renal Cell Cancer, and Results

FH Genetic Test: Hereditary Leiomyomatosis, Renal Cell Cancer, and Results

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Understand FH genetic testing for hereditary leiomyomatosis and renal cell cancer, including who should test, result meanings, kidney surveillance, and family risk.

An FH genetic test looks for an inherited pathogenic variant in the fumarate hydratase gene. A disease-causing variant can establish FH tumor predisposition syndrome, historically called hereditary leiomyomatosis and renal cell cancer, or HLRCC. The condition can cause painful skin leiomyomas, early and numerous uterine fibroids, and a risk of an aggressive form of renal cell carcinoma. Testing may begin with blood or saliva because the clinically important inherited change is present throughout the body. Tumor testing, including loss of FH protein or accumulation of 2-succinocysteine, may first raise suspicion but does not by itself prove that the change is inherited. A positive germline result changes kidney surveillance and allows targeted testing for relatives. A negative result may be reassuring only when the test includes both sequence analysis and deletion or duplication analysis and when the family’s causal variant is known. Results should be reviewed with genetics and kidney-cancer specialists familiar with this uncommon syndrome.

  • A pathogenic or likely pathogenic germline FH variant confirms FH tumor predisposition syndrome and supports lifelong renal surveillance.
  • The condition is autosomal dominant, so each child of an affected person has a 50% chance of inheriting the family variant.
  • Renal tumors can spread while still small, so the usual “watch until 3 cm” approach used for some hereditary kidney cancers does not apply.
  • Annual thin-slice renal MRI is generally preferred, often beginning in childhood; ultrasound should not replace MRI for primary surveillance.
  • An FH-deficient uterine fibroid or kidney tumor may be sporadic, so tumor findings usually require confirmation in a non-tumor sample.

Table of Contents

The FH gene and tumor predisposition syndrome

FH provides instructions for fumarate hydratase, also called fumarase, an enzyme in the tricarboxylic acid cycle. This pathway helps cells convert nutrients into energy. The enzyme changes fumarate into malate. When both copies of FH are inactive in a tumor cell, fumarate accumulates and alters multiple cellular processes, including oxygen-sensing pathways, DNA and protein regulation, and antioxidant responses. FH therefore acts as a tumor-suppressor gene.

People with FH tumor predisposition syndrome inherit one nonworking FH copy. A cell can become tumor-forming after the remaining working copy is lost or inactivated. This “two-hit” mechanism explains why the inherited variant is found in every cell while tumors show more complete FH loss.

The syndrome has three classic manifestations:

  • Cutaneous leiomyomas. These are benign smooth-muscle growths in the skin. They often appear as firm, skin-colored, reddish, or brown papules or nodules on the trunk or limbs. They may be tender or sharply painful with touch, pressure, cold, or emotional stress. They often begin in the second to fourth decades and increase over time.
  • Uterine leiomyomas. Fibroids often develop younger than in the general population and may be numerous, large, or symptomatic. Heavy menstrual bleeding, pelvic pressure, pain, anemia, infertility, and pregnancy complications can occur. Some affected people need myomectomy or hysterectomy at an unusually young age.
  • FH-deficient renal cell carcinoma. The lifetime risk is lower than the chance of skin or uterine leiomyomas, with many current estimates around 10% to 15%. The kidney cancer is clinically important because it can metastasize early, even when the primary mass is small.

Not every carrier develops every feature. One person may have only skin lesions, another may first present with fibroids, and another may develop kidney cancer without an obvious family history. The syndrome can be underrecognized because fibroids are common and skin nodules may be mistaken for other benign lesions.

A small subset of specific FH variants has also been associated with pheochromocytoma or paraganglioma. This is not a universal risk for all FH carriers. Surveillance for these neuroendocrine tumors is usually considered only when the family variant or history supports that association.

FH tumor predisposition syndrome differs from autosomal recessive fumarase deficiency, a severe metabolic and neurologic disorder. Fumarase deficiency occurs when a child inherits pathogenic variants in both FH copies. Most people with the cancer-predisposition syndrome have one heterozygous variant and do not have the childhood metabolic condition.

Who should consider FH genetic testing

Testing is appropriate when personal, family, or tumor findings suggest FH loss. Because no single feature is present in every carrier, clinicians look for combinations, unusually early presentation, and characteristic pathology.

Reasons to consider germline testing include:

  • one or more painful cutaneous leiomyomas, especially multiple or segmental lesions;
  • numerous, large, or symptomatic uterine fibroids at a young age;
  • hysterectomy or repeated myomectomy substantially earlier than expected;
  • renal cell carcinoma with FH-deficient morphology or immunostaining;
  • kidney cancer at a young age, particularly with skin or uterine leiomyomas;
  • a relative with a pathogenic FH variant;
  • a family pattern of renal cancer, painful skin nodules, and early fibroids;
  • a uterine leiomyoma showing loss of FH protein or positive 2-succinocysteine staining; or
  • a tumor-sequencing result showing a suspicious FH alteration.

Pathologists can identify clues in kidney and uterine tumors. FH-deficient renal cell carcinoma has a broad range of microscopic patterns and is now considered a molecularly defined renal tumor rather than simply “type 2 papillary” cancer. Loss of FH staining and strong diffuse 2-succinocysteine staining support functional FH deficiency. The stains are useful screening tools, but neither determines whether the cause is germline or confined to the tumor.

FH-deficient uterine leiomyomas are uncommon. Many result from two somatic changes limited to the fibroid and are not inherited. Germline testing becomes more important when the person is young, has multiple or atypical fibroids, has cutaneous leiomyomas, has renal findings, or has a suggestive family history. A pathology report that recommends genetics evaluation should not be ignored even when the fibroid was benign.

Kidney cancer genetic evaluation is especially important because management differs from other hereditary renal syndromes. A person with an early-onset, bilateral, multifocal, unusual, or FH-deficient renal tumor may be offered a hereditary cancer gene panel rather than FH-only testing. A panel can assess other renal cancer genes such as VHL, FLCN, MET, BAP1, SDHB, and TSC1 or TSC2 when the diagnosis is uncertain.

Absence of family history does not rule out the syndrome. The variant may be new in the affected person, relatives may be young, the family may be small, or prior cancers may have been misclassified. Some relatives may carry the variant but show few features.

Before testing, genetic counseling should cover possible results, insurance and privacy considerations, family implications, surveillance, and the difference between tumor and germline testing. A detailed three-generation history should include kidney tumors, fibroids and gynecologic procedures, skin lesions, pheochromocytoma or paraganglioma, ages at diagnosis, and pathology when available.

How FH testing is performed

Germline FH testing typically uses blood, saliva, or a cheek-swab sample. Blood is often preferred when prior bone marrow transplant, active blood cancer, or other factors could complicate interpretation. The laboratory analyzes DNA from non-tumor cells to determine whether a variant is constitutional.

A complete single-gene evaluation generally includes two components:

  1. Sequence analysis detects single-letter changes and small insertions or deletions. It identifies about 90% of known pathogenic FH variants in affected families.
  2. Deletion and duplication analysis detects loss or gain of one or more exons or the entire gene. These structural changes account for roughly another 10% and may be missed by routine sequence analysis.

A negative sequence-only test is therefore incomplete if deletion or duplication analysis was not performed. Laboratories may use next-generation sequencing, Sanger sequencing, multiplex ligation-dependent probe amplification, read-depth analysis, or another validated method.

A multigene panel can be efficient when several hereditary kidney cancer syndromes are possible. It may also increase the chance of finding a variant of uncertain significance. Panel selection should reflect the person’s features rather than using the largest available test without a clear reason. The related FLCN test for Birt-Hogg-Dubé syndrome, for example, addresses a different pattern that includes lung cysts, spontaneous pneumothorax, fibrofolliculomas, and characteristic renal tumors.

Tumor testing serves a different purpose. A kidney tumor, uterine leiomyoma, or other lesion may undergo:

  • FH immunohistochemistry to evaluate protein expression;
  • 2-succinocysteine immunohistochemistry to detect protein succination caused by fumarate accumulation;
  • tumor DNA sequencing to identify one or two FH alterations;
  • copy-number or loss-of-heterozygosity analysis; or
  • methylation or broader molecular profiling in difficult cases.

A tumor with two FH hits may still be sporadic. Conversely, a tumor panel may detect one variant at an allele fraction that suggests possible germline origin. Confirmation requires a dedicated germline sample and a laboratory that is validated for inherited testing.

Testing a known family variant is simpler than testing an unaffected person with no identified familial cause. Once a pathogenic variant is established in one relative, others can have targeted testing for that exact change. A true negative in that setting usually means the person did not inherit the family syndrome and does not need FH-specific surveillance.

Turnaround time commonly ranges from two to several weeks. Results may take longer when the laboratory needs deletion analysis, RNA studies, family samples, or variant review. The ordering clinician should obtain the full report, including transcript, DNA and protein notation, classification, test limitations, and laboratory contact information.

Positive, negative, and uncertain results

A positive result means the laboratory found a pathogenic or likely pathogenic germline FH variant. This establishes a molecular diagnosis in the tested person. It supports renal surveillance, symptom-directed dermatologic and gynecologic care, and targeted testing for relatives.

“Likely pathogenic” generally means the evidence strongly supports disease causation, although absolute certainty is not possible. In clinical genetics, pathogenic and likely pathogenic variants are usually managed similarly. The report should identify the exact variant so relatives can be tested accurately.

A positive result does not predict whether or when a person will develop renal cancer. It also does not determine the number of skin lesions or severity of fibroids. Risk estimates come from groups and may be affected by how families were identified. Surveillance is recommended because kidney cancer can be aggressive and because individual risk cannot be predicted precisely.

A negative result has different meanings depending on context:

  • If the family’s pathogenic variant is known and the person tests negative for it, this is a true negative. Their FH-related risk generally returns to population risk, although unrelated personal medical issues still need care.
  • If no family variant is known, an uninformative negative does not fully exclude FH tumor predisposition syndrome. A causal change may be outside assay coverage, technically difficult to detect, or in another gene.
  • If only tumor testing was negative, hereditary testing may still be appropriate when clinical features are strong.
  • If only sequence analysis was performed, deletion or duplication testing may be needed.

A variant of uncertain significance, or VUS, is not a positive diagnosis. Evidence is insufficient to classify the change as disease-causing or benign. Medical management should be based on personal and family history, tumor pathology, and established risk—not on the VUS alone. Predictive testing of healthy relatives for a VUS is usually not useful unless a genetics team recommends a structured segregation study.

Variant classifications can change as laboratories collect population, functional, and family evidence. Patients should keep the laboratory report and update contact information with the ordering clinic. A periodic review may be reasonable, but reclassification is not guaranteed and laboratories differ in notification practices. A pathogenic, benign, and VUS result guide can help clarify the terminology.

Sometimes a result identifies a pathogenic FH variant associated with recessive fumarase deficiency but with uncertain or low penetrance for tumors. The genetics team should examine the specific variant, published cases, biochemical evidence, family history, and laboratory interpretation. Broad statements about “an FH mutation” can be misleading because variant effects are not always identical.

Cancer risk and recommended surveillance

Renal surveillance is the most urgent preventive component because FH-deficient renal cell carcinoma can grow and spread aggressively. Current expert guidance generally favors annual renal MRI with contrast and thin slices, often 1 to 3 mm through the kidneys. Pediatric recommendations commonly begin around age 10, though exact timing may be individualized by the specialist and family history.

MRI avoids ionizing radiation and offers better sensitivity than ultrasound for small renal lesions. Ultrasound may help characterize a cyst found on MRI, but it should not replace MRI as the primary surveillance test. Computed tomography can be used when MRI is not possible, with attention to cumulative radiation and contrast risks.

Surveillance should occur through a center experienced with hereditary renal cancer whenever possible. The imaging order should state the FH diagnosis so the protocol is optimized and small suspicious lesions receive prompt review. Comparing the current scan with prior images is important.

The management threshold differs from conditions such as von Hippel-Lindau syndrome, in which selected renal tumors may be observed until they approach a size threshold. A suspicious solid renal lesion in an FH carrier requires rapid assessment by an expert urologic oncology surgeon. Prompt surgery with a wide margin is generally favored rather than prolonged active surveillance, regardless of small size. The operation may be partial or radical nephrectomy depending on location, anatomy, and oncologic safety; lymph-node evaluation may also be considered.

Skin surveillance commonly includes an examination every one to two years from diagnosis, with earlier review for a changing, ulcerated, rapidly growing, or unusually painful lesion. Cutaneous leiomyomas are benign, but pain can be substantial. Treatment options include excision, laser or destructive procedures for selected lesions, and medicines aimed at neuropathic pain or smooth-muscle vasodilation. No single approach works for everyone.

People with a uterus should have gynecologic care based on symptoms and reproductive plans. There is no single imaging schedule that suits every carrier. Heavy bleeding, pelvic pain, rapid uterine enlargement, anemia, fertility concerns, or pregnancy planning warrant evaluation. Treatment may include medication, myomectomy, uterine-artery procedures in selected situations, or hysterectomy. Surgical decisions should consider future fertility and the possibility of multiple recurrent fibroids.

Pheochromocytoma and paraganglioma screening is not routinely applied to every FH carrier. It may include blood pressure assessment, plasma or urine metanephrines, and whole-body MRI for people with specific associated variants or family histories. Symptoms such as episodic severe headache, palpitations, sweating, or marked blood-pressure spikes require medical evaluation.

Routine health measures remain important. Avoiding tobacco, controlling blood pressure, maintaining kidney health, and reporting blood in the urine, unexplained flank pain, or an abdominal mass can support overall care, but these actions do not replace imaging surveillance.

Family testing and reproductive options

FH tumor predisposition syndrome follows autosomal dominant inheritance. A person with a germline pathogenic variant has a 50% chance of passing it to each child, regardless of sex. Siblings may also be at risk if a parent carries the variant. More distant relatives can be reached through the side of the family in which the variant arose.

Cascade testing should use the exact family variant. Testing at-risk children is recommended because surveillance begins before adulthood. This differs from adult-onset conditions for which childhood testing offers no medical benefit. A genetics team can help choose an age that allows results, counseling, and imaging to be coordinated without unnecessary delay.

When a child tests positive, care should include age-appropriate education, a renal imaging plan, and a transition strategy from pediatric to adult services. When a child tests negative for the known family variant, FH-specific screening is generally unnecessary.

A new, or de novo, variant can occur, so both parents may test negative. Even then, the affected person’s children remain at 50% risk. In some families, parental mosaicism can create a small residual recurrence risk, which a genetic counselor can explain.

Reproductive options include natural conception with prenatal diagnostic testing, in vitro fertilization with preimplantation genetic testing for monogenic disease, use of donor eggs or sperm, adoption, or choosing not to test during pregnancy. These are personal choices rather than required steps. Testing requires the laboratory to know the familial pathogenic variant and usually benefits from planning before pregnancy.

Because two pathogenic FH variants can cause severe fumarase deficiency, partner testing may be discussed when the partner has suggestive ancestry, a family history, or a known FH variant. The chance is generally low, but the consequences for a child can be serious. Carrier and reproductive counseling should distinguish the recessive metabolic disorder from the dominant tumor syndrome.

Sharing results with relatives can be difficult. Clinics may provide a family letter that states the gene, variant, inheritance pattern, and how to arrange testing without disclosing unnecessary medical detail. Privacy laws often limit a clinic’s ability to contact relatives directly, so the tested person usually plays a central role.

Next steps after an FH result

After a positive result, arrange care rather than waiting for symptoms. The initial plan usually includes a genetics visit, renal imaging if not current, referral to hereditary kidney-cancer expertise, skin review, and gynecologic evaluation when relevant. Confirm that the imaging protocol uses thin kidney slices and that a clinician is responsible for tracking annual studies.

Bring the following questions to the results appointment:

  1. Is the variant pathogenic or likely pathogenic, and is it associated with pheochromocytoma or paraganglioma risk?
  2. Did the test include deletion and duplication analysis?
  3. When should annual renal MRI begin or continue, and where should it be performed?
  4. Which urologic oncology team will review any renal lesion promptly?
  5. Do my skin or uterine findings need pathology review or treatment?
  6. Which relatives should receive targeted testing, including children?
  7. Should my partner be offered FH testing for reproductive reasons?
  8. How will the laboratory communicate a future reclassification?

After a negative or VUS result, ask whether the original clinical suspicion remains. Review whether testing was complete, whether tumor pathology should be re-examined, whether a broader multigene panel is appropriate, and whether surveillance should continue based on personal history. Do not stop an established renal screening plan solely because of an uninformative result without specialist review.

People who already have FH-deficient renal cancer need treatment from a multidisciplinary kidney-cancer team. Germline results can influence surgical urgency, surveillance of the remaining kidney, clinical-trial selection, and relatives’ care. Systemic therapy for advanced disease is chosen according to current renal cancer evidence and may include combinations designed around the biology of FH-deficient tumors; it is not determined by germline status alone.

Keep copies of the germline report, relevant tumor pathology, imaging, and operative notes. Record the exact variant in standard notation rather than relying on a handwritten gene name. Make sure primary care, dermatology, gynecology, urology, oncology, and genetics teams know who is coordinating surveillance.

Prompt review is warranted for blood in the urine, persistent flank or abdominal pain, a newly discovered renal mass, rapidly changing skin lesions, severe fibroid-related bleeding, or symptoms suggestive of catecholamine excess. Most day-to-day symptoms will not be cancer, but an established FH diagnosis lowers the threshold for focused assessment.

An FH test provides its greatest benefit when the result produces an organized lifelong plan. The plan should identify who orders renal MRI, where suspicious lesions are referred, how relatives obtain testing, and when the family returns to genetics for updates.

References

Disclaimer

This article provides general education and cannot diagnose FH tumor predisposition syndrome or replace individualized genetic counseling. Surveillance ages, imaging methods, and management of renal lesions should be determined by clinicians experienced in hereditary kidney cancer. Seek prompt medical care for concerning kidney, bleeding, skin, or blood-pressure symptoms.

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