Hereditary leiomyomatosis and renal cell carcinoma (HLRCC, OMIM #150800) is a genetic disease caused by mutations in the FH gene. It is characterized by the occurrence of cutaneous leiomyomas, uterine leiomyomas (fibroids), and/or solitary renal tumors.

Key Data

< swipe to see entire table >
Synonym HLRCC
Gene FH
Gene product FH (fumarate hydratase)
Function Tumor suppressor
Inactivation of fumarate hydratase leads to an intracellular accumulation of fumarate and thereby a reduced degradation of HIF (hypoxia-induced factor). The resulting increase in HIF-1α activity increases the expression of growth factors.
Heredity Autosomal dominant
Prevalence More than 300 families with HLRCC have been described to date.
Genotype-phenotype correlation Unknown
Penetrance High but incomplete
< swipe to see entire table >


Suspected Diagnosis

The occurrence of multiple histopathologically confirmed leiomyomas of the skin should suggest HLRCC. In addition, HLRCC is suspected if there are ≥ 2 of the following findings:

  • Symptomatic and/or multiple uterine leiomyomas requiring an operation before the age of 40

  • Type 2 papillary renal cell carcinoma before the age of 40

  • A first-degree relative with one of the above criteria

Clinical Diagnostic Criteria

The diagnosis of HLRCC is confirmed by detection of a heterozygous mutation in the FH gene in combination with one of the following clinical findings:

  • Multiple cutaneous leiomyomas (≥ 1 histologically verified leiomyoma) without a concomitant family history of HLRCC

  • 1 cutaneous leiomyoma in conjunction with a positive family history

  • ≥ 1 collecting duct carcinoma, tubular/papillary or type 2 papillary renal cell carcinoma (independent of a family history)

Genetic Diagnostics

Genetic proof is provided by identifying a heterozygous germline mutation in the FH gene through sequence analysis or deletion/duplication analysis. It may be helpful to use panel examinations consisting of multiple genes.

Differential Diagnoses

  • Sporadic, non-syndromic uterine leiomyomatosis

  • Von Hippel-Lindau syndrome

  • Birt-Hogg-Dubé syndrome

  • Hereditary papillary renal carcinoma

Clinical Presentation

HLRCC is characterized by the occurrence of cutaneous leiomyomas, uterine leiomyomas, and/or renal cell tumors. The severity of the disease varies greatly within the same family and between families.

Cutaneous Leiomyomas

These skin manifestations, which usually occur on the trunk or extremities, less frequently on the head and neck, appear as skin-colored or light-brown papules or nodules. The average age when they occur is 25 (with a range of 10-47 years), whereby the number and size of the leiomyomas increase with age. Leiomyomas are typically described as painful. The pain may be intensified due to cold, heat, or touching.

The number of cutaneous leiomyomas associated with the HLRCC varies a lot – either multiple leiomyomas or only one single leiomyoma may occur. The complete absence of any skin manifestations is possible as well.

Uterine Leiomyomas (Fibroids)

Uterine leiomyomas occur in approximately 80% of female HLRCC patients. Compared to the population as a whole, uterine leiomyomas associated with an HLRCC occur earlier, at an average age of 30 (with a range of 18-52 years), meaning that surgical interventions such as myomectomies or hysterectomies are performed at a much younger age (35 years on average) as well. The leiomyomas are typically large and numerous and frequently cause irregular and severe menstrual bleeding along with abdominal pain.

Renal Carcinomas

The renal diseases that occur as part of HLRCC are type 2 papillary or tubular/papillary renal cell carcinomas and collecting duct carcinomas. Most of these tumors are unilateral and solitary and prove to be more aggressive than other hereditary renal cell carcinomas. Renal cell carcinomas occur in approximately 10-16% of HLRCC patients, whereby the average age is 41 at the time of diagnosis. Symptoms may include hematuria, low back pain, or a palpable space-occupying lesion, although an asymptomatic progression is possible as well.

Therapeutic Considerations

Cutaneous Leiomyomas

Treating cutaneous leiomyomas is difficult. The following options are available:

  • Surgical excision of painful solitary lesions

  • Cryoablation and/or laser therapy

  • With medication: calcium channel blockers, α-blockers, nitroglycerin, antidepressants, and anticonvulsants may reduce the pain.

Uterine Leiomyomas (Fibroids)

  • With medication: GnRH agonists, antihormonal, and pain therapy before the operation to reduce the size of the leiomyomas and/or as temporary symptomatic therapy

  • Myomectomy as uterus-preserving surgical treatment

  • Hysterectomy

Renal Carcinomas

  • Early surgical resection, whereby a nephrectomy should be considered due to the aggressiveness of the tumor

Surveillance Recommendations

Surveillance Recommendations

There are no standard surveillance recommendations to date. The American Association for Cancer Research suggests the following:

  • Annual MRI of the kidneys as of 8 years of age

  • Annual dermatological examination by a pediatrician or dermatologist once a diagnosis has been made

  • Annual gynecological examination, possibly with an ultrasound, starting with the first gynecological appointment, although no later than as of 20 years of age or at the onset of symptoms

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with hereditary leiomyomatosis and renal cell carcinoma that we can recommend to you for more information.

Support Groups