Hereditary Leiomyomatosis and Renal Cell Carcinoma – Definition
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC, OMIM #150800) is a genetic disease caused by pathogenic variants in the FH gene. It is characterized by the occurrence of cutaneous leiomyomas, uterine leiomyomas (fibroids), and/or solitary renal tumors.
Synonyms:
HLRCC
Gene:
FH
Gene product:
FH (Fumarat 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.
Patterns of inheritance:
Autosomal dominant
Prevalence:
More than 300 families with HLRCC have been described to date.
Genotype-phenotype correlation:
Unknown
Penetrance:
High, but incomplete
Hereditary Leiomyomatosis and Renal Cell Carcinoma – Diagnosis
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 pathogenic variant 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 pathogenic germline variant 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.
Special Features of Treatment
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
Diagnosis of Hereditary Leiomyomatosis and Renal Cell Carcinoma- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of Hereditary Leiomyomatosis and Renal Cell Carcinoma - What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
According to the latest AACR guidelines, the following screening tests are recommended for patients with HLRCC:
Renal cell carcinoma
- MRI of the kidneys yearly from the age of 10
Uterine and cutaneous leiomyomas
- Information about possible symptoms (menstrual changes, abdominal pain, regional skin changes with pain) from adolescence
Only for certain FH variants (Thr234Ala and Cys434Tyr): Early detection of pheochromocytoma and paraganglioma
- Whole-body MRI (neck to pelvis) incl. special MRI of the neck and kidneys alternating annually from the age of 10
- Blood pressure measurement annually from the age of 10
- Plasma methytyramine and plasma free metanephrines (PFM) or fractionated metanephrines in 24-hour urine from age 10 years annually
