What is hereditary leiomyomatosis and renal cell carcinoma?

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a genetic disease caused by mutations – or genetic changes – in the FH gene. It is characterized by the occurrence of benign tumors of the skin (cutaneous leiomyomas), benign tumors of the uterus (uterine leiomyomas), and/or malignant kidney tumors (renal cell carcinomas).

How is hereditary leiomyomatosis and renal cell carcinoma diagnosed?

Suspected Diagnosis

The occurrence of multiple leiomyomas (benign tumors) of the skin should point to HLRCC. In addition, HLRCC is suspected if ≥ 2 of the following present:

  • Symptomatic and/or multiple leiomyomas (benign tumors) of the uterus that require surgery before the age of 40

  • A specific form of kidney cancer (type 2 papillary renal cell carcinoma) before the age of 40

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

Clinical Diagnosis

The diagnosis of HLRCC is confirmed by detection of a mutation – or genetic change – in the FH gene, in combination with one of the following clinical findings:

  • Multiple leiomyomas of the skin if there is no incidence of HLRCC in the family

  • 1 cutaneous leiomyoma if there is incidence of HLRCC in the family

  • ≥ 1 of the following malignant kidney tumors: collecting duct carcinoma, tubular/papillary or type 2 papillary renal cell carcinoma (independent of the family history)

Genetic Diagnostics

Genetic evidence is provided by identifying a mutation – or genetic change – in the FH gene.

What is the risk of cancer?

HLRCC patients have a greatly increased risk of malignant kidney tumors (renal cell carcinomas). In addition, HLRCC is characterized by the occurrence of benign skin tumors (cutaneous leiomyomas) and benign tumors of the uterus (uterine leiomyomas). The severity of the disease can vary greatly from patient to patient.

Renal Cell Carcinomas

Renal cell carcinomas, or malignant kidney tumors, occur in around 10-16% of patients with HLRCC. Most of these tumors are located on one side of the body, occur separately, and are more aggressive than hereditary renal cell carcinomas. The average age at the time of diagnosis is 41 years. Clinical signs of renal cell carcinomas may be blood in the urine, lower back pain, or a palpable space-occupying lesion in one flank. However, it is possible that these tumors will not produce any symptoms at all.

Leiomyomas of the Skin

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

The number of leiomyomas of the skin 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.

Leiomyomas of the Uterus

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

What causes hereditary leiomyomatosis and renal cell carcinoma?

Hereditary leiomyomatosis and renal cell carcinoma is caused by mutations – or genetic changes – in the FH gene. This gene encodes for the FH protein, which normally helps break down another protein (HIF), thereby blocking the release of growth factors.

Now if the FH gene is present in an altered form, the FH protein will not be produced correctly. This will prevent the HIF protein being broken down correctly, leading to an accumulation of the HIF protein. The resulting increased release of growth factors can lead to the development of benign and malignant tumors.

HLRCC can be passed on by parents to their children. In these cases, it is inherited as an autosomal dominant disease. It is also possible for the genetic change in the FH gene to occur as a spontaneous or new mutation, called a de novo mutation.

Is there a treatment?

Leiomyomas of the Skin

Treating leiomyomas of the skin is difficult. The following options are available:

  • Surgical removal of painful individual lesions

  • Cold and/or laser therapy

  • Medicinal therapies can reduce the pain.

Leiomyomas of the Uterus

  • With medication: antihormonal treatment and pain therapy prior to surgery to reduce the size of leiomyomas and/or temporarily as symptomatic therapy

  • Surgical removal of leiomyomas in order to preserve the uterus

  • Surgical removal of the uterus

Renal Carcinomas

  • Early surgical removal, whereby removing the kidney completely should be considered due to the aggressiveness of the tumor

Surveillance Recommendations for the Early Detection of Cancer

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 examination of the skin by a pediatrician or a dermatologist following diagnosis

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

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as changes in the skin occur, mainly in the form of painful nodules. Symptoms such as back pain, blood in the urine, or space-occupying lesions in the area of the flank should be noted and reported to a doctor as well. You should also see a doctor right away if you notice any other newly occurring anomalies or symptoms, such as severe menstrual bleeding and abdominal pain.

Support Groups and Additional Information