Hereditary leiomyomatosis and renal cell cancer syndrome

Other Names: LRCC; HLRCC; Familial leiomyomatosis; Multiple cutaneous and uterine leiomyomata; MCUL; Reed's syndrome; Multiple cutaneous leiomyomata; MCL

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a condition that causes benign tumors of smooth muscle tissue in the skin (cutaneous leiomyomas) and in the uterus in females (uterine leiomyomas, or fibroids). The condition also increases the risk of kidney cancer. About 10% to 16% of people with HLRCC develop a type of kidney cancer called renal cell cancer.

Cause

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by changes (mutations) in the FH gene. This gene gives the body instructions for making an enzyme called fumarase which is needed for a series of reactions that lets cells use oxygen and energy (the citric acid cycle, or Krebs cycle). People with HLRCC are born with one mutated copy of the FH gene in each cell. The second copy of the gene in some cells can mutate later on from factors in the environment, such as radiation from the sun or an error during cell division. A mutation can interfere with fumarase's role in the citric acid cycle, which may affect the regulation of oxygen levels in cells. Long-term oxygen deficiency in cells with two mutated copies of the FH gene may contribute to tumors growth and the tendency to develop leiomyomas and/or renal cell cancer.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is inherited in an autosomal dominant pattern, which means that having one mutated copy of the gene in each cell is enough to cause symptoms of the condition. In some cases, an affected person inherits the mutated copy of the gene from an affected parent. Other cases result from new mutations in the gene and that occur for the first time in in the affected individual. When an individual with an autosomal dominant condition has children, each child has a 50% (1 in 2) risk to inherit the mutated gene. This is the case regardless of which parent has the condition.

Signs and symptoms

Signs and symptoms of hereditary leiomyomatosis and renal cell cancer (HLRCC) typically begin in adulthood at an average age of 25.

The skin growths (cutaneous leiomyomata) appear as skin-colored or light brown bumps on the torso and extremities, and occasionally on the face. They usually increase in size and number with age. They may be more sensitive than the surrounding skin and be painful.

Uterine leiomyomata (fibroids) also occur in almost all affected women and tend to be large and numerous. Most women with these have irregular or heavy periods and pelvic pain. A renal tumor occurs in about 10% to 16% of affected individuals (at an average age of 44 years) and may cause blood in the urine, lower back pain, and a palpable mass. Some people with renal cell cancer have no symptoms until the cancer is advanced. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the musculature(Muscular abnormality)
• Cutaneous leiomyoma
• Multiple cutaneous leiomyomas

30%-79% of people have these symptoms

• Pruritus(Itching)

5%-29% of people have these symptoms

• Barrett esophagus
• Cataract(Clouding of the lens of the eye)
• Cutaneous leiomyosarcoma
• Papillary renal cell carcinoma type 2
• Uterine leiomyoma
• Uterine leiomyosarcoma
• Vaginal neoplasm
• Vaginal tumor

Diagnosis

The diagnosis is made either by testing of the fumarate hydratase activity in cultured skin fibroblasts or lymphoblastoid cells and demonstrating reduced activity (≤60%) or by molecular genetic testing. Special stains that may be of use in the diagnosis include Masson's trichrome, Van Gieson's stain and phosphotungstic acid–haematoxylin.

Treatment

Skin growths (cutaneous leiomyomas) associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) should be examined by a dermatologist. Treatment of these may include surgery to remove a painful growth; cryoablation and/or lasers; and/or medications such as calcium channel blockers, alpha blockers, nitroglycerin, antidepressants, and/or antiepileptic drugs (AEDs), which have been reported to reduce pain. Uterine fibroids should be evaluated by a gynecologist. However, most women with HLRCC need medication and/or surgical removal of the fibroids (myomectomy) at a younger age. Medications may include gonadotropin-releasing hormone agonists (GnRHa), antihormonal drugs, and pain relievers. Hysterectomy should be performed only when necessary. Early detection of kidney tumors in HLRCC is important because they grow aggressively. Total nephrectomy may be strongly considered in individuals with a detectable renal mass.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Sorafenib (Brand name: Nexavar)Treatment of patients with advanced renal cell carcinoma.
• Aldesleukin (Brand name: Proleukin®) Treatment of adults (>18 years old) with metastatic renal cell carcinoma.
• Temsirolimus (Brand name: Torisel®): Treatment of advanced renal cell carcinoma.

Prognosis

A 2006 review stated that RS often leads renal cancer between ages 30-50. Renal cancer kills about 1 in 3 people, but 5-year survival rates improved between 1974-1976 and 1995-2000, from 52% to 64%.

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