Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a disorder in which affected individuals tend to develop benign tumors containing smooth muscle tissue (leiomyomas) in the skin and, in females, the uterus. This condition also increases the risk of kidney cancer.

In this disorder, growths on the skin (cutaneous leiomyomas) typically develop in the third decade of life. Most of these growths arise from the tiny muscles around the hair follicles that cause "goosebumps". They appear as bumps or nodules on the trunk, arms, legs, and occasionally on the face. Cutaneous leiomyomas may be the same color as the surrounding skin, or they may be darker. Some affected individuals have no cutaneous leiomyomas or only a few, but the growths tend to increase in size and number over time. Cutaneous leiomyomas are often more sensitive than the surrounding skin to cold or light touch, and may be painful.

Most women with HLRCC also develop uterine leiomyomas (fibroids). While uterine fibroids are very common in the general population, women with HLRCC tend to have numerous large fibroids that appear earlier than in the general population.

Approximately 10 percent to 16 percent of people with HLRCC develop a type of kidney cancer called renal cell cancer. The signs and symptoms of renal cell cancer may include lower back pain, blood in the urine, or a mass in the kidney that can be felt upon physical examination. Some people with renal cell cancer have no symptoms until the disease is advanced. People with HLRCC are commonly diagnosed with kidney cancer in their forties.

This disorder, especially if it appears in individuals or families without renal cell cancer, is also sometimes called multiple cutaneous leiomyomatosis (MCL) or multiple cutaneous and uterine leiomyomatosis (MCUL).

Mutations in the FH gene cause HLRCC. The FH gene provides instructions for making an enzyme called fumarase (also known as fumarate hydratase). This enzyme participates in an important series of reactions known as the citric acid cycle or Krebs cycle, which allows cells to use oxygen and generate energy. Specifically, fumarase helps convert a molecule called fumarate to a molecule called malate.

People with HLRCC are born with one mutated copy of the FH gene in each cell. The second copy of the FH gene in certain cells may also acquire mutations as a result of environmental factors such as ultraviolet radiation from the sun or an error that occurs as DNA copies itself during cell division.

FH gene mutations may interfere with the enzyme's role in the citric acid cycle, resulting in a buildup of fumarate. Researchers believe that the excess fumarate may interfere with the regulation of oxygen levels in the cell. Chronic oxygen deficiency (hypoxia) in cells with two mutated copies of the FH gene may encourage tumor formation and result in the tendency to develop leiomyomas and renal cell cancer.

Normal Function

The FH gene provides instructions for making an enzyme called fumarase (also known as fumarate hydratase). Fumarase participates in an important series of reactions known as the citric acid cycle or Krebs cycle, which allows cells to use oxygen and generate energy. Specifically, fumarase helps convert a molecule called fumarate to a molecule called malate.

Health Conditions Related to Genetic Changes

Fumarase deficiency

More than 20 FH gene mutations have been identified in people with fumarase deficiency, a condition that primarily affects the brain and is often fatal in infancy. Fumarase deficiency occurs in individuals who inherit two mutated copies of the FH gene in each cell. Most of these mutations replace one protein building block (amino acid) with another amino acid in the fumarase enzyme. These changes disrupt the ability of the enzyme to help convert fumarate to malate, interfering with the function of this reaction in the citric acid cycle. Impairment of the process that generates energy for cells is particularly harmful to cells in the developing brain, and this impairment results in the signs and symptoms of fumarase deficiency.

Hereditary leiomyomatosis and renal cell cancer

More than 70 mutations in the FH gene that cause hereditary leiomyomatosis and renal cell cancer (HLRCC) have been reported. Most of these mutations replace one amino acid with another amino acid in the fumarase enzyme.

HLRCC is a disorder in which affected individuals tend to develop benign tumors containing smooth muscle tissue (leiomyomas) in the skin and, in females, the uterus. This condition also increases the risk of kidney cancer. People with HLRCC are born with one mutated copy of the FH gene in each cell. The second copy of the FH gene in certain cells may also acquire mutations as a result of environmental factors such as ultraviolet radiation from the sun or an error that occurs as DNA copies itself during cell division. These changes are called somatic mutations and are not inherited.

FH gene mutations may interfere with the enzyme's role in the citric acid cycle, resulting in a buildup of fumarate. Researchers believe that the excess fumarate may interfere with the regulation of oxygen levels in the cell. Chronic oxygen deficiency (hypoxia) in cells with two mutated copies of the FH gene may encourage tumor formation and result in the tendency to develop leiomyomas and renal cell cancer.

Primary macronodular adrenal hyperplasia

MedlinePlus Genetics provides information about Primary macronodular adrenal hyperplasia

Other Names for This Gene

• fumarase
• fumarase hydratase
• FUMH_HUMAN
• HLRCC
• LRCC
• MCL
• MCUL1

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Children born with two mutated copies of the FH gene in each cell have a different condition called fumarase deficiency, which is often fatal in infancy. These individuals inherit one mutated copy of the gene from each parent. People with HLRCC can contribute one mutated copy of the gene to a child and are potential carriers of fumarase deficiency, but they do not have signs or symptoms of that condition.

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. These are typically treated in the same manner as those that occur in the general population. 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.