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Hereditary leiomyomatosis and renal cell cancer

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Description

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).

Frequency

HLRCC is a rare condition that has been reported in approximately 300 families worldwide. Researchers suggest that it may be under-diagnosed.

Causes

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.

Inheritance

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.

Other Names for This Condition

  • hereditary leiomyomatosis and renal cell carcinoma
  • HLRCC
  • leiomyomatosis and renal cell cancer
  • LRCC
  • MCL
  • MCUL
  • multiple cutaneous and uterine leiomyomata
  • multiple cutaneous leiomyoma
  • Reed's syndrome

Additional Information & Resources

Genetic and Rare Diseases Information Center

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Adamane S, Desai S, Menon S. Hereditary leiomyomatosis and renal cell cancer syndrome associated renal cell carcinoma. Indian J Pathol Microbiol. 2017 Jan-Mar;60(1):108-110. doi: 10.4103/0377-4929.200025. Citation on PubMed
  • Adams A, Sharpe KK, Peters P, Freeman M. Hereditary leiomyomatosis and renal cell cancer (HLRCC): cutaneous and renal manifestations requiring a multidisciplinary team approach. BMJ Case Rep. 2017 Apr 11;2017. pii: bcr-2016-215115. doi: 10.1136/bcr-2016-215115. Citation on PubMed
  • Arenas Valencia C, Rodríguez López ML, Cardona Barreto AY, Garavito Rodríguez E, Arteaga Díaz CE. Hereditary leiomyomatosis and renal cell cancer syndrome: identification and clinical characterization of a novel mutation in the FH gene in a Colombian family. Fam Cancer. 2017 Jan;16(1):117-122. doi: 10.1007/s10689-016-9922-4. Citation on PubMed
  • Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomäki K, Tomlinson I, Richard S, Linehan WM. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer. 2014 Dec;13(4):637-44. doi: 10.1007/s10689-014-9735-2. Review. Citation on PubMed or Free article on PubMed Central
  • Patel VM, Handler MZ, Schwartz RA, Lambert WC. Hereditary leiomyomatosis and renal cell cancer syndrome: An update and review. J Am Acad Dermatol. 2017 Jul;77(1):149-158. doi: 10.1016/j.jaad.2017.01.023. Epub 2017 Mar 14. Review. Citation on PubMed
  • Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis. 2014 Jun 20;7:253-60. doi: 10.2147/IJNRD.S42097. eCollection 2014. Review. Citation on PubMed or Free article on PubMed Central
  • Teh J, Kinnear N, Douglass-Molloy H, Hennessey DB. Hereditary leiomyomatosis and renal cell cancer syndrome: a family affair. BMJ Case Rep. 2017 Jan 25;2017. pii: bcr2016218270. doi: 10.1136/bcr-2016-218270. Citation on PubMed
  • Vocke CD, Ricketts CJ, Merino MJ, Srinivasan R, Metwalli AR, Middelton LA, Peterson J, Yang Y, Linehan WM. Comprehensive genomic and phenotypic characterization of germline FH deletion in hereditary leiomyomatosis and renal cell carcinoma. Genes Chromosomes Cancer. 2017 Jun;56(6):484-492. doi: 10.1002/gcc.22452. Epub 2017 Mar 31. Citation on PubMed
  • Wong MH, Tan CS, Lee SC, Yong Y, Ooi AS, Ngeow J, Tan MH. Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC). Fam Cancer. 2014 Jun;13(2):281-9. doi: 10.1007/s10689-014-9703-x. Review. Citation on PubMed
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