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Last updated: 5/2/2024
Years published: 2014, 2017, 2020, 2024
NORD gratefully acknowledges Eamonn R. Maher, MD, FRCP, Department of Medical Genetics, University of Cambridge and Aston University, Birmingham, UK for assistance in the preparation of this report.
Summary
Hereditary leiomyomatosis and renal cell carcinoma, also known as HLRCC, is a rare genetic disorder characterized by smooth muscle growths (leiomyomas) on the skin and uterus and an increased risk of developing kidney (renal) cancer. Skin growths may appear as small, firm bumps (papules) or tiny lumps (nodules) and are not cancerous (benign). Uterine leiomyomas, also known as uterine fibroids, may be numerous and are also benign, but can cause symptoms such as heavy menstrual periods or pelvic pressure or pain. Affected individuals are at an increased risk of developing kidney cancer, particularly a form known as type II papillary renal cell carcinoma. Kidney cancer associated with HLRCC is cancerous (malignant) and can be aggressive and spread (metastasize) to other areas of the body. HLRCC is caused by changes (pathogenic variants) in the fumarate hydratase (FH) gene and is inherited in an autosomal dominant pattern.
Introduction
HLRCC is classified as a hereditary renal cancer syndrome, a group of disorders characterized by a genetic predisposition to renal cancer along with other symptoms. There are at least 10 identified hereditary renal cancer syndromes including Von-Hippel-Lindau disease, Birt-Hogg-Dube syndrome and hereditary papillary renal cell carcinoma. The association of leiomyomas and uterine fibroids as a genetic disorder was described in the medical literature by Dr. Reed in 1973 and subsequently termed multiple cutaneous and uterine leiomyoma (MCUL) or Reed’s syndrome. The additional association with renal carcinoma was not established until 2001.
The symptoms and progression of HLRCC can vary widely from one person to another, even among members of the same family. Some individuals who inherit a gene variant for HLRCC will not develop any symptoms. The susceptibility to developing symptoms varies among family members as well. For example, if a parent develops kidney cancer, it does not necessarily mean that an affected child will.
The most common symptom is benign skin lesions called leiomyomas or leiomyomata. Leiomyomas are small growths that are usually skin-colored, brownish or reddish. Sometimes they can resemble a rash. They most often appear on the trunk, arms and legs (extremities) and face. These lesions are sensitive to touch and cold temperatures and, in rare cases, may be painful. Some individuals may have widespread disease, with multiple small leiomyomas covering a large area of the body; other individuals may only develop a few bumps. Some individuals may only have one small skin growth (leiomyoma) or have no detectable growths. Leiomyomas usually become apparent between 10 and 50 years of age (with a mean age of 25) and generally increase in size and number as an affected individual ages.
Females with HLRCC may develop leiomyomas in the uterus (uterine fibroids). These growths are common in females in the general population and often go unnoticed because they do not cause any symptoms (asymptomatic). In females with HLRCC, uterine fibroids are more numerous, larger and have an early age of onset, most often being diagnosed between 18 and 52 years of age (with a mean age of 30). Affected females may have abnormally heavy menstrual periods and feel pelvic pressure or pain. Females with HLRCC tend to undergo a hysterectomy or myomectomy for symptomatic relief at a younger age than females in the general population.
Individuals with HLRCC are at an increased risk of developing kidney (renal) cancer than individuals in the general population. However, most affected individuals do not develop kidney cancer. In individuals who have developed kidney cancer, the most common form has been type II papillary renal cell carcinoma, a potentially aggressive malignant cancer that can spread (metastasize) quickly. Most affected individuals develop a solitary kidney tumor, but even a small primary tumor can spread. Individuals with kidney cancer may not develop any outward symptoms. Symptoms that can develop include blood in the urine (hematuria), lower back pain and the presence of mass that can be felt (palpable). Additional forms of kidney cancer have occurred in individuals with HLRCC including tubulo-papillary and renal collecting duct carcinomas.
In extremely rare cases, some affected females have developed uterine leiomyosarcomas, a malignant tumor that arises from the smooth muscle lining the walls of the uterus (myometrium). (For more information on this disorder, choose “uterine leiomyosarcoma” as your search term in the Rare Disease Database.)
Several other benign and malignant forms of cancer have been described in individuals with HLRCC including breast cancer, bladder cancer, gastrointestinal stromal tumors (GISTs), adrenal incidentaloma, Leydig-cell tumors of the testes and ovarian cystadenomas. However, it is unknown whether these are coincidental findings or somehow related to HLRCC. Variants in the FH gene can be found in people with HLRCC and fumarase deficiency but also in a subset of people with pheochromocytoma/paraganglioma. Nevertheless, it appears that it is uncommon for patients diagnosed with HLRCC to develop a pheochromocytoma or paraganglioma (though this possibility should be considered if there are symptoms such as high blood pressure).
HLRCC is caused by variant in the FH gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.
The FH gene is a tumor suppressor gene. The FH gene creates (encodes) a protein known as fumarate hydratase, also known as fumarase. A variant in the FH gene results in a deficiency of functional fumarate hydratase, which leads to a buildup of fumarate which plays a role in the development of the symptoms of HLRCC including cancer. The exact reasons how fumarate accumulation in cells ultimately leads to the symptoms of HLRCC are complex but are gradually becoming understood.
In rare cases, variants in the FH gene have resulted in the development of other forms of tumor known as pheochromocytoma and paraganglioma which may be malignant.
The FH gene variant is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
HLRCC affects males and females in equal numbers. The disorder may be recognized more readily in females because of the development of uterine fibroid and associated symptoms. The exact incidence and prevalence of HLRCC in the general population is not well defined but it is generally considered to be underdiagnosed.
A diagnosis of HLRCC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Various clinical criteria have been suggested for diagnosing HLRCC including multiple cutaneous leiomyomas with at least one histologically confirmed leiomyoma or
a single cutaneous leiomyoma or papillary renal cancer in the presence of a positive family history of HLRCC.
A leiomyoma cannot be diagnosed by its appearance on the skin because it can resemble other skin conditions. A skin biopsy, which is the surgical removal and microscopic study of a small sample of skin tissue, is necessary in order to confirm the presence of leiomyomas.
The activity of fumarate hydratase, the enzyme encoded by the FH gene, can be measured in certain types of cells including skin fibroblasts and lymphoblastoid cells. Reduced activity of functional fumarate hydratase is indicative of HLRCC.
Molecular genetic testing is the most common method of confirming a diagnosis of HLRCC. Identification of a deletion or disease-causing variant in the FH gene confirms the diagnosis.
Pathologists may stain sections of leiomyomas and kidney cancers to detect protein changes which indicate the presence of increased fumarate in the tumor tissue.
Clinical Testing and Workup
Individuals with HLRCC should receive regular (annual) screening for renal tumors. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are more sensitive than ultrasound scans and generally MRI is preferred to avoid repeated radiation. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An ultrasound is another X-ray technique sometimes used to detect kidney cancer. The exact age at which kidney screening should start requires careful discussion between parents and doctors and can differ between families but experts have agreed that screening should usually be considered from age 10 years.
Treatment
The treatment of HLRCC is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including pediatricians, general internists, plastic surgeons, dermatologists, kidney specialists (nephrologists), gynecologists, oncologists and other healthcare professionals but HLRCC can frequently be associated with few symptoms. Psychosocial support for the entire family can be essential.
Genetic counseling is important for affected individuals and their families. Genetic testing can usually determine which family members may be at risk of symptoms and require surveillance.
Skin lesions may not require treatment and many dermatologists do not recommend surgical excision because it can lead to scarring and damage to the skin. Surgical excision is most often used for a solitary, painful lesion. If painful or unsightly or tightly packed together skin lesions do require removal, two methods that have been used are cryotherapy and CO2 laser ablation.
Cryotherapy is the use of extreme cold to freeze and destroy the tissue and cells of skin lesions and is a minimally invasive treatment option. With cryotherapy a freezing substance such as liquid nitrogen or argon gas is applied directly to the lesion. Cryotherapy is most effective for single or small lesions. CO2 laser ablation is the use of a laser beam to directly destroy skin lesions.
Pain relief is necessary for some individuals with HLRCC and can include a variety of medications including calcium channel blockers, alpha blockers, anti-depressants, nitroglycerine and anti-seizure (anti-epileptic) medications.
When uterine fibroids cause symptoms, treatment may include the gonadotropin-releasing medications, anti-hormonal medications and pain relievers. Uterine fibroids, in females with HLRCC, often eventually require surgery including surgery designed to remove symptomatic fibroids and repair the damage to the uterus (myomectomy). In some females, the surgical removal of the uterus (hysterectomy) may be necessary. These procedures generally prove necessary at a younger age than is normally found in the general population.
Kidney tumors may be removed surgically. Because even a small, solitary tumor can be aggressive and metastasize, complete removal of the kidney (total nephrectomy) should be considered if there is any doubt that a partial nephrectomy would be curative.
Researchers are studying various medications as potential treatments for individuals with HLRCC. This includes drugs that blocks the growth of new blood vessels that tumors need to grow and spread (angiogenesis inhibitors). In addition, botulinum toxin (Botox) is being studied to treat cutaneous leiomyomas. More research is necessary to determine the long-term safety and effectiveness of these medications for individuals with HLRCC.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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;13:637-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574691/
Castro-Vega LJ, Buffet A, De Cubas AA, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/24334767
Chen YB, Brannon AR, Toubaji A, et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunochemistry. Am J Surg Pathol. 2014; [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/24441663
Sanz-Ortega J, Vocke C, Stratton P, Linehan WM, Merino MJ. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 2013;37:74-80. http://www.ncbi.nlm.nih.gov/pubmed/23211287
Verine J, Pluvinage A, Bousquet G, et al. Hereditary renal cancer syndromes: an update of a systematic review. Eur Urol. 2010;58:701-710. http://www.ncbi.nlm.nih.gov/pubmed/20817385
Bayley JP, Launonen V, Tomlinson IPM. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet. 2008;9:20. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2322961/
Refae MA, Wong N, Patenaude F, Begin LR, Foulkes WD. Hereditary leiomyomatosis and renal cell cancer: an unusual and aggressive form of hereditary renal carcinoma. Nat Clin Pract Oncol. 2007;4:256-261. http://www.ncbi.nlm.nih.gov/pubmed/17392716
Sundarshan S, Pinto PA, Neckers L, Linehan WM. Mechanisms of disease: hereditary leiomyomatosis renal cell cancer – a distinct form of hereditary kidney cancer. Nat Clin Pract Urol. 2007;4:104- 110. http://www.ncbi.nlm.nih.gov/pubmed/17287871
Alam NA, Olpin S, Rowan A, et al. Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. J Mol Diagn. 2005;7:437-443. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1888487/
Toro JR, Nickerson ML, Ming-Hui W, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003;73:95-106. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180594/
Choyke PL, Glenn GM, Walther MM, Zbar B, Linehan WM. Hereditary renal cancers. Radiology. 2003;226:33-46. http://www.ncbi.nlm.nih.gov/pubmed/12511666
Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci. 2001;98:3387-3392. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC30663/
INTERNET
Kamihara J, Schultz KA, Rana HQ. FH Tumor Predisposition Syndrome. 2006 Jul 31 [Updated 2020 Aug 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1252/ Accessed April 11, 2024.
HLRCC. Online Mendelian Inheritance in Man (OMIM). Entry No:150800; Last Update: 11/16/2020. Available at: http://www.omim.org/entry/150800 Accessed April 11, 2024.
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