Hereditary leiomyomatosis and renal cell cancer (ORPHA:523)
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by a predisposition to cutaneous and uterine leiomyomas and, in some families, to renal cell cancer.
Epidemiology
The prevalence is unknown. Over 200 families with HLRCC have been reported.
Clinical description
Disease onset can occur at any age, but is more common in young adults and elderly patients. Multiple or single benign cutaneous leiomyomas are common and usually present at around the age of 25 (range from 10-47 years) as firm papules or nodules that are skin colored to light brown. They are usually localized to the trunk and extremities but sometimes on the face. They tend to increase in size and number with age and are usually sensitive to touch and/or cold temperature and, in some, are painful. Uterine leiomyomas (present in 77% of women with HLRCC), also known as fibroids, usually appear around the age of 30 but age at diagnosis can range from 18-52 years. Symptoms of pelvic pain and irregular or heavy menstrual bleeding often occur before they are discovered. Renal tumors (mean age of presentation: 44) are less commonly seen in this syndrome (10-16% of cases) and may present with back pain, although some may be asymptomatic. They are mainly papillary type II renal cell carcinoma and are usually aggressive, often rapidly progressing to metastatic disease and death.
Etiology
HLRCC is caused by a mutation in the FH gene (1q42.1),which is thought to act as a tumor suppressor gene, encoding the enzyme fumarate hydratase (FH) that metabolizes the fumarate produced during the purine nucleotide cycle and arginine synthesis in the cytoplasm. It is still unclear how a deficiency in FH is involved in oncogenesis.
Diagnostic methods
Diagnosis of HLRCC is based on either the presence of multiple cutaneous leiomyomas with at least 1 histologically confirmed leiomyoma (interlacing bundles of smooth muscle fibers with centrally located long blunt-edged nuclei, occasional multinucleated cells, and no mitotic figures) or the presence of a single leiomyoma with a positive family history of the disease. Reduced enzymatic activity of FH is found in all patients and can be measured in cultured skin fibroblasts or lymphoblastic cells. MRI is the most accurate imaging technique for visualizing uterine leiomyomas. Molecular genetic testing can identify mutations in the FH gene, confirming diagnosis.
Differential diagnosis
Differential diagnoses include familial renal cancer syndromes such as Von Hippel-Lindau syndrome, Birt-Hogg-Dubé syndrome and hereditary papillary renal cancer (see these terms), as well as uterine fibroids and cutaneous lesions.
Antenatal diagnosis
Prenatal testing is possible in families with a known disease causing mutation.
Genetic counseling
HLRCC is inherited autosomal dominantly and genetic counseling is recommended.
Management and treatment
Management and treatment are multidisciplinary. Cutaneous leiomyomas can be treated by botulinum toxin type A injections, cryoablation and lasers. Solitary painful lesions can be surgically removed. Medications given to reduce pain include alpha blockers, calcium channel blockers (ex. nifedepine), antiepileptic drugs, nitroglycerine and antidepressants. Uterine fibroids can be treated with gonadotropin-releasing hormone agonists, pain relievers and antihormonal medications or surgically with a myomectomy. In some severe cases a hysterectomy may be necessary. As renal tumors associated with HLRCC are highly aggressive, a total nephrectomy is recommended for those with a renal mass. Adjuvant therapy (i.e. VEGF inhibitors) may be necessary in advanced cases. Annual clinical examinations and imaging assessments are recommended to monitor any changes. Family members of patients with HLRCC should equally be screened for the presence of lesions.
Prognosis
The prognosis of HLRCC is poor but treatments with new molecular targets may improve survival in the future.

                            Last update: 
                            July 2014


                            - Expert reviewer(s): 
                            Dr Maria MERINO