Familial multiple cutaneous leiomyomas in short

• Familial multiple cutaneous leiomyomas is a hereditary cancer syndrome characterized by a predisposition to cutaneous and uterine leiomyomas and, in some families, to renal cell cancer.

Synonyms

• Familial leiomyomatosis and renal cell cancer
• Familial leiomyomatosis cutis et uteri
• Familial leiomyomatosis with renal carcinoma
• HLRCC
• Hereditary leiomyomatosis
• Hereditary leiomyomatosis with renal carcinoma
• Hereditary multiple cutaneous leiomyomas
• MCUL
• Multiple cutaneous and uterine leiomyomas
• Reed syndrome

Prevalence: Unknown

Inheritance: Autosomal dominant

Age of onset: Adolescent, Adult, Elderly

What are the symptoms of Familial multiple cutaneous leiomyomas?

Very frequent symptoms

• Abnormality of the musculature
• Cutaneous leiomyoma
• Multiple cutaneous leiomyomas

Frequent symptoms

• Pruritus

Occasional symptoms

• Barrett esophagus
• Cataract
• Esophageal neoplasm
• Papillary renal cell carcinoma type 2
• Uterine leiomyoma
• Uterine leiomyosarcoma
• Vaginal neoplasm 

Epidemiology

The exact prevalence remains undetermined. Currently, documentation exists for more than 200 families affected by HLRCC.

Clinical description

The condition can manifest at any stage of life, though it predominantly affects young adults and older individuals. Cutaneous leiomyomas, either multiple or solitary, typically emerge around age 25 (with a range spanning 10-47 years), appearing as firm, raised lesions varying from flesh-colored to light brown. These growths commonly develop on the trunk and limbs, occasionally affecting facial areas.

They typically proliferate in both size and quantity over time, exhibiting sensitivity to physical contact and temperature changes, often causing discomfort. Uterine leiomyomas, or fibroids, (affecting 77% of female HLRCC patients) generally develop around age 30, though diagnosis may occur between ages 18-52.

These often manifest through symptoms like pelvic discomfort and irregular or heavy menstrual cycles before detection. Renal tumors (typically presenting at age 44) occur less frequently in this syndrome (10-16% of cases) and may cause back pain, though some patients remain asymptomatic.

These tumors, predominantly papillary type II renal cell carcinoma, typically demonstrate aggressive behavior, frequently advancing to metastatic stages with fatal outcomes.

Etiology

HLRCC develops due to mutations in the FH gene (1q42.1), believed to function as a tumor suppressor gene. This gene encodes fumarate hydratase (FH), an enzyme responsible for metabolizing fumarate produced during cytoplasmic purine nucleotide cycling and arginine synthesis. The precise mechanism linking FH deficiency to cancer development remains unclear.

Diagnostic methods

HLRCC diagnosis relies on either multiple cutaneous leiomyomas with at least one histologically confirmed case (showing interwoven smooth muscle fiber bundles, centrally positioned long blunt-edged nuclei, occasional multinucleated cells, without mitotic figures) or a single leiomyoma with positive family history.

All patients exhibit reduced FH enzymatic activity, measurable in cultured skin fibroblasts or lymphoblastic cells. MRI provides the most reliable visualization of uterine leiomyomas. Genetic testing can detect FH gene mutations, confirming the diagnosis.

Differential diagnosis

Alternative diagnoses include familial renal cancer conditions like Von Hippel-Lindau syndrome, Birt-Hogg-Dubé syndrome, hereditary papillary renal cancer, along with uterine fibroids and cutaneous lesions.

Antenatal diagnosis

Families with identified disease-causing mutations can access prenatal testing.

Genetic counseling

HLRCC follows an autosomal dominant inheritance pattern, making genetic counseling advisable.

Management and treatment

Management and treatment require a multidisciplinary approach. For cutaneous leiomyomas, treatment options include botulinum toxin type A injections, cryoablation, and laser therapy. Individual painful lesions may be surgically excised. Pain management medications encompass alpha blockers, calcium channel blockers (such as nifedipine), antiepileptic medications, nitroglycerin, and antidepressants.

Uterine fibroids can be managed through gonadotropin-releasing hormone agonists, pain medications, and antihormonal therapies, or surgically via myomectomy.

In severe cases, hysterectomy might be required. Given the aggressive nature of renal tumors in HLRCC, complete nephrectomy is advised for patients with renal masses. Advanced cases may necessitate adjuvant therapy (including VEGF inhibitors).

Regular annual clinical examinations and imaging studies are essential for monitoring progression. Screening is recommended for family members of HLRCC patients to detect potential lesions.

Prognosis

While HLRCC currently carries a poor prognosis, emerging molecular-targeted therapies may enhance survival rates in the future.