Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare inherited genetic syndrome that can affect several parts of the body. It increases an individual’s likelihood of developing benign smooth muscle tumors, known as leiomyomas, which often appear on the skin and, in women, in the uterus. The condition also raises the risk for a specific, aggressive form of kidney cancer.
The Genetic Basis of HLRCC
HLRCC arises from a change in a specific gene called Fumarate Hydratase, or FH. This gene provides instructions for making the fumarate hydratase enzyme, which plays a role in the Krebs cycle, which helps cells produce energy. When a mutation occurs in the FH gene, the enzyme cannot function correctly, leading to an accumulation of fumarate within cells. This buildup of fumarate contributes to uncontrolled cell growth and tumor formation.
The inheritance pattern for HLRCC is autosomal dominant, meaning only one copy of the altered FH gene is needed for a person to develop the condition. If one parent has HLRCC, each child has a 50% chance of inheriting the mutated gene. The condition can appear in every generation, though symptom severity can vary widely among affected family members.
Clinical Manifestations
Individuals with HLRCC often develop distinct physical signs, beginning with cutaneous leiomyomas, which are benign skin tumors. These tumors typically present as firm, small bumps or nodules that can be skin-colored, brownish, or reddish. They commonly appear on the torso, limbs, and occasionally the face, tending to increase in size and number over time. These skin lesions can be sensitive to touch or cold and may cause pain.
Women with HLRCC frequently experience uterine leiomyomas, also known as uterine fibroids, often at a younger age than typical. These fibroids are usually more numerous and larger, leading to symptoms such as heavy menstrual bleeding, pelvic pain, and a feeling of pressure or fullness in the pelvis. In some cases, these fibroids can also contribute to fertility issues.
HLRCC increases the risk of developing kidney cancer, specifically type 2 papillary renal cell carcinoma. This cancer can be aggressive and tends to occur at a younger age. The estimated lifetime risk for developing kidney cancer in individuals with an FH gene mutation is approximately 15% to 20.8%.
Diagnostic Process
A diagnosis of HLRCC is often suspected when an individual presents with characteristic clinical features. The presence of multiple cutaneous leiomyomas, or early-onset and severe uterine fibroids, frequently raises this suspicion. A biopsy of a suspicious skin lesion can confirm it is a leiomyoma, supporting the possibility of HLRCC.
The definitive diagnosis of HLRCC relies on genetic testing that identifies a pathogenic variant in the FH gene. This testing is recommended for individuals with suggestive symptoms, such as multiple skin leiomyomas or early-onset uterine fibroids, and for family members of someone already diagnosed with HLRCC. Genetic counseling can guide individual risk and testing options.
Following an initial diagnosis, cascade testing is important, where relatives of a person with a confirmed FH gene mutation are offered genetic testing. This approach identifies other family members who may carry the mutation, allowing for early surveillance and management strategies.
Surveillance and Health Management
Regular kidney screening is a primary component of HLRCC health management. Annual magnetic resonance imaging (MRI) scans of the abdomen are generally recommended for kidney surveillance, with screening often beginning at ages 8 to 10 years. The goal is to detect kidney tumors at an early stage, when they are small and more amenable to treatment. MRI is preferred over computed tomography (CT) scans to limit radiation exposure over a person’s lifetime.
Dermatological management involves regular skin examinations by a dermatologist to monitor cutaneous leiomyomas. While these skin lesions are benign, treatment aims to alleviate symptoms like pain. Options may include medications to reduce pain or surgical removal for symptomatic or particularly bothersome lesions, though extensive removal is often avoided due to potential scarring.
Women with HLRCC require regular gynecological care to manage uterine fibroids. This involves ongoing check-ups to monitor fibroid growth and address symptoms such as heavy bleeding or pelvic discomfort. Treatment options can range from medications to surgical procedures like myomectomy, which removes fibroids while preserving the uterus, or hysterectomy, which involves removal of the uterus, especially in cases of severe or rapidly growing fibroids.
Managing HLRCC requires a coordinated approach involving a team of medical specialists. A multidisciplinary team, including geneticists, dermatologists, urologists, and gynecologists, works together to address the diverse manifestations of the condition. This collaborative care ensures comprehensive monitoring and timely interventions.