Hereditary leiomyomatosis and renal cell cancer syndrome

Overview

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome is a rare inherited disorder that predisposes individuals to the development of cutaneous and uterine leiomyomas (smooth muscle tumors) and an aggressive form of kidney cancer known as type 2 papillary renal cell carcinoma. It follows an autosomal dominant inheritance pattern and is caused by mutations in the FH (fumarate hydratase) gene. Early diagnosis is critical, as renal tumors associated with HLRCC can be aggressive and metastasize quickly.

Causes

HLRCC is caused by mutations in the FH gene, which provides instructions for making fumarate hydratase, an enzyme involved in the citric acid (Krebs) cycle. When this enzyme is deficient due to mutation, it leads to an accumulation of fumarate, which may contribute to tumor formation through mechanisms such as impaired DNA repair, increased oxidative stress, and activation of oncogenic pathways. The condition is inherited in an autosomal dominant pattern, meaning only one altered copy of the gene is sufficient to cause the syndrome.

Symptoms

The clinical features of HLRCC can vary but typically include the following:

• Cutaneous leiomyomas: Painful, skin-colored or reddish papules or nodules, often appearing on the trunk or limbs

• Uterine leiomyomas (fibroids): Common in affected females, often large, numerous, and appearing at a younger age than typical fibroids; may lead to abnormal uterine bleeding, pelvic pain, or infertility

• Renal cell carcinoma: Usually a solitary, unilateral tumor; often type 2 papillary renal cell carcinoma, which is aggressive and may metastasize early

Less commonly, individuals may experience symptoms such as hematuria (blood in the urine), flank pain, or a palpable abdominal mass due to kidney involvement.

Diagnosis

Diagnosis of HLRCC is based on clinical features, family history, and genetic testing. Diagnostic steps include:

• Physical examination: Evaluation of skin lesions and uterine symptoms

• Imaging: MRI or CT scans to detect renal tumors

• Skin biopsy: Histological confirmation of cutaneous leiomyomas

• Genetic testing: Identification of pathogenic variants in the FH gene confirms the diagnosis

• Family history assessment: May reveal a pattern of early-onset uterine fibroids or kidney cancer

Screening of at-risk family members is recommended if a mutation is identified in a proband.

Treatment

Treatment for HLRCC focuses on managing symptoms and early detection of renal cancer. Management strategies include:

• Cutaneous leiomyomas: May be treated with pain management, surgical excision, or laser therapy

• Uterine fibroids: Options include hormonal therapy, myomectomy, or hysterectomy for symptom relief

• Renal tumors: Surgical resection (partial or radical nephrectomy) is the preferred treatment; early and aggressive intervention is critical due to high metastatic potential

• Surveillance: Regular renal imaging (e.g., annual MRI starting in childhood or adolescence) for early detection of kidney tumors

• Genetic counseling: Essential for affected individuals and at-risk family members

Prognosis

The prognosis for individuals with HLRCC depends on the presence and early detection of renal cell carcinoma. While cutaneous and uterine leiomyomas are benign and manageable, the kidney tumors associated with this syndrome are often aggressive and may metastasize early. With regular surveillance and early surgical treatment, the outlook can be improved. Lifelong monitoring and personalized care are necessary to reduce cancer-related risks and improve long-term outcomes.