Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

Hereditary leiomyomatosis and renal cell cancer syndrome is an autosomal dominant disorder caused by germline FH variants, with cutaneous and uterine leiomyomas and an aggressive form of papillary renal cell carcinoma. Renal tumours can metastasise when small, so early detection and surgery matter.

Pathophysiology. FH encodes fumarate hydratase. Loss of function causes fumarate accumulation, which blocks prolyl hydroxylases, stabilises hypoxia inducible factors and alters epigenetic control, driving tumour growth.

Biallelic loss causes the recessive fumarate hydratase deficiency, a severe infantile encephalopathy.

Renal cancer risk is lower than for the skin and uterine disease, but outcomes are poor when it arises.

• Multiple cutaneous leiomyomas: firm pink or brown papules or nodules, painful with cold or touch
• Uterine leiomyomas (fibroids) at a young age, with heavy bleeding
• Renal cell carcinoma: often type 2 papillary or collecting duct, unilateral and solitary
• Haematuria, flank pain or mass in renal cancer
• Rarely uterine leiomyosarcoma
• Adrenal and other tumours in some

• Genetic testing of FH with deletion and duplication analysis, in people with multiple cutaneous leiomyomas, early onset fibroids or papillary renal cancer with a suggestive family history.
• Skin biopsy of a lesion showing smooth muscle tumour.
• Renal imaging: contrast enhanced MRI of the abdomen, which is preferred to CT.
• Pelvic ultrasound for fibroids.
• Immunohistochemistry of renal tumours: loss of fumarate hydratase or raised succinated protein (2SC) supports the diagnosis.
• Cascade testing of relatives from adolescence.

Differential diagnosis.

• Birt-Hogg-Dubé syndrome
• Hereditary papillary renal carcinoma
• Von Hippel-Lindau disease
• Succinate dehydrogenase deficient renal cancer
• Sporadic papillary renal cell carcinoma
• Multiple cutaneous leiomyomas of other cause

• Renal surveillance: yearly contrast enhanced MRI of the abdomen from about 8 to 10 years of age.
• Renal lesions: any solid lesion needs urgent surgical removal with wide margins (partial or radical nephrectomy, with retroperitoneal lymph node dissection in suspicious cases). Active surveillance is not advised.
• Metastatic disease: bevacizumab 10 mg/kg intravenously every 2 weeks with erlotinib 150 mg orally daily, or other systemic therapy including cabozantinib 60 mg daily or immune checkpoint combinations, in a specialist centre.
• Cutaneous leiomyomas: surgical excision, cryotherapy or laser for symptomatic lesions. For pain, use nifedipine 10 to 30 mg orally three times daily, doxazosin 1 to 4 mg daily, gabapentin 300 mg increasing to 900 to 1800 mg daily in divided doses, or amitriptyline 10 to 50 mg at night. Botulinum toxin injection is an option.
• Uterine fibroids: hormonal control of bleeding, myomectomy or hysterectomy. Examine tissue for leiomyosarcoma, and avoid morcellation.
• Skin check: yearly review for change.
• Genetic counselling: 50% chance of the variant for each child.

Special groups.

• Pregnancy: fibroids and cutaneous lesions may enlarge, and MRI is delayed until after delivery unless urgent.

Monitoring. Yearly renal MRI, skin review and gynaecological review. Kidney function before and after contrast.

Referral and escalation. Refer to clinical genetics, urology and dermatology. Urgent for haematuria, flank pain, a new renal lesion, or rapid fibroid growth.