Reed Syndrome (Hereditary Leiomyomatosis and Renal Cell Carcinoma – HLRCC)

Hereditary leiomyomatosis; HLRCC; Multiple cutaneous and uterine leiomyomas (MCUL); Fumarate hydratase-deficiency syndrome.

Reed Syndrome is a rare, autosomal dominant genodermatosis characterized by the triad of multiple cutaneous leiomyomas, early-onset uterine fibroids, and an increased risk of developing aggressive papillary type 2 renal cell carcinoma (RCC). It is caused by germline mutations in the FH (fumarate hydratase) gene.

Extremely rare. Exact prevalence is unknown, estimated at <1:200,000. Symptoms typically manifest in young adulthood. Both sexes affected, though women are more symptomatic due to uterine involvement.

Part of the hereditary cancer predisposition syndromes, specifically FH-related tumor syndromes.

Caused by germline loss-of-function mutations in the FH gene (chromosome 1q43), encoding fumarate hydratase—an essential enzyme of the Krebs cycle. Fumarate accumulation leads to pseudo-hypoxic signaling and oncogenesis via HIF stabilization. Inheritance is autosomal dominant with high penetrance.

• Cutaneous leiomyomas (piloleiomyomas):
  • Multiple painful, firm, skin-colored to reddish-brown papules or plaques
  • Commonly affect the trunk, limbs, and face
  • Pain may be spontaneous or triggered by cold, pressure, or tactile stimuli
• Uterine leiomyomas (in women):
  • Multiple, early-onset, often treatment-refractory
  • Frequently symptomatic: dysmenorrhea, menorrhagia, infertility
• Renal cell carcinoma:
  • Typically papillary type 2 RCC, unilateral, aggressive, and early metastatic
  • Onset typically in early adulthood (20s–40s)

• Clinical: multiple painful cutaneous nodules ± family history
• Histology (skin biopsy): interlacing bundles of smooth muscle cells with central nuclei, no atypia
• Genetic testing: identification of germline FH mutation
• Surveillance: annual renal MRI recommended from adolescence onward

• Skin: predominantly limbs, trunk
• Uterus (in women)
• Kidneys (often unilateral, but bilateral possible)

Young adults presenting with painful skin nodules and/or family history of fibroids or RCC. In men, the first manifestation may be RCC.

Well-circumscribed dermal tumors composed of intersecting bundles of smooth muscle cells. Immunohistochemistry: positive for SMA, desmin, calponin; FH loss can be demonstrated immunohistochemically.

• High lifetime risk of RCC (~15–30%)
• Severe uterine bleeding, infertility
• Chronic pain and psychological burden due to cutaneous tumors

Depends on organ involvement. Cutaneous and uterine manifestations are benign but may be symptomatic. RCC is potentially life-threatening—early detection is critical for survival.

• Predictive genetic testing in at-risk family members
• Lifelong renal MRI screening
• Routine gynecologic follow-up in women

1. Menko FH, et al. HLRCC: Clinical features, management, and molecular insights. Eur J Hum Genet. 2014;22(2):160–166.
2. Toro JR, et al. FH mutations in hereditary leiomyomatosis and RCC. Am J Hum Genet. 2003;73(1):95–106.
3. Alam NA, et al. Multiple cutaneous and uterine leiomyomatosis. Br J Dermatol. 2005;153(3):506–512.
4. Gardie B, et al. FH inactivation in hereditary and sporadic RCC. J Pathol. 2011;224(2):270–280.
5. Lehtonen HJ. HLRCC: Clinical and molecular overview. Fam Cancer. 2011;10(2):397–411.
6. Smit DL, et al. FH mutation genotype–phenotype correlations. Clin Genet. 2020;97(1):85–95.
7. Pithukpakorn M, et al. Hereditary cutaneous leiomyomatosis and RCC. Dermatol Clin. 2004;22(3):271–281.
8. Gill AJ. SDH- and FH-deficient tumors. Histopathology. 2018;72(1):106–116.
9. Merino MJ, et al. RCC in HLRCC: Morphology and outcomes. Am J Surg Pathol. 2007;31(6):881–891.
10. Shuch B, et al. Understanding hereditary kidney cancer. Nat Rev Urol. 2015;12(12):701–711.