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Cancer syndrome ยท TCA cycleFH (1q43)

Hereditary leiomyomatosis and renal cell cancer

HLRCC; Reed syndrome (older term โ€” particularly in dermatology literature); multiple cutaneous and uterine leiomyomatosis (MCUL โ€” older designation before the renal phenotype was recognised)

Hereditary leiomyomatosis and renal cell cancer is an autosomal dominant cancer-predisposition syndrome caused by germline loss-of-function mutations of fumarate hydratase (FH) on chromosome 1q43 โ€” an enzyme of the tricarboxylic acid (Krebs) cycle. Affected patients develop multiple painful cutaneous piloleiomyomas (smooth-muscle tumours arising from arrector pili) from young adulthood, and women almost universally develop uterine leiomyomas (fibroids) at a young age, frequently requiring multiple myomectomies or early hysterectomy. The most clinically critical feature is the lifetime risk of an aggressive type 2 papillary renal cell carcinoma (15โ€“20% lifetime risk in HLRCC families) โ€” characterised by early metastasis even from small tumours. Recognition by the dermatologist of the multiple painful cutaneous leiomyomas is frequently the first diagnostic opportunity for a syndrome in which annual renal MRI surveillance from childhood saves lives.

CurrentLast reviewed 26 April 2026

Genetics

  • Germline loss-of-function mutations of fumarate hydratase (FH) on chromosome 1q43 โ€” encodes a TCA cycle enzyme that converts fumarate to malate.
  • Loss of FH function in tumour cells leads to accumulation of fumarate, which inhibits prolyl hydroxylases that normally degrade HIF1ฮฑ, leading to pseudohypoxic activation and tumourigenesis.
  • Autosomal dominant; high (~80โ€“90%) penetrance for cutaneous and uterine leiomyomas; ~15โ€“20% renal cell cancer risk.
  • Biallelic FH mutations (homozygous / compound heterozygous) cause the rare fumarate hydratase deficiency syndrome โ€” severe paediatric metabolic encephalopathy.
  • Confirm by germline FH testing.

Cutaneous leiomyomas

  • Multiple firm, skin-coloured to red-brown papules, 0.5โ€“2 cm.
  • Distribution โ€” trunk, extremities, face; often grouped in clusters along Blaschko lines or dermatomes.
  • Onset typically late adolescence to early adulthood; progressive accumulation through life.
  • Pain โ€” characteristic feature; spontaneous and triggered by cold, pressure, emotional stress; often severe and disabling. One of the classical "painful skin tumour" mnemonic entries (along with glomus tumour, eccrine spiradenoma, neuroma, angiolipoma).
  • Smooth-muscle origin from arrector pili.
  • Differential โ€” dermatofibroma, neurofibroma, glomus tumour, spiradenoma, scar.

Uterine leiomyomas

  • ~80% of women with HLRCC develop multiple uterine fibroids by age 35.
  • Symptoms โ€” heavy menstrual bleeding, dysmenorrhoea, infertility, pressure symptoms.
  • Frequently require multiple myomectomies; early hysterectomy common.
  • Counsel about reproductive planning before hysterectomy.

Renal cell carcinoma

  • Lifetime risk in HLRCC families ~15โ€“20%; median age at diagnosis 30โ€“40 years (much younger than sporadic RCC).
  • Type 2 papillary renal cell carcinoma โ€” characteristic histology; aggressive behaviour with early haematogenous and lymph-node metastasis even from small (<3 cm) primaries.
  • Often unilateral, single tumour (vs the multifocal RCC of Birt-Hogg-Dubรฉ or VHL).
  • Standard surveillance recommendation โ€” annual abdominal MRI from age 8 (some guidance supports beginning at age 8โ€“10).
  • Surgical resection of any suspicious lesion โ€” partial or total nephrectomy depending on size / location; do not use active surveillance for small lesions in HLRCC because of the aggressive biology.
  • Metastatic disease โ€” limited response to standard targeted therapy; bevacizumab + erlotinib showed modest activity in clinical trials; immunotherapy emerging.

Diagnosis

  • Clinical suspicion in:
    • Multiple cutaneous leiomyomas (especially painful, in clusters).
    • Single cutaneous leiomyoma plus family history of cutaneous / uterine leiomyomas or RCC.
    • Solitary leiomyoma at a young age (<25).
    • Type 2 papillary renal cell carcinoma at a young age.
    • Multiple severe uterine fibroids in a young woman, particularly with cutaneous lesions or family history.
  • Skin biopsy โ€” characteristic piloleiomyoma histology.
  • Refer to clinical genetics for germline FH testing.
  • Cascade testing of first-degree relatives.

Management

  • Multidisciplinary care โ€” dermatology, gynaecology, urology / nephrology, clinical genetics.
  • Cutaneous leiomyomas โ€” surgical excision of painful / symptomatic / atypical lesions; COโ‚‚ laser, cryotherapy of smaller lesions; medical pain management โ€” ฮฑ-adrenergic blockers (doxazosin, phenoxybenzamine), calcium-channel blockers (nifedipine), gabapentin, pregabalin, AED with neuropathic pain effect.
  • Uterine leiomyomas โ€” myomectomy (preserves fertility), hysterectomy when childbearing complete; hormonal management (GnRH analogues) in selected cases; uterine artery embolisation case-by-case.
  • RCC surveillance โ€” annual abdominal MRI from age 8; immediate surgical resection of any suspicious lesion (do not active surveillance).
  • Genetic counselling and cascade testing.

References

  1. Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer โ€” review. Fam Cancer; 2011.
  2. Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis; 2014.

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