Hereditary Leiomyomatosis and Renal Cell Cancer

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

What is Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)/FH tumour predisposition syndrome?

HLRCC/FH tumour predisposition syndrome (OMIM#150800, ORPHA:523) is reported in more than 300 families and is likely to be an under-recognized genetic disorder. Prevalence is unknown, older estimates suggest 1:200.000 individuals.

Affected individuals are at an increased risk of developing the following benign and malign tumours:

  • Cutaneous leiomyomas (50%), mean age of 30 years. They are skin coloured to light brown papules or nodules distributed mainly over the trunk and extremities and often painful or sensitive to touch;
  • Uterine leiomyomas (90% of females), mean age of 30 years. Women often undergo hysterectomy or myomectomy for symptomatic uterine fibroids at a younger age (median age of 35) compared to the general population;
  • Renal cancer (15%), usually papillary type 2, median age of 40 years (1% to 2% before age 20). Most tumours are unilateral, solitary, aggressive and a large number of individuals are asymptomatic;
  • Pheochromocytoma, paraganglioma, uterine and skin leiomyosarcomas have also been described;
  • Other tumours reported in individuals with germline FH pathogenic variants, like breast cancer, require further data.

What causes HLRCC/FH tumour predisposition syndrome?

HLRCC/FH tumour predisposition syndrome is caused by a germline heterozygous pathogenic variant in the fumarate hydratase gene (FH).

How is HLRCC/FH tumour predisposition syndrome inherited?

HLRCC/FH tumour predisposition syndrome is inherited in an autosomal dominant manner, meaning that each child of an affected individual has a 50% chance to inherit the familial FH likely pathogenic/pathogenic variant and is at risk of developing disease. Preimplantation and prenatal genetic testing are possible if the pathogenic variant has been identified.
Germline pathogenic variants in both copies of FH gene lead to fumarate hydratase deficiency, an autosomal recessive syndrome. Affected children have a short lifespan and a severe neurologic impairment (OMIM#606812, ORPHA:606812). This should be considered in genetic counselling.

What are the surveillance options for HLRCC/FH tumour predisposition syndrome?

Individuals at risk should have periodic dermatological and gynaecological evaluation. Yearly renal MRI should be performed from an early age (8-10 years).

 
Clinical practice guideline

Currently unavailable

 

Care pathway

Currently unavailable

 

Patient journey

Currently unavailable