Familial Cancer

, Volume 10, Issue 2, pp 397–411 | Cite as

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

  • Heli J. LehtonenEmail author


Hereditary leiomyomatosis and renal cell cancer (HLRCC, also known as multiple cutaneous and uterine leiomyomatosis, MCUL) is a highly penetrant autosomal dominant tumor predisposition syndrome characterized by benign leiomyomas of the skin and the uterus. Renal cell carcinomas, occurring in a subset of the HLRCC families, are exceptionally aggressive. Therefore careful, frequent surveillance strategies are recommended. Association of malignant smooth-muscle tumors, leiomyosarcomas, with HLRCC has been observed but the risk appears to be smaller than initially estimated. To date inactivating heterozygous mutations in the fumarate hydratase (FH, fumarase) gene, predisposing to HLRCC, have been found in approximately 180 families worldwide. The most extensively studied hypothesis on molecular mechanisms of HLRCC tumorigenesis is activation of the hypoxia pathway due to aberrant stabilization of the HIF1 transcription factor. HIF1 regulates transcription of genes relevant for vascularization, glucose transport and glycolysis, processes that facilitate tumor growth. However, additional mechanisms underlying tumor formation are likely to exist.


Fumarate hydratase (FH) HIF1 HLRCC Kidney Leiomyoma Leiomyosarcoma MCUL Renal cell cancer Tricarboxylic acid cycle 





Collecting duct carcinoma


Cutaneous leiomyoma


Fumarate hydratase


Fumarate hydratase deficiency


Factor inhibiting HIF


Hypoxia inducible factor 1


Hereditary leiomyomatosis and renal cell cancer


Hereditary papillary renal carcinoma


Glucose transporter 1


Lactate dehydrogenase A


Loss of heterozygosity


Multiple cutaneous and uterine leiomyomatosis


Multiplex ligation-dependent probe amplification


Magnetic resonance imaging


Positron emission tomography-computed tomography


Prolyl hydroxylase domain protein


Renal cell cancer


Succinate dehydrogenase subunit A, B, C or D

TCA cycle

Tricaboxylic acid cycle


Uterine leiomyoma


Uterine leiomyosarcoma


Vascular endothelial growth factor A


Vascular endothelial growth factor receptor


Von Hippel Lindau syndrome



Prof Lauri Aaltonen is acknowledged for the comments on the manuscript. Prof Kristiina Aittomäki and Dr Pia Alhopuro are thanked for consultation on surveillance guidelines and Prof Johanna Arola for help on histopathological items. Ms Johanna Kondelin is thanked for editing the text. Figure 1 is presented by the courtesy of Dr Erik Björck and Fig. 3 is formulated with kind help of Dr Iulia Diaconu.


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© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, Haartman InstituteUniversity of HelsinkiHelsinkiFinland

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