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A retrospective review of 48 individuals, including 12 families, molecularly diagnosed with hereditary leiomyomatosis and renal cell cancer (HLRCC)

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Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by autosomal dominant germline mutations in the fumarate hydratase (FH) gene and is characterized by cutaneous leiomyomas, uterine leiomyomas and aggressive renal malignancies. We conducted a retrospective chart review to characterize the patients referred to our Regional Genetics Program for assessment of HLRCC from 2004 to mid-2016. Forty-eight of 69 (69.5%) referred individuals were positive for a pathogenic or likely pathogenic variant in FH; they had an average age of 39.1 years. There were 11 different FH variants among them. As expected, the most sensitive indications for a positive genetic test were papillary renal cell carcinoma (RCC) at a young age (5/5; 100%) and multiple cutaneous leiomyomas (18/19; 95%). However, only twenty-two of 48 (46%) individuals with a positive molecular test had cutaneous leiomyomas, which is considerably lower than previously reported and supports the likelihood of ascertainment bias in previous reports. Notably, we have experience with 1 large family in which there were no cutaneous leiomyomas across a large age range. We confirm that multiple cutaneous leiomyomas and papillary RCCs at a young age have a high positive predictive value for a molecular diagnosis of HLRCC, but that cutaneous leiomyomas are less prevalent in HLRCC than previously understood, and therefore the condition is likely to be under-ascertained. Our understanding of the phenotypic spectrum of HLRCC is still evolving.

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Abbreviations

FA:

Fumaric aciduria

FH:

Fumarase hydratase

HIF:

Hypoxia inducible factor

HLRCC:

Hereditary leiomyomatosis and renal cell cancer

NRF2:

Nuclear erythroid 2-like 2 transcription factor

RCC:

Renal cell carcinoma

2SC:

S-(2-succinyl) cysteine

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Authors and Affiliations

  1. Department of Genetics, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada

    Priya T. Bhola, Cathy Gilpin, Amanda Smith & Gail E. Graham

  2. Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada

    Gail E. Graham

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  1. Priya T. Bhola
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  2. Cathy Gilpin
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  3. Amanda Smith
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  4. Gail E. Graham
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Correspondence to Priya T. Bhola.

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Bhola, P.T., Gilpin, C., Smith, A. et al. A retrospective review of 48 individuals, including 12 families, molecularly diagnosed with hereditary leiomyomatosis and renal cell cancer (HLRCC). Familial Cancer 17, 615–620 (2018). https://doi.org/10.1007/s10689-018-0076-4

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  • DOI: https://doi.org/10.1007/s10689-018-0076-4

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