This protocol covers testing for dominant pathogenic variants in the fumarate hydratase (FH) gene which are associated with the familial tumour syndrome, hereditary leiomyomatosis and renal cell carcinoma (HLRCC). This protocol does not cover pathogenic variant testing for the recessive metabolic disorder fumarate hydratase deficiency.
1. An individual with clinical features suggestive of HLRCC:
- renal cell carcinoma (RCC) with histopathology consistent with HLRCC*r and/or FH deficient on immunohistochemistry or
- multiple cutaneous leiomyomas (at least one histopathologically confirmed) or
- uterine leiomyoma with atypical FH-associated pathology and/or which is FH deficient on immunohistochemistry.r
2. An individual with two or more of the following:
- a single cutaneous leiomyoma (histopathologically confirmed)
- multiple symptomatic uterine leiomyomas
- RCC with HLRCC-associated pathology (expert pathology review may be required)*
- AND a first-degree relative with a clinical feature of HLRCC.
If there are two individuals affected with symptomatic uterine leiomyomas, then another HLRCC feature must also be present to consider HLRCC.
3. First degree relative of a child with fumarate hydratase deficiency due to biallelic pathogenic variants in the FH gene.
4. Where a known germline pathogenic variant identified in a relative.*
5. Where a specific pathogenic variant has been identified on somatic tumour testing *
*In these settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective.
Genetic testing is important for good clinical care of individuals who are suspected of having a heritable pathogenic variant in this gene.
*HLRCC-associated RCCs are predominantly high-grade with a papillary growth pattern. However, HLRCC-associated RCCs have been described to show tubulopapillary, tubulocystic, tubular, solid and cystic areas and may overlap morphologically with collecting duct carcinomas. Multiple architectural patterns, including sarcomatoid and rhabdoid components, may be seen within the same tumour. Large nuclei with prominent orangiophilic or eosinophilic nucleolus surrounded by a clear halo are often observed.rr