Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers

We addressed uncertainties regarding hereditary leiomyomatosis and renal cell carcinoma ( HLRCC ) by exploring all French cases, representing the largest series to date. Fumarate hydratase ( FH ) germline testing was performed with Sanger sequencing and qPCR / MLPA . Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S‐(2‐succino)‐cysteine ( 2SC )/fumarate hydratase immunohistochemistry. We estimated survival using non‐parametric Kaplan‐Meier. There were 182 cases from 114 families. Thirty‐seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, 13 were papillary type 2. There were 4 papillary RCC of unspecified type, 3 unclassified, 2 tubulocystic, and 1 collecting duct ( CD ) RCC , all 2SC + and most (8/10) FH −. Of the remaining 14, papillary type 2, papillary unspecified, CD , and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95% CI : 11‐29). 133 cases (73%) had a history of cutaneous leiomyomas, 3 developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only 2 cases had pheochromocytomas/paraganglioma. Conclusion Our findings have direct implications regarding the identification and management of HLRCC patients.