Piloleiomyoma and renal cell carcinoma in a 30-year-old woman with hereditary leiomyomatosis and renal cell cancer syndrome

A 30-year-old woman was referred to our oncogenodermatology clinic following her first cousin’s diagnosis of hereditary leiomyomatosis and renal cell cancer (HLRCC), associated with a germline pathogenic variant in the fumarate hydratase gene (FH). Our physical examination revealed several firm, tender nodules on her back and arm (Figure 1). She reported heavy, irregular menses, and pelvic ultrasonography showed a small uterine fibroid. Genetic testing confirmed she had the familial FH variant, and baseline abdominal magnetic resonance imaging (MRI) showed an 8-mm enhancing lesion in the left kidney (Figure 2). She underwent a partial nephrectomy, and the pathologist confirmed the mass was a renal cell carcinoma typical of HLRCC (Appendix 1, Figures S1 and S2, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.251507/tab-related-content). She remained disease free 10 months later.

Figure 1:

Cutaneous piloleiomyomas, appearing as well-circumscribed, firm, reddish-brown papules, on the back of a 30-year-old woman with hereditary leiomyomatosis and renal cell cancer.

Figure 2:

Axial magnetic resonance imaging, including T₁-weighted (A) precontrast and (B) post-contrast (nephrographic phase) images, showed an 8-mm enhancing lesion in the left kidney (yellow arrow), detected shortly after genetic testing confirmed she had the familial fumarate hydratase variant.

Hereditary leiomyomatosis and renal cell cancer is an autosomaldominant cancer predisposition syndrome caused by germline pathogenic variants in FH.¹ Population sequencing data sets have indicated that the carrier frequency of FH germline pathogenic variants is roughly 1 in 1000 to 1 in 1300.² Missed diagnosis can lead to death from aggressive renal cancer. More than 90% of affected individuals develop piloleiomyomas (firm, sometimes painful skin nodules) between the ages of 20 and 40 years.³ The presence of at least 1 biopsy-proven piloleiomyoma has more than a 90% positive predictive value for HLRCC and is a major diagnostic criterion, as is FH-deficient renal cancer.³ Nearly all females with this germline pathogenic variant develop uterine fibroids, usually before age 40 years; these are often larger and more symptomatic than sporadic fibroids and frequently necessitate early hysterectomies. ¹ The lifetime risk of renal cancer in HLRCC is roughly 15%, but tumours are aggressive and often metastasize.^1,2 Red flags that should prompt investigation for HLRCC include cutaneous piloleiomyomas, early-onset uterine fibroids, renal cancer, or a first-degree relative with a red flag (Appendix 1, Figure S3).^1,3 Recognition of these features warrants referral to a geneticist. Patients with HLRCC require multidisciplinary care (e.g., from gynecology, urology, dermotology), including annual renal MRI starting at 8 to 10 years of age, fertility counselling, renal lesion assessment, and piloleiomyoma management.¹ Cascade testing — starting with first-degree relatives and expanding outward — can identify additional variant carriers.