Abstract C012: Further insights into the variable expressivity of fumarate hydratase (FH) – tumor predisposition syndrome

Abstract

Fumarate hydratase (FH) – tumor predisposition syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the fumarate hydratase (FH) gene, which may ultimately lead to clinical manifestations of cutaneous leiomyomata, uterine leiomyomata (fibroids), renal cell carcinoma (RCC), pheochromocytomas, and/or paragangliomas. While the natural history and penetrance pattern of FH-RCC remains unknown, it usually occurs in adults about 30-40 years of age, presents as a solitary lesion, and is highly aggressive. Here, we describe a 16-year-old male with a past medical history of cortical dysplasia with intractable epilepsy (status post (s/p) hemispherectomy and sequelae of left hemiparesis, partial blindness, mild cognitive impairments), and erythrocytosis who presented with fatigue, weight loss, cough, and abdominal pain. Physical exam showed eczematous skin changes, scattered papules, ruddy complexion, and abdominal distention. Initial imaging revealed significant mediastinal lymphadenopathy which prompted subsequent imaging that showed a left renal mass, diffuse bony lesions throughout the skeleton, and widespread lymphadenopathy. Biopsy and next-generation sequencing (NGS) of a prominent iliac lesion revealed a diagnosis of widely metastatic FH-deficient RCC. NGS analysis identified a loss of function missense mutation in the FH gene (FH p.H235D) at a high allelic burden (79%) in exon 5 along with copy number gains of chromosomes 7 and 17. Furthermore, germline testing corroborated this diagnosis with detection of a likely pathogenic variant, FH p.H235D. Family history was notable for uterine fibroids in mother (s/p hysterectomy), colonic polyps and arrhythmia in father, and various cancer types in distant, older relatives. Cascade testing revealed the exact same pathogenic variant, FH p.H235D, in patient’s older sister and mother. Fortunately, patient’s mother and sister remain healthy and are now followed routinely to ensure appropriate tumor surveillance. Unlike these family members, our patient presented with advanced stage RCC requiring a combination of upfront Bevacizumab and Erlotinib therapy, followed by palliative radiation. His disease progressed quickly and therapy was changed to dual immune checkpoint inhibitors, followed by Belzutifan therapy, and then Cabozantinib monotherapy. His disease continued to progress, and he died about 11 months following diagnosis. Interestingly, it remains unclear if our patient’s previous cortical dysplasia (brain) and longstanding erythrocytosis influenced the underlying biology of his FH-RCC. Our case study highlights the unique presentation of widely metastatic, treatment-resistant FH-RCC in a pediatric patient and the importance of germline, somatic, and cascade genetic testing. Moreover, our experience provides further evidence to improve our understanding of FH variant pathogenicity, the natural history pattern of FH-RCC, molecular underpinnings of tumor development, and optimal disease surveillance in pediatric patients with FH-tumor predisposition syndrome.