Pathogenic variants in the tumor suppressor gene NF1 cause neurofibromatosis type 1 (NF1), one of the most common hereditary cancer predisposition syndromes. Pathogenic NF1 variants have been associated with an increased risk of several cancers; however, the relationship between NF1 variation and colon cancer remains underreported. We report a 41-year-old woman with a mosaic monoallelic germline pathogenic NF1 variant, NM_000267.3:c.1756_1759del (p.Thr586Valfs*18), previously detected on germline multigene panel testing in saliva at a variant allele frequency of approximately 35%. She later presented with fatigue, dyspnea on exertion, and iron-deficiency anemia. Computed tomography, colonoscopy, biopsy, mismatch repair immunohistochemistry, surgical pathology, and tumor next-generation sequencing led to the diagnosis of right-sided colon adenocarcinoma that was mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H). She underwent right hemicolectomy, recovered postoperatively, and entered standard surveillance; at the time of manuscript development, she was also receiving systemic therapy. This case highlights the co-occurrence of an NF1 variant and dMMR colorectal cancer and underscores the need for further studies to determine whether this represents a coincidental finding or a biologically meaningful association.
Feras Alsabagh, Karam M. Chaaban, M. Girardo et al.· Exploration of Neuroscience· 0 citations
Background Loeys–Dietz syndrome (LDS) is a heritable connective tissue disorder caused by pathogenic variants in genes of the transforming growth factor‐β (TGF‐β) signaling pathway. Although genotype–phenotype correlations have been suggested, comprehensive comparative data across LDS subtypes remain limited. Improved understanding of these correlations is essential to guide individualized surveillance and management strategies. Methods We conducted a retrospective cohort study of adults with genetically confirmed LDS evaluated between 2018 and 2024 across Mayo Clinic sites. Patients with pathogenic, likely pathogenic, or suspicious variants in TGFBR1, TGFBR2, or SMAD3 were included. Clinical characteristics, physical examination findings, cardiovascular and noncardiovascular manifestations, surgical interventions, and mortality were compared across genotypes. Categorical variables were analyzed using chi‐square tests and continuous variables using parametric or nonparametric methods as appropriate. Results A total of 93 patients were included (29 TGFBR1, 33 TGFBR2, 31 SMAD3). Demographics and mortality did not differ significantly between groups. Patients with TGFBR1 and TGFBR2 demonstrated trends toward higher rates of ascending aortic aneurysm and aortic dissection compared with SMAD3 patients, though these differences were not statistically significant. Renal artery aneurysms were significantly more common in TGFBR1 patients (13.8%, p = 0.010). SMAD3 patients had significantly higher rates of mitral regurgitation (54.8%, p = 0.04), peripheral neuropathy (29.0%, p = 0.018), and trends toward increased atrial fibrillation and osteoarthritis. A novel association was identified between TGFBR1 variants and migraine, which was significantly more prevalent in this group (62.1%, p = 0.017). The rates of major cardiovascular surgical interventions were high and comparable across all genotypes. Conclusion Distinct genotype–phenotype associations exist among LDS subtypes. TGFBR1 and TGFBR2 variants are associated with a greater burden of aggressive vascular disease, whereas SMAD3 variants are linked to mitral valve disease, peripheral neuropathy, and osteoarthritis. We also identified a novel association between TGFBR1 genotype and migraine. These findings reinforce the importance of comprehensive genetic testing to inform personalized surveillance and management strategies in LDS.
Hussein Abdul Nabi, L. Dreher, Jack Hartnett et al.· Human Mutation· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
