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Approximately 40% of paragangliomas and pheochromocytomas are attributed to hereditary mutations. SDHD mutations account for 7% of inherited mutations (PGL1 syndrome), is maternally imprinted and has variable penetrance. SDHD pathogenic variants (PV) have been previously described extensively in Dutch pedigrees, with a varying lifetime risk for tumor development. Here we report a large family (Fig 1) displaying a SDHD c.129G>A (p.W43X) variation in 12 family members, 10 of whom had screening or tumor history available. The presentation and age of diagnosis in family members showed variable penetrance. Age at first diagnosis of a pheochromocytoma/paraganglioma ranged from 10 - 45 years. Family members displayed bilateral pheochromocytomas, bilateral carotid body tumors, and paragangliomas of the head, neck and trunk with variable recurrence rates (none to multiple). No malignant lesions were detected to date. Pheochromocytomas were norepinephrine producing. Paragangliomas ranged from non-functional to dopamine and norepinephrine producing. Compared to previous reports of other SDHD mutations, the SDHD c.129G>A (p.W43X) variation displayed an earlier age at first diagnosis with a highly variable phenotype ranging from one benign, non-secreting paraganglioma to bilateral pheochromocytomas and recurrent parganagliomas along the parasympathetic chain from head to abdomen. This report contributes to the evolving understanding of the phenotypic presentations of various genetic mutations. We propose that expert guidelines that suggest screening family members with the SDHD c.129G>A (p.W43X) variation at the age of 8 for early detection of pheochromocytomas and paragangliomas is beneficial.

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Tylosis (palmoplantar keratoderma) with esophageal cancer (TOC) also known as Howel-Evans syndrome has been associated with pathogenic mutations in RHBDF2. A potential TOC family was referred for clinical evaluation at the Family Cancer Assessment Clinic (FCAC) at Huntsman Cancer Institute, Salt Lake City, Utah. Multiple relatives of the proband had hyperkeratosis on the areas of skin associated with pressure and friction, especially the feet, as well as oral leukoplakia. The proband’s father, paternal aunt, paternal grandfather, and paternal great grandfather had been diagnosed with esophageal cancer. Clinical testing was unable to identify a germline mutation in RHBDFR2 that explained the observed phenotype and inheritance pattern. As part of Heritage 1K Project (University of Utah), Pediatric & Adult Cancer Section, we performed whole genome sequencing (WGS) on 5 family members, 4 that were affected with the hyperkeratosis, and 1 unaffected family member, to identify other potential genetic causes for the observed TOC phenotype. We prioritized variants via VAAST (Variant Annotation, Analysis and Search Tool). Reducing our genes of interest to those involved in palmoplantar keratoderma with PHEVOR (Phenotype Driven Variant Ontological Re-ranking Tool), we identified a pathogenic mutation: KRT16 c.379C>T p.Arg127Cys. This mutation is reported in a large palmoplantar keratoderma family (without esophageal cancer) and is listed as pathogenic in Clinvar (www.ncbi.nlm.nih.gov/clinvar). KRT16 c.379C>T p.Arg127Cys was present in each of the affected family members, but not in the unaffected relative. Our analysis is the first of its kind to suggest carriers of pathogenic variants in KRT16 are at-risk for esophageal cancer, and may benefit from esophageal surveillance. Additionally, patients presenting with a family history of esophageal cancer should be considered for germline testing for KRT16 mutations along with RHBDF2 mutations. Citation Format: Erin L. Young, Lance Pflieger, Luke Maese, Trent Fowler, Kinley Garfield, N. Jewel Samadder, Bella Johnson, Clinton C. Mason, Barry Moore, Shawn Ryanearson, Mark Yandell, Wendy Kohlmann, Joshua D. Schiffman. KRT16 germline mutation associated with familial syndrome of tylosis with esophageal cancer (TOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2706. doi:10.1158/1538-7445.AM2017-2706