Genetic Risk Factors for Early-Onset Merkel Cell Carcinoma.

Importance: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Of the patients who develop MCC annually, only 4% are younger than 50 years. Objective: To identify genetic risk factors for early-onset MCC via genomic sequencing. Design, Setting, and Participants: The study represents a multicenter collaboration between the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Allergy and Infectious Diseases (NIAID), and the University of Washington. Participants with early-onset and later-onset MCC were prospectively enrolled in an institutional review board-approved study at the University of Washington between January 2003 and May 2019. Unrelated controls were enrolled in the NIAID Centralized Sequencing Program (CSP) between September 2017 and September 2021. Analysis was performed from September 2021 and March 2023. Early-onset MCC was defined as disease occurrence in individuals younger than 50 years. Later-onset MCC was defined as disease occurrence at age 50 years or older. Unrelated controls were evaluated by the NIAID CSP for reasons other than familial cancer syndromes, including immunological, neurological, and psychiatric disorders. Results: This case-control analysis included 1012 participants: 37 with early-onset MCC, 45 with later-onset MCC, and 930 unrelated controls. Among 37 patients with early-onset MCC, 7 (19%) had well-described variants in genes associated with cancer predisposition. Six patients had variants associated with hereditary cancer syndromes (ATM = 2, BRCA1 = 2, BRCA2 = 1, and TP53 = 1) and 1 patient had a variant associated with immunodeficiency and lymphoma (MAGT1). Compared with 930 unrelated controls, the early-onset MCC cohort was significantly enriched for cancer-predisposing pathogenic or likely pathogenic variants in these 5 genes (odds ratio, 30.35; 95% CI, 8.89-106.30; P < .001). No germline disease variants in these genes were identified in 45 patients with later-onset MCC. Additional variants in DNA repair genes were also identified among patients with MCC. Conclusions and Relevance: Because variants in certain DNA repair and cancer predisposition genes are associated with early-onset MCC, genetic counseling and testing should be considered for patients presenting at younger than 50 years.

Bilateral Internal Carotid Artery Agenesis in a Patient With a Family History of Intracranial Pathology.

Background: Agenesis of the internal carotid artery (ICA) is a rare congenital malformation that is often asymptomatic until the fourth or fifth decade. ICA agenesis is associated with several intracranial pathologies, the most reported being intracranial aneurysms, thought to be attributable to the increased flow in the collateral vessels supplying the anterior circulation. The cause of ICA agenesis is largely unknown and has not been consistently associated with any genetic mutations or syndromes. Case Report: We present the case of a 37-year-old female who was incidentally found to have bilateral agenesis of the ICA system. Patient history revealed that the patient's father and 12 of his 14 siblings died from either ruptured brain aneurysms or cerebrovascular accidents before the age of 50 years. Presenting symptoms included right eye pain radiating to her right posterior neck, a 2-month history of diplopia, and associated nausea and vomiting. Differential diagnoses included immunoglobulin G4-related disease, sarcoidosis, lymphoma, and vasculitis. Absent internal carotids were attributed to congenital agenesis vs hypoplasia. The patient was seen by neurology and initiated on prednisone 80 mg by mouth once daily with a 2-week taper to treat systemic inflammation. The patient was deemed stable for discharge after a 2-day hospital admission and was scheduled for follow-up appointments with genetics, neurology, rheumatology, and ophthalmology. Conclusion: Bilateral ICA agenesis is a rare occurrence, with only 33 cases documented in a case report and literature review published in 2016. Because of the otherwise normal anatomy of the patient and the pervasive intracranial pathology seen in late adulthood in her family, we propose the likelihood of an inheritable form of bilateral ICA agenesis vs vascular disease or familial aneurysms.

Digital Papillary Adenocarcinoma: Case of a Rare Malignant Cutaneous Tumor of the Eccrine Sweat Gland.

Digital papillary adenocarcinoma (DPA) is a rare cutaneous tumor originating from the eccrine sweat glands. These lesions occur almost exclusively on the digits of the hands and feet, where there is a high concentration of eccrine glands. The diagnosis is made histologically, and the course of the malignancy tends to be very aggressive with high rates of recurrence and early metastasis at the time of diagnosis. Due to the low incidence of these lesions, there have been minimal objective data from clinical studies to recommend specific treatment strategies. Wide local excision versus digital amputation proximal to the lesion has been debated for primary treatment, while there are no data to support routine implementation of adjuvant chemotherapy or radiation, despite its metastatic nature. This article presents a case of long-standing, previously undiagnosed DPA. The lesion appeared more inconspicuous on gross examination than other reports in the literature, and diagnosis was made with punch biopsy and confirmed postsurgically. To date, the patient has not had recurrence, although she is being monitored for potential metastatic deposits in her lungs. Clinical dermatologists should be aware of the high mortality burden this lesion may inflict if left undiagnosed or mistreated.