; for the Regeneron Genetics Center (RGC) Research Team IMPORTANCE Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. OBJECTIVE To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. DESIGN, SETTING, AND PARTICIPANTS A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. MAIN OUTCOMES AND MEASURES Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. RESULTS Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009). CONCLUSIONS AND RELEVANCE This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

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Infantile digital fibromatosis (IDF), or inclusion body fibromatosis, is a rare benign tumor that commonly presents as a solitary nodule composed of spindle cells within the dermis on the digits of infants and children. Evaluation often includes a biopsy and typical therapies include observation, intralesional corticosteroid injections, and complete surgical resection. Given the rarity of IDF, few clinicians have direct or extensive experience diagnosing or treating it. Here we present a comprehensive review of the presentation, diagnosis, and treatment for IDF.

According to the recommendations of the European League Against Rheumatism, a diagnostic finding in temporal artery DUS in a patient with GCA symptoms may be sufficient to make a positive diagnosis. 1 In our cohort, DUS findings indicative of GCA were significantly associated with positive TAB results.The length of the artery specimen biopsied determines the likelihood of a positive TAB result, increased by 3.4% with every additional millimeter. Samples shorter than 0.5 cm are more likely to give a negative result. 5 We observed in our study that longer length of biopsy specimen was correlated with higher probability of a positive result. Current guidelines recommend specimens of between 1 and 2 cm. 1 The main limitation of our study is its retrospective design and the sample size as this disease is infrequent. Our results should be confirmed in a larger and prospective study.In conclusion, dermatologists are qualified to perform TAB, with results comparable with those of other surgical specialists. TAB is still the gold standard for diagnosis of GCA, although DUS findings may be highly predictive of biopsy results. Patients with high suspicion of GCA should first undergo a noninvasive study such as DUS, and TAB should be considered if the DUS results are inconclusive. A standardized surgical protocol is needed to guarantee an adequate length of the artery specimen.

Algorithm based smartphone apps to assess risk of skin cancer in adults: systematic review of diagnostic accuracy studies. BMJ 2020; 368: m127.