Severe neonatal hypercalcemia caused by subcutaneous fat necrosis without any apparent cutaneous lesion.

International audienceSubcutaneous fat necrosis is a classic, albeit uncommon, cause of neonatal hypercalcemia. It occurs in newborn infants within the first month of life following a complicated delivery. The diagnosis is usually easy because of the presence of red-purple plaques in fatty areas along with firm subcutaneous nodules. A 1-month-old neonate, born strangled by her umbilical cord, presented with diarrhea and hypercalcemia (3.46 mM) with an initial physical examination considered normal. Her biological evaluations were as follows: P = 1.37 mM (1.6-2.2); PTH = 3 ng/L (12-65); 25-OH vitamin D = 87 nM (23-113); (1,25)-OH(2) vitamin D = 192 ng/L (20-46). The third day, a careful exam of the whole cutaneous surface revealed small firm subcutaneous nodules in the ischial region. Despite the absence of any visible skin modification, the association of perinatal stress and high (1,25)-OH(2) vitamin D level with subcutaneous nodules led to the diagnosis of subcutaneous fat necrosis. She was treated with oral prednisone for 45 days. Serum calcium levels normalized within a week, and the nodules disappeared without complications. Conclusion: Subcutaneous fat necrosis may induce severe hypercalcemia without any visible cutaneous lesion

{DNA} methylation heterogeneity defines a disease spectrum in {Ewing} sarcoma

Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine