Mastocitosi cutanee: il mastocitoma in età pediatrica

Background: Mastocytosis is a rare disease involving mast cells (MC) and their CD34+ progenitors. According to the WHO consensus classification, cutaneous mastocytosis (CM) is considered a benign disease confined to the skin, preferentially seen in young children with a marked tendency to regress spontaneously. Aim of our study was the long-term assessment of the outcome of solitary (SM) and multiple (MM) mastocytomas in a pediatric population. Materials and methods: From January 1996 to December 2010, 241 pediatric patients with a diagnosis of CM were followed-up at the outpatient division of pediatric dermatology of the University of Bologna. We focused our retrospective evaluation on patients affected by SM or MM. We collected, through the analysis of medical records and with a telephone questionnaire for patients and their families, information on clinical aspects of the disease evolution and on the efficacy of topical steroid therapy. Results: Over the 241 considered patients we recorded: SM or MM in 176 (73%) pts., urticaria pigmentosa in 53 (22%) pts., telangiectasia macularis eruptiva perstans in 9 (4%) pts., diffuse CM in 2 (0,9%) pts. and polymorph CM in 1 (0,4%) pt. On 176 children affected by SM or MM (97 M vs. 79 F), 130 (74%) patients were followed-up with a mean of 56,3 (r. 4-142) months. A satisfactory outcome was recorded in 99 (76%) cases of whom 52 (53%) treated with topic steroids. Mean time to complete regression was 16.4 m. on treated patients vs. 34.7 m. on non treated patients (p=0,001). Conclusions: From our study emerged that resolution of the disease is independent from therapy, but the time to regression and to complete recovery of the coetaneous lesions is faster and favored by the application of topic steroid with an improvement of the quality of life for children and their families.

The KIT gene in familial mastocytosis

Familial cutaneous mastocytosis is an exceptional condition of unknown etiology. In this study we report the largest series of patients with familial cutaneous mastocytosis without other manifestations (18 affected subjects from seven unrelated families), and we investigate the role of germ-line KIT mutations in the pathogenesis of the disease. The mean age at onset was 5.4 years (range from birth to 22 years), and the clinical behavior was variable over a mean follow up period of 15.1 years (range 2-36): improvement in seven, stability in eight and worsening in the remaining three patients. The pattern of inheritance was compatible with an autosomal dominant trait with incomplete penetrance; a female preponderance (14 females vs 4 males, ratio 3.5:1) was noted; among the six women who have been pregnant at least once, three experienced important clinical changes during pregnancy. No germ-line mutation was found in the exons 10, 11, and 17 of the KIT proto-oncogene, which are the most commonly mutated exons in sporadic mastocytosis. However, in the majority of affected subjects we found the Met541Leu polymorphic variant of the KIT gene, which seems to confer a growth advantage to mast cells in vitro. This observation further suggests that the Met541Leu may be a predisposing factor of cutaneous mastocytosis, although it seems to be neither necessary nor sufficient for the development of the disease.

Resetting SETD2/H3K36ME3 deficiency in advanced systemic mastocytosis

Systemic Mastocytosis (SM) is a hematological disorder characterized by abnormal proliferation of mast cells in various organs, ranging from indolent variants to advanced entities with poor prognosis. The KIT D816V gene mutation drives mast cell growth, but its presence alone is not fully transforming. The SETD2 gene, responsible for maintaining genomic integrity, is often impaired in advanced SM (advSM), leading to reduced expression of histone marker H3K36Me3. Proteasome inhibitors are effective in restoring SETD2 function and suppressing mast cell growth, offering an alternative therapy for patients resistant to tyrosine kinase inhibitors. Aberrant expression of Plk1 and Aurora kinase A correlates with SETD2 loss and can be targeted with inhibitors like alisertib and volasertib, leading to reduced cell growth and apoptosis. Additionally, inhibition of Wee1 enhances apoptosis and reduces colony growth in SM cells. Molecular diagnostic techniques like droplet digital polymerase chain reaction (ddPCR) offer a less invasive and reliable method for detecting the D816V mutation in peripheral blood, and efforts to standardize molecular assays across laboratories show promising reproducibility. Overall, this research provides new insights into the mechanisms of advanced SM, identifies potential therapeutic targets, and validates molecular diagnostic tools for SM diagnosis.