When Mast Cells Run Amok: A Comprehensive Review and Case Study on Severe Neonatal Diffuse Cutaneous Mastocytosis

Abstract

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is in the KIT gene. We report a rare case of a boy, born at term, already presenting at birth with generalized subcutaneous nodules on the face, scalp, trunk, back, hands, and feet. The spleen, liver, and inflammatory markers were normal at birth. Tryptase was significantly elevated. A bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin-fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical and inguinal adenopathy, while the skin nodules persisted, especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation; however, compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive, and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement.

Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease

“…According to current knowledge, genetic drivers, epigenetics, and both hormonal and metabolic factors involved in the pathogenesis of pediatric mastocytosis are poorly understood [ 1 , 3 , 8 ]. However, numerous studies show that children with DCM can carry different somatic mutations in exon 17 of KIT (D816V, D816Y, or D816I), as well as mutations in other exons (Del419, K509I, or internal tandem duplication A502_Y503dup) [ 18 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Familial mastocytosis is a specific form of the disease in which mostly germline KIT mutations are detected in affected family members [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ].…”

“…Furthermore, numerous studies have shown that rubbing and scratching of the skin, sudden temperature changes (such as hot baths or exposure to heat), teething, viral infections, or vaccinations may induce blistering or provoke other MC mediator-related symptoms [ 13 , 28 , 40 , 58 , 59 ]. A brief review of case reports on DCM, published since 1962, is presented in Table 2 [ 28 , 35 , 36 , 38 , 39 , 40 , 41 , 52 , 53 , 54 , 58 , 60 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ].…”

“…Furthermore, numerous studies have shown that rubbing and scratching of the skin, sudden temperature changes (such as hot baths or exposure to heat), teething, viral infections, or vaccinations may induce blistering or provoke other MC mediator-related symptoms [13,28,40,58,59]. A brief review of case reports on DCM, published since 1962, is presented in Table 2 [28,35,36,[38][39][40][41][52][53][54]58,60,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]. As mentioned above, the familial occurrence of DCM has also been reported [52][53][54].…”

Current Challenges in the Diagnosis of Pediatric Cutaneous Mastocytosis

“…Extensive blistering, presenting as both small vesicular lesions and large hemorrhagic bullae, is a dominant clinical manifestation in infancy (Figure 5), while a leather-like appearance and hyperpigmentation (brown or yellow colour of the skin) develops in the further course of DCM [7,9,43,52,54,55]. DCM is associated with severe MC mediator-related symptoms and a higher risk of anaphylactic shock than in other forms of CM [39,42,48,50,54,58,59]. The large MC infiltration of the infant's entire skin and an unfavorable ratio of the body weight to body surface area are the reasons for DCM patients usually presenting with elevated serum tryptase levels [7,9,26,42,53].…”

“…In children with CM, the most common are cutaneous MC mediator-related symptoms, including pruritus, flushing, blistering and dermographism, regardless of the subtype of CM [39,41,47,59]. Pruritus is the most commonly reported symptom [6].…”