[MACULOPAPULAR CUTANEOUS MASTOCYTOSIS HARBORING A KIT MUTATION (ASP419DEL): A CASE REPORT].

A 2-year-old, male patient presented with an 18-month history of scattered, brown macules and nodules up to 2 cm in size on his trunk and extremities. These macules were accompanied by pruritus and were positive for Darier's sign. A skin biopsy of a brown macule on the left thigh revealed a dense accumulation of CD117-positive, round or oval cells with amphophilic cytoplasm within the upper to middle dermis. The patient was otherwise healthy and had normal laboratory and imaging test results. Sequence analysis of genomic DNA from a skin biopsy demonstrated the presence of an Asp419del mutation in exon 8 of the KIT gene. Based on these findings, maculopapular cutaneous mastocytosis (MPCM) was diagnosed. The patient received H 1-antihistamine. Although the pruritus resolved, the brown macules remained for one year after the initial treatment. To the best of our knowledge, only three cases of cutaneous mastocytosis (CM) with an Asp419del mutation, including the present case, have been reported in the Japanese literature to date; moreover, while the previous two cases were of DCM, the present case was the first instance of MPCM. Normally, the symptoms of childhood-onset MPCM are dormant until puberty. However, a recent study reported that many MPCM patients may experience persistent or exacerbated symptoms. The present study therefore evaluated 53 Japanese cases of childhood onset MPCM with a KIT gene mutation and discussed the patients' clinical outcomes.

Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease.

Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM) is a rare and most severe form of cutaneous mastocytosis, which typically occurs in childhood. There have been reports of a familial DCM with specific gene mutations, indicating both sporadic and hereditary factors involved in its pathogenesis. DCM is associated with severe MC mediator-related symptoms and an increased risk of anaphylaxis. The diagnosis is based on the appearance of skin lesions, which typically show generalized thickening, erythroderma, blistering dermographism, and a positive Darier's sign. Recognition, particularly in infants, is challenging due to DCMs resemblance to other bullous skin disorders. Therefore, in unclear cases, a skin biopsy is crucial. Treatment focuses on symptom management, mainly including antihistamines and mast cell stabilizers. In extremely severe cases, systemic steroids, tyrosine kinase inhibitors, phototherapy, or omalizumab may be considered. Patients should be equipped with an adrenaline autoinjector. Herein, we conducted a comprehensive review of literature data on DCM since 1962, which could help to better understand both the management and prognosis of DCM, which depends on the severity of skin lesions, intensity of mediator-related symptoms, presence of anaphylaxis, and treatment response.

Mastocytosis in the skin in dogs: A multicentric case series.

Canine cutaneous mastocytosis (CM) is rare in contrast to canine mast cell tumours. In humans, CM commonly affects children and is usually indolent with possible spontaneous resolution. Systemic mastocytosis (SM) with bone marrow involvement typically affects adults, can have a poor outcome, and often includes skin lesions. 'Mastocytosis in the skin' (MIS) is the preferred term of skin lesions, if bone marrow evaluations are not available, which is often the cases in dogs. In human SM and CM, KIT mutations are often detected. The veterinary literature suggests clinical resemblances between human and canine MIS, but data is limited, and KIT mutations are rarely assessed. This retrospective study describes clinicopathological findings, treatment and outcome of 11 dogs with suspected MIS. Dogs with multiple mast cell tumours were excluded. Histopathology reports (n = 5) or slides (n = 6) were reviewed. KIT mutation analysis including exons 8, 9, 11, 14 and 17 were analysed in eight dogs. Median age at diagnosis was 4 years (range, 1-12). Typical clinical signs included multifocal to generalised nodules and papules. Histologically, skin lesions were characterised by dermal infiltration of well-differentiated mast cells. KIT mutations were detected in 3/8 dogs (exon 9: n = 2; exon 11: n = 1). One dog had mastocytaemia suggesting possible SM. Glucocorticoids were mostly successful with lesion improvement in all treated dogs (n = 8). This cohort highlights resemblances between human and canine MIS. Further studies are required to confirm these findings and establish diagnostic criteria for CM and MIS associated with SM in dogs.

Characteristics of an ethnically diverse cohort of children with pediatric cutaneous mastocytosis: One institution's experience.

There has been limited research exploring how the demographic characteristics of children with pediatric cutaneous mastocytosis (PCM) may influence both the cutaneous and systemic symptoms. In this observational retrospective study of 51 children with PCM, we found a significantly higher rate of gastrointestinal (GI) symptoms in children of Hispanic ethnicity (4/21,19%) compared to non-Hispanics (0/30, 0%, p = 0.024). While this finding may reflect the high proportion of Hispanics in our population, a racial predisposition toward distinct systemic symptoms may be possible. We also found a significantly lower proportion of Hispanic children being diagnosed with PCM under the age of 3 years (47.6%) when compared with non-Hispanic children (76.7%, p = 0.03), suggesting that more data are needed to further assess the role of ethnicity and healthcare disparities in PCM diagnosis. Larger prospective studies are necessary to better evaluate the association between ethnicity, early diagnosis, and systemic symptoms in PCM and to describe its impact on long-term outcomes.

Evaluation of Ki67, Bax, Bcl-2 and KIT in canine cutaneous mast cell tumours and their relationship with histopathology and prognosis.

Canine cutaneous mast cell tumours (CCMCTs) are common in dogs and exhibit many unpredictable behaviors. This study aimed to encourage pathology laboratories in developing countries to routinely assess prognosis by applying commonly used histopathological grading systems and immunohistochemistry (IHC) markers. We performed histological grading according to both the Patnaik and Kiupel systems, determined the mitotic count (MC) and carried out IHC for the detection of Ki67, Bax, Bcl-2 and KIT in 54 CCMCT cases. MC was associated with both grading systems in terms of survival following diagnosis and prognostic factors differed among cases categorized by the cut-off value of 5. KIT patterns were associated with grading systems and MC. The cohort with pattern II had a lower survival rate than those with patterns I and III. Ki67 was associated with survival when evaluated over the cut-off value of 0.018. Bax expression was associated with both grading systems. Median survival time was longer in patients with lower Bax expression level. Immunohistochemical detection of KIT, Ki67 and Bax improves histopathology in predicting the prognosis. If IHC is unavailable, reports regarding MC and values from both grading systems are the most effective, convenient and cost-effective way to provide the most reliable prognostic data and guidance for the clinicians.

An Unusual Transition from Cutaneous to Systemic Mastocytosis in a Pediatric Patient.

Background: Cutaneous mastocytosis (CM) occurs when abnormal mast cells accumulate in the skin, whereas in systemic mastocytosis (SM), accumulation also occurs in other tissues. A transition from CM to SM is an atypical occurrence in pediatric patients. Case Presentation: An 8-month-old female presented with a 3-month history of whole body hyperpigmented macules with a normal serum tryptase level, consistent with a diagnosis of CM. At age 2.5 years, cutaneous lesions increased and repeat serum tryptase levels were elevated. Subsequent positive peripheral blood KIT D816V mutation testing furthered concern for a monoclonal mast cell disorder; therefore, prompting a bone marrow biopsy which was consistent with a diagnosis of SM. Conclusion: Our case depicts the possible transition from CM to SM in a pediatric patient. Despite an initial presentation consistent with a diagnosis of CM, watchful monitoring for signs and symptoms indicative of systemic involvement may be warranted in some pediatric patients.

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

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.

Pediatric and Hereditary Mastocytosis.

To a large extent, the clinical picture of pediatric mastocytosis depends on the age at which it is diagnosed. A neonate with diffuse cutaneous mastocytosis may frequently present in a severe state requiring treatment. Toddlers may require long-term anti-mediator therapy, and this may lead to concerns such as organizing preschool education due to the need for epinephrine injections. A teenager may have to face cutaneous disease persistence or a diagnosis of systemic mastocytosis. Further studies are needed to refine the available treatment options and prognosis for different age groups.

[Mastocytosis in children]. / Mastozytose bei Kindern.

Mastocytosis in children is a rare disease characterized by an abnormal accumulation of tissue mast cells. Mastocytosis in children presents with typical skin alterations that are classified as maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis, or mastocytoma. Some patients also develop mast cell mediator symptoms, such as pruritus, flush, and anaphylaxis. In many children, the disease is characterized by a benign and usually self-limiting course; systemic mastocytosis with extracutaneous involvement and a chronic or progressive course is found only rarely. Therapeutically, H1 antihistamines are primarily used on an as-needed basis or as continuous treatment, depending on the severity. Children, parents and caregivers should be thoroughly educated about the clinical picture and possible trigger factors of mast cell mediator release. For children with extensive skin alterations and severe symptoms, the prescription of an epinephrine auto-injector is recommended for emergency treatment.

Cutaneous mastocytosis in 8 young dogs and review of literature.

Cutaneous mastocytosis (CM) is a rare condition in young dogs characterized by multicentric cutaneous proliferation of neoplastic mast cells. Clinical data from 8 dogs that met inclusion criteria (age of onset less than 1.5 years, greater than 3 lesions) were obtained via a standardized survey. Biopsy samples were classified by the Kiupel/Patnaik grading systems and analyzed for c-KIT mutations. The median age of onset was 6 months (range: 2-17 months). Dogs had 5 to more than 50 lesions characterized as nodules, plaques, and papules. Seven dogs were pruritic. Clinical staging in 2 dogs did not reveal visceral involvement. No dogs had systemic illnesses at diagnosis. Histologically, CM was similar to cutaneous mast cell tumor (cMCT). Two dogs had neoplasms classified as high-grade/grade II while 6 dogs had low-grade/grade II neoplasms. No dogs had mutations in c-KIT exons 8 and 11. Treatment included antihistamines (8/8), corticosteroids (7/8), lokivetmab (3/8), and toceranib (1/8). Six dogs were alive with lesions at the end of the study with a median follow-up time of 898 days, while 2 dogs were euthanized. In dogs with high-grade/grade II neoplasms, one continued to develop lesions at 1922 days post-diagnosis, while the other dog was euthanized at 56 days post-diagnosis. One dog was euthanized 621 days post-diagnosis due to rupture of a neoplasm. CM occurs in young dogs and is histologically indistinguishable from cMCT. Current histologic grading systems did not apply uniformly to the dogs of the study and further studies are needed.

Updates in diagnosis and management of paediatric mastocytosis.

PURPOSE OF REVIEW: Paediatric mastocytosis is a rare clonal disorder characterized by the overproduction and organ infiltration of mast cells. Symptoms are due to mast cell mediator release. Cutaneous mastocytosis is the most common presentation in children with systemic disease being rare. Our aim is to provide a practical guideline in differentiating subtypes of paediatric mastocytosis while providing actionable recommendations on diagnosis, clinical management, follow-up and prognosis. RECENT FINDINGS: Longitudinal cohort studies of paediatric cutaneous mastocytosis have shown spontaneous remission with favourable prognosis. Hereditary alpha-tryptasemia may coexist with mastocytosis; thus, screening for this disorder is recommended. There is an emerging role for serum tryptase in asthma endotyping and potential for using therapeutic tryptase inhibitors. SUMMARY: Morbidity in paediatric mastocytosis typically arises from symptoms secondary to mast cell mediator release. Prognosis for nonaggressive disease is typically favourable; however, risks for anaphylaxis and psychosocial morbidity may be underestimated. Symptomatic management and anticipatory guidance may help support patients and families throughout the disease course.

Mastocytosis in children: a single-center long-term follow-up study.

BACKGROUND: Mastocytosis is a heterogeneous group of rare disorders characterized by the accumulation of clonal mast cells in organs such as the skin and bone marrow. The diagnosis of cutaneous mastocytosis (CM) is based on clinical findings, positive Darier's sign, and histopathology, if necessary. METHODS: Medical records of 86 children with CM diagnosed during a 35-year long period were reviewed. Most patients (93%) developed CM during the first year of life (median age 3 months). Clinical features at presentation and during the follow-up period were analyzed. Baseline serum tryptase level was measured in 28 patients. RESULTS: A total of 85% of patients had maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), 9% had mastocytoma, and 6% had diffuse cutaneous mastocytosis (DCM). Boy to girl ratio was 1.1:1. Fifty-four of 86 patients (63%) were followed from 2 to 37 years (median 13 years). Complete resolution was registered in 14% of mastocytoma cases, 14% of MCPM/UP, and in 25% of DCM patients. After the age of 18, skin lesion persisted in 14% mastocytoma, 7% MCPM/UP, and 25% children with DCM. Atopic dermatitis was diagnosed in 9.6% of patients with MPCM/UP. Three of 28 patients had elevated serum tryptase. Prognosis in all patients was good, and there were no signs of progression to systemic mastocytosis (SM). CONCLUSION: To the best of our knowledge, our results represent the longest single-center follow-up study of childhood-onset CM. We found no complications of massive mast cell degranulation or progression to SM.

Mastocytosis and related entities: a practical roadmap.

Mastocytosis is a complex heterogenous multisystem disorder that is characterized by pathologic activation or accumulation of neoplastic mast cells (MCs) in one or more organs. This clonal MC expansion is often associated with a somatic gain-of-function mutation (D816V in most of the cases) in the KIT gene, encoding for the MC surface receptor KIT (CD117), a stem cell growth factor receptor. Based on clinical and biochemical criteria, the World Health Organization (WHO) divided mastocytosis into different subclasses. The exact prevalence of mastocytosis remains elusive, but it is estimated that the disease affects approximately 1 in 10,000 persons. The clinical presentation of mastocytosis varies significantly, ranging from asymptomatic patients to a life-threatening disease with multiple organ involvement, potentially leading to cytopenia, malabsorption, hepatosplenomegaly, lymphadenopathy, ascites or osteolytic bone lesions with pathological fractures. Patients with mastocytosis may experience symptoms related to release of MC mediators, such as flushing or diarrhea or even more severe symptoms such as anaphylaxis. Recently, a new genetic trait, hereditary alpha tryptasemia (HaT), was described which involves a copy number variation in the TPSAB1-gene. Its role as standalone multisystem syndrome is heavily debated. There is emerging evidence suggesting there might be a link between HaT and due to the increased prevalence of HaT in patients with SM. The aim of this review is to provide a practical roadmap for diagnosis and management of mastocytosis and its associated entities, since there are still many misconceptions about these topics.Abbreviations: AdvSM: Advanced systemic mastocytosis; ASM: Aggressive systemic mastocytosis; aST: acute serum tryptase; BM: Bone marrow; BMM: Bone marrow mastocytosis; bST: baseline serum tryptase; CM: Cutaneous mastocytosis; DCM: Diffuse cutaneous mastocytosis; HVA: Hymenoptera venom allergy; HaT: Hereditary alpha tryptasemia; ISM: Indolent systemic mastocytosis; MC: Mast cell; MCA: Mast cell activation; MCAS: Mast cell activation syndrome; MCL: Mast cell leukemia; MIS: Mastocytosis in the skin; MMAS: Monoclonal mast cell activation syndrome; MPCM: Maculopapular cutaneous mastocytosis; SM: Systemic mastocytosis; SM-AHN: Systemic mastocytosis with associated hematological neoplasm; SSM: Smouldering systemic mastocytosis; VIT: Venom immunotherapy.

A widespread blistering eruption: diffuse cutaneous mastocytosis.

Diffuse cutaneous mastocytosis with bullous formation is a rare childhood disease. We report a 5-month-old male who presented with a 3-week history of cutaneous bullae and pruritus. On examination, he had erythema of the cheeks bilaterally and diffuse slightly hyperpigmented, indurated skin on his trunk and abdomen. There were tense vesicles, bullae, and erosions linearly arranged on his trunk and extremities. Both the laboratory and imaging workup were normal. Subsequently, a punch biopsy of a vesicle on the abdomen was obtained and findings confirmed a diagnosis of diffuse cutaneous mastocytosis. An EpiPen(r) was prescribed due to the slightly increased anaphylaxis risk compared to other forms of mastocytosis. There are many purported triggers of diffuse cutaneous mastocytosis and there is currently no known cure which makes management of this disease challenging. This case highlights a rare condition for which official treatment guidelines do not exist. A prompt dermatologic diagnosis is necessary to ensure proper workup and regulation is in place.