A rare case of KIT-negative indolent systemic mastocytosis without anaphylaxis Free

Introduction Mastocytosis is a clonal neoplastic disorder characterized by abnormal proliferation and accumulation of mast cells, most commonly in the skin, bone marrow, GI tract, liver, and spleen. It is classified as cutaneous or systemic mastocytosis (SM). One subtype of SM is indolent systemic mastocytosis (ISM). ISM is diagnosed based on World Health Organization (WHO) criteria by meeting 1 major and 1 minor or 3 minor criteria along with absence of organ dysfunction (“C findings”). The major criterion involves identifying multifocal clusters of mast cells in the bone marrow or another extracutaneous tissue. Minor criteria include abnormal mast cell morphology, detection of a KIT D816V mutation, CD2 and/or CD25 expression, and serum tryptase persistently >20 ng/mL. Approximately 90–95% of patients with ISM have the activating KIT mutation, and Hymenoptera venom induced anaphylaxis is also a common presenting feature. This case highlights a rare clinical scenario of ISM in a young adult with a negative KIT mutation and no history of anaphylaxis from confirmed Hymenoptera stings, exemplifying the importance of maintaining clinical suspicion for ISM even when typical clinical and molecular markers are absent.

Case Presentation A 21-year-old Caucasian male with a history of fatigue and recurrent upper respiratory tract infections, including ENT complications requiring ear tubes, initially presented to dermatology in 2022 for evaluation of “red spots” on the skin. A biopsy of the left forearm revealed dermal mast cell infiltrates, prompting referral to Vanderbilt for further evaluation. Initial assessment showed elevated serum tryptase and no allergies on testing. Subsequent bone marrow biopsy showed a hypocellular marrow (50–60%) with involvement by a mast cell neoplasm. Molecular testing was negative for the KIT D816V mutation. Serum tryptase levels have remained stable between 47–57 mcg/L. Additional findings included mild anemia, high-normal IgG, and normal ferritin. A diagnosis of ISM was made in April 2023, and the patient was prescribed an epinephrine autoinjector. Notably, he has had 3 confirmed Hymenoptera stings since the diagnosis with no anaphylaxis. In March 2025, an abdominal ultrasound performed for left upper quadrant pain revealed a normal spleen and mild hepatomegaly. That same month, he began cetirizine 10mg daily for diffuse pruritus, later increased to cetirizine 10mg twice a day and 10mg famotidine daily for abdominal pain.

Discussion This case represents an atypical presentation of ISM for several reasons. First, the patient was diagnosed at age 22, which is much younger than the median age of approximately 45. Second, he tested negative for the KIT D816V mutation, despite 90–95% of ISM cases being KIT-positive. KIT-negative ISM may involve alternative signaling pathways, lower mast cell burden, more variable tryptase levels, and limited response to KIT-targeted therapies. It is also less studied in the literature, making clinical management more challenging.

Another unusual feature is the absence of anaphylaxis, despite three confirmed Hymenoptera stings since diagnosis. This may reflect the protective effect of lacking the KIT mutation or suggest a distinct, lower-risk ISM phenotype. Additionally, the patient initially presented only with cutaneous lesions, without other mediator symptoms like flushing, pruritus, or GI issues. Despite the rarity of this presentation, the diagnostic process was relatively straightforward, involving referral from dermatology to allergy then hematology. However, it required referral to a tertiary center.

This case highlights the importance of considering ISM even when only a single hallmark feature, such as skin lesions, anaphylaxis, pruritus, flushing, or gastrointestinal symptoms, is present. If left untreated, ISM can result in significant morbidity from chronic mast cell mediator effects, risk of life-threatening anaphylaxis, nutritional deficiencies, bone disease, psychological distress, organ involvement, and delayed diagnosis or care.

Conclusion Clinicians should maintain a high index of suspicion for indolent systemic mastocytosis even when only a single hallmark symptom is present. Recognizing atypical presentations such as this one is essential to avoid delays in diagnosis and ensure timely care that can prevent worsening symptoms and complications.