Mendelian Inheritance Of Elevated Tryptase Associated With Atopy and Connective Tissue Abnormalities

Abstract

Mendelian diseases of atopy are rare, but have revealed important insights and novel pathways in the pathophysiology of allergic disease. A large cohort of patients and their families were referred for evaluation of suspected mast cell disorders, severe atopy, and/or eosinophilic inflammation. Comprehensive clinical evaluations were performed and fractionated serum tryptase levels were obtained. Bone marrow biopsies were performed as clinically indicated, and mast cell number was quantified in the marrow. In vitro basophil activation was assayed and patients were subjected to cutaneous vibratory challenge. Nine families were identified with inherited elevations in basal serum tryptase (mean, 21.9 ng/mL) following an autosomal dominant pattern. Episodic flushing, abdominal pain, gastrointestinal distress and/or urticaria were seen in 26/32 individuals with elevated tryptase. Atopic disease, anaphylaxis, connective tissue abnormalities, chronic musculoskeletal pain, eosinophilic esophagitis, autonomic dysregulation and neuropsychiatric illness were additional common features. Upon cutaneous vibratory challenge, all tested individuals (n = 16) rapidly developed pruritis and expansive erythema. Bone marrow biopsies were performed in 5 index patients revealing an increase in mast cell number without pathologic changes or evidence of clonality. Basophil activation was also significantly reduced in vitro, among all affected individuals assayed (n = 10). This is the first clinical description of a dominantly inherited atopic syndrome characterized by elevated basal serum tryptase, allergic disease, connective tissue abnormalities, and diminished in vitro basophil activation.