A 6-month-old previously healthy infant is brought to clinic for evaluation of a persistent rash on the trunk and extremities for the past 2 months. The lesions are asymptomatic. The rash began as scattered hyperpigmented macules and has slowly increased in number. On physical exam, multiple brown macules and small papules are noted on the torso, arms, and legs.

Stroking one of the lesions with a tongue depressor leads to localized urtication and erythema within a few minutes.

Which of the following is the most likely underlying pathophysiology?

A. IgE-mediated mast cell degranulation
B. Clonal proliferation of mast cells due to c-KIT mutation
C. Delayed-type hypersensitivity to unknown antigen
D. Mutations in the filaggrin gene
E. Autoantibody-mediated attack on desmoglein 3

Rationale: 

The scenario is characteristic of urticaria pigmentosa now known as maculopapular cutaneous mastocytosis. This is the most common cutaneous manifestation of mastocytosis in children. The hallmark is the Darier sign, where stroking a lesion leads to localized erythema and swelling due to mast cell degranulation. While mast cell activation may involve IgE in other disorders, this is not the primary mechanism in urticaria pigmentosa. This condition often presents in infancy and may spontaneously regress over time. Systemic involvement is rare in children, unlike adult-onset mastocytosis.

Correct answer: B. Clonal proliferation of mast cells due to c-KIT mutation

Most cases involve a somatic activating mutation in the c-KIT proto-oncogene, leading to clonal proliferation of mast cells in the skin.

Incorrect answer choices:

A. IgE-mediated mast cell degranulation is involved in allergic urticaria and anaphylaxis, not in mastocytosis. Although mast cells are involved in both, the trigger in urticaria pigmentosa is mechanical, not antigen-mediated via IgE.

C. Delayed-type hypersensitivity to unknown antigen describes a Type IV hypersensitivity reaction, such as in contact dermatitis. The presentation here is not consistent with contact allergen exposure and lacks associated pruritus or vesiculation.

D. Mutations in the filaggrin gene are a hallmark of ichthyosis vulgaris and are also implicated in atopic dermatitis, due to impaired skin barrier function. However, urticaria pigmentosa is unrelated to filaggrin or epidermal barrier defects.

E. Autoantibody-mediated attack on desmoglein 3 underlies pemphigus vulgaris, which presents with flaccid blisters and mucosal involvement. These findings are not seen in this infant.

Additional reading at Weinberg's Color Atlas of Pediatric Dermatology Section 20: Disorders of the Dermis (Infiltrates, Atrophies, and Nodules)