Acral necrotic ulcers in infancy are rare but have been described in type I interferonopathies. Herein, we present a case of an 8-year-old child who presented at the age of one month with severe ulceronecrotic lesions on the face and limbs with exacerbations following exposure to cold weather. Despite extensive investigation the case remains undiagnosed to this day. We hypothesize that this case represents a novel and yet unknown autoinflammatory disease.

Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder that typically presents in infancy or early childhood as painless, sometimes pruritic exfoliation of the acral skin that heals spontaneously without scarring. Triggering factors include trauma, exposure to water, occlusion, and sweating. Most reported cases of APSS are caused by mutations in the gene TGM5, encoding transglutaminase 5, a protein involved in the cross-linking of the cornified cell envelope in the superficial epidermis. Recently, loss-of-function mutations in the gene CSTA, encoding cystatin A, were linked to APSS with exfoliative ichthyosis. 1 APSS secondary to CSTA mutations is characterized by deeper acral peeling, while TGM5 mutations cause a more superficial form of acral peeling. 1 Cystatin A is a protease inhibitor found in the cornified cell envelope that has a multifunctional key role in the skin. In addition to its inhibiting action against endogenous proteases, it also protects the skin from exogenous proteases, such as dust mite allergens.Furthermore, a single nucleotide variant of Cystatin A (CSTA+344C) has also been associated with atopic dermatitis. 2 To this date, only five families have been reported with APSS due to mutations in CSTA. This report describes two new unrelated cases of APSS associated with exfoliative ichthyosis caused by a novel homozygous mutation in the gene CSTA.