Multiple self-healing palmoplantar carcinoma D23L

Autosomal dominant skin disease (mutations in NLRP1) in which eruptive, multiple, often ulcerated, hyperkeratotic, painless, reddish-brown or skin-colored nodules and nodules (keratoacanthomas/healing squamous cell carcinomas) develop predominantly on the plantar and palmar skin.

This clinical picture can be associated with familial keratosis lichenoides chronica (Zhong FL et al. 2016).

This syndrome is caused by germline mutations in the inflammasome sensor NLRP1. The mutation in this gene leads to functional gains in the pyrin domain of the encoded protein. Keratinocytes from patients with these NLRP1 mutations undergo spontaneous inflammasome activation and paracrine IL1 signaling, which apparently leads to lichenoid dermatitis (familial keratosis lichenoides chronica) on the one hand and epidermal hyperplasia on the other.

The cytokine IL-1β was the most upregulated cytokine in keratinocyte cultures from MSPC and familial keratosis lichenoides chronica patients, followed by TNFα, IL1RA,(CD121a) IL1α, TGFα and GM-CSF. These results demonstrate that keratinocytes from MSPC and FKLC patients are capable of spontaneous inflammasome activation and cytokine release in culture. This overlapping clinical picture is genetic evidence of a link between NLRP1 mutations, inflammatory skin syndromes and a predisposition to skin cancer (Zhong FL et al. 2016).

Clinically and histologically, these lesions resemble rapidly growing benign keratoacanthomas. However, MSPC patients showed an increased susceptibility to malignant squamous cell carcinoma. In addition, 12 of 15 patients (80 %) developed keratotic lesions of the sclera, which were histologically characterized by dyskeratotic squamous proliferations.

The MSPC locus was found on chromosome 17p (Mamaï et al. 2015). This represents a different genetic etiology than an analogous proliferative skin disease, the so-called "multiple self-healing squamous cell carcinomas (= keratoacanthomas, multiple, self-healing Ferguson-Smith type)", a disease pattern caused by mutations in TGFBR1.

MSPC has also been described in association with multiple localized but also confluent lichenoid papules on the arms, legs and lower trunk, diagnosed as keratosis lichenoides chronica (KLC ). Other associated clinical phenomena are plantar keratoses, follicular hyperkeratoses and macular amyloidosis.

Alterations in the NLRP1 gene can lead to two different phenotypes:

• multiple self-healing palmoplantar carcinoma (MSPC)

and

• familial keratosis lichenoides chronica.

MSPC is associated with recurrent keratoacanthomas, preferentially on the palms and soles(!) as well as with intraepithelial corneal dyskeratosis, corneal opacity with dyskeratosis, palmoplantar hyperkeratosis, dyshidrosis, decalcification of the maxilla with tooth loss and hyperkeratosis pilaris. Mamaï O et al (2015) described autosomal dominant MSPC in 27 individuals in a Tunisian family, with the life cycle of KAs lasting an average of 3 months. The skin lesions begin as papules with gradual growth, eventually ulcerating before spontaneously regressing.

Clinical and genetic overlap between multiple self-healing palmoplantar carcinomas (MSPC) and familial keratosis lichenoides chronica may occur in individual affected family members.

1. Mamaï O et al. (2015) Multiple self-healing palmoplantar carcinoma: a familial predisposition to skin cancer with primary palmoplantar and conjunctival lesions. J Invest Dermatol 135: 304-308

2. Scheufele C et al. (2019) Multiple self-healing palmoplantar carcinoma: An aberrance of the inflammasome JAAD Case Rep 5: 261-263.

3. Zhong FL et al. (2016) Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell 167:187-202.e17.