NLRP1-associated autoinflammatory disease
NLRP1 was the first inflammasome sensor discovered, but the link between NLRP1 and AID has only recently become elucidated. Activation of NLRP1 leads to downstream release of proinflammatory mediators such as caspase-1 and subsequent activation of IL-1β and IL-18. NLRP1 is primarily expressed in keratinocytes and manifests predominantly as skin disease when mutated. The NLRP1-AID family of diseases typically manifests with hyperkeratosis and dyskeratosis of the skin and often corneal epithelium.
MSPC is characterized by recurrent keratoacanthomas mainly affecting epithelial tissues that are devoid of hair follicles, such as the palmoplantar skin, conjunctiva, and corneal epithelium. Age of onset is usually early but can vary from age 1 to 25 years, with an average age of 8.8 years.
FKLC, also known as Nekam disease, manifests with findings of MSPC with additional multiple discrete brown-purple scaly lichenoid papules and nodules on the arms, legs, and lower trunk that do not respond to topical steroids. The lesions are usually asymptomatic but can be itchy, and they are arranged in a linear or reticular pattern and are symmetrically distributed. Hyperkeratosis tends to be more follicular, but patients also have palmoplantar keratosis. Macular amyloidosis is a unique manifestation. The causative mutation is an activating germline in-frame deletion in the NLRP1 gene.
JRRP is characterized by recurrent papillomas (warts) developing on the epithelial cells of the upper respiratory airway, especially the larynx. Clinical manifestations in early childhood include a hoarse voice and airway obstruction leading to respiratory stridor in severe cases. Mild dermatologic abnormalities are usually found.
NAIAD/AIADK is the most recently described syndrome, characterized by recurrent fever, widespread skin dyskeratosis, chronic infection, and arthritis. Disseminated vitamin A deficiency-associated follicular hyperkeratosis (phrynoderma) and palmoplantar keratoderma are also seen.
The inheritance pattern for NLRP1-AID is mostly autosomal dominant, although JRRP and NAIAD/AIADK are autosomal recessive. Both sexes are affected equally.
M04.9 – Autoinflammatory syndrome, unspecified
128139000 – Inflammatory disorder
782964007 – Genetic disease
Differential Diagnosis & Pitfalls
- Multiple self-healing squamous epithelioma (MSSE) – causative mutations in TGFBR1; transformation to SCC with metastases only seen in patient subjected to radiotherapy, smaller size of tumors, lack of conjunctival keratoacanthomas, later age of onset, primary lesions in sun-exposed areas
- Grzybowski syndrome
- Witten-Zak syndrome
- Muir-Torre syndrome – causative mutation in MSH2 / MLH1 genes
- Hereditary benign intraepithelial dyskeratosis (HBID) – Native American ancestry, clear corneal regions and rarely manifests with visual impairment, onset typically at birth / childhood, lack of general skin involvement, oral lesions of white spongy plaques of the mucosa
- Punctate palmoplantar-specific genodermatosis
- Dyskeratosis congenita – associated with bone marrow failure
- Other inherited multiple keratoacanthomas – involving follicular skin epithelium
- Lichen planus – pruritic and responds to topical / systemic corticosteroids
- Lichen planopilaris – associated with scarring alopecia
- Discoid lupus erythematosus – associated with scarring alopecia
- Cutaneous lupus erythematosus – usually photosensitive
- Epidermodysplasia verruciformis (EV) – flat warts
- "Tree man" syndrome (TMS) – bulky hyperkeratotic cutaneous horns primarily on the hands and feet
- Systemic juvenile idiopathic arthritis (sJIA)
- Familial Mediterranean fever (FMF) – MEFV gene mutation
- Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) – MEFV gene mutation
- Aicardi-Goutières syndrome – IFIH1 gene mutation
- Adenosine deaminase 2 deficiency – CECR1 gene mutation