Autoinflammatory Keratinization Diseases-The Concept, Pathophysiology, and Clinical Implications

Abstract

Recent advances in medical genetics elucidated the background of diseases characterized by superficial dermal and epidermal inflammation with resultant aberrant keratosis. This led to introducing the term autoinflammatory keratinization diseases encompassing entities in which monogenic mutations cause spontaneous activation of the innate immunity and subsequent disruption of the keratinization process. Originally, autoinflammatory keratinization diseases were attributed to pathogenic variants of CARD14 (generalized pustular psoriasis with concomitant psoriasis vulgaris, palmoplantar pustulosis, type V pityriasis rubra pilaris), IL36RN (generalized pustular psoriasis without concomitant psoriasis vulgaris, impetigo herpetiformis, acrodermatitis continua of Hallopeau), NLRP1 (familial forms of keratosis lichenoides chronica), and genes of the mevalonate pathway, i.e., MVK, PMVK, MVD, and FDPS (porokeratosis). Since then, endotypes underlying novel entities matching the concept of autoinflammatory keratinization diseases have been discovered (mutations of JAK1, POMP, and EGFR). This review describes the concept and pathophysiology of autoinflammatory keratinization diseases and outlines the characteristic clinical features of the associated entities. Furthermore, a novel term for NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) describing the spectrum of autoinflammatory keratinization diseases secondary to NLRP1 mutations is proposed.

Keywords: Autoinflammation; Autoinflammatory keratinization diseases; CARD14; IL36RN; NADED; NLRP1.

Fig. 1

Pathogenesis of the most significant autoimmune keratinization diseases associated with (1) increased IL-36R signaling caused by deficiency of IL-36RA, (2) CARD14 hyperactivation causing the upregulation of NF-κB, (3) NLRP1 inflammasome activation, and (4) mevalonate pathway abnormalities causing impaired synthesis of isoprenoids. CARD14—caspase recruitment domain family member 14; CCL-20—chemokine C-C motif ligand 20; FDPS—farnesyl diphosphate synthase; IL—interleukin; CXCL-1—chemokine C-X-C motif ligand 1; IL-36R—interleukin 36 receptor; IL-36RA—interleukin 36 receptor antagonist; MVD—mevalonate decarboxylase; MVK—mevalonate kinase; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP1—nucleotide-binding oligomerization domain-like receptor containing a PYRIN domain 1; PMVK—phosphomevalonate kinase; TNF—tumor necrosis factor

Fig. 2

Suggested diagnostic approach to the autoinflammatory keratinization diseases. This figure shows the most significant disorders. ACH—acrodermatitis continua of Hallopeau; AGEP—acute generalized exanthematous pustulosis; DIRA—deficiency of the interleukin-1-receptor antagonist; GPP—generalized pustular psoriasis; NADED—NLRP1-associated autoinflammatory disease with epithelial dyskeratosis; PRP—pityriasis rubra pilaris

Fig. 3

Sterile pustules in generalized pustular psoriasis. a, b Histology shows Munro microabscesses and spongiform pustules of Kogoj c occasionally accompanied by typical features of psoriasis vulgaris (acanthosis, confluent parakeratosis, elongation of rete ridges, and dilation of papillary blood vessels)

Fig. 4

Palmoplantar pustulosis. Sterile pustules limited to palms (a) and/or soles (b) which may rupture and produce fissures and erosions, thereby impairing fine motor skills and walking

Fig. 5

Acrodermatitis continua of Hallopeau. Pustular lesions occupying the distal phalanges of the hands (a) and/or the feet (b). There is a prominent involvement of the nail apparatus resulting in onychodystrophy

Fig. 6

Generalized pustular lesions in a child with confirmed deficiency of the IL-36 receptor antagonist (DITRA)

Fig. 7

NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED). The patient presented dyskeratotic cutaneous lesions in the form of crateriform plaques, which resolved with scarring (a). Histology showed numerous dyskeratotic cells and acanthosis (b). Photos by courtesy of Dr. Felipe Velásquez

Fig. 8

Pityriasis rubra pilaris and CARD14-associated papulosquamous eruption (CAPE). Patient with pityriasis rubra pilaris presented typical diffuse hyperkeratotic papules which progressed to erythroderma with characteristic islets of sparing, i.e., foci of uninvolved skin (a). The second patient with CARD14-activating mutation showed lesions mimicking psoriasis (b). Histology of pityriasis rubra pilaris revealing follicular plugging, preserved granular layer or hypergranulosis, and alternating areas of ortho- and parakeratosis (c)

Fig. 9

Linear porokeratosis—segmental hyperkeratotic plaques in a child (a). In histology, the most typical phenomenon is the presence of cornoid lamellae, i.e., thin columns of parakeratotic cells overlying foci of hypogranulosis and vacuolated keratinocytes (b)