Generalized pustular psoriasis

About: Generalized pustular psoriasis is a research topic. Over the lifetime, 708 publications have been published within this topic receiving 13682 citations. The topic is also known as: psoriasis 14, pustular & Acrodermatitis Continua of Hallopeau.

Interleukin-36–Receptor Antagonist Deficiency and Generalized Pustular Psoriasis

Abstract: Background Generalized pustular psoriasis is a life-threatening disease of unknown cause. It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis. Methods We performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on protein expression and conformation, stability, and function. Results We identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin-36–receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proli...

Generalized pustular psoriasis. A clinical and epidemiological study of 104 cases.

Abstract: SUMMARY.— A series of 104 cases of generalized pustular psoriasis has been studied. The syndrome occurs predominantly in the second half of life, affecting both sexes. Two quite distinct sub-groups were discernible. In the first the pre-pustular phase of psoriasis began early in life, was typical through-out and was prolonged. At least one third of these cases were apparently precipitated by the withdrawal of systemic corticosteroid therapy. Others were provoked by pregnancy or infection. It is likely that this type is usually extraneously provoked. In the second, the psoriasis was of late onset and atypical, acral or flexural patterns predominating in the pre-pustular phase. In these progress to generalized pustular disease was rapid and apparently spontaneous. Four clinical patterns of generalized pustular phase were apparent and have been named the Zumbusch, annular, localized and exanthematic types. The Zumbusch type was characterized by widespread fiery erythema, sheeted pustulation and scarlatiniform peeling, accompanied by malaise, fever and often leucocytosis. The annular type was a more low-grade sub-acute affection characterized by gyrate and annular pustular lesions and little systemic disturbance. The exanthematic type arose de novo, usually as a single short-lived episode following infection or drug exposure. In the localized type restricted areas of pustular psoriasis developed in and around ordinary psoriatic plaques. Two thirds were erythrodermic at some stage and one third had polyarthritis. Oral lesions occurred in 5 and hypocalcaemia in 5 during pustular phases. The different clinical patterns of pustular psoriasis have been interpreted in terms of the balance between vascular hypertrophy, epidermopoiesis and leucocytic immigration into the epidermis.

Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis

Abstract: Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.

PSORS2 Is Due to Mutations in CARD14

Abstract: Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.