PSTPIP 1 gene mutation in a pyoderma gangrenosum, acne and suppurative hidradenitis ( PASH ) syndrome

Dear Editor, Pyoderma gangrenosum (PG), acne and suppurative hidradenitis (PASH) syndrome is a recently described condition that belongs to the spectrum of autoinflammatory diseases (AIDs).1 AIDs form a group of heterozygous disorders characterized by dysregulation of the innate immune response.2 PSTPIP1 gene mutations affecting proteins of the inflammasome complex or proteins that regulate its function, responsible for the inflammatory pathway, are associated with AIDs.3 4 The molecular basis of PASH syndrome is not fully understood, and the absence of pathogenic mutations in the PSTPIP1 gene has been used in some way to differentiate it from other AIDs, such as PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and PAPASH (pyogenic arthritis and PASH), with which PASH syndrome exhibits some clinical overlap.5 PASH syndrome has been recently associated with a pathogenic mutation in the NCSTN gene,6 which has also been found in a family with hidradenitis suppurativa.7 Other gene mutations in NOD (nucleotide‐binding oligomerization domain) genes, MEFV and the immunoproteasome have also been observed in some cases of PASH syndrome.5 8 However, even though these are known to be involved in distinct AIDs, genotype–phenotype correlations cannot be held causative for the clinical manifestations in patients with PASH syndrome, and may be rather casual findings.8 Mutations in PSTPIP1, which have been strongly linked to PAPA syndrome, to our knowledge have not been described to date in patients diagnosed with PASH syndrome.5 We present a 48‐year‐old otherwise healthy man, without any relevant family history for dermatological or rheumatic diseases. He had experienced severe acne, which left serious scars on his face and neck, from his youth (Fig. 1a). He debuted with flares of hidradenitis suppurativa at the age of 27 years with posterior worsening and persistence of severe disease (Hurley stage III) in the sacrococcygeal region, intergluteal fold and perianal region for the last 5 years (Fig. 1b). Finally, he presented multiple recurrent episodes of ulcerative painful lesions (Fig. 1c), which lasted from 4 to 6 months and affected the upper and lower limbs; these healed spontaneously and left behind typical cribriform scars (Fig. 1d). (a–d) Clinical manifestations. (a) Severe acne scars. (b) Suppurative hidradenitis involving the intergluteal fold and perianal and sacrococcygeal regions. (c) Pyoderma gangrenosum on the left hand. (d) Remission of pyoderma gangrenosum with cribriform scar. (e) Haematoxylin–eosin‐stained skin biopsy from a pustule. Dense dermal inflammatory infiltrate composed of neutrophils compatible with pyoderma gangrenosum, magnification 20×. The more detailed picture (below‐right), magnification 100×. (f) Direct sequencing of the coding sequence of the PSTPIP1 gene revealed a heterozygous C>T missense mutation at position 1213 of the cDNA sequence. (g) The SH3 domain of the human PSTPIP1 protein with R405 (blue) and E400 (orange) residues. The patient consulted due to a new acute painful ulceronecrotic lesion with satellite pustules on the dorsal aspect of his left hand (Fig. 1c), which had started 2 weeks prior to consultation, similar to those he had exhibited for the last 5 years. Histopathological examination revealed an intense neutrophilic inflammatory infiltrate affecting the dermis, consistent with PG (Fig. 1e). The patient remained afebrile during the flares and denied symptoms of arthritis. Routine blood analysis showed an increased leucocyte count of 2·08 × 109 cells L−1, with 90% neutrophils and elevated inflammatory markers, elevated erythrocyte sedimentation rate (103 mm h−1) and a C‐reactive protein of 10 mg L−1, whereas the autoimmunity study was normal. Microbiological studies of the hand lesion (including cultures for bacteria, mycobacteria and fungus) were sterile, and radiology imaging was within normal parameters. The patient underwent oral treatment with prednisone 30 mg per day and topical clobetasol dipropionate with clear improvement, until complete remission was achieved during the next 2 weeks, leaving behind the typical cribriform scars (Fig. 1d). Genetic analysis for the PSTPIP1 gene was conducted through massive sequencing and was later validated through conventional Sanger sequencing, detecting a heterozygous missense mutation c.1213 C>T (p.Arg405Cys) in exon 15 of the PSTPIP1 gene (Fig. 1f). (The polymerase chain reaction primers and program will be provided upon request.) Conservation analysis using PhyloP (http://compgen.cshl.edu/phast/background.php) indicated that the Arg405 residue is highly conserved among species. The VAAST Variant Prioritization Score (http://www.hufflab.org/software/vaast/) was 75, suggesting a probable deleterious mutation in terms of protein function and structure. On the other hand, Polyphen2 (http://genetics.bwh.harvard.edu/pph2), SIFT (http://sift.jcvi.org) and PROVEAN (http://provean.jcvi.org) resulted in tolerability or neutrality for this mutation, and it was predicted to be disease causing by Mutation Taster (www.mutationtaster.org). While the in silico analysis used for computed estimation of the potential pathogenicity of this missense mutation to disturb protein function displayed contradictory results, a previously functional evaluation of the same missense mutation had demonstrated it as pathogenic in a patient with an aggressive form of PG.3 The molecular dynamics simulation of the wild‐type and Arg405Cys mutant also seemed to indicate a probable influence of that residue change on the β‐sheets of the barrel structure present in the SH3 domain, and therefore probably on functional impairment (Fig. 1g). This variation was reported in the 1000 Genomes and ExAC Browser databases (dbSNP ID rs201253322), with an allele frequency < 0·1%, and no homozygous individuals were reported. Also, this mutation was absent from our 119 control samples (data not shown). According to these data, the variation could not be excluded as a possible disease mutation. PASH syndrome was first described in 2012, distinguishing it from PAPA syndrome, in the absence of pyogenic arthritis and the lack of a pathogenic mutation in the PSTPIP1 gene. Nevertheless, lack of onset of arthritis in a female patient with PAPA has also been reported.7 PSTPIP1 encodes proline–serine–threonine phosphatase‐interacting protein 1, which is known to be a cytoskeleton‐associated adaptor protein of the inflammasome, a fundamental protein complex, which has been implicated in the inflammatory signalling pathway.1 Via an increased binding affinity to pyrin, PSTPIP1 mutations lead to the upregulation of caspase‐1 and the activation of cytokines, primarily interleukin‐1, which triggers the release of proinflammatory markers producing a final neutrophil‐mediated autoinflammatory response.3 4 Our patient shows clinical findings compatible with PASH syndrome in the presence of a mutation in the PSTPIP1 gene. PSTPIP1 mutations have not been associated with PASH syndrome to date (Table 1), and thus this assertion should be taken with caution. However, the Arg405Cys mutation in this protein, which is harboured by our patient, was previously found to be responsible for one case of PG without PASH through a well‐built functional study.3 As PG is a cardinal clinical feature in PASH syndrome and PSTPIP1 takes part in the innate inflammatory cascade, we can suggest that this gene might be implicated in the PASH syndrome phenotype to some extent. Summary of clinical presentations in the current case and in a literature review of patients with pyoderma gangrenosum (PG), acne and suppurative hidradenitis (SH) syndrome M, male; F, female; NS, not specified. aReported in the Infevers database (http://fmf.igh.cnrs.fr/ISSAID/infevers/). Summary of clinical presentations in the current case and in a literature review of patients with pyoderma gangrenosum (PG), acne and suppurative hidradenitis (SH) syndrome M, male; F, female; NS, not specified. aReported in the Infevers database (http://fmf.igh.cnrs.fr/ISSAID/infevers/). Other phenotypically related disorders such as PAPASH syndrome, associating pyogenic arthritis, and PsAPASH syndrome, which exhibits psoriasis, have been described and linked to pathogenic mutations in the PSTPIP1 gene.9 10 Recently PASS syndrome was proposed, adding axial spondyloarthritis to the triad of PASH, although no genetic studies were carried out in that patient.11 Finally there is PAC syndrome, consisting of PG, acne and ulcerative colitis, where a pathogenic mutation in the PSTPIP1 gene has also been identified.12 We can observe a clear overlap between PASH syndrome and these entities. Our findings suggest that PASH syndrome, together with PAPA and PAPASH, might be part of the same pathogenic spectrum. However, the genetic basis of PASH syndrome remains unknown. As these form an emerging group of new entities, further studies will need to investigate whether there are other factors implicated in the aetiology and pathogenesis of this complex AID. In summary, we report the first PSTPIP1 gene mutation in a patient with PASH syndrome, expanding the phenotypic spectrum associated with the PSTPIP1 disorders. We are grateful to the patient who participated in our study. Funding sources: none. Conflicts of interest: none declared.