CED

Clinical dermatology • Original article

Clinical and Experimental Dermatology

Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene T. Zeeli,1 G. Padalon-Brauch,1 E. Ellenbogen,1 A. Gat,2 O. Sarig1 and E. Sprecher1 Departments of 1Dermatology and 2Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel doi:10.1111/ced.12585

Summary

Background. Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare hereditary, autosomal dominant, auto-inflammatory disease caused by mutations in the PSTPIP1 gene, which encodes proline–serine–threonine phosphatase interacting protein 1. The fact that PSTPIP1 is involved in immune regulation provides a rationale for treatment of this rare disease with interleukin (IL)-1 signalling blocking agents. Aim. We investigated a 33-year-old man with a long-standing history of ulcerative colitis, severe acne and recurrent skin ulcerations, and a 3-year history of a recalcitrant pustular rash. Methods. We used direct sequencing to search for mutations in the PSTPIP1 gene. Results. Examination of biopsies obtained from pustules and skin ulcers revealed folliculitis and ulceration with a diffuse neutrophilic dermal infiltrate, consistent with a diagnosis of pyoderma gangrenosum. Because of the known association of acne and pyoderma gangrenosum in PAPA syndrome, we determined the entire coding sequence of the PSTPIP1 gene, and identified a hitherto unreported heterozygous mutation predicted to alter a highly conserved residue (p.G403R) and to be damaging to the protein function. Based on this finding, we initiated treatment with a human IL-1 receptor antagonist, anakinra, which led to a dramatic improvement in the patient’s condition. Conclusions. We describe a novel mutation in PSTPIP1 resulting in pyoderma gangrenosum, acne and ulcerative colitis. This novel constellation of clinical manifestations, which we term ‘PAC syndrome’, suggests the need to regroup all PSTPIP1-associated phenotypes under one aetiological group.

Introduction Autoinflammatory diseases differ from autoimmune and allergic diseases by the presence of an unprovoked persistent inflammation without evidence of circulating autoantibodies or an antigen-specific T-cell response.1 Interleukin (IL)-1 is a key regulator in systemic and cutaneous inflammatory responses, and is implicated in the pathogenesis of autoinflammatory Correspondence: Dr Tal Zeeli, Department of Dermatology, Sourasky Medical Center, 6 Weizmann St., Tel Aviv, Israel 64239 E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 26 August 2014

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diseases and fever syndromes.2 The discovery of the inflammasome as a key intracellular sensing complex essential for IL-1 secretion has illuminated the pathomechanisms involved in autoinflammation. Mutations affecting proteins of the inflammasome complex or proteins that regulate the function of the inflammasome are associated with autoinflammatory diseases.3 These diseases typically feature multisytemic manifestations, in addition to involvement of the skin. They are characterized by neutrophil recruitment to the inflammatory lesions, and respond to therapies directed against IL-1. In the present study, we describe a hitherto unreported association between severe acne, pyoderma gangrenosum (PG) and ulcerative colitis (UC).

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PAC in a patient with a novel mutation in the PSTPIP1 gene  T. Zeeli et al.

Case report The patient was a 33-year-old man, who had a 5-year history of UC, for which he had received oral prednisone (40 mg/day tapered down gradually over 1 year) and parenteral infliximab, neither of which had any long-lasting therapeutic benefit. Ciclosporin was added, but quickly stopped after the patient developed sepsis and the UC worsened. Total colectomy was then performed, and subcutaneous adalimumab was initiated. Two years after the onset of UC, the patient noticed the appearance of a pustular rash over his face, scalp, back, buttocks and thighs, for which he was treated with minocycline 100 mg/day for 3 months, with no benefit. A year later, he presented to us with two skin ulcers over his lower abdomen and right thigh, and he was hospitalized 3 days later. The lesions responded to treatment with prednisone (80 mg/day with gradual tapering down up to 40 mg within a month) but recurred as soon as prednisone was tapered below 40 mg/day. Of note, the acneiform lesions that preceded the treatment with prednisone also improved under prednisone treatment. On physical examination, three types of eruption were evident. First, there were erythematous and oedematous papules and coalescing pustules on the patient’s scalp (Fig. 1a). Second, on the patient’s face (Fig. 1b) and upper trunk (Fig. 1c), there was a polymorphic rash consisting of open comedones, papules and pustules, as well as some deeply set cysts, in association with numerous hyperpigmented scars. Finally, two well-demarcated superficial ulcers, covered by yellow secretions and surrounded by a purple halo, were seen over the patient’s left pubic region (Fig. 1d) and his posterior right thigh. Histological examination of skin biopsies obtained from a pustule on the back and from an ulcer in the pubic area revealed neutrophilic folliculitis and a diffuse neutrophilic dermal infiltrate, consistent with PG (Fig. 2). Repeated cultures from pustules and ulcers were sterile. Routine blood tests and an extended rheumatic disease serology panel gave normal results. Gene sequencing

Although the association of PG and UC is not unusual, the presence of severe acne and the lack of response to corticosteroids and infliximab, suggested that our patient might have a PAPA syndrome variant, known to be associated with mutations in the PSTPIP1 gene.4 Accordingly, direct sequencing of the gene (supplementary data) revealed the existence of a heterozygous

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G>C transversion at cDNA position 1207 (Fig. 3). This mutation is predicted to result in the substitution of a glycine for an arginine residue at amino acid position 403 of the protein sequence. Although this mutation is novel, three sets of data support its pathogenicity: (i) the mutation affects a highly conserved residue [conservation score by Conseq (http://conseq.tau.ac.il/) was 8 (range 1–9)]; (ii) the maximum score was attributed to the mutation by the protein function prediction browsers Poly-Phen-2 [http://genetics.bwh.harvard.edu/pph2/index.shtml; score of 1 (range 0–1)] and SIFT [http://sift.jcvi.org/www/SIFT_enst_submit.html; score of 0, range 1–0]; and (iii) the mutation was found in the Exome Sequencing Project (ESP) database in a single individual out of a total of 6267 sequences (reported as rs369113632: C/C = 0, C/ G = 1, G/G = 6266 in the European American and African American cohorts together), suggesting that it does not represent a common neutral polymorphism. Based on previous studies showing that the presence of PSTPIP1 mutations predicts a good therapeutic response to IL-1 blockade,5,6 treatment with anakinra 100 mg daily, administered subcutaneously, was initiated, with dramatic improvement in our patient’s condition (Fig. 1e–h). After 2 months of anakinra treatment, supplemented with decreasing doses of prednisone, the pustular rash had resolved and the PG lesions had disappeared. Of note, although anakinra did produce partial improvement of the facial acne, isotretinoin had to be added to achieve complete clearance. The patient is now receiving anakinra 100 mg daily, prednisone 10 mg every other day and isotretinoin 40 mg three times a week, with no recurrence more than 1 year after treatment initiation.

Discussion In 1997, Lindor et al.7 coined the term ‘PAPA syndrome’ (OMIM/604416) for the triad of pyogenic sterile arthritis, PG and acne. This hereditary, autosomal dominant, auto-inflammatory disease is now known to be caused by mutations in the PSTPIP1 gene.8 PSTPIP1 is a cytoskeleton-associated adaptor protein, highly expressed in haematopoietic cells. It acts on CD2 and binds PEST (proline-rich, glutamic acidrich, serine-rich and threonine-rich) type phosphatases to their substrates.9 Moreover, it interacts with other immunity-related proteins such as the Wiskott–Aldrich syndrome protein (WASP) and the familial Mediterranean fever-associated pyrin.10 The correct function of PSTPIP1 is dependent upon an intact tubulin cytoskeleton, and the

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PAC in a patient with a novel mutation in the PSTPIP1 gene  T. Zeeli et al.

(a)

(e)

(b)

(f)

(c)

(g)

(d)

(h)

Figure 1 (a–d) Despite treatment with high doses of prednisone, the patient displayed (a) a pustular rash over his scalp, (b,c) cystic acne-like rash over his face and upper back, and (d) a well-demarcated ulcer over his pubic area. (e–h) All cutaneous findings disappeared 2 months after initiation of anakinra treatment.

distribution of this network can be modulated by pyrin. Pyrin can recruit PSTPIP1 into aggregates (specks) of ASC (apoptosis-associated Speck-like

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protein containing a caspase recruitment domain), another pyrin-binding protein. ASC specks are associated with inflammasome activity. PAPA syndrome-

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PAC in a patient with a novel mutation in the PSTPIP1 gene  T. Zeeli et al.

(a)

(b)

Figure 2 (a,b) Biopsy from the patient’s back showed a perifollicular dermal infiltrate composed largely of neutrophils, while (b) a

biopsy taken from the right thigh showed an ulcer and a diffuse dermal neutrophilic infiltrate. Haematoxylin and eosin, original magnification (a) 9400; (b) 940.

Figure 3 Direct sequencing of the coding sequence of the PSTPIP1 gene revealed a heterozygous G>C transversion at position 1207 of the cDNA sequence (lower panel). The wild type (Wt) sequence is given for comparison (upper panel).

causing mutations in PSTPIP1 increase the affinity of hyperphosphorylated PSTPIP1 molecules to pyrin, which recruits them to ASC specks.11 These mutations also prevent PSTPIP1 from binding protein tyrosine phosphatase (PTP)–PEST phosphatases, leading to upregulation of lymphocyte activation, disruption of the suppressive effect of pyrin on inflammation, and overproduction of active IL-1b.

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Recent reports have shed light on the variable nature of the phenotypic expression of PSTPIP1 mutations. Braun-Falco et al.12 described two unrelated patients with a clinical triad of PG, acne and hidradenitis suppurativa (termed PASH syndrome), which was found to be associated with a microsatellite repeat in the PSTPIP1 promoter region. The true significance of these findings is unclear, as this increased number of repeats is also found in healthy individuals.15 Marzano et al.13 reported a man with PASH syndrome following bowel bypass surgery, but no genetic alterations were found in exons 10 or 11 of the PSTPIP1 gene. The same group later described an adolescent female patient with pyogenic arthritis, PG, acne and hidradenitis suppurativa (PAPASH syndrome), caused by a missense mutation in the PSTPIP1 gene.14 In fact, isolated PG has also been shown to be associated with mutations in the PSTPIP1 gene.15 Our patient presented with a triad of PG, acne and UC, which we term ‘PAC syndrome’. His disease was recalcitrant to tumour necrosis factor-a blockade, and flared whenever prednisone was tapered below 40 mg/day. However, he had an outstandingly good response to anakinra. We also treated the patient with isotretinoin to achieve complete clearance of his acne. Isotretinoin has been reported in the past to exacerbate inflammatory bowel

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PAC in a patient with a novel mutation in the PSTPIP1 gene  T. Zeeli et al.

disease,16 but more recent data have indicated that there is no correlation.17

Conclusion Collectively, the data from this and previous studies emphasize the fact that the combination of PG and other inflammatory cutaneous and extracutaneous conditions warrant molecular analysis for mutations in PSTPIP1, which in turn are predictive of a good response to IL-1 blockade. It is unclear at this stage what underlies the variable phenotypic expression of mutations in PSTPIP1, although the influence of modifier genes is likely.

Acknowledgement We are grateful to our patient for his participation in this study.

What’s already known about this topic? • Mutations in PSTPIP1 have been found to

underlie PAPA syndrome. • Such mutations predict a good therapeutic

response to IL-1 signalling blocking agents.

What does this study add? • We report a novel mutation in PSTPIP1 in a

patient with PG, acne and UC. • We term this condition PAC syndrome. • Taken together, PAPA, PASH and PAC syn-

dromes demarcate a group of disorders sharing a possible common aetiology and which are likely to respond to IL-1 signalling blocking agents.

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3 Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature 2012; 481: 278–86. 4 Smith EJ, Allantaz F, Bennett L et al. Clinical, molecular, and genetic characteristics of PAPA syndrome: a review. Curr Genomics 2010; 11: 519–27. 5 Brenner M, Ruzicka T, Plewig G et al. Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol 2009; 161: 1199–201. 6 Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology 2005; 44: 406–8. 7 Lindor NM, Arsenault TM, Solomon H et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 1997; 72: 611–15. 8 Wise CA, Gillum JD, Seidman CE et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 2002; 11: 961–9. 9 Veillette A, Rhee I, Souza CM, Davidson D. PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders. Immunol Rev 2009; 228: 312–24. 10 Shoham NG, Centola M, Mansfield E et al. Pyrin binds the PSTPIP1⁄CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci USA 2003; 100: 13501–6. 11 Waite AL, Schaner P, Richards N et al. Pyrin modulates the intracellular distribution of PSTPIP1. PLoS One 2009; 4: e6147. 12 Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH): a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol 2012; 66: 409–15. 13 Marzano AV, Ishak RS, Colombo A et al. Pyoderma gangrenosum, acne and suppurative hidradenitis syndrome following bowel bypass surgery. Dermatology 2012; 225: 215–19. 14 Marzano AV, Trevisan V, Gattorno M et al. Pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH): a new autoinflammatory syndrome associated with a novel mutation of the PSTPIP1 gene. JAMA Dermatol 2013; 149: 762–4. 15 Nesterovitch AB, Hoffman MD, Simon M et al. Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with pyoderma gangrenosum. Clin Exp Dermatol 2011; 36: 889–95. 16 Crockett SD, Porter CQ, Martin CF et al. Isotretinoin use and the risk of inflammatory bowel disease: a case-

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control study. Am J Gastroenterol 2010; 105: 1986–93. 17 Etminan M, Bird ST, Delaney JA et al. Isotretinoin and risk for inflammatory bowel disease: a nested casecontrol study and meta-analysis of published and unpublished data. JAMA Dermatol 2013; 149: 216–20.

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Supporting Information Additional Supporting Information may be found in the online version of this article: Data S1. Materials and methods. Table S1. Oligonucleotide sequences.

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Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene.

Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare hereditary, autosomal dominant, auto-inflammatory disease caused b...
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