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Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome
Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome Elvira Lindwall, MD, Shikha Singla, MDn, William E. Davis, MD, Robert J. Quinet, MD Rheumatology, Ochsner Medical Center, New Orleans, LA
a r t i c l e in fo
Keywords: Pyogenic arthritis Pyoderma gangrenosum and acne syndrome PAPA syndrome
a b s t r a c t Introduction: Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disease that usually presents in childhood with recurrent sterile arthritis. As the child ages into puberty, cutaneous features develop and arthritis subsides. We report the case of a now 25-year-old male patient with PAPA syndrome with the E250K mutation in PSTPIP1. We also present a systematic literature review of other PAPA cases. Method: We conducted a literature search of PubMed using the following search terms: E250K mutation, PSTPIP1, and PAPA. Results: PAPA syndrome is caused by mutations on chromosome 15q affecting the proline-serinethreonine phosphatase-interacting protein 1 (PSTPIP1) gene, also known as CD2-binding protein 1 (CD2BP1). The reported cases of PAPA syndrome currently in the literature involve mutations in A230T and E250Q. One case of a novel E250K mutation has been reported, which presented with a different phenotype to previously described cases of PAPA syndrome. Conclusion: With variation present between disease presentations from case to case, it is possible that the spectrum of PAPA syndrome is wider than currently thought. Further research is needed which may uncover an as-yet undiscovered genetic abnormality linking these interrelated diseases together. & 2015 Elsevier Inc. All rights reserved.
Introduction Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disease first reported by Lindor et al. [1] in 1997. PAPA syndrome usually presents in childhood with recurrent sterile arthritis. Arthritis occurs spontaneously or following trauma and can cause joint erosions and destruction. As the child ages into puberty, cutaneous features develop and arthritis subsides. Cutaneous features include cystic acne and recurrent non-healing ulcers resembling pyoderma gangrenosum [1]. PAPA syndrome is caused by mutations on chromosome 15q affecting the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene, also known as CD2-binding protein 1 (CD2BP1). PSTPIP1/CD2BP1 is a regulatory phosphatase protein that modulates T-cell activation [2], cytoskeletal organization and IL1 production [3]. Two mutations at E250Q and A230T have been previously identified in PAPA syndrome kindreds [1,4], with a third mutation being recently identified at E250K [5]. These mutations may interfere with the ability of
n Correspondence to: Shikha Singla, MD, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail address: [email protected] (S. Singla).
http://dx.doi.org/10.1016/j.semarthrit.2015.02.012 0049-0172/& 2015 Elsevier Inc. All rights reserved.
PSTPIP1 to phosphorylate targets including pro inflammation pyrin domains [6]. The resulting alterations to IL1 activity activates an auto-inflammatory disease state characterized by a breakdown of tolerance without production of auto-antibodies. Here we present a case of PAPA syndrome in a now 25-year-old man. This is only the second reported case of PAPA syndrome caused by a novel mutation in PSTPIP1, E250K.
Case report The patient is a 25-year-old man who carries the E250K PSTPIP1 mutation. He first presented at 4 years of age with recurrent symmetrical arthritis of the knees and elbows. Hyper-mobile joints and increased skin elasticity were also noted. The arthritis persisted throughout his childhood and teenage years and began to remit several years ago. At age 6 he developed persistent scalp pyoderma, which over subsequent years spread to involve his neck, back, abdomen, and legs. At age 18 he also developed cystic acne. Currently the patient is being managed for chronic leg pain secondary to multiple pyoderma gangrenosum ulcerations involving his thighs and legs. He denies any recent joint pain, swelling, morning stiffness, oral or nasal ulcers, dry eyes, and Raynaud’s phenomenon. He feels
2
E. Lindwall et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
generally well, however, he reports 4.5 kg of unintentional weight loss over 5 months and occasional nausea. He denies any further systemic symptoms of fevers, chills, or night sweats. He denies any other pain in his neck, back, or muscles. The systems review was negative for chest pain, shortness of breath, cough, or abdominal pain. No loss of sensation in the upper or lower extremities was present. His past medical history is significant for iron-deficiency anemia, beta-thalassemia trait, neutropenia, osteomyelitis, and epistaxis. The patient has been hospitalized numerous times with complications from pyoderma gangrenosum including severe sepsis and septic shock with acute renal failure and acute respiratory failure. Admissions have also been due to cellulitis of the face and lower limbs, non-specific colitis, and acute cholecystitis. No surgical history is reported. No family history of PAPA syndrome or related illness was reported, however, his mother suffers from psoriatic arthritis. No other family history of rheumatological disorders including SLE, scleroderma, or rheumatoid arthritis was reported. The patient is a non-smoker and non-drinker Currently the patient is maintained on 10 mg of prednisone daily. He was previously treated with infliximab which was unsuccessful at treating his PG and was ceased due to an infusion reaction. Allergies to sulfonamides, ciprofloxacin, vancomycin, and rocephin were present. Examination showed a slim cushingoid patient. Multiple large ulcerations were present on both lower limbs. The ulcers had granulating bases, irregular margins, and some showed near circumferential involvement around the limb. Significant scarring is present over the scalp, face, chest, back, and arms. Prominent acne scarring is present on the face. Flexion contractures of the knees and elbows were present as well as atrophy of the lower limb muscles. No other abnormalities were noted on the musculoskeletal examination. Both the liver and spleen were palpable approximately 2 cm below the costal margin. The remainder of his gastrointestinal, cardiovascular and respiratory examination was unremarkable. Findings from investigations showed an ESR of 90, a CRP of 65 and an LDH of 2500. A microcytic anemia and thrombocytosis was also present. X-rays of his knees show severe degenerative joint disease. Plate like densities were noted in both lung bases suggestive of scarring or atelectasis. Aspirates from his joints during his childhood years were culture negative and contained white cells counts in the 50,000 range suggestive of inflammatory arthritis. Rheumatoid factor and ANA were negative.
Method We conducted a literature search of PubMed using the following search terms: E250K mutation, PSTPIP1, and PAPA.
Results While we report a case of PAPA syndrome with the E250K mutation in PSTPIP1, the reported cases of PAPA syndrome currently in the literature involve mutations in A230T and E250Q [1,4]. One case of a novel E250K mutation has been reported previously, which presented with a different phenotype to previously described cases of PAPA syndrome [5]. Additional features present in both cases with the E250K mutation include splenomegaly, bleeding diathesis, and increased propensity towards developing serious infections.
PAPA syndrome is an auto-inflammatory disorder sharing similarities with Familial Mediterranean Fever (FMF) including sterile arthritis, neutrophilic dermatoses, and elevated production of IL1. FMF, the first auto-inflammatory disease described, is a recessive disorder caused by mutations in the pyrin encoding gene. The relationship between FMF and PAPA syndrome was made clear by linking pyrin with PSTPIP1 in the disease state. PSTPIP1 mutation leads to hyperphosphorylation of PSPTP1, which results in a marked increase in the strength of binding with pyrin [6]. Increased pyrin binding by mutant PSTPIP1 may release pyrin autoinhibition and result in the overproduction of IL1 [7]. For this reason IL1 has emerged as a target for treating both FMF and PAPA syndrome. Anakinra, a recombinant IL1 receptor antagonist has been shown to be effective in controlling flares in some PAPA syndrome patients [8,9]. To date only one case of PAPA syndrome caused by the E250K PSTPIP1 mutation has been reported by Demidowich et al. [5] in a Swedish female. In this case the patient developed splenomegaly, cervical lymphadenopathy, thrombocytopenia and hemolytic anemia by the age of 6 months. During childhood the thrombocytopenia resolved, however, the patient suffered from epistaxis. Sterile arthritis developed at age 8 and recurrent pyoderma gangrenosum developed at age 18. She did not develop cystic acne at any point. Corticosteroids were initiated in early childhood. She was treated with cyclosporine, which improved her PG, however, this was poorly tolerated. Tacrolimus caused neutropenia and treatment was not successful. Anakinra prior to her death was not successful. She died at 36 years of age of sepsis-associated multi-organ failure. This case shares many similarities and a few differences with our case. Both our case and the Swedish case developed the characteristic arthritis and pyoderma gangrenosum of PAPA syndrome at similar ages, however, the Swedish case never developed cystic acne. Unique to the E250K mutation, both patients showed a bleeding diathesis with epistaxis, but no thrombocytopenia was present past infancy in either case. Also unique to the E250K mutation, both patients showed splenomegaly and recurrent serious infections of the skin and lungs, which persisted into adulthood. The Swedish case also reported cervical lymphadenopathy, hemolytic anemia, and granulocytosis, none of which were present in our case. Although various immunosuppressant and biological agents were tried in both cases, corticosteroids remained the only effective treatment option for both patients.
Discussion Currently it is not clear whether the E250K mutation can account for the additional features seen in the two case reports. Furthermore, with variation present between disease presentations from case to case, it is possible that the spectrum of PAPA syndrome is wider than currently thought. This could possibly mean that we are only seeing the tip of the iceberg with autoinflammatory sterile arthropathies. Further research is needed which may uncover an as-yet undiscovered genetic abnormality linking these interrelated diseases together. References [1] Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum and acne: PAPA syndrome. Mayo Clin Proc 1997;72:611–5. [2] Yang H, Reinherz E. CD2BP1 modulates CD2-dependent T cell activation via linkage to protein tyrosine phosphatase (PTP)-PEST. J Immunol 2006;176: 5898–907. [3] Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial mediterranean fever and
E. Lindwall et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]] PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A 2003;100:13501–6. [4] Tallon B, Corkill M. Peculiarities of PAPA syndrome. Rheumatology (Oxford) 2006;45:1140–3. [5] Demidowich AP, Freeman AF, Kuhns DB, Aksentijevich I, Gallin JI, et al. Brief report: genotype, phenotype, and clinical course in five patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. Arthritis Rheum 2012. http://dx.doi.org/10.1002/art.34332. [6] Waite AL, Schaner P, Richards N, Balci-Peynircioglu B, Masters SL, Brydges SD, et al. Pyrin modulates the intracellular distribution of PSTPIP1. PLoS ONE 2009;4:e6147.
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[7] Yu JW, Fernandes-Alnemri T, Datta P, Wu J, Juliana C, Solorzano L, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell 2007;28:214–27. [8] Brenner M, Ruzicka T, Plewig G, Thomas P, Herzer P. 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 2006;161: 1199–201. [9] Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatol 2005;44:406–8.
Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome Elvira Lindwall, MD, Shikha Singla, MDn, William E. Davis, MD, Robert J. Quinet, MD Rheumatology, Ochsner Medical Center, New Orleans, LA
a r t i c l e in fo
Keywords: Pyogenic arthritis Pyoderma gangrenosum and acne syndrome PAPA syndrome
a b s t r a c t Introduction: Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disease that usually presents in childhood with recurrent sterile arthritis. As the child ages into puberty, cutaneous features develop and arthritis subsides. We report the case of a now 25-year-old male patient with PAPA syndrome with the E250K mutation in PSTPIP1. We also present a systematic literature review of other PAPA cases. Method: We conducted a literature search of PubMed using the following search terms: E250K mutation, PSTPIP1, and PAPA. Results: PAPA syndrome is caused by mutations on chromosome 15q affecting the proline-serinethreonine phosphatase-interacting protein 1 (PSTPIP1) gene, also known as CD2-binding protein 1 (CD2BP1). The reported cases of PAPA syndrome currently in the literature involve mutations in A230T and E250Q. One case of a novel E250K mutation has been reported, which presented with a different phenotype to previously described cases of PAPA syndrome. Conclusion: With variation present between disease presentations from case to case, it is possible that the spectrum of PAPA syndrome is wider than currently thought. Further research is needed which may uncover an as-yet undiscovered genetic abnormality linking these interrelated diseases together. & 2015 Elsevier Inc. All rights reserved.
Introduction Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disease first reported by Lindor et al. [1] in 1997. PAPA syndrome usually presents in childhood with recurrent sterile arthritis. Arthritis occurs spontaneously or following trauma and can cause joint erosions and destruction. As the child ages into puberty, cutaneous features develop and arthritis subsides. Cutaneous features include cystic acne and recurrent non-healing ulcers resembling pyoderma gangrenosum [1]. PAPA syndrome is caused by mutations on chromosome 15q affecting the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene, also known as CD2-binding protein 1 (CD2BP1). PSTPIP1/CD2BP1 is a regulatory phosphatase protein that modulates T-cell activation [2], cytoskeletal organization and IL1 production [3]. Two mutations at E250Q and A230T have been previously identified in PAPA syndrome kindreds [1,4], with a third mutation being recently identified at E250K [5]. These mutations may interfere with the ability of
n Correspondence to: Shikha Singla, MD, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail address: [email protected] (S. Singla).
http://dx.doi.org/10.1016/j.semarthrit.2015.02.012 0049-0172/& 2015 Elsevier Inc. All rights reserved.
PSTPIP1 to phosphorylate targets including pro inflammation pyrin domains [6]. The resulting alterations to IL1 activity activates an auto-inflammatory disease state characterized by a breakdown of tolerance without production of auto-antibodies. Here we present a case of PAPA syndrome in a now 25-year-old man. This is only the second reported case of PAPA syndrome caused by a novel mutation in PSTPIP1, E250K.
Case report The patient is a 25-year-old man who carries the E250K PSTPIP1 mutation. He first presented at 4 years of age with recurrent symmetrical arthritis of the knees and elbows. Hyper-mobile joints and increased skin elasticity were also noted. The arthritis persisted throughout his childhood and teenage years and began to remit several years ago. At age 6 he developed persistent scalp pyoderma, which over subsequent years spread to involve his neck, back, abdomen, and legs. At age 18 he also developed cystic acne. Currently the patient is being managed for chronic leg pain secondary to multiple pyoderma gangrenosum ulcerations involving his thighs and legs. He denies any recent joint pain, swelling, morning stiffness, oral or nasal ulcers, dry eyes, and Raynaud’s phenomenon. He feels
2
E. Lindwall et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]]
generally well, however, he reports 4.5 kg of unintentional weight loss over 5 months and occasional nausea. He denies any further systemic symptoms of fevers, chills, or night sweats. He denies any other pain in his neck, back, or muscles. The systems review was negative for chest pain, shortness of breath, cough, or abdominal pain. No loss of sensation in the upper or lower extremities was present. His past medical history is significant for iron-deficiency anemia, beta-thalassemia trait, neutropenia, osteomyelitis, and epistaxis. The patient has been hospitalized numerous times with complications from pyoderma gangrenosum including severe sepsis and septic shock with acute renal failure and acute respiratory failure. Admissions have also been due to cellulitis of the face and lower limbs, non-specific colitis, and acute cholecystitis. No surgical history is reported. No family history of PAPA syndrome or related illness was reported, however, his mother suffers from psoriatic arthritis. No other family history of rheumatological disorders including SLE, scleroderma, or rheumatoid arthritis was reported. The patient is a non-smoker and non-drinker Currently the patient is maintained on 10 mg of prednisone daily. He was previously treated with infliximab which was unsuccessful at treating his PG and was ceased due to an infusion reaction. Allergies to sulfonamides, ciprofloxacin, vancomycin, and rocephin were present. Examination showed a slim cushingoid patient. Multiple large ulcerations were present on both lower limbs. The ulcers had granulating bases, irregular margins, and some showed near circumferential involvement around the limb. Significant scarring is present over the scalp, face, chest, back, and arms. Prominent acne scarring is present on the face. Flexion contractures of the knees and elbows were present as well as atrophy of the lower limb muscles. No other abnormalities were noted on the musculoskeletal examination. Both the liver and spleen were palpable approximately 2 cm below the costal margin. The remainder of his gastrointestinal, cardiovascular and respiratory examination was unremarkable. Findings from investigations showed an ESR of 90, a CRP of 65 and an LDH of 2500. A microcytic anemia and thrombocytosis was also present. X-rays of his knees show severe degenerative joint disease. Plate like densities were noted in both lung bases suggestive of scarring or atelectasis. Aspirates from his joints during his childhood years were culture negative and contained white cells counts in the 50,000 range suggestive of inflammatory arthritis. Rheumatoid factor and ANA were negative.
Method We conducted a literature search of PubMed using the following search terms: E250K mutation, PSTPIP1, and PAPA.
Results While we report a case of PAPA syndrome with the E250K mutation in PSTPIP1, the reported cases of PAPA syndrome currently in the literature involve mutations in A230T and E250Q [1,4]. One case of a novel E250K mutation has been reported previously, which presented with a different phenotype to previously described cases of PAPA syndrome [5]. Additional features present in both cases with the E250K mutation include splenomegaly, bleeding diathesis, and increased propensity towards developing serious infections.
PAPA syndrome is an auto-inflammatory disorder sharing similarities with Familial Mediterranean Fever (FMF) including sterile arthritis, neutrophilic dermatoses, and elevated production of IL1. FMF, the first auto-inflammatory disease described, is a recessive disorder caused by mutations in the pyrin encoding gene. The relationship between FMF and PAPA syndrome was made clear by linking pyrin with PSTPIP1 in the disease state. PSTPIP1 mutation leads to hyperphosphorylation of PSPTP1, which results in a marked increase in the strength of binding with pyrin [6]. Increased pyrin binding by mutant PSTPIP1 may release pyrin autoinhibition and result in the overproduction of IL1 [7]. For this reason IL1 has emerged as a target for treating both FMF and PAPA syndrome. Anakinra, a recombinant IL1 receptor antagonist has been shown to be effective in controlling flares in some PAPA syndrome patients [8,9]. To date only one case of PAPA syndrome caused by the E250K PSTPIP1 mutation has been reported by Demidowich et al. [5] in a Swedish female. In this case the patient developed splenomegaly, cervical lymphadenopathy, thrombocytopenia and hemolytic anemia by the age of 6 months. During childhood the thrombocytopenia resolved, however, the patient suffered from epistaxis. Sterile arthritis developed at age 8 and recurrent pyoderma gangrenosum developed at age 18. She did not develop cystic acne at any point. Corticosteroids were initiated in early childhood. She was treated with cyclosporine, which improved her PG, however, this was poorly tolerated. Tacrolimus caused neutropenia and treatment was not successful. Anakinra prior to her death was not successful. She died at 36 years of age of sepsis-associated multi-organ failure. This case shares many similarities and a few differences with our case. Both our case and the Swedish case developed the characteristic arthritis and pyoderma gangrenosum of PAPA syndrome at similar ages, however, the Swedish case never developed cystic acne. Unique to the E250K mutation, both patients showed a bleeding diathesis with epistaxis, but no thrombocytopenia was present past infancy in either case. Also unique to the E250K mutation, both patients showed splenomegaly and recurrent serious infections of the skin and lungs, which persisted into adulthood. The Swedish case also reported cervical lymphadenopathy, hemolytic anemia, and granulocytosis, none of which were present in our case. Although various immunosuppressant and biological agents were tried in both cases, corticosteroids remained the only effective treatment option for both patients.
Discussion Currently it is not clear whether the E250K mutation can account for the additional features seen in the two case reports. Furthermore, with variation present between disease presentations from case to case, it is possible that the spectrum of PAPA syndrome is wider than currently thought. This could possibly mean that we are only seeing the tip of the iceberg with autoinflammatory sterile arthropathies. Further research is needed which may uncover an as-yet undiscovered genetic abnormality linking these interrelated diseases together. References [1] Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum and acne: PAPA syndrome. Mayo Clin Proc 1997;72:611–5. [2] Yang H, Reinherz E. CD2BP1 modulates CD2-dependent T cell activation via linkage to protein tyrosine phosphatase (PTP)-PEST. J Immunol 2006;176: 5898–907. [3] Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial mediterranean fever and
E. Lindwall et al. / Seminars in Arthritis and Rheumatism ] (2015) ]]]–]]] PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A 2003;100:13501–6. [4] Tallon B, Corkill M. Peculiarities of PAPA syndrome. Rheumatology (Oxford) 2006;45:1140–3. [5] Demidowich AP, Freeman AF, Kuhns DB, Aksentijevich I, Gallin JI, et al. Brief report: genotype, phenotype, and clinical course in five patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. Arthritis Rheum 2012. http://dx.doi.org/10.1002/art.34332. [6] Waite AL, Schaner P, Richards N, Balci-Peynircioglu B, Masters SL, Brydges SD, et al. Pyrin modulates the intracellular distribution of PSTPIP1. PLoS ONE 2009;4:e6147.
3
[7] Yu JW, Fernandes-Alnemri T, Datta P, Wu J, Juliana C, Solorzano L, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell 2007;28:214–27. [8] Brenner M, Ruzicka T, Plewig G, Thomas P, Herzer P. 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 2006;161: 1199–201. [9] Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatol 2005;44:406–8.