Letters to the Editor
The patient was treated with emollient for dry skin, which was given to the parents with a maintenance protocol and instructions to follow up regularly. The patient was admitted to the hospital to manage heat tolerance when pulmonary infection was suspected.
ACKNOWLEDGMENTS: This study was supported in part by a grant from Takeda Science Foundation, Japan, to Y. S. and a grant from National Center for Child Health and Development to H. N. CONFLICT OF INTEREST:
The authors have no conflicts
of interest to declare.
Yuichi KURIHARA,1 Ryota HAYASHI,2 Emiko WATANABE,1 Shun-ichi MIYAKAWA,1 Kumiko KAJIWARA,3 Maiko MATSUDA,4 Kazue YOSHIDA,4 Yutaka SHIMOMURA,2 Hironori NIIZEKI4
Graduate School of Medical and Dental Sciences, Niigata, 3Division of Pediatrics, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, and 4 Department of Dermatology, National Center for Child Health and Development, Tokyo, Japan doi: 10.1111/1346-8138.12701
REFERENCES 1 Kere J, Srivastava AK, Montonen O et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996; 13: 409–416. s M, Hartung AJ, Ezer S et al. The anhidrotic ectodermal dyspla2 Baye sia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. Hum Mol Genet 1998; 7: 1661–1669. 3 Elomaa O, Pulkkinen K, Hannelius U, Mikkola M, Saarialho-Kere U, Kere J. Ectodysplasin is released by proteolytic shedding and binds to the EDAR protein. Hum Mol Genet 2001; 10: 953–962. 4 Huang C, Yang Q, Ke T et al. A novel de novo frame-shift mutation of the EDA gene in a Chinese Han family with hypohidrotic ectodermal dysplasia. J Hum Genet 2006; 51: 1133–1137.
1
Division of Dermatology, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, 2Laboratory of Genetic Skin Diseases, Niigata University
Inflammatory response to heparinoid and heparin in a patient with tumor necrosis factor receptor-associated periodic syndrome: The second case with a T61I mutation in the TNFRSF1A gene Dear Editor, Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant disorder characterized by recurrent episodes of systemic inflammation including fever, myalgia, arthralgia, abdominal pain, conjunctivitis and skin eruptions.1 Recently, we reported a TRAPS patient exacerbated by a heparin injection and topical application of heparinoid, and suggested the possibility that heparin served as a stimulant of the inflammasome.2 Here, we describe a second case of a TRAPS patient who was sensitive to heparinoid and discuss the potential of heparin and heparinoid to trigger inflammatory symptoms in TRAPS. A 3-year-old Japanese girl was referred to us with a 1-year history of episodic fever, arthralgia and skin eruption. Clinical examination disclosed diffuse erythema and red papules on her cheeks, neck and extremities without underlying myalgia (Fig. 1a). However, she did not suffer from abdominal pain or conjunctivitis. Laboratory examination revealed an elevated white blood cell count of 11 500/lL (normal, 3500–9500) and normal C-reactive protein of 0.01 mg/dL (normal, 0.0–0.2). Her father also suffered recurrent episodes of idiopathic inflammation. We suspected that she had hereditary periodic fever syndrome and performed genomic DNA analysis after obtaining
informed consent. Genetic evaluation revealed a missense mutation T61I in exon 3 of the TNFRSF1A gene in the patient and her father, leading to the diagnosis of TRAPS. Interestingly, she had an episode of hyperresponse to topical heparinoid application which caused painful erythema without itching. Open patch test with vaseline (as is), urea (10%) and heparinoid (0.3%) was performed and the only heparinoid caused erythematous rash within 20 min (Fig. 1b). Furthermore, we evaluated whether heparin stimulated peripheral blood mononuclear cells (PBMC) to produce inflammatory cytokines, because we have experienced a case of TRAPS exacerbated by heparin with the same TNFRSF1A mutation.2 PBMC from the patient, her father with the same mutation and healthy subjects were incubated with or without heparin (1 unit/mL) for 12 h. Then we performed intracellular cytokine staining and investigated interleukin-1b (IL-1b) synthesis by flow cytometric analysis. Heparin increased the frequency of IL-1b+ CD14+ cells in PBMC in the patient and her father with a T61I mutation, but not in healthy subjects (Fig. 1c). Tumor necrosis factor receptor-associated periodic syndrome is a rare autoinflammatory disease associated with enhanced innate immune responsiveness and abnormal intracellular traffick-
Correspondence: Shun Ohmori, M.D., Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8556, Japan. Email: [email protected]
1112
© 2014 Japanese Dermatological Association
Letters to the Editor
(a)
(b)
(c)
We present the second case of TRAPS with a T61I mutation exacerbated by heparin and heparinoid, while there is a consideration that heparin has both pro- and anti-inflammatory effects depending on the concentration.5 Heparin usually displays an anti-inflammatory effect in pharmacological concentration (0.1–1.0 unit/mL). Although we are not able to disclose the genetic mechanism in this report, the T61I substituted TNFR1 itself may influence the genetic abnormality and hypersensitivity to heparin and heparinoid even in low concentration.
CONFLICT OF INTEREST:
The authors declare no financial
or other conflict of interest.
Shun OHMORI, Ryosuke HINO, Motonobu NAKAMURA Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan doi: 10.1111/1346-8138.12689
REFERENCES
Figure 1. (a) Diffuse erythema and red papules on her knee. (b) Erythematous rash by open patch test with heparinoid (arrow). (c) Increased frequency of interleukin-1b+ CD14+ cells stimulated by heparin in the patient and her father with a T61I mutation, compared with those unstimulated or those stimulated in a healthy subject. ing of the type 1 tumor necrosis factor receptor (TNFR1) owing to missense mutations in TNFRSF1A.3 The accumulation of mutant TNFR1 causes spontaneous c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and for PBMC from TRAPS patients to overproduce inflammatory cytokines in response to low-dose lipopolysaccharide.4 It means that minor triggers which stimulate the innate immune system can lead to the inflammatory cytokine production in TRAPS.
1 Toro JR, Assentijevich I, Hull K, Dean J, Kastner DL. Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations. Arch Dermatol 2000; 136: 1487–1494. 2 Ohmori S, Hino R, Nakamura M, Tokura Y. Heparin serves as a natural stimulant of the inflammasome and exacerbates the symptoms of tumor necrosis factor receptor-associated periodic syndrome (TRAPS). J Dermatol Sci 2012; 66: 82–84. 3 McDermott MF, Assentijevich I, Galon J et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 1999; 97: 133–144. 4 Simon A, Park H, Maddipati R et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic syndrome. Proc Natl Acad Sci USA 2010; 107: 9801–9806. 5 Hochart H, Jenkins PV, Preston RJ, Smith OP, White B, O’Donnell J. Concentration-dependent roles for heparin in modifying lipopolysaccharide-induced activation of mononuclear cells in whole blood. Thromb Haemost 2008; 99: 570–575.
Development of systemic sclerosis in patients with Behc ß et’s disease: Remission of Behc ß et’s disease in parallel with the progression of skin sclerosis Dear Editor, The T-helper (Th)1/Th2 paradigm potentially explains the high concurrence and mutual exclusiveness of certain immunemediated diseases in each individual patient, and rare cases
with overlap of Th1- and Th2-mediated diseases are insightful to understand the in vivo negative cross-regulation between Th1- and Th2-mediated immune responses.1–3 We recently experienced two cases of systemic sclerosis (SSc)
Correspondence: Yoshihide Asano, M.D., Ph.D., Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
1113
The patient was treated with emollient for dry skin, which was given to the parents with a maintenance protocol and instructions to follow up regularly. The patient was admitted to the hospital to manage heat tolerance when pulmonary infection was suspected.
ACKNOWLEDGMENTS: This study was supported in part by a grant from Takeda Science Foundation, Japan, to Y. S. and a grant from National Center for Child Health and Development to H. N. CONFLICT OF INTEREST:
The authors have no conflicts
of interest to declare.
Yuichi KURIHARA,1 Ryota HAYASHI,2 Emiko WATANABE,1 Shun-ichi MIYAKAWA,1 Kumiko KAJIWARA,3 Maiko MATSUDA,4 Kazue YOSHIDA,4 Yutaka SHIMOMURA,2 Hironori NIIZEKI4
Graduate School of Medical and Dental Sciences, Niigata, 3Division of Pediatrics, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, and 4 Department of Dermatology, National Center for Child Health and Development, Tokyo, Japan doi: 10.1111/1346-8138.12701
REFERENCES 1 Kere J, Srivastava AK, Montonen O et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996; 13: 409–416. s M, Hartung AJ, Ezer S et al. The anhidrotic ectodermal dyspla2 Baye sia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. Hum Mol Genet 1998; 7: 1661–1669. 3 Elomaa O, Pulkkinen K, Hannelius U, Mikkola M, Saarialho-Kere U, Kere J. Ectodysplasin is released by proteolytic shedding and binds to the EDAR protein. Hum Mol Genet 2001; 10: 953–962. 4 Huang C, Yang Q, Ke T et al. A novel de novo frame-shift mutation of the EDA gene in a Chinese Han family with hypohidrotic ectodermal dysplasia. J Hum Genet 2006; 51: 1133–1137.
1
Division of Dermatology, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, 2Laboratory of Genetic Skin Diseases, Niigata University
Inflammatory response to heparinoid and heparin in a patient with tumor necrosis factor receptor-associated periodic syndrome: The second case with a T61I mutation in the TNFRSF1A gene Dear Editor, Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant disorder characterized by recurrent episodes of systemic inflammation including fever, myalgia, arthralgia, abdominal pain, conjunctivitis and skin eruptions.1 Recently, we reported a TRAPS patient exacerbated by a heparin injection and topical application of heparinoid, and suggested the possibility that heparin served as a stimulant of the inflammasome.2 Here, we describe a second case of a TRAPS patient who was sensitive to heparinoid and discuss the potential of heparin and heparinoid to trigger inflammatory symptoms in TRAPS. A 3-year-old Japanese girl was referred to us with a 1-year history of episodic fever, arthralgia and skin eruption. Clinical examination disclosed diffuse erythema and red papules on her cheeks, neck and extremities without underlying myalgia (Fig. 1a). However, she did not suffer from abdominal pain or conjunctivitis. Laboratory examination revealed an elevated white blood cell count of 11 500/lL (normal, 3500–9500) and normal C-reactive protein of 0.01 mg/dL (normal, 0.0–0.2). Her father also suffered recurrent episodes of idiopathic inflammation. We suspected that she had hereditary periodic fever syndrome and performed genomic DNA analysis after obtaining
informed consent. Genetic evaluation revealed a missense mutation T61I in exon 3 of the TNFRSF1A gene in the patient and her father, leading to the diagnosis of TRAPS. Interestingly, she had an episode of hyperresponse to topical heparinoid application which caused painful erythema without itching. Open patch test with vaseline (as is), urea (10%) and heparinoid (0.3%) was performed and the only heparinoid caused erythematous rash within 20 min (Fig. 1b). Furthermore, we evaluated whether heparin stimulated peripheral blood mononuclear cells (PBMC) to produce inflammatory cytokines, because we have experienced a case of TRAPS exacerbated by heparin with the same TNFRSF1A mutation.2 PBMC from the patient, her father with the same mutation and healthy subjects were incubated with or without heparin (1 unit/mL) for 12 h. Then we performed intracellular cytokine staining and investigated interleukin-1b (IL-1b) synthesis by flow cytometric analysis. Heparin increased the frequency of IL-1b+ CD14+ cells in PBMC in the patient and her father with a T61I mutation, but not in healthy subjects (Fig. 1c). Tumor necrosis factor receptor-associated periodic syndrome is a rare autoinflammatory disease associated with enhanced innate immune responsiveness and abnormal intracellular traffick-
Correspondence: Shun Ohmori, M.D., Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8556, Japan. Email: [email protected]
1112
© 2014 Japanese Dermatological Association
Letters to the Editor
(a)
(b)
(c)
We present the second case of TRAPS with a T61I mutation exacerbated by heparin and heparinoid, while there is a consideration that heparin has both pro- and anti-inflammatory effects depending on the concentration.5 Heparin usually displays an anti-inflammatory effect in pharmacological concentration (0.1–1.0 unit/mL). Although we are not able to disclose the genetic mechanism in this report, the T61I substituted TNFR1 itself may influence the genetic abnormality and hypersensitivity to heparin and heparinoid even in low concentration.
CONFLICT OF INTEREST:
The authors declare no financial
or other conflict of interest.
Shun OHMORI, Ryosuke HINO, Motonobu NAKAMURA Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan doi: 10.1111/1346-8138.12689
REFERENCES
Figure 1. (a) Diffuse erythema and red papules on her knee. (b) Erythematous rash by open patch test with heparinoid (arrow). (c) Increased frequency of interleukin-1b+ CD14+ cells stimulated by heparin in the patient and her father with a T61I mutation, compared with those unstimulated or those stimulated in a healthy subject. ing of the type 1 tumor necrosis factor receptor (TNFR1) owing to missense mutations in TNFRSF1A.3 The accumulation of mutant TNFR1 causes spontaneous c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and for PBMC from TRAPS patients to overproduce inflammatory cytokines in response to low-dose lipopolysaccharide.4 It means that minor triggers which stimulate the innate immune system can lead to the inflammatory cytokine production in TRAPS.
1 Toro JR, Assentijevich I, Hull K, Dean J, Kastner DL. Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations. Arch Dermatol 2000; 136: 1487–1494. 2 Ohmori S, Hino R, Nakamura M, Tokura Y. Heparin serves as a natural stimulant of the inflammasome and exacerbates the symptoms of tumor necrosis factor receptor-associated periodic syndrome (TRAPS). J Dermatol Sci 2012; 66: 82–84. 3 McDermott MF, Assentijevich I, Galon J et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 1999; 97: 133–144. 4 Simon A, Park H, Maddipati R et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic syndrome. Proc Natl Acad Sci USA 2010; 107: 9801–9806. 5 Hochart H, Jenkins PV, Preston RJ, Smith OP, White B, O’Donnell J. Concentration-dependent roles for heparin in modifying lipopolysaccharide-induced activation of mononuclear cells in whole blood. Thromb Haemost 2008; 99: 570–575.
Development of systemic sclerosis in patients with Behc ß et’s disease: Remission of Behc ß et’s disease in parallel with the progression of skin sclerosis Dear Editor, The T-helper (Th)1/Th2 paradigm potentially explains the high concurrence and mutual exclusiveness of certain immunemediated diseases in each individual patient, and rare cases
with overlap of Th1- and Th2-mediated diseases are insightful to understand the in vivo negative cross-regulation between Th1- and Th2-mediated immune responses.1–3 We recently experienced two cases of systemic sclerosis (SSc)
Correspondence: Yoshihide Asano, M.D., Ph.D., Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
1113
