REVIEWS Pediatric Dermatology Vol. 32 No. 4 437–446, 2015
A Review and Proposed Approach to the Neutrophilic Dermatoses of Childhood Kate Webb, M.B.B.C.H., M.Med., F.C.Paed.Rheum.(SA),*,† Carol Hlela, M.D., Ph.D.,*,† H. Francois Jordaan, MB.CHB,M.MED,M.AKAD(SA),‡ Sara Suliman, Ph.D.,§ Thomas Scriba, Ph.D.,§ Dan Lipsker, M.D., Ph.D.,¶ and Chris Scott, M.B.ChB., F.C.Paed.(SA), Grad. Cert. Paed. Rheum. (UWA)* Departments of *Rheumatology and †Dermatology, School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa, ‡Division of Dermatology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Stellenbosch, South Africa, §South African TB Vaccine Initiative, University of Cape Town, Cape Town, South Africa, ¶Facult e de M edecine, Universit e de Strasbourg and H^ opitaux Universitaires de Strasbourg, Strasbourg, France
Abstract: Neutrophilic dermatoses (NDs) are inflammatory skin conditions that are not associated with infection. The classification and clinical approach to these conditions in children is poorly described. This review classifies these conditions into five nosological subtypes: Sweet’s syndrome, pyoderma gangrenosum, aseptic pustules, neutrophilic urticarial dermatoses, and Marshall’s syndrome. In addition, we review the various secondary diseases that need to be excluded in the clinical management of the NDs of childhood, with a focus on the autoinflammatory conditions that the reader may not be familiar with. We propose a practical clinical approach to these disorders.
Neutrophilic dermatoses (NDs) are defined as aseptic polymorphonuclear infiltrations of the epidermis, dermis, or subcutaneous fat. Neutrophilic skin infiltrations usually indicate infection, but NDs are disorders without primary infection of the skin. In the adult literature, it has been noted that these disorders are on a common spectrum because of shared histologic profiles, the possibility of extracutaneous neutrophilic infiltrates, and associations with other systemic diseases (1). In children, these diseases are rare and not well classified. We review the various
syndromes and diseases that have been associated with aseptic neutrophilic infiltrates in children. SWEET’S SYNDROME Robert Douglas Sweet first described Sweet’s syndrome in 1964 (2). It is a phenotypic description of an acute febrile dermatosis. Von den Driesch et al (3) developed diagnostic criteria for Sweet’s syndrome for adults in 1994 (Table 1). Children present with well-demarcated, erythematous, edematous
Address correspondence to Kate Webb, Red Cross Children’s Hospital, Klipfontein Road, 7700, Cape Town, South Africa, or e-mail:
[email protected]. DOI: 10.1111/pde.12502
© 2015 Wiley Periodicals, Inc.
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TABLE 1. Von Driesch et al (3) Sweet syndrome classification* Major criteria Minor criteria
Abrupt onset of tender or painful erythematous plaques or nodules, occasionally with vesicles, pustules or bullae. Predominantly neutrophilic infiltration of dermis without leukocytoclastic vasculitis. Preceded by nonspecific gastrointestinal or upper respiratory tract infection or vaccination, associated with autoimmune diseases, infections, pregnancy, or hemoproliferative or solid malignancies. Accompanied by general malaise and fever >38°C. Laboratory values at onset; three of four necessary: erythrocyte sedimentation rate >20 mm/hr, C-reactive protein positive, leucocytes >8,000/lL, bands and neutrophils >70%. Excellent response to treatment with systemic steroids or potassium iodide.
*At least two major and two minor criteria are necessary for diagnosis.
papules and plaques (4). The lesions may also demonstrate pathergy, arcuate lesions, pseudovesiculation, hemorrhage, and violaceus color. The lesions typically do not scar and are symmetrical (5). The lesions are often associated with fever, raised inflammatory markers, and neutrophilic leukocytosis. Arthritis, myalgia, and malaise are common, and extracutaneous lesions can occur in the eyes, lungs, bones and joints, meninges, large vessels, heart, and kidneys. Sweet’s syndrome may be classified as classic/ idiopathic Sweet’s syndrome, which is often recurrent, and secondary Sweet’s syndrome. In a review of the literature, Hospach et al (6) reviewed 64 cases of Sweet’s syndrome in children. In this review, 42% of patients had classicor/idiopathic disease. Of these, 21% had no associated disease and 21% had had prior transient disease, mostly respiratory tract infections. Of the 52% with secondary causes, 33% were classified as parainflammatory and 25% as paramalignant. The parainflammatory category included autoimmune diseases such as central nervous system vasculitis, aortitis (often associated with cutis laxa), arthritis, systemic lupus erythematosus (7–9), and chronic recurrent multifocal osteomyelitis (CRMO), sometimes associated with dyserythropoietic anaemia in the context of Majeed syndrome (10,11). The parainflammatory group also included children with immune deficiencies such as chronic granulomatous disease, lymphopenia associated with trisomy 21, human immunodeficiency virus (HIV) infection, and humoral immune deficiency. The paramalignant group included acute myelogenous leukaemia, acute lymphoblastic leukaemia, Fanconi’s anemia, myelodysplastic syndrome, and juvenile chronic myelogenous leukemia (6). In another literature review of 66 children by Halpern et al (12), it was noted that 20% of the cases had associated pathergy and 30% had associated postinflammatory scarring with cutis laxa. The most common associated disease was bony disease (20%)
with arthritis, osteomyelitis, or arthralgia. Twentyfour percent of these patients had Sweet’s syndrome secondary to malignancy and 10% had associated immune deficiency. Overall, 95% had a high white cell count (>8 9 109/L), 45% had neutrophilia (>75% of total white cell count), 94% had anemia (20 mm/hr; 15% of these patients had cardiac complications, 40% of whom died. These included pericarditis, great vessel dilatation, valve disease, and myocardial infarction. Overall there was 9% mortality (12). There have been various reports of Sweet’s syndrome in children being the initial manifestation of autoimmune diseases such as systemic lupus erythematosus (9,13–16) and sarcoidosis (17). Sweet’s syndrome in children has also been associated with certain drugs, such as azathioprine (18), granulocyte colony-stimulating factor (G-CSF) (19), and all-trans retinoic acid (20). This is difficult to confirm as causal, because all of these medications are used to treat diseases that have been associated with Sweet’s syndrome. In 2012, Gray et al (21) performed another excellent review of Sweet’s syndrome presenting in 20 children younger than 6 months old. This younger group had Sweet’s syndrome due to probable viral infections (6), primary immune deficiency (4), HIV infection (1), neonatal lupus erythematosus (3) and “genetic” Sweet’s syndrome (5). Three of these five “genetic” cases turned out to be chronic atypical ND with lipodystrophy and elevated temperature (CANDLE) syndrome or Nakajo–Nishimura syndrome, which is now a defined autoinflammatory condition. CANDLE syndrome is a recently described syndrome in children with lipodystrophy, periorbital erythema, finger or toe swelling, hepatosplenomegaly, fevers, failure to thrive, and recurrent erythematous cutaneous plaques. These patients have a PSMB8 mutation that encodes the immunoproteasome and causes a clinical interferonopathy (22–24).
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8. Rochael MC, Pantaleao L, Vilar EA et al. Sweet’s syndrome: study of 73 cases, emphasizing histopathological findings. An Bras Dermatol 2011;86:702–707. 9. Germanas JP, Mehrabi D, Carder KR. Palisaded neutrophilic granulomatous dermatitis in a 12-yearold girl with systemic lupus erythematosus. J Am Acad Dermatol 2006;55(2 Suppl):S60–S62. 10. Majeed HA, El-Shanti H. Majeed syndrome. In: Pagon RA, Bird TD, Dolan CR et al., eds. GeneReviews. Seattle, WA: University of Washington, 1993. 11. Ferguson PJ, Bing X, Vasef MA et al. A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis. Bone 2006;38:41–47. 12. Halpern J, Salim A. Pediatric sweet syndrome: case report and literature review. Pediatr Dermatol 2009;26:452–457. 13. Burnham JM, Cron RQ. Sweet syndrome as an initial presentation in a child with systemic lupus erythematosus. Lupus 2005;14:974–975. 14. Misago N, Narisawa Y, Tada Y et al. Palisaded neutrophilic granulomatous dermatitis caused by cellulitis in a patient with systemic lupus erythematosus. Int J Dermatol 2011;50:1583–1585. 15. Obermoser G, Sontheimer RD, Zelger B. Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus 2010;19:1050–1070. 16. Camarillo D, McCalmont TH, Frieden IJ et al. Two pediatric cases of nonbullous histiocytoid neutrophilic dermatitis presenting as a cutaneous manifestation of lupus erythematosus. Arch Dermatol 2008;144:1495– 1498. 17. Mahmoodi M, Ahmad A, Bansal C et al. Palisaded neutrophilic and granulomatous dermatitis in association with sarcoidosis. J Cutan Pathol 2011;38:365–368. 18. Kim MJ, Jang KT, Choe YH. Azathioprine hypersensitivity presenting as Sweet syndrome in a child with ulcerative colitis. Indian Pediatr 2011;48:969–971. 19. Prendiville J, Thiessen P, Mallory SB. Neutrophilic dermatoses in two children with idiopathic neutropenia: association with granulocyte colony-stimulating factor (G-CSF) therapy. Pediatr Dermatol 2001;18:417–421. 20. Yan ZS, Li DP, Jiang EL et al. Development of sweet syndrome in an acute promyelocyte leukemia patient during treatment with all-trans retinoic acid—case report and literature review. Zhonghua Xue Ye Xue Za Zhi 2007;28:462–465. 21. Gray PE, Bock V, Ziegler DS et al. Neonatal Sweet syndrome: a potential marker of serious systemic illness. Pediatrics 2012;129:e1353–e1359. 22. Torrelo A, Patel S, Colmenero I et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol 2010;62:489–495. 23. Liu Y, Ramot Y, Torrelo A et al. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 2012;64:895–907. 24. Goldbach-Mansky R. Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of
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based on adult practice. Dapsone or systemic steroids are effective first-line therapies initially and may induce remission (43). Other therapies described include potassium iodide, colchicine, clofazimine, indomethacin, cyclosporine, and other immunomodulatory agents (43). ND WITH POSTINFLAMMATORY CUTIS LAXA (MARSHALL’S SYNDROME) This variant deserves a special mention in the spectrum of ND because it seems to affect children specifically. One review reported that 30% of children may have cutis laxa after the acute ND stage (12). This is not as common a feature in the adult literature, and it is important because of the association with cardiac disease. Marshall et al (44) first described this clinical entity in 1966, 2 years after Sweet’s article. They described five children in the Western Cape of South Africa with neutrophilic skin lesions, raised inflammatory markers, systemic inflammation, and post-lesional cutis laxa (35,43–45). These children were all
