Pediatrics

Sweet syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has pediatric Sweet syndrome? What are the typical findings for this disease?

Sweet syndrome, or acute febrile neutrophilic dermatosis, is a neutrophilic dermatosis rarely seen in the pediatric population, accounting for only 5% to 8% of all cases of Sweet syndrome. It is characterized by four cardinal features.

  1. Acute onset of painful erythematous papules and plaques

  2. Fever

  3. Leukocytosis

  4. Dense neutrophilic dermal infiltrate on histology

Cutaneous manifestation of Sweet syndrome in children typically presents as well-demarcated erythematous to violaceous edematous papules and/or irregularly-shaped plaques ranging from 0.5 to 4 cm. However, lesions can be variable, ranging from skin-colored to violaceous and from macules and patches to annular and necrotic plaques. Lesions may have pseudo-vesiculations or even vesicles depending on the amount of edema. Pustules and pseudopustules have also been reported. Pathergy, the appearance of pustules at the site of minor trauma, is seen in 20% of cases. Examples of the various appearances of Sweet syndrome are shown in (Figure 1,Figure 2 and Figure 3)

Figure 1.

Classic Sweet syndrome lesions showing erythematous pseudovesiculating plaques with prominent surrounding erythema

Figure 2.

Sweet syndrome presenting as erythematous plaque with pustule formation and minimal surrounding erythema

Figure 3.

Sweet syndrome lesions presenting with prominent pseudovesiculation

Extremities are most often involved (90%), with the hands being the most common initial site affected, followed by the head (70%) and less commonly the trunk (25%). The majority of children have fever (86%) at the time of presentation and half report that the lesions are painful or tender. Bony disease is also a common finding (20%), presenting as arthralgia or bone pain. Cardiovascular involvement occurs in 15% of pediatric cases, presenting as aortitis, sterile pericarditis, dilatation of the great vessels, valvular disease, and myocardial infarction. The majority of pediatric cases (60%) report a prodromal illness.

Laboratory abnormalities include leukocytosis (95%), anemia (95%), neutrophilia (45%), thrombocytosis (50%), and elevated erythrocyte sedimentation rate (95%).

The diagnosis of pediatric Sweet syndrome is confirmed by skin biopsy. Histology demonstrates a dense dermal infiltrate of mature neutrophils with prominent papillary dermal edema. The infiltrate may extend into the subcutaneous tissue. A few eosinophils may be present in the infiltrate, and older lesions may have a few perivascular lymphocytes. Endothelial swelling and leukocytoclasia without vasculitis are typically seen, but there have been reported cases of vasculitis, and its presence does not rule out Sweet syndrome.

What other disease/condition shares some of these symptoms?

The skin eruption associated with Sweet syndrome in children is rarely diagnostic. The morphology of the lesions and the histopathology require one to consider many diagnoses on the differential. Several of the diseases are listed below.

  • Erythema multiforme

  • Bacterial ecthyma

  • Community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infection

  • Early herpes simplex virus infection

  • Early varicella/zoster infection

  • Granuloma faciale

  • Halogenoderma

  • Urticaria

  • Pyoderma gangrenosum

  • Erythema nodosum

  • Neutrophilic eccrine hidradenitis

  • Bowel-associated neutrophilic dermatosis

  • Leukocytoclastic vasculitis

  • Idiopathic recurrent palmoplantar hidradenitis (IRPH)

  • Pernio (chilblains)

  • Pseudomonas hot-foot syndrome

  • Drug reaction

  • Lupus erythematosus

  • Behçet's disease

  • Pustular eruption of ulcerative colitis

  • Vesicular eruption associated with hepatobiliary disease

  • Subcorneal pustular dermatosis

  • Pustular psoriasis

  • Secondary syphilis

  • Leukemia cutis

  • Arthus reaction

  • Hereditary periodic fever syndromes

  • Erysipelas/cellulitis

  • Thrombophlebitis

  • Pruritic urticarial papules and plaques of pregnancy (polymorphous eruption of pregnancy)

What caused this disease to develop at this time?

Sweet syndrome is known to be associated with other diseases or conditions and is subdivided into several categories, including classic/idiopathic, paraneoplastic, parainflammatory, pregnancy-associated, and drug-induced. The majority of pediatric Sweet syndrome cases fall into the classic/idiopathic category (42%), followed by parainflammatory (33%), and paraneoplastic (25%). Drug-induced cases are often categorized according to the underlying disease. The vast majority of pediatric Sweet syndrome cases will have a prodromal illness.

  • Classic/Idiopathic: This category encompasses patients with no known associated disease or with transient infections, commonly otitis media, respiratory tract infection, or gastrointestinal infection. Approximately 60% of pediatric cases have a prodromal illness. Inquiring about recent infectious symptoms will be vital to the history.

  • Paraneoplastic: Approximately 25% of pediatric cases fall into this category, which includes premalignant and malignant diseases. Malignancies associated with pediatric cases have all been hematologic, with the majority being acute myelogenous leukemia (AML), but also acute lymphoplastic leukemia (ALL) and juvenile chronic myelogenous leukemia (CML). Premalignant conditions that have been reported in association with pediatric Sweet syndrome include myelodysplastic syndrome, aplastic anemia, and Fanconi anemia. In general, Sweet syndrome never precedes the malignancy or premalignant disease; however, it is often a presenting sign. Malignancy-related pediatric cases have not been reported in children less than 3 years of age.

  • Parainflammatory: Diseases with chronic or recurrent inflammation are encompassed in this group, including autoimmune and recurrent infections. Autoimmune diseases that have been reported in pediatric Sweet syndrome include systemic lupus erythematosus, vasculitis, and arthritis.

    Chronic recurrent multifocal osteomyelitis (CRMO) has also been associated with Sweet syndrome, with diagnosis either preceding or occurring simultaneously with CRMO.

    Primary and secondary immunodeficiencies are also included in this category. They are much more strongly associated with pediatric cases than adult cases.

    Reported associations include chronic granulomatous disease, neutropenia, and glycogen storage disease, primary T-cell immunodeficiency with CD3 lymphopenia and abnormal response to antigens, and HIV infection. It should be noted that Sweet syndrome precedes all diagnoses of immunodeficiency.

    CBC with differential should be one of the initial laboratory studies obtained. If abnormalities are present, peripheral smear should be evaluated. Finally, a bone marrow biopsy should be obtained should the peripheral smear reveal anomalies. A thorough review of systems is essential to help identify any clues to a parainflammatory process.

  • Pregnancy-associated: Sweet syndrome during pregnancy has been reported in the adult literature and needs to be considered in the pregnant pediatric patient. A pregnancy test in all menstruating female patients should be obtained to rule out this association.

  • Drug-induced: Drug-induced Sweet syndrome in the pediatric population is rare, with less than 10 cases being reported in the literature. Only four drugs have been reported; G-CSF, all-trans-retinoic acid, trimethoprim-sulfamethoxazole, and azathioprine. Vaccinations have also been reported in association with Sweet syndrome. Obtaining a complete drug history will help identify or rule out an offending drug.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

CBC with differential: Greater than 95% of patients have leukocytosis (>8 x 109/L) and anemia (Hg < 12 g/dL). In almost half of the patients there is neutrophilia (>70% neutrophils) and thrombocytosis (Plt > 400,000/mm3).

Skin biopsy : As one of the major criteria for diagnosis, all patients have a neutrophilic infiltrate on skin histology. Histopathology demonstrates a dense dermal infiltrate of mature neutrophils with prominent papillary dermal edema. The infiltrate may extend into the subcutaneous tissue. A few eosinophils may be present in the infiltrate and occasionally, lymphocytes and histiocytes may also be seen. Endothelial swelling and leukocytoclasia without vasculitis are typically seen, but there have been reported cases of Sweet syndrome with vasculitis, and its presence does not rule out Sweet syndrome. There is a histologic variant with exclusive subcutaneous involvement in a lobular panniculitis pattern that occurs in 5% of the cases, presenting as nodules and plaques on the extremities (lower > upper).

Skin biopsies may also be performed to rule out infectious etiologies of the skin lesions. Tissue gram stain and cultures for bacterial, atypical mycobacterial, fungal, and viral to rule out infectious causes are typically negative.

Inflammatory markers: Over 95% of patients have an elevated erythrocyte sedimentation rate (ESR) (> 20 mm/hour).

Pregnancy test: Pregnancy testing should be performed in all menstruating females to help diagnose or rule out pregnancy-induced Sweet syndrome.

Additional laboratory tests to rule out infectious etiologies, such as blood cultures, cerebrospinal fluid (CSF) analysis and culture, urine analysis and culture, viral studies, antistreptolysin-O antibody/anti-DNase antibody are not usually necessary for most presentations, but when obtained are typically negative.

If cardiac signs or symptoms are present, EKG and/or echocardiography are warranted.

Would imaging studies be helpful? If so, which ones?

Imaging is usually not warranted for the diagnosis of Sweet syndrome.

Imaging should be performed when a patient presents with concurrent bone pain or arthralgia. Arthritis and osteomyelitis (CRMO) occur in 20% of pediatric cases; therefore, consideration of imaging (X-ray or MRI) may be warranted. Imaging should also be performed when a patient presents with cardiac signs or symptoms. Cardiovascular involvement increases mortality to 40%; therefore, further investigation with echocardiography needs to be considered.

Confirming the diagnosis

Revised diagnostic criteria for Sweet syndrome have been proposed, requiring two major and at least two minor criteria.

Major Criteria

  • Abrupt onset of painful erythematous plaques or nodules

  • Predominantly neutrophilic infiltration in the dermis without evidence of leukocytoclastic vasculitis

Minor Criteria

  • Preceded by a nonspecific respiratory or gastrointestinal tract infection or vaccination OR associated with an underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy

  • Temperature >38oC

  • Laboratory values during onset: ESR >20 mm/hr, positive C-reactive protein, segmented-nuclear neutrophils and bands >70% in peripheral blood smear, leukocytes >8000/microliter (three out of four of these values are necessary)

  • Excellent response to treatment with systemic steroids or potassium iodide

The diagnostic criteria for drug-induced Sweet syndrome were proposed by Walker and Cohen in 1996. All five criteria are required for diagnosis.

  • Abrupt onset of painful erythematous plaques or nodules

  • Histopathologic evidence of a dense neutrophilic infiltrate without leukocytoclastic vasculitis

  • Temperature >38oC

  • Temporal relationship between drug ingestion and clinical presentation OR temporally-related recurrence after oral rechallenge

  • Temporally-related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids

If you are able to confirm that the patient has pediatric Sweet syndrome, what treatment should be initiated?

  • Systemic corticosteroids are the first-line therapy for the majority of patients, including patients with known underlying malignancy. Because systemic corticosteroid treatment can cause significant rise in peripheral blood neutrophil counts, laboratory studies should be performed prior to starting therapy. There is no standard dosing regimen, although a commonly used dose is 2 mg/kg/day followed by a tapering dose. Schachner recommends 0.5-1.5 mg/kg/day x 10 days then taper slowly. Heron et al. treated two children successfully with different dosing regimens; 1 mg/kg/day x 3 weeks then taper, and 2 mg/kg/day x 1 week then taper over 5 weeks. Tapering needs to be slow as the disease can flare with lower doses of systemic corticosteroids.

    Corticosteroids should not be used in conditions where temporary immunosuppression would add significantly to the morbidity of the underlying condition, such as when Sweet syndrome is triggered by underlying sepsis.

  • Alternative first-line agents when systemic corticosteroids are contraindicated include saturated solution of potassium iodide and colchicine. Other alternative agents that have been used include dapsone, cyclosporine, intravenous immunoglobulin (IVIG), doxycycline, clofazamine, methotrexate, indomethacin, and interferon-alpha.

  • Patients with focal lesions, recurrences, or who opt out of systemic therapies can be offered topical or intralesional corticosteroids or topical dapsone. Aspirin and/or NSAIDs can be considered, as the disease is a hypersensitivity reaction, especially if a thrombocytosis is present.

  • In patients with known drug-induced Sweet syndrome, discontinuation of the offending agent often results in clearing of skin lesions. If an underlying malignancy is the cause of Sweet syndrome, treatment or remission of malignancy often correlates with resolution of skin lesions.

What are the adverse effects associated with each treatment option?

Prednisone

  • Pediatric: growth impairment

  • Hypothalamic-pituitary-adrenal (HPA) axis: steroid withdrawal syndrome, Addisonian crisis

  • Metabolic: hyperglycemia, increased appetite (weight gain), hypertension, congestive heart failure (CHF), hypokalemia, hypertriglyceridemia, Cushingoid changes, menstrual changes

  • Bone: osteoporosis, osteonecrosis, hypocalcemia

  • Gastrointestinal: peptic ulcer disease, bowel perforation, fatty liver changes, esophageal reflux, nausea, vomiting

  • Ocular: cataracts, glaucoma, infections (especially Staphylococcal), refraction changes

  • Psychiatric: psychosis, agitation or personality changes, depression

  • Neurologic: pseudotumor cerebri, epidural lipomatosis, peripheral neuropathy

  • Infectious: tuberculosis reactivation, opportunistic infections (deep fungal, others), prolonged herpes virus infections

  • Muscular: myopathy

  • Pulse IV therapy: electrolyte shifts, cardiac dysrhythmias, seizures

  • Other: "opportunistic" malignancies (typically seen in immunocompromised patients), teratogenicity (doubtful)

Potassium Iodide

  • Endocrine: goiter with or without hypothyroidism, thyroid adenoma

  • Cutaneous: rash

  • Gastrointestinal: GI irritation,

  • Neurologic: paresthesia

  • Immunologic: immune hypersensitivity reaction

Colchicine

  • Gastrointestinal: diarrhea, nausea, vomiting, dehydration, hepatic failure

  • Neurologic: late central nervous system disorders, myopathy

  • Metabolic: hypocalcemia

  • Mucocutaneous: alopecia, stomatitis, porphyria cutanea tarda

  • Hematologic: myelosuppression

Dapsone

  • Gastrointestinal: gastric irritation, anorexia, hepatitis, cholestatic jaundice, hypoalbuminemia, pancreatitis,

  • Hematologic: hemolytic anemia, methemoglobinemia (headache, lethargy), leukopenia, agranulocytosis

  • Immunologic: hypersensitivity syndrome (mononucleosis-like)

  • Cutaneous: morbilliform eruption, exfoliative erythroderma, toxic epidermal necrolysis (TEN)

  • Neurologic: peripheral neuropathy,

  • Psychiatric: psychosis, suicidal intent (rare)

Cyclosporine

  • Renal: renal dysfunction

  • Cardiovascular: hypertension

  • Neurologic: tremor, headache, paresthesia, hyperesthesia, seizure, encephalopathy

  • Mucocutaneous: hypertrichosis, gingival hyperplasia

  • Gastrointestinal: nausea, abdominal discomfort, diarrhea, hepatotoxicity

  • Musculoskeletal: myalgia, lethargy, arthralgia

  • Laboratory abnormalities: hyperkalemia, hyperuricemia, hypomagnesemia, hyperlipidemia,

IVIG

  • Infusion-related: headache, myalgia, chills, flushing, fever, nausea, vomiting, low back pain, wheezing, chest pain, blood pressure changes, tachycardia, anaphylactic response (particularly with IgA deficiency)

  • Cutaneous: dermatitis, erythema multiforme, purpura, alopecia

  • Renal: acute renal failure due to sucrose-containing IVIg preparations

  • Hematologic: neutropenia, hemolysis, thromboembolic events

  • Neurologic: aseptic meningitis

  • Infectious: theoretical risk of transmission of infectious diseases

Doxycycline

  • Gastrointestinal: epigastric burning, abdominal discomfort, nausea, vomiting, esophagitis, pancreatitis, hepatotoxicity

  • Teeth: brown discoloration of teeth in children

  • Musculoskeletal: delayed bone growth in children

  • Neurologic: vestibular toxicity, phototoxic, pseudotumor cerebri

  • Cutaneous: may exacerbate psoriasis, rash, drug hypersensitivity reaction, Stevens-Johnson syndrome, drug-induced lupus, serum sickness-like reaction, blue-black pigmentation (more common in minocycline)

  • Endocrine: gynecomastia

  • Cardiovascular: hypertension

  • Hematologic: leukocytosis with atypical lymphocytes, toxic granulation of granulocytes, thrombocytopenia purpura

Clofazamine

  • Cutaneous: reversible orange-brown discoloration (body secretions can also be discolored), generalized xerosis, nail changes, pedal edema, exacerbation of vitiligo

  • Gastrointestinal: abdominal cramping, nausea, diarrhea, crystal deposition in small bowel can result in fatal enteropathy, splenic infarction, eosinophilic enteritis

  • Cardiovascular: one case report of cardiac dysrhythmia with preexisting electrolyte disturbance

Methotrexate

  • Gastrointestinal: nausea, vomiting, diarrhea, ulcerative stomatitis, hepatotoxicity, cirrhosis

  • Pulmonary: acute pneumonitis, pulmonary fibrosis

  • Hematologic: pancytopenia

  • Malignancy: lymphoma

  • Reproductive: potent teratogen and abortifacient

  • Renal: renal toxicity secondary to precipitation in renal tubules in high doses used for chemotherapy

  • Cutaneous: mild alopecia, potentially phototoxic, acral erythema, papular eruption, epidermal necrosis, cutaneous ulceration, vasculitis

  • Bone: osteopathy, stress fractures

  • Immunologic: anaphylaxis

  • Constitutional: fatigue

Indomethacin

  • Pediatric: hyponatremia in neonates, transitory neonatal hyperkalemia, necrotizing enterocolitis in fetus or newborn, newborn renal dysfunction, neonatal cardiovascular disorder, bronchopulmonary dysplasia of newborn, persistent pulmonary hypertension of the newborn

  • Cutaneous: Stevens-Johnson syndrome

  • Gastrointestinal: abdominal pain, constipation, diarrhea, indigestion, nausea, hemorrhage, perforation, ulcer, inflammatory disorder, elevated liver function tests (LFTs), hepatic necrosis, hepatitis, liver failure

  • Neurologic: dizziness, headache, somnolence, vertigo, tinnitus, hearing loss, cerebrovascular accident, seizure, ventricular hemorrhage

  • Cardiovascular: dysrhythmia, congestive heart failure, myocardial infarction, thrombotic tendency

  • Immunologic: anaphylactoid reactions

  • Ophthalmic: retinal disorder, retinopathy of prematurity

  • Renal: renal failure

  • Pulmonary: bronchospasm, pulmonary hemorrhage

Interferon-alpha

  • Constitutional: influenza-like symptoms (fever, chills, headache, arthralgia)

  • Musculoskeletal: myalgias, fatal rhabdomyolysis

  • Cardiovascular: hypotension, dysrhythmia, tachycardia

  • Psychiatric: depression, suicidal behavior

  • Gastrointestinal: nausea, diarrhea

What are the possible outcomes of pediatric Sweet syndrome?

In the majority of cases, the disease is self-limited and the prognosis is good. Even without treatment, the natural course of the disease is for the lesions to modestly increase in size and persist for 1-12 months, then resolve without sequelae. However, outcome depends on the severity of the associated systemic disease and the presence of extracutaneous manifestations. The majority of cases will resolve without sequelae. Rapid response of skin lesions and dermatosis-related symptoms to systemic corticosteroids is typical.

Approximately 25% of patients experience recurrences, especially during corticosteroid taper. Recurrences are more common (45%) when Sweet syndrome is associated with an underlying malignancy.

The overall mortality of Sweet syndrome in the pediatric population is 9%, with a higher mortality in children under 3 years of age (12%). The presence of cardiovascular involvement increases mortality to 40%.

With corticosteroid treatment, the disease typically improves rapidly over days. However, even with treatment, some patients may take up to one year to experience resolution of disease flares.

What causes this disease and how frequent is it?

  • Sweet syndrome is considered a type of neutrophilic hypersensitivity reaction. Sweet syndrome occurs worldwide and has no racial predilection. It is a rare condition in children, with pediatric cases accounting for between 5% and 8% of all cases. A review article from 2009 identified 66 reported pediatric cases in the literature.

  • The majority of pediatric cases are associated with transient infections, including most commonly otitis media, respiratory and gastrointestinal infections. Seasonal variation and mode of transmission will be related to the underlying infection. Drug-induced cases and cases associated with underlying parainflammatory or paraneoplastic diseases will be sporadic.

  • There are several case reports of genetic abnormalities involving chromosomes 1q and 3q in patients with Sweet syndrome associated with an underlying malignancy. Majeed syndrome, which is characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia and Sweet syndrome, has been associated with various mutations in LPIN2. Majeed syndrome is very rare; there are only three affected families reported to date, all from the Middle East.

How do these pathogens/genes/exposures cause the disease?

The pathogenesis of Sweet syndrome is unknown but is likely to be multifactorial. The current hypothesis is one of a hypersensitivity reaction to infectious or tumor antigens with an inappropriate regulation of cytokines. Central to the pathologic process is T-lymphocyte activation. Several cytokines that have been implicated include IL-1, IL-8, IFN-gamma, G-CSF, and GM-CSF. Both G-CSF and IL-1 have been implicated in granulocyte activation, granulopoiesis, and defective granulocyte function in Sweet syndrome.

Other clinical manifestations that might help with diagnosis and management

Mucosal involvement and chest infiltrates have each been seen in 5% of pediatric cases. There has been one case of concurrent small vessel vasculitis in a pediatric case.

Additional sites of extracutaneous manifestations reported in the adult cases of Sweet syndrome include central nervous system, ears, eyes, kidneys, intestines, liver, lung, muscles, and spleen. Ocular manifestations, such as conjunctivitis, may be the presenting feature in adult cases.

What complications might you expect from the disease or treatment of the disease?

Secondary infection of cutaneous lesions can occur. Postinflammatory scarring and/or acquired cutis laxa occur in 30% of pediatric cases. Of the 10 cases reported in the literature of acquired cutis laxa following childhood Sweet syndrome, three had cardiovascular involvement. Pathergy was seen in 20% of patients, and 60% of them had postinflammatory scarring and/or acquired cutis laxa.

There have been rare reports of epiglottitis requiring a tracheostomy, gastrointestinal hemorrhage, and skin necrosis necessitating amputation of an arm.

The overall mortality of Sweet syndrome in the pediatric population is 9%, and the presence of cardiovascular involvement increases mortality to 40%.

A specific complication from systemic corticosteroids in the pediatric population is growth impairment, which may need to be addressed if long-term corticosteroid therapy is considered.

Are additional laboratory studies available; even some that are not widely available?

In the absence of infectious etiology, Sweet syndrome in the pediatric population warrants further investigation for an underlying malignancy or primary immunodeficiency.

Hospach et al. proposed screening for associations at the initial diagnosis of pediatric Sweet syndrome; they are listed below:

  • Erythrocyte sedimentation rate (ESR)

  • Complete blood count

  • Peripheral blood smear

  • Antinuclear antibody (ANA)

  • Lactate dehydrogenase (LDH)

  • Uric acid

  • Human immunodeficiency virus (HIV)

  • Immunoglobulin levels (IgG and subclasses, IgM, IgE, IgA)

  • Tetanus and diphtheria titers

  • Granulocyte and lymphocyte function tests

  • Blood pressure

  • Anemia: test for Fanconi anemia by diepoxybutane cytogenetic studies

Hospach et al. also proposed follow-up screening of weekly ESR and CBC with differential while disease is active and for patients with cutis laxa, an echocardiography every three months (probably into adulthood).

In patients who meet the clinical criteria for Majeed syndrome, molecular genetic testing of LPIN2 gene is available.

How can pediatric Sweet syndrome be prevented?

There are no prophylactic drugs or vaccines available to prevent Sweet syndrome. Treating underlying associations, such as malignancy and autoimmune diseases, may decrease recurrences.

There are no known behavioral factors associated with Sweet syndrome.

Majeed syndrome, which is characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia and Sweet syndrome, is inherited in an autosomal recessive pattern. Prenatal testing in affected families is available. Other genetic links that have been reported in Sweet syndrome were in association with underlying malignancies.

There are no known nutritional factors associated with Sweet syndrome.

What is the evidence?

Abbas, O, Kibbi, AG, Rubeiz, N. "Sweet's syndrome: retrospective study of clinical and histologic features of 44 cases from a tertiary care center". Int J Dermatol. vol. 49. 2010. pp. 1244-9.

This retrospective review article examines the clinical and histologic features of 44 cases of Sweet syndrome reported in their tertiary care facility in Beirut, Lebanon from 1971 to 2008. The results are generally comparable to previously published except for a relatively higher frequency of pediatric age group (16%), for which they partly explained is due to the fact that their institution is the only pediatric cancer center in the country. Level of evidence 4.

James, WD, Berger, TG, Elston, DM. "Andrews' diseases of the skin: clinical dermatology". Saunders Elsevier. 2006.

This a comprehensive dermatology textbook authored by three practicing general dermatologists. The primary intent of this textbook is that it be utilized by the practicing dermatologist as a reference tool for diagnosis and treatment. Level of evidence 5.

Cohen, PR. "Sweet's syndrome--a comprehensive review of an acute febrile neutrophilic dermatosis". Orphanet J Rare Dis. vol. 2. 2007. pp. 34.

This review article by Cohen gives a complete overview of current definition, diagnostic criteria, epidemiology, clinical description, pathology, etiology, diagnostic methods, management, and prognosis of Sweet syndrome. The author performed a complete literature review, citing 435 references. Even though this article is not specific to pediatrics, it provides a complete review of the disease and identifies possible clinical presentations and complications in the adult population that has not yet been reported in the pediatric literature. Level of evidence 4.

Colovic, M, Jankovic, G, Suvajdzic, N, Nikolic, M. "Structural chromosomal abnormality of 1q in acute leukemia with Sweet syndrome". Cancer Genet Cytogenet. vol. 139. 2002. pp. 84-5.

This letter to the editor reports a case of Sweet syndrome in a 40-year-old female with associated AML in which an abnormality was noted on chromosome 1q. Level of evidence 5.

Colovic, MD, Jankovic, GM, Novak, AZ. "Sweet's syndrome associated with paracentric inversion of chromosome 3q in a patient with multiple myeloma". Eur J Haematol. vol. 57. 1996. pp. 188-9.

In this letter to the editor, the authors report a case of a 61-year-old female with multiple myeloma and Sweet syndrome. Cytogenetic analysis revealed a paracentric inversion of chromosome 3q. Level of evidence 5.

Halpern, J, Salim, A. "Pediatric sweet syndrome: case report and literature review". Pediatr Dermatol. vol. 26. 2009. pp. 452-7.

This review article and report of a case of pediatric Sweet syndrome discusses etiology, clinical presentation, associated diseases, treatment, prognosis, and complications seen in pediatric Sweet syndrome. It also discusses disparities between pediatric and adult cases of Sweet syndrome. This article identifies significant differences in cases of pediatric Sweet syndrome occurring under and over the age of three years. Level of evidence 4.

Herron, MD, Coffin, CM, Vanderhooft, SL. "Sweet syndrome in two children". Pediatr Dermatol. vol. 22. 2005. pp. 525-9.

This is a case report of two children with Sweet syndrome. The authors address the challenge of managing Sweet syndrome in the pediatric population due to its tendency to recur after cessation of corticosteroid therapy. Level of evidence 4.

Hospach, T, von den Driesch, P, Dannecker, GE. "Acute febrile neutrophilic dermatosis (Sweet's syndrome) in childhood and adolescence: two new patients and review of the literature on associated diseases". Eur J Pediatr. vol. 168. 2009. pp. 1-9.

This review article of pediatric Sweet syndrome focuses on associated diseases. The authors suggest careful screening for premalignant/malignant diseases, immunodeficiencies, cardiovascular involvement, autoimmune diseases, and drug associations. They have proposed screening guidelines during initial diagnosis of Sweet syndrome and during follow-up. Level of evidence 4.

Kim, MJ, Choe, YH. "EPONYM. Sweet syndrome". Eur J Pediatr. vol. 169. 2010. pp. 1439-44.

This is a review article of pediatric Sweet syndrome and report of a 9-year-old female with azathioprine-induced Sweet syndrome associated with ulcerative colitis. The authors focus on drug-induced Sweet syndrome in the pediatric population. Level of evidence 4.

Kourtis, AP. "Sweet syndrome in infants". Clin Pediatr (Phila). vol. 41. 2002. pp. 175-7.

This is a case report of Sweet syndrome in a 6-week-old male who developed pathergy. Level of evidence 4.

Majeed, HA, El-Shanti, H, Pagon, RA, Bird, TD, Dolan, Cr, Stephens, K. "Majeed Syndrome". GeneReviews [Internet]. University of Washington, Seattle. 1993. http://www.ncbi.nlm.nih.gov/books/NBK1974.

This chapter reviews Majeed syndrome, discussing diagnosis, clinical descriptions, differential diagnosis, management, and genetic counseling. Level of evidence 5.

Mijovic, A, Novak, A, Medenica, L. "Sweet's syndrome associated with inversion of chromosome 3q in a patient with refractory anemia". Eur J Haematol. vol. 49. 1992. pp. 156-7.

In this letter to the editor, the authors report an additional case of MDS with an inversion of chromosome 3q and Sweet syndrome in a 63-year-old female. Level of evidence 5.

Mohr, MR, Torosky, CM, Hood, AF. "Sweet syndrome in infancy". Pediatr Dermatol. vol. 27. 2010. pp. 208-9.

This is a case report of Sweet syndrome occurring in a 10-week-old male with preceding upper respiratory and gastrointestinal symptoms. The authors recommend work-up for an immunodeficiency syndrome in infants presenting with Sweet syndrome, as well as a review of the peripheral smear to rule out rare cases of malignancy. Level of evidence 4.

O'Regan, GM, Ho, WL, Limaye, S. "Sweet's syndrome in association with common variable immunodeficiency". Clin Exp Dermatol. vol. 34. 2009. pp. 192-4.

This is a case report of Sweet syndrome occurring in a 4-month-old male who subsequently developed common variable immunodeficiency (CVID), which was confirmed at the age of seven years. Level of evidence 4.

Rapini, RP. "Practical dermatopathology". Elsevier Mosby. 2005.

This text is intended as a supplement to existing dermatopathology texts. Level of evidence 5.

Schachner, LA, Hansen, RC. "Pediatric dermatology". Mosby Elsevier. 2003.

This encyclopedic textbook on pediatric dermatology was written by authors from around the world. Level of evidence 5.

Thompson, DF, Montarella, KE. "Drug-induced Sweet's syndrome". Ann Pharmacother. vol. 41. 2007. pp. 802-11.

This is a review article focusing on drug-induced Sweet syndrome. All case reports were evaluated against an expanded Naranjo scale with specific criteria for Sweet syndrome. The authors found that many drugs have been implicated in causing Sweet syndrome, but only granulocyte colony-stimulating factor, all-trans-retinoic acid, and vaccines had sufficient evidence to meet criteria. Level of evidence 4.

Timmer, DE, Mik, L, Broekhuijsen-VAN Henten, DM, Oldhoff, JM. "Acquired cutis laxa in childhood Sweet's syndrome". Pediatr Dermatol. vol. 26. 2009. pp. 358-60.

This is a case report of Sweet syndrome in an 8-month-old male with preceding otitis media. The patient's case was complicated by cutis laxa. The authors review the literature on postinflammatory cutis laxa following Sweet syndrome in the pediatric population. Level of evidence 4.

von den Driesch, P. "Sweet's syndrome (acute febrile neutrophilic dermatosis)". J Am Acad Dermatol. vol. 31. 1994. pp. 535-60.

This review article of 38 patients with Sweet syndrome discusses epidemiology, clinical spectrum, histologic features, laboratory results, differential diagnosis, pathogenesis, associated diseases, and treatment. The authors modify the diagnostic criteria proposed by Su and Liu in 1986. Level of evidence 4.

Walker, DC, Cohen, PR. "Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome". J Am Acad Dermatol. vol. 34. 1996. pp. 918-23.

In this case report and review of the literature, the authors describe a 50-year-old female with trimethoprim-sulfamethoxazole-induced Sweet syndrome and discuss drug-induced Sweet syndrome. Level of evidence 4.

Weedon, D. "Skin pathology". Elsevier Health Sciences. 2002.

This is a textbook of dermatopathology. It provides basic clinical descriptions and in depth histopathologic descriptions of dermatologic diseases. Level of evidence 5.

Wolverton, SE. "Comprehensive dermatologic drug therapy". Elsevier Health Sciences. 2007.

This textbook is designed as a reference for dermatologic therapeutics, including dosing, side effects, and monitoring of dermatologic medications. Level of evidence 5.

Buck, T, González, LM, Lambert, WC, Schwartz, RA. "Sweet's syndrome with hematologic disorders: a review and reappraisal". Int J Dermatol. vol. 47. 2008. pp. 775-82.

This review of the literature focuses on Sweet syndrome in adult patients with hematologic disorders. Level of evidence 4.

Ongoing controversies regarding etiology, diagnosis, treatment

Currently, there is no consensus on the timing and frequency of screening for malignancy in the otherwise asymptomatic patient with idiopathic Sweet syndrome.

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