Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations.
BACKGROUND
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an inflammatory disorder characterized by prolonged episodes of periodic fever and localized inflammation and dominantly inherited mutations in TNFRSF1A, the gene encoding the 55-kDa tumor necrosis factor receptor. To our knowledge, the cutaneous pathologic characteristics of TRAPS have not been described previously.


OBJECTIVE
To characterize the dermatologic manifestations of TRAPS by clinical, microscopic, and molecular methods, and to investigate its immunophenotype.


METHODS
At the National Institutes of Health Clinical Center, Bethesda, Md, a tertiary care referral center, 25 patients with a clinical and molecular diagnosis of TRAPS were evaluated clinically and 10 biopsy specimens of lesional skin were examined by light microscopy and immunohistochemistry. Patients were screened for mutations in TNFRSF1A, the gene coding for the p55 tumor necrosis factor receptor.


METHODS
Clinical, light microscopic, and immunohistochemical features.


RESULTS
The skin eruption usually lasted 4 to 21 days (mean, 13 days). Of 25 patients, 21 (84%) presented with migratory erythematous macules and patches and 10 (40%) had edematous dermal plaques. Conjunctivitis, characterized by pain and redness and/or periorbital edema, was present in 11 patients (44%). Most patients had their first skin eruption during the first 2 years of life. All patients had fever associated with the skin eruption. Most patients had associated abdominal pain (22 [88%]) and myalgia (20 [80%]). Other symptoms included arthralgia (13 [52%]), pleuritic chest pain (10 [40%]), and headache (17 [68%]). Microscopic examination of 10 biopsy specimens of lesional skin showed a superficial and deep perivascular and interstitial infiltrate of lymphocytes and monocytes. None of the biopsy specimens showed multinucleated macrophages or granulomatous or leukocytoclastic vasculitis. The results of immunohistochemistry showed a perivascular infiltrate of CD3+, CD4+, CD8+, CD68+, CD79a-, and CD20- cells. All the mutations were missense mutations in exons 2 through 4 of TNFRSF1A, directly affecting the extracellular domain of the protein.


CONCLUSIONS
TRAPS is characterized by a spectrum of dermatologic findings, including migratory patches, edematous plaques, periorbital edema, and/or conjunctivitis. TRAPS is characterized by a perivascular dermal infiltrate of lymphocytes and monocytes.
Toro
J R
JR
National Cancer Institute, National Institutes of Health, Bldg 10, Room 12N-238, 10 Center Dr, MSC 1908, Bethesda, MD 20892-1908, USA. torojo@exchange.nih.gov
Aksentijevich
I
I
Hull
K
K
Dean
J
J
Kastner
D L
DL
D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D010505:Familial Mediterranean Fever / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012871:Skin Diseases / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D013577:Syndrome
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I