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CUTANEOUS LEUKOCYTOCLASTIC VASCULITIS IN A CHILD WITHINTERLEUKIN-12 RECEPTOR BETA-1 DEFICIENCY

NECIL KUTUKCULER, MD, FERAH GENEL, MD, GUZIDE AKSU, MD, BULENT KARAPINAR, MD, CAN OZTURK, MD,CENGIZ CAVUSOGLU, MD, JEAN-LAURENT CASANOVA, MD, PHD, AND CLAIRE FIESCHI, MD, PHD

We report a patient with complete interleukin-12 receptor beta-1 deficiency associated with cutaneous leukocytoclasticasculitis. The patient experienced Bacille Calmette Guérin, Mycobacterium chelonae, and Salmonella enteritidis infection.asculitis affecting both small arteries and postcapillary venules due to deposition of immune complexes was probably causedy S. enteritidis and/or M. chelonae infection. (J Pediatr 2006;148:407-9)

acille Calmette Guérin (BCG) vaccines, environmental nontuberculous mycobacteria (NTM), and nontyphoidalSalmonella have limited pathogenecity. However, these microorganisms are the main pathogens in patients with geneticdefects in either chain of the interferon (IFN) gamma receptor (IFN-�R1 or IFN-�R2), the signal transducer and

ctivator of transcription-1, or interleukin-12 (IL-12 p40) and interleukin-12 receptor beta-1 (IL-12R�1).1,2 Various dominantnd recessive mutations that result in complete or partial deficiencies of these receptors have been described, and 9 distinctisorders have been reported.1,2

The common clinical presentations of patients with disorders in the IL-12/IFN-� axis are peripheral and visceralymphadenopathy, liver and spleen infection, osteomyelitis, or skin and lung infections caused by BCG and/or NTM, as wells adenitis, osteitis, and sepsis caused by nontyphoidal Salmonella species.3-7 Clinical disease caused by virulent Mycobacteriumuberculosis also can occur. Here we report the first patient with an inherited disorder of the IL-12/IFN-� pathway (completeL-12R�1 deficiency) with cutaneous leukocytoclastic vasculitis (CLV).

An 8-year-old girl born to first-cousin parents was admitted to our hospital with recurrent lymphadenitis and subcutaneousbscesses of the lower extremities. The patient had 1 healthy brother. She was vaccinated with BCG at 17 days of age. At agemonths, she developed left axillary lymphadenitis that was treated with rifampin and isoniazid for 6 months. At age 13 months,

he exhibited enlarged axillary and submandibular lymph nodes and hepatosplenomegaly. Suppurative nongranulomatousistiocytosis and acid-fast bacilli were found in lymph node biopsy specimens. Exploratory laparotomy revealed a right psoasbscess from which Mycobacterium bovis (BCG) was isolated. The patient was treated with rifampin and isoniazid (for 2 years),larithromycin and ciprofloxacin (for 1 year), and amikacin (for 4 months). The subcutaneous abscess disappeared and peripheralymph nodes decreased in size, but hepatosplenomegaly did not resolve.

At age 6 and again at age 7 years, the patient exhibited similar clinical findings and was treated with antimycobacterialgents. At age 7 years, she also experienced recurrent episodes of petechiae and purpura of the lower extremities.

The patient was first admitted to our hospital at age 8 years. On physical exami-ation, her weight and height were in the 10th percentile. The liver (2 cm) and spleen (4m) were palpable below the costal margin. Submandibular lymph nodes were enlarged.dema and purpuric eruptions were present on the lower extremities. Histological

xamination of a skin biopsy specimen showed superficial and deep perivascular infiltratef lymphocytes, along with predominantly neutrophilic infiltrate and thickening ofapillary dermal vessel walls. Immunofluorescence revealed C3 and IgM deposition. Nomyloid deposition was found by Congo-red dye. Nuclear debris, extravasation of redlood cells, and edema of dermal-epidermal interface were also seen. The subcutaneous fatas unremarkable. Features were compatible with CLV.

Normal results were found on the following laboratory tests: serum hepatic en-ymes, activated partial thromboplastin time, prothrombin time, and D-dimer levels.

CG Bacille Calmette GuérinLV Cutaneous leukocytoclastic vasculitis

FN Interferon

IL-12R�1 Interleukin-12 receptor beta-1NTM Nontuberculous mycobacteriaWBC White blood cell

From the Department of Pediatrics andDepartment of Microbiology and ClinicalMicrobiology, Ege University MedicalSchool, Izmir, Turkey and Laboratory ofHuman Genetics of Infectious Diseases, Pe-diatric Immunology and Hematology Unit,Necker Medical School, Paris, France.

Submitted for publication June 8, 2005; lastrevision received August 11, 2005; ac-cepted October 3, 2005.

Reprint requests: Dr. Necil Kutukculer, EgeUniversity Faculty of Medicine, Departmentof Pediatrics, 35100 Bornova-Izmir, Turkey.E-mail: necil@med.ege.edu.tr.

0022-3476/$ - see front matter

Copyright © 2006 Elsevier Inc. All rightsreserved.

L Interleukin

10.1016/j.jpeds.2005.10.003

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esting for cryoglobulinemia was negative. No proteinuria,ematuria, or impaired renal function was detected. Serologicests were negative for cytomegalovirus; Epstein-Barr virus;epatitis A, B, and C virus; rubella, human immunodeficiencyirus; brucellosis; and toxoplasmosis. No pathogens were iso-ated from blood, stool, urine, throat, or morning gastricspirate cultures. Cervical lymph node biopsy showed reactiveyperplasia; no mycobacterium were isolated, but Salmonellanteritidis was isolated, and the serum Salmonella agglutina-ion test was positive. Antinuclear antibody, liver-kidney mi-rosomal antibody, anti–smooth muscle antibody, antineutro-hil cytoplasmic antibody, and anti-Ro and anti-Lantibodies were all negative. During the patient’s hospitaliza-ion, the causative agent of her vasculitis was thought to be S.nteritidis infection.

Serum IgG, IgM, and IgA levels were 3520 mg/dL,56 mg/dL, and 1430 mg/dL, respectively. Serum C3 and C4evels and lymphocyte subsets and phagocyte respiratory burstssay by flow cytometry were normal.

We also carried out flow cytometry at Necker-Enfantsalades Hospital, Paris with peripheral blood samples to ana-

yze the expression of IL-12R and IFN-�R. Phytohemaggluti-in-driven T lymphoblasts did not express IL-12R�1, andFN-�R levels were normal. IL-12R�1 sequence analysis re-ealed a homozygous mutation, R173P, resulting in the replace-ent of an arginine by a proline at amino acid position 173.5

Ciprofloxacin treatment for S. enteritidis infection andubcutaneous IFN-� treatment were initiated. Two monthsater, the patient’s white blood cell (WBC) count (2130/mm3)nd platelet count (108,000/mm3) were decreased. The spleenas enlarged, and total splenectomy was performed due toypersplenism. After the splenectomy, hemoglobin, platelet,nd WBC counts increased to 8650/mm3, 11 g/dL, and44,000/mm3, respectively. In the sixth month of IFN-� andiprofloxacin treatment, the patient’s clinical and laboratoryesults improved.

In the eleventh month after the splenectomy, duringonotherapy with ciprofloxacin, multiple cervical, axillary,

nguinal lymph nodes and purpuric eruptions on the lowerxtremities reappeared. Mycobacterium chelonae was isolatedrom axillary lymph node specimens 1 month after the ces-ation of all antibiotics. After excluding other etiologies andalmonella infection, the cause was considered to be dissem-nated M. cholonea infection. Clinical signs and symptoms ofasculitis resolved after 4 months of treatment with clarithro-ycin, ciprofloxacin, and IFN-�.

DISCUSSIONCLV is an inflammatory vascular disorder affecting

oth small arteries and postcapillary venules due to the dep-sition of immune complexes in dermal vessels.8 Depositionf this type is also a predominant feature of Henoch-Schoen-ein purpura, mixed cryoglobulinemia, and other connectiveissue diseases.8 To our knowledge, this is the first known casef CLV in a patient with a deficiency in the IL-12/IFN-�

athway. 7

08 Kutukculer et al

It has been suggested that infectious agents play directr indirect roles in the pathogenesis of vasculitis. Lambotte etl8 reported a case of CLV associated with S. typhi. Fincher etl9 reported a case of CLV complicating gastroenteritis causedy S. typhimurium. Chiu and Ou10 reported that nontyphoidalalmonella is a major cause of vasculitis, with S. enteritidis theost commonly isolated serotype. In another report, group C

almonella infection (S. choleraesuis) was found to be a positiveredictor of endovascular infection in adult patients withacteremia.11

Mycobacterial infections also have been reported to bessociated with CLV. Minguez et al12 described 1 patientith such an infection, and Lee et al13 described 2 patientsith a rare association of pulmonary tuberculosis and CLV. A

ase of tuberculous lymphadenitis presenting with CLV haslso been reported.14

Demonstration of a causal link between an infectiousgent and CLV relies on (1) the temporal relationshipetween the inciting event and the appearance of CLV, (2)ocumented presence of organisms in a sterile body fluid orissue with evidence of infection, (3) exclusion of othertiologies by laboratory tests, and (4) resolution of CLVfter removal of the inciting agent.15 In our case, thenciting agents (S. enteritis in the first attack and M.helonae in the second) were documented to coexist withhe histologically proven CLV. Successful elimination ofhe bacteremia by antibiotics was followed by the disap-earance of the vasculitis. Furthermore, other possibleauses of CLV, such as drugs and autoimmune disease,ere excluded on the basis that markers for autoimmuneisease were negative and that the patient had no history ofrug intake preceding the vasculitis apart from ciprofloxa-in, which is not known to cause vasculitis. In this patientith IL-12R�1 deficiency, vasculitis was associated with S.

nteritidis and/or M. chelonae infection.After excluding common etiologies, a diagnosis of CLV

n children should lead to a search for nontyphoidal Salmo-ella and environmental Mycobacteria, and for an underlyingenetic defect of the IL-12/IFN-� axis.3,4,6,7

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eceptor deficiency. Science 1998;280:1432-1435.. De Jong R, Altare F, Haagen IA, Elferink DG, Boer T, van Bredariesman PJ, et al. Severe mycobacterial and Salmonella infections in

nterleukin-12 receptor– deficient patients. Science 1998;280:1435-1438.. Fieschi C, Dupuis S, Catherinot E, Feinberg J, Bustamante J, Breiman, et al. Low penetrance, broad resistance, and favorable outcome of inter-

eukin 12 receptor beta-1 deficiency: medical and immunological implica-ions. J Exp Med 2003;197:527-535.. Fieschi C, Casanova JL. The role of interleukin-12 in human infectiousiseases: only a faint signature. Eur J Immunol 2003;33:1461-1464.

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l. Mycobacterium fortuitum– chelonae complex infection in a child withomplete interleukin-12 receptor beta-1 deficiency. Pediatr Infect Dis J001;20:551-553.. Lambotte O, Debord T, Castagne C, Roue R. Unusual presentation ofyphoid fever, cutaneous vasculitis, pancreatitis, and splenic abscess. J Infect001;42:161-162.. Fincher RE, Threadgill ST, Cranford MS, Webster JS, Hanly MG.ase report: salmonellosis complicated by leukocytoclastic vasculitis. Am Jed Sci 1991;302:296-297.

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