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SHAH ET AL 909

J Oral Maxillofac Surg68:909-911, 2010

Interleukin 12 Receptor �1 ChainDeficiency in a Child With Disseminated

Tuberculosis: A Case ReportPriya Shah, MFDS,* Mohammed El-Maaytah, PhD, MSc, FDS,†

Waseem Jerjes, PhD,‡ Tahwinder Upile, FRCS,§ and

Peter Ayliffe, FDS, FRCS�

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nterleukin (IL) 12 receptor �1 chain (IL-12R�1) de-ciency is 1 of 5 rare genetic defects of Mendelianusceptibility to mycobacterial disease. The knownutations in the IL-12R�1 genes are autosomal reces-

ive and associated with the abolition of the responseo IL-12 and IL-23. Affected individuals have an in-reased susceptibility to Mycobacterium tuberculosisnd non-typhoid salmonellosis. Etiologic agents in-lude bacille Calmette-Guérin (BCG) vaccine, envi-onmental nontuberculous mycobacteria (NTM), andon-typhoid Salmonella species.1-3

The typical onset is in early childhood. The patientay present with disseminated lymphadenopathy, re-

uiring medical and sometimes surgical intervention.owever, the prognosis is poor and may cause death

n the first decade of life. Less frequently, when thenset of the disease is delayed until adulthood, there

s a better prognosis.4 Antimycobacterial therapy ishe treatment of choice. Because there is a high inci-ence of relapse, this therapy may even have to beontinued after complete healing has been achieved.

eceived from University College London Hospitals, London, En-

land.

*Senior House Officer, Department of Oral and Maxillofacial

urgery, Eastman Dental Hospital.

†Consultant in Oral Surgery, Department of Oral Surgery, East-

an Dental Hospital.

‡Senior Clinical Fellow, Department of Oral and Maxillofacial

urgery, Eastman Dental Hospital.

§Senior Lecturer, Department of Surgery.

�Consultant, Department of Oral and Maxillofacial Surgery, Great

rmond Street Hospital.

Address correspondence and reprint requests to Dr Ayliffe: De-

artment of Oral and Maxillofacial Surgeon, Great Ormond Street

ospital, Great Ormond Street, London, England WC1N 3JH;

-mail: peter.ayliffe@uclh.org

2010 American Association of Oral and Maxillofacial Surgeons

278-2391/10/6804-0033$36.00/0

oi:10.1016/j.joms.2009.04.116Sf

ther interventions include surgery, involving re-oval of affected lymph nodes and wound curet-

age.1,2,4 We report a case of IL-12R�1 deficiency in a-year-old Asian child. Disseminated tuberculosis de-eloped after administration of the BCG vaccine inhis patient. The clinical features and surgical manage-ent are presented.

eport of a Case

A 2-year-old Asian child, born to consanguineous parents,as referred by his general medical practitioner to theepartment of Maxillofacial Surgery, Great Ormond Streetospital, London, England. The initial presentation was of

eft cervical lymphadenopathy with draining cutaneous si-uses (Fig 1).The family history showed that the patient had 4 siblings:brothers and 2 sisters. One of his older sisters presentedith disseminated tuberculosis, mainly affecting the left

xilla, at 5 months of age, after a BCG vaccination. Antimy-obacterial therapy was applied, but the infection dissemi-ated to the right axilla. After 20 months of continuousntimycobacterial therapy, there was a complete healing

IGURE 1. Initial presentation, showing left lateral view of facend neck. The skin is erythematous and ulcerated.

hah et al. IL-12R�1 Deficiency and Tuberculosis. J Oral Maxillo-ac Surg 2010.

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910 IL-12R�1 DEFICIENCY AND TUBERCULOSIS

esponse. Relapse was reported 5 months after remission.he patient presented with left axillary lymphadenitis, withischarging sinuses, and radiologic investigations showedsteomyelitis of the left clavicle. Aggressive antimycobacte-ial therapy was applied, followed by surgical debridement.edical therapy continued for a year but was discontinued

fter adverse drug effects occurred. These included an ex-ensive bilateral rash of the lower limbs, with associateddema and pain and swelling of the joints. Subsequently,he presented with abdominal pain and diarrhea, and clin-cal examination showed para-aortic lymphadenopathy. Theiagnosis of IL-12R�1 chain deficiency was made on geneticnd immunologic grounds.

Our patient was administered with the BCG vaccinehortly after birth. Five months later, bilateral axillaryymphadenopathy developed, and cultures showed growthf mycobacteria. Gastric washings identified the presencef acid-fast bacilli. At the age of 6 months, a diagnosis ofL-12R�1 chain deficiency was confirmed. Conventional an-imycobacterial therapy combined with interferon-� wastarted immediately. However, the response was incom-lete, and the infection disseminated to involve the lefteck and inguinal regions. Surgical removal of infectedervical lymph nodes was performed at the age of 1 year.ggressive medical therapy was then applied (resistance)

ollowed by laparotomy and removal of infected para-aorticymph nodes.

In April 2006, at 2 years of age, the patient was readmit-ed with left widespread cervical lymphadenopathy. Theargest swelling was 7 � 3 cm arising from the deep cervicalhain. There were multiple cutaneous draining sinuses,hrough which pus and blood exuded (Fig 1).

Medical therapy included ethambutol, ciprofloxacin, cy-loserine, interferon-�, and broad-spectrum antibiotics. Thendings of hematologic and biochemical laboratory investi-ations were unremarkable, other than a raised erythrocyteedimentation rate and C-reactive protein level. Furthernvestigation showed a reduction in the proliferation rate of

cells in response to tuberculin. However, the rate wasormal with the addition of IL-2.Despite the use of antipyretic agents, there was a persis-

ent elevating temperature. Previously, uninvolved cervical

IGURE 2. Left lateral view of face and neck after debridement.he wounds are still open and the affected tissue has been cleaned,ith most of the involved gland and pus removed.

hah et al. IL-12R�1 Deficiency and Tuberculosis. J Oral Maxillo-ac Surg 2010.

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ymph nodes close to the surgical site started to swell, andraining cutaneous sinuses developed adjacent to the para-ortic lymph nodes. Subsequently, the patient underwenturgical removal of those cervical and para-aortic nodes. Pusontinued to drain from the wound for 2 to 3 weeks post-peratively. Further debridement of nonviable tissue waserformed 3 weeks thereafter (Fig 2). Blood and tissueultures showed mycobacterial infection, consistent withhe BCG organism that is resistant to rifampin, isoniazid,yrazinamide, and ethambutol.Six weeks after admission, diffuse bilateral cervical

ymphadenopathy of the superficial and deep chains wasoted. The patient started taking amikacin, cycloserine,iprofloxacin, and clarithromycin. After this therapy, a sig-ificant improvement was noted. The wound was managedonservatively with a vacuum dressing (Figs 3, 4). Recon-truction with a myocutaneous flap was an option to beonsidered in the future.

FIGURE 3. Dressings applied.

hah et al. IL-12R�1 Deficiency and Tuberculosis. J Oral Maxillo-ac Surg 2010.

IGURE 4. Healing of neck wound. There is reduced erythemand inflammation, and discharge is evident. There is also markedoft tissue healing.

hah et al. IL-12R�1 Deficiency and Tuberculosis. J Oral Maxillo-ac Surg 2010.

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SHAH ET AL 911

iscussion

We describe a 2-year-old child with disseminateduberculosis and inherited IL-12R�1 deficiency. Theatient was resistant to conventional medical therapynd had to undergo several aggressive medical andurgical interventions.

Lichtenauer-Kaligis et al5 described one of the larg-st case series of patients with IL-12R�1 deficiency. Itncluded 11 Turkish patients in whom unusual Myco-acterium bovis BCG infections developed after vac-ination. The authors found that most patients (n � 8)ere deficient in IL-12R�1 expression and function.hey also found that idiopathic, unusually severe in-

ections due to M bovis BCG may be caused by com-lete as well as partial IL-12R�1 deficiency.Two siblings with complete IL-12R�1 deficiencyere described by Altare et al.4 In the first child,isseminated BCG infection developed in childhood.he second child had no adverse reactions to 3 inoc-lations with live BCG, but abdominal tuberculosiseveloped. NTM infection developed in neither pa-ient, despite exposure to these microorganisms. Thishows that resistance to BCG and lack of NTM infec-ion are not sufficient to exclude a diagnosis of IL-2R�1 deficiency.Another study, by Caragol et al,6 described 3 sib-

ings with IL-12R�1 deficiency, with no infectiousisease caused by BCG or NTM infection. One childad disseminated tuberculosis, the second had ex-raintestinal salmonellosis and pulmonary tuberculo-is, and the third remained asymptomatic. This studyonfirmed that considerable intrafamilial and interfa-ilial clinical heterogeneity exists in terms of vulner-

bility to Salmonella, BCG, and NTM infection.Özbek et al1 reported a case of an 11-year-old girlith disseminated tuberculosis, associated with sec-ndary hemophagocytosis. The patient was one ofhe first cases ever reported in which there was noelevant personal or family history. The authors con-

luded that the diagnosis of this disorder should be

onsidered for children with disseminated tuberculo-is, even in the absence of a relevant personal oramily history of prior infection by weakly pathogenicalmonella and Mycobacterium species. In their pa-ient, the disorder appeared to follow an unusualourse, whereas previous reports showed a history ofisseminated tuberculosis,6,7 abdominal tuberculo-is,4 or even pulmonary tuberculosis.6

In this case there was previous evidence from theamily history of an adverse event after BCG vaccina-ion resulting, in effect, in an iatrogenic disseminatednfection. In a child born to consanguineous parents,are inherited disorders are not uncommon. Weould recommend vigilance and thorough family his-

ory taking, particularly noting and investigating anyelevant previous adverse events in any closely relatedamily members. Once such an event does occur, weecommend early genetic testing of the individual andis or her family, as well as aggressive medical andurgical treatment.

eferences. Özbek N, Fieschi C, Yilmaz BT, et al: Interleukin-12 receptor

beta 1 chain deficiency in a child with disseminated tuberculo-sis. Clin Infect Dis 40:e55, 2005

. Cleary AM, Tu W, Enright A, et al: Impaired accumulation andfunction of memory CD4 T cells in human IL-12 receptor beta 1deficiency. J Immunol 170:597, 2003

. Fieschi C, Dupuis S, Catherinot E, et al: Low penetrance, broadresistance, and favorable outcome of interleukin 12 receptorbeta1 deficiency: Medical and immunological implications. J ExpMed 197:527, 2003

. Altare F, Ensser A, Breiman A, et al: Interleukin-12 receptorbeta1 deficiency in a patient with abdominal tuberculosis. J In-fect Dis 184:231, 2001

. Lichtenauer-Kaligis EG, de Boer T, Verreck FA, et al: SevereMycobacterium bovis BCG infections in a large series of novelIL-12 receptor beta1 deficient patients and evidence for theexistence of partial IL-12 receptor beta1 deficiency. Eur J Immu-nol 33:59, 2003

. Caragol I, Raspall M, Fieschi C, et al: Clinical tuberculosis in 2 of3 siblings with interleukin-12 receptor beta1 deficiency. ClinInfect Dis 37:302, 2003

. Fieschi C, Bosticardo M, de Beaucoudrey L, et al: A novel form

of complete IL-12/IL-23 receptor beta1 deficiency with cell sur-face-expressed nonfunctional receptors. Blood 104:2095, 2004