pedia_nr-4_2012_art-8

REVISTA ROMN DE PEDIATRIE VOLUMUL LXI, NR. 4, AN 2012388

Adresa de coresponden:Dr. Monica Alexoae, Universitatea de Medicin i Farmacie Gr.T. Popa, Str. Universitii nr. 16, 700115, Iasi, Romniae-mail: [email protected]

SINDROM JOB FORM AUTOSOMAL RECESIV

Monica Alexoae, Ileana Ioniuc, E. Carasievici1, M. Covic2, Stela GoiaClinica II Pediatrie, Universitatea de Medicin i Farmacie Gr.T. Popa, Iai

1Laboratorul Imunologie, Universitatea de Medicin i Farmacie Iai2Genetic Clinic, Universitatea de Medicin i Farmacie Iai

REZUMAT Sindromul hiper-IgE (SHE), sau sindromul Job, este un defi cit imun primar rar, cu transmitere autosomal dominant sau recesiv care asociaz hiperimunoglobulinemia E extrem cu o inciden crescut a infeciilor i modifi cri ale esutului conjunctiv. Este prezentat un caz cu manifestri severe nc din perioada de sugar, care se ncadreaz n forma autosomal recesiv, cu evoluie fatal, agravat de anemia cronic i malnutriie, excesul de corticoterapie i antibioterapie.

Cuvinte cheie: hiper-IgE, infecii, alergie

PREZENTRI DE CAZ8

INTRODUCERE

Sindromul hiper-IgE (termen introdus de Buckley n 1972), original raportat ca sindrom Job (Davis, 1966), este o imunodefi cien primar cu transmitere autosomal dominant sau recesiv (fi ind posibile i cazuri sporadice), mutaiile genice fi ind identifi cate. Consecinele clinice severe ale defi citului imun (infecii recurente severe, alergii, eczem), exprimate precoce, se asociaz cu grade variabile de anomalii faciale i ale scheletului, n funcie de modalitile transmisiei genetice (1). Valoarea excesiv a IgE serice este o trstur con-stant, nu ntotdeauna corelat cu severitatea bolii i cu tendin de a se diminua odat cu vrsta.

PREZENTARE DE CAZ

NA, 4,5 ani, mediu rural, a fost transferat n Cli-nic pentru: pneumonie trenant, dermatit supra-infectat, malnutriie.

Antecedente heredo-colaterale: mama 30 ani numeroase pete caf-au-lait i efelide faciale i axi-lare sugestive pentru diagnosticul de neurofi bro ma-toz tip I (Figura 1) (fr consult medical an te rior); tata 28 ani afi rmativ sntos. Alt patologie fa-milial a fost negat.

FIGURA 1. Pete cafe-au-lait la mam

Antecedente personale fi ziologice primul copil al cuplului provenit dintr-o sarcin nemonitorizat, nscut natural la termen n prezentaie cranian, Gn = 3.100 g, scor Apgar necunoscut (aparent fr su-ferin perinatal), alimentat artifi cial de la na tere, diversifi cat incorect la 6 luni, vaccinat in complet, profi laxia rahitismului i anemiei feriprive efectuat incorect (intermitent, doze insufi ciente).

Antecedente personale patologice: intoxicaie cu nitrii (4 luni), otite i pneumopatii repetate, n afebrilitate dup vrsta de 1 an (cure numeroase i prelungite de antibiotice i cortizon parenteral, oral), urticarie alimentar (ou) cu angioedem labial (1,5 ani), dermatit atopic (2 ani), blefaro conjunc-tivite purulente recidivante, ulcer cornean OD (3,5 ani).

REVISTA ROMN DE PEDIATRIE VOLUMUL LXI, NR. 4, AN 2012 389

Istoricul bolii: Transferat dup 15 zile de spitali-zare ntr-un spital judeean pentru agravarea simpto-matologiei respiratorii, anemie sever (Hb 5,6g/dl) hipocrom (HEM 13,5 pg, CHEM 26,7 g/dl) micro-citar (VEM 513), intens sindrom biologic in-fl amator (VSH 120 mm/h, fg 5,87 g/l, CRP 67,6 mg/l), valori sczute ale IgA serice (valori normale ale globulinelor), hipoalbuminemie, hiper2globu-linemie. A fost tratat cu antibiotice cu spectru larg i transfuzii de snge.

Starea la internare (elemente patologice): hipo-trofi e staturo-ponderal (G -5,88DS, T -4,25 DS), perimetru cranian normal (Pc -1,16 DS), facies dis-morfi c (Figura 2), xeroz cutanat, leziuni maculo-papuloeritematoase intens pruriginoase pe fa, trunchi i membre, mai accentuate la pliurile de fl e-xie (axilar, inghinal) i retroauricular, placarde atro fi ce depigmentate i numeroase leziuni de pio-dermit, excoriaii postgrataj, distrofi i i carii den-tare (Figura 3), escar fesier sngernd (Figura 4), fi suri ale buzelor, unghii n sticl de ceasornic, hi perlaxitate n articulaiile cotului, pumnului, dege telor, arahnodactilie, tuse inefi cient, raluri sub crepitante la baza plmnului drept, abdomen mrit de volum, depresibil, marginea inferioar a fi catului la 4 cm sub rebordul costal, tumefacie scrotal dreap t, dureroas.

FIGURA 2. Dismorfi e facial i leucom cornean OD

FIGURA 3. Distrofi i dentare

FIGURA 4. Escar fesier suprainfectat

Investigaii imunologice: eozinofi lie (780/mm3), IgA < 4 mg/dl (normal 48-345), IgG 1.266 mg/dl (nor mal 500-1.300), IgM 55,8 mg/dl (normal 40-180), IgE 8.450 UI/ml (normal


fi erul seric sczute) i aplastice (eritropoieza medu-lar normocrom normoplazic).

Investigarea defi citului staturo-ponderal cu vrs-t osoas ntrziat a eliminat sindroamele de mal-absorbie examen coprologic al digestiei normal, Ac antitransglutaminaz normali, iontoforeza nor-mal.

Procesele expansive la nivelul eii turceti excluse prin CT scan cerebral.

Alte imunodefi ciene:sindrom Wiskott Aldrich exclus prin aspectul sever al dermatitei, numrul i aspectul normal al trombocitelor, absena sdr he-moragipar;boala granulomatoas cronic boal X- linkat care se prezint cu infecii severe cu-tanate, osoase, viscerale, dar nu asociaz der-matit, valori crescute ale IgE totale; diagnosticul de certitudine este susinut de valoarea patologic a testului NBT;sindrom Omenn caracterizat prin imuno defi cien sever combinat ce asociaz eritro-dermie sever, diaree, hepatosplenomegalie, hipereozinofi lie i cretere marcat a IgE, dar cu valori extrem de sczute sau absente ale celorlalte clase de Ig serice;imunodefi ciena comun variabil valori normale ale IgE, dermatit mai puin sever;imunodefi cien, poliendocrinopatie, enteropatie, X-linkate (IPEX) asociaz DZ insu-lino-dependent cu debut precoce, enteropatie sever (diaree apoas sau hemoragic), insu-fi ciena creterii, sensibilizri alimentare mul tiple i eczem/alopecie i valori crescute ale IgE;infecia HIV exclus serologic.

TratamentAntibioterapie intit ciprofl oxacin 20 mg/kg,

2 sptmni, trimetoprim (TMP)/sulfometoxazol 20 mg/kg TMP, 4 sptmni, antifungice fl uco-nazol, toaleta escarei fesiere, corecia dezechilibrelor hidro-electrolitice i nutriie parenteral-oral, apoi diet hiperproteic 4 g/kg/zi (formul extensiv hidrolizat, carne de pui, legume, fructe i orez).

Evoluie i prognosticAmeliorare iniial cu tendina la vindecare a

leziunii fesiere i spor ponderal (2 kg/2 sptmni); panariiu la indexul minii stngi (incizie n Clinica Chirurgie Pediatric); agravarea simptomatologiei respiratorii (insufi cien respiratorie ireversibil,

apa riia a numeroase opaciti trabeculo-micro-nodulare diseminate n ambele cmpuri pulmonare i a unei opaciti nesistematizate retrocardiac drept n treimea medie) i deces n Secia Terapie In-tensiv. Examenul histopatologic al piesei de ne-cropsie evideniaz aspecte tipice pentru infecia pulmonar cu germeni agresivi: Pneumocystis ca-rinii, citomegalovirus, virus sinciial respirator.

DISCUIIDiagnosticul SHIE n copilrie este difi cil n-

truct simptomatologia se contureaz n timp (2). A fost propus un scor de probabilitate pentru diagnostic bazat pe 19 trsturi clinice i valoarea IgE totale (3). Un scor de cel puin 15 este foarte sugestiv pen tru SHIE; la pacientul prezentat, valoarea aces-tuia este 49, realizat de: IgE > 2.000 UI/ml (10 pct), > 8 abcese piodermice (8 pct), >3 pneumonii (8 pct), alte localizri infecioase (4 pct), evoluie fatal (4 pct), eozinofi lie 700-800/mm3 (3 pct), dermatit sever (4 pct), otite (3 pct), candidoz digestiv (1 pct), hiperlaxitate articular (4 pct). Aplicarea acestui scor faciliteaz diagnosticul di-ferenial cu dermatita atopic sever, boal frecvent caracterizat prin eczem pruriginoas cu supra-infecii bacteriene i fungice, sensibilizri i alergii, hiperIgE; abcesele sunt rare, nu prezint anomalii ale esutului conjunctiv (4).

n SHIE defi citele imunologice sunt complexe: chemotaxia granulocitar redus (5), defi cit al popu laiei de celule T (valori sczute ale Th17), producere sczut de imunoglobuline serice, defi cit al IFN i altele (6,7).

Particularitatea cazuluiEvoluia fatal a unui caz de sindrom Job, cu

ma nifestri severe nc din perioada de sugar, agra-vat de anemie cronic i malnutriie proteino-caloric, excesul de corticoterapie i antibiote-rapie.

CONCLUZII

Asocierea infeciilor severe, prelungite, refrac-tare la terapiile obinuite, cu diferite localizri, mai ales pulmonare, cu manifestri alergice precoce (ur ticarie cu angioedem, dermatit cronic) i ano-malii fenotipice impune explorarea precoce imu-nologic, genetic i asisten nutriional corect, dispensarizare continu, deoarece trsturile sindro-mului Job se contureaz n timp, iar prognosticul este rezervat.


Job Syndrome Autosomal recessive type

Monica Alexoae, Ileana Ioniuc, E. Carasievici1, M. Covic2, Stela GotiaII Pediatrics Clinic, Gr.T. Popa University, Iasi

1Imunology Laboratory, UMF Iasi2Clinical Genetics, UMF Iasi

ABSTRACT HiperIgE syndrome or Job syndrome is a rare primary immune defi ciency with autosomal dominant or recessive transmission manifested by extreme hyperimmunoglobulinemia E with an increased incidence of infections and connective tissue abnormalities. The authors present one fatal case with severe symptoms since infancy, aggravated by chronic anemia and malnutrition, and exceed corticotherapy and antibiotherapy, included as an autosomal recessive type.

Key words: HiperIgE, infections, allergy

INTRODUCTION

Hyperimmunoglobulin E syndrome (HIES), term introduced by Buckley in 1972, primary re-ported as Job syndrome (Davis, 1966) is a rare pri-mary immunodefi ciency , autosomal or recessive dominant. Its been identifi ed the genic mutations. The clinical consequences of the immune defi cit (recurrent infections, allergies, chronic dermatitis) early expressed, associate various degrees of facial and skeletal abnormalities, according to genetic pattern. (1) Extreme increased serum IgE, some-times decreasing with growth represents a charac-teristic feature, not always correlated with diseases severity,.

CASE PRESENTATION Patient N.A., 4,5 years old, from rural area, was

transferred in II Pediatric Clinic with train pneumo-nia, infected dermatitis, malnutrition.

Familial history: mother, 30 years old, with nu-merous facial and axillary caf-au-lait spots (Fig-ure 1) suggestive for type I neurofi bromatosis (with-out medical consultation); father, 28 years old, apparently in good health; without another family pathology.

FIGURE 1. Mothers abdominal caf-au-lait spots

Personal history couples fi rst child, from an unmonitored pregnancy, natural born, at 38 weeks gestation, cranial presentation, birth weight 3.100 g, Apgar score unknown, (apparently without pre-natal pathology), artifi cially fed from birth, incom-pletely vaccinated, incorrect iron defi ciency anemia and rickets prophylaxis (intermittent, insuffi cient doses).

Pathologic personal history nitrite poisoning (4 moth), frequent ear infections and lung diseases after the age of 1 year, most of them without fever (numerous and prolonged antibiotherapy and corti-cotherapy orally or intravenous), food allergy (egg) with labial angioedema (1.5 years), atopic dermatitis (2 years), recidivated purulent blepharo-conjunctivitis, corneal ulcer at right eye (3.5 years).

Diseases history NA was transferred after 15 days of treatment, from an local hospital to our clinic for worsening respiratory symptoms, severe anemia (hemoglobin 5.6 g/dl) with hypochromy (HEM 13.5 pg, CHEM 26.7 g/dl) and microcytosis (VEM 513), intense biological infl ammatory syn-drome (VSH 120 mm/h, fi brinogen 5.87 g/l, CRP 67.6 mg/l, hyper2globulinemia), low levels of se-rum IgA (normal values of globulines), hypoalbu-minemia. He was treated with broad-spectrum anti-biotics and blood transfusions.

Admission status (pathologic elements): im-paired growth (weight -5.88 DS, height -4.25 DS), normal head circumference (-1.16 DS), dysmorphic face (Figure 2), dry skin, intense itching eritematho-us lesions on the face, trunk and limbs, more pro-nounced in the fl exion folds (armpits, inguinal) and retro auricular, numerous atrophic depigmented le-sions and pyoderma, scratch excoriation, dental dystrophies (Figure 3), bleeding gluteal bed-sore (Figure 4), cracking lips, Hipocratic fi ngers, incre-


ased laxity in the elbow joints, wrist, fi ngers, arach-nodactyly, ineffective cough, subcrepitant rales in the right lung, abdominal depressible distention, the lower edge of the liver at 4 cm below the costal margin, right scrotal painful swelling.

FIGURE 2. Dysmorphic face and RE leukoma

FIGURE 3. Dental dystrophies

FIGURE 4. Infected gluteal bed-sore

Immunologic investigations: eosinophilia (780/ mm3), IgA < 4 mg/dl (normal 48-345), IgG 1.266 mg/dl (normal 500-1.300), IgM 55.8 mg/dl (normal 40-180), IgE 8450 UI/ml (normal


IPEX (immunodysregulation polyendocrino- pathy enteropathy X-linked syndrome) characterized by the association between in-sulin dependent diabetes with severe en-teropathy chronic diarrhea with watery or hemorrhagic stools, impaired growth, multi-ple food allergies, dermatitis/alopecia and high total serum IgE levels) HIV infection serologic excluded.

TreatmentTargeted antibiotherapy ciprofl oxacin 20 mg/

kg, 2 weeks, trimethoprim (TMP)/sulfamethox-azole 20 mg/kg TMP, 4 weeks, antifungal therapy fl uconazole, bed-sore local treatment, replacing lost fl uid and electrolytes by endovenous perfu-sions and parenteral nutrition, than hyper caloric diet 4 g/kg/day (extensively hydrolyzed formu-las, chicken, vegetables, fruits and rice).

Evolution and prognosisInitial improvement of bed-sore and weight gain

(2kg in 2 weeks); left hand index nail infection; worsening respiratory symptoms (irreversible res-piratory failure, hypoxemia SaO2 76-84%, the emergence of disseminated micronodular opacities in both lung and an right retrocardiac unorganized opacities) and death in the ICU department. Histo-pathologic examination showed the characteristic aspects of pulmonary pneumocystosis and cito-megalic and respiratory sincitial virus.

DISCUSIONS

HiperIgE syndrome is diffi cult in childhood be-cause symptoms are emerging over time (2). It was assessed a diagnostic probability score based on 19 clinical features and total serum IgE values (3). A score of at least 15 is very suggestive for HIES; our patients score was 49: IgE> 2,000 IU / ml (10 pts), > 8 pyodermic abscesses (8 pts), > 3 pneumonias (8 pts), other infectious (4 pts), fatal outcome (4 pts),

eosinophilia 700-800/mm3 (3 pts), severe dermati-tis (4 pts), otitis (3 pts), gastrointestinal candidiasis (1 pt), characteristic facies (5 points), joints hyper laxity (4 pts). This score facilitates the differential diagnosis with severe atopic dermatitis character-ized by itching eczema and fungal or bacterial in-fections, sensitizations and allergies, hiperIgE; ab-scesses are rare and not associated with connective tissue abnormalities (4)

There are many immunologic abnormalities in HIES: reduced granulocytes chemotaxis (5), T cell defi ciencies (reduced Th17), decreased production of serum immunoglobulin, IFN defi ciency (6,7).

Case particularity: a fatal case of Job syndrome wit severe symptoms since infancy, aggravated by chronic anemia and malnutrition, excess of corti-costeroids and antibiotics.

Conclusion: severe, prolonged infections, re-fractory to usual therapies (especially lung infecti-on) associated to early allergic symptoms (hives, angioedema, chronic dermatitis) and phenotypic abnormalities, requires exploration of immunologi-cal, genetic and correct nutritional support and con-tinuous follow-up, because Job syndrome features emerge over time and the prognosis is worse.

Grimbacher B.1. Hiper-IgE syndrome with recurrent infections an autosomal dominant multisystem disorder. The New England Journal of Medicine 1999; 340:692-700Buckley R.H., Wray B.D., Belmaker E.2. Extreme hyperimmunoglobulinemia E and susceptibility to infection. Pediatrics 1972; 49:59-70Jynouchi H.3. Hyperimmunoglobulinemia E (Job) syndrome. emediciene.medscape.com, 2012Ohamje N., Loveless J.W., Saini S.S.4. Atopic dermatitis or hyper-IgE syndrome? Allergy and Asthma Proceedings 2006, 27(3):289-291Forceman A.F., Holland S.M. 5. Clinical manifestations, etiology and pathogenesis of the hyper-IgE syndromes. Pediatr Res 2009; 65:32R-7RNotarangelo L.D., Fischer A., Geha R.S., Casanova J.R. et al.6. Primary immunodefi ciencies: 2009 update. J.Allergy Clin.Immunol. 2009; 124:1161-1178Freeman A.F., Holland S.M.7. Clinical manifestation, etiology and pathoogenesis of the hiperIgE syndromes. Pediatrics 2009; 65:32R-7R

REFERENCES

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