M. Ouederni

Clinical Features of Candidiasis in Patients With Inherited Interleukin 12 Receptor β1 Deficiency

BACKGROUND Interleukin 12Rβ1 (IL-12Rβ1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency. RESULTS Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. CONCLUSIONS Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.

Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients

Inherited deficiency of major histocompatibility complex (MHC) class II molecules impairs antigen presentation to CD4(+) T cells and results in combined immunodeficiency (CID). Autosomal-recessive mutations in the RFXANK gene account for two-thirds of all cases of MHC class II deficiency. We describe here the genetic, clinical, and immunologic features of 35 patients from 30 unrelated kindreds from North Africa sharing the same RFXANK founder mutation, a 26-bp deletion called I5E6-25_I5E6 + 1), and date the founder event responsible for this mutation in this population to approximately 2250 years ago (95% confidence interval [CI]: 1750-3025 years). Ten of the 23 patients who underwent hematopoietic stem cell transplantation (HSCT) were cured, with the recovery of almost normal immune functions. Five of the patients from this cohort who did not undergo HSCT had a poor prognosis and eventually died (at ages of 1-17 years). However, 7 patients who did not undergo HSCT (at ages of 6-32 years) are still alive on Ig treatment and antibiotic prophylaxis. RFXANK deficiency is a severe, often fatal CID for which HSCT is the only curative treatment. However, some patients may survive for relatively long periods if multiple prophylactic measures are implemented.

Oral HPV infection and MHC class II deficiency (A study of two cases with atypical outcome)

BackgroundMajor histocompatibility complex class II deficiency, also referred to as bare lymphocyte syndrome is a rare primary Immunodeficiency disorder characterized by a profondly deficient human leukocyte antigen class II expression and a lack of cellular and humoral immune responses to foreign antigens. Clinical manifestations include extreme susceptibility to viral, bacterial, and fungal infections. The infections begin in the first year of life and involve usually the respiratory system and the gastrointestinal tract. Severe malabsorption with failure to thrive ensues, often leading to death in early childhood. Bone marrow transplantation is the curative treatment.Case reportsHere we report two cases with a late outcome MHC class II deficiency. They had a long term history of recurrent bronchopulmonary and gastrointestinal infections. Bone marrow transplantation could not be performed because no compatible donor had been identified. At the age of 12 years, they developed oral papillomatous lesions related to HPV (human papillomavirus). The diagnosis of HPV infection was done by histological examination. HPV typing performed on the tissue obtained at biopsy showed HPV type 6. The lesions were partially removed after two months of laser treatment.ConclusionsViral infections are common in patients with MHC class II and remain the main cause of death. Besides warts caused by HPV infection do not exhibit a propensity for malignant transformation; they can cause great psychosocial morbidity.

Successful Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in a Severe Combined Immune Deficiency Patient: a First Report

Allogeneic hematopoietic stem cell transplantation (HSCT) is still the mainstay of treatment in the majority of severe combined immune deficiency (SCID) patients [1]. In the absence of a matched related donor (MRD), several alternative stem cell sources are available, including unrelated volunteer donors (UD), umbilical cord blood (UCB) units, or haploidentical transplantation (HT) [2]. Although overall survival rates after HT have improved significantly over time for SCID patients, problems with ex vivo T cell depletion still exist, including graft manipulation, high technology cost, slow immune recovery, and high rate of infections [1, 2]. T cell replete grafts with post-transplant cyclophosphamide (PT-CY) is an emerging recent approach to HT in adult patients with malignant hematological conditions. It seems to overcome many of the obstacles associated with ex vivo Tdepleted HT [3–5]. We report, to our knowledge, the first successful haploidentical transplantation using T cell replete graft and PT-CY in a SCID patient.

High frequency of exon 15 deletion in the FANCA gene in Tunisian patients affected with Fanconi anemia disease: implication for diagnosis

Tunisian population is characterized by its heterogeneous ethnic background and high rate of consanguinity. In consequence, there is an increase in the frequency of recessive genetic disorders including Fanconi anemia (FA). The aim of this study was to confirm the existence of a founder haplotype among FA Tunisian patients and to identify the associated mutation in order to develop a simple tool for FA diagnosis. Seventy‐four unrelated families with a total of 95 FA patients were investigated. All available family members were genotyped with four microsatellite markers flanking FANCA gene. Haplotype analysis and homozygosity mapping assigned 83 patients belonging to 62 families to the FA‐A group. A common haplotype was shared by 42 patients from 26 families at a homozygous state while five patients from five families were heterozygous. Among them, 85% were from southern Tunisia suggesting a founder effect. Using multiplex ligation‐dependent probe amplification (MLPA) technique, we have also demonstrated that this haplotype is associated with a total deletion of exon 15 in FANCA gene. Identification of a founder mutation allowed genetic counseling in relatives of these families, better bone marrow graft donor selection and prenatal diagnosis. This mutation should be investigated in priority for patients originating from North Africa and Middle East.

Hypertransaminasemia revealing a clinically silent muscular dystrophy in a child with sickle cell disease

Dear Editor, Here, we report a case of a 13-year-old Tunisian boy, a second child of consanguineous parents, with noncontributory family history apart from his parents having heterozygous sickle cell trait. He was fully vaccinated with normal perinatal and developmental history. This child was initially referred to our department at the age of 10 months for pallor. He was diagnosed with homozygous sickle cell disease on the basis of peripheral blood showing regenerative normocytic normochromic anemia and hemoglobin electrophoresis revealing HbA2 2.3%, HbS 78.4% and HbF 19.3%. Physical examination revealed an eutrophic child with mild pallor and jaundice with unremarkable examination of other systems. He was also symptomatic with more than four painful vasoocclusive crises per year requiring admissions and two episodes of acute chest syndrome. His medications included prophylactic oral penicillin, folic acid and hydroxyurea (HU). The initial laboratory test results were as follows: Hb, 8.5 g/dL; hematocrit, 12.2%; mean corpuscular volume, 89 μm; reticulocyte count, 12.2%; white blood cell count 15.000/μL; platelet count 317,000/μL. The liver function tests revealed a moderate cytolysis on a repeat testing (Fig. 1), total bilirubin 20 mmol/L (normal, 0 to 17) and conjugated bilirubin 7 mmol/L (normal, 0 to 5), alkaline phosphatase 557 U/ L, protein serum electrophoresis and prothrombin time were within reference ranges; serum creatine level was normal. Further tests were performed to establish the etiology of cytolysis: the serology tests for hepatitis B and C and for HIV were negative; mean serum ferritin level, 250 μg/L (normal range 30 to 400 μg/L); anti-nuclear antibodies, anti-mitochondrial antibody, anti-smooth muscle antibodies, anti-liver-kidney microsomes-1 antibodies, anti-endomysial antibodies IgA, anti-transglutaminases IgA, TSH, FT3, and FT4 were all negative or within normal limits for age. Hepatobiliary ultrasound was normal. Serological analysis showed creatine kinase (CK) level to be elevated to 7089 U/L (Fig. 2). The diagnosis of limbgirdle muscular dystrophy type 2C was made on the results of high serum marker levels of CK, electromyography, muscle biopsy, and genetic analysis. The outcome was marked by recurrent abdominal pain, fatigue, repeated falls, difficulty in climbing stairs, and rising from the floor. In view of the severity of sickle cell disease, myeloablative stem cell transplantation from an HLAgenoidentical healthy brother was performed at 11 years of age. The conditioning regimen comprised intravenous busulfan (16 mg/kg total dose) and cyclophosphamide (200 mg/kg total dose), rabbit antithymocyte globulin. Donor bone marrow was harvested with a target yield of 6 × 10 nucleated cells infused per kilogram body weight of the recipient on day 0. Graft-versus host disease prophylaxis consisted of intravenous cyclosporine (1.5 mg/kg every 12 h) beginning the day prior to transplant (day 1) and methotrexate 10 mg/m intravenous bolus on days + 1, + 3 and + 6. The regimen was well tolerated, and the patient had hematopoietic recovery. He was stably engrafted off immunosuppression and without * Naouel Guirat Dhouib nawel.guirat@yahoo.fr

SFP PC-67 – Les syndromes myélodysplasiques de l’enfant (SMD): 8 cas tunisiens

Objectifs etudier les particularites cliniques, biologiques et therapeutiques des SMD de l’enfant. Materiels et methodes etude retrospective des cas de SMD colliges sur 13 ans (2000–2013) au service d’Immuno-Hematologie pediatrique. Resultats On a collige 8 cas de SMD, d’âge moyen au diagnostic 5ans (6 mois-10ans) avec une consanguinite (5cas) Le delai diagnostic moyen etait de 25mois (1mois-6ans). Le tableau comprenait un syndrome anemique (7cas), hemorragique (5cas), tumoral (2cas), infectieux (3cas) et dysmorphique (1cas); une anemie (8cas), une thrombopenie (5 cas) et une neutropenie (4cas). Le myelogramme a confirme la myelodysplasie dans tous les cas avec une monosomie7 (3cas). Un cas de SMD est secondaire a une neutropenie congenitale severe, 7 cas sont primitifs classes selon OMS 2008: RCUD (4cas), AREB-1(3cas), CRDM (1cas). Le traitement etait symptomatique (4cas) au profit de besoins transfusionnels eleves (3cas). Quatre patients ont eu une allogreffe de moelle osseuse (GMO) (delai moyen de 7.5 mois), suivie d’une guerison complete. Le recul moyen est de 6 ans (1–13ans). Conclusion les SMD de l’enfant sont rares, heterogenes et meconnus. L’atteinte megacaryocytaire est frequente et le caryotype medullaire est souvent normal. La GMO donne des resultats encourageants.

SFP CO-04 - Manifestations auto-immunes des déficits immunitaires primitifs

Objectifs Etudier la frequence des manifestations auto-immunes (MAI) dans les deficits immunitaires primitifs (DIP). Materiels et methodes Etude retrospective des dossiers d’enfants atteints de DIP, au service d’Immuno-Hematologie pediatrique sur 27 ans (1987-2013). Resultats 30 cas de MAI ont ete colliges parmi 710 patients atteints de DIP (4,2%). Ces MAI sont survenues chez 14 /126 cas de DIP humoraux: 12/49 cas de deficit immunitaire commun variable (DICV) et 2/32 cas de deficit en IgA. Sept parmi 203 cas de DIP combines avaient des MAI : 2 /58 cas de SCID, 2/30 cas de syndrome d’hyperIgM, 1/7cas de lymphopenie CD4, 2/56 cas de defaut d’expression des CMH classe II. Un /32 cas de syndrome de susceptibilite mendelienne aux mycobacteries avaient des MAI. Les 8 cas de syndrome lymphoproliferatif avec auto-immunite avaient des MAI. Les MAI sont une anemie hemolytique auto-immune (AHAI) (15 cas), une thrombopenie auto-immune (4cas), des arthralgies (5cas), un Vitiligo (3cas), un Lupus erythemateux systemique (2cas) et une insuffisance ovarienne auto-immune (1cas). Conclusion Les manifestations AI sont constantes dans les DIP definis par l’AI et sont relativement frequentes dans les autres DIP, domines par le DICV. L’AHAI est la manifestation AI la plus frequente des DIP.

SFCE P-15 - Les déficits immunitaires primitifs et cancers

Objectif Etudier les particularites epidemiologiques des cancers dans les deficits immunitaires primitifs (DIP). Materiel et methodes Etude retrospective des cas de deficit immunitaire primitif (DIP) qui ont developpe un cancer sur une periode de 27 ans (1987-2013) au service d’Immuno-Hematologie pediatrique. Resultats Nous avons collige 8 cas de cancers parmi 710 patients atteints de DIP (1.1%). Les patients sont repartis comme suit: 2/112cas de syndrome d’ataxie telangiectasie, 2/49cas de deficit immunitaire commun variable, 1/40 cas d’agammaglobulinemie de Burton, 1/30 cas de syndrome d’hyperIgM, 1/7cas de lymphopenie CD4 severe, et 1/6cas de syndrome de Wiskott Aldrich. L’âge moyen de decouverte du cancer est de 5,5ans (2–16ans). Les cancers se repartissaient en: 4 cas de lymphomes : 2 lymphomes hodgkiniens et 2 lymphomes malins non hodgkiniens, une leucemie aigue lymphoblastique, un sarcome de Kaposi, un carcinome boncho-alveolaire a petites cellules, et un cancer de la tete du pancreas. L’evolution a ete marquee par le deces dans 5 cas. Conclusion Les DIP predisposent a des cancers d’origine multifactorielle. Les DIP humoraux et les syndromes bien definis de DIP sont les plus incrimines. Les lymphomes sont predominants avec un pronostic severe.

SFP P-039 – Expression phénotypique du syndrome de Wiskott Aldrich (SWA) en Tunisie

Objectif Decrire le profil clinique, biologique et evolutif des patients ayant un SWA. Materiels et methodes Etude retrospective sur 27ans (1987-2013) des cas de SWA suivis au service d’Immuno-hematologie Pediatrique. Resultats On a collige 8 garcons d’âge median au diagnostic 14mois (2-48mois), avec des cas familiaux (n=2). La clinique etait marquee par les manifestations infectieuses (n=8), hemorragiques (n=8), allergiques a type d’eczema (n=8), auto-immunes (n=3) et tumorales (n=1). La NFS trouvait une microthrombopenie constante et une anemie (n=4) auto-immune dans 3 cas. La triade: infections repetees, eczema et microthrombopenie evoquait le SWA. L’etude de l’immunite trouvait une augmentation des IgE(n=8=); une baisse des IgG, IgA et IgM (n= 2). Le taux des lymphocytes(Lc) TCD3+ etait normal avec une inversion CD4+/CD8+. La proliferation des Lc T etait normale a la PHA et faible a l’anti CD3 et aux antigenes specifiques chez 3 malades evaluables. Six deces etaient notes a un âge median de 2ans (10mois-8.5ans). Un patient etait allogreffe de moelle osseuse(GMO) avec succes. Conclusion Le SWA est rare et caracterise par un phenotype clinique variable. La microthrombopenie et l’augmentation des IgE sont caracteristiques. Le pronostic est severe en dehors de la GMO.