Publications (19)48.45 Total impact
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Article: Budd-Chiari Syndrome in a Boy With β Thalassemia Major (A Study of a New Case).
Journal of Pediatric Hematology/Oncology 04/2013; 35(3):237. · 1.16 Impact Factor -
Article: Cytogenetic Assessment of Fanconi Anemia in Children with Aplastic Anemia in Tunisia.
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ABSTRACT: BACKGROUND:: Chromosome breakage hypersensitivity to alkylating agents is the gold standard test for Fanconi anemia (FA) diagnosis. The aim of the present study was to assess the proportion of FA cases among aplastic anemia (AA) in Tunisian pediatric patients. OBSERVATION:: Investigation of mitomycin C-induced chromosomal breakage was carried out in 163 pediatric patients with AA and siblings of the cases where diagnosis of FA was confirmed. We identified 31 patients with FA whose percentage of unstable mitoses ranges from 65% to 100%. Among 18 siblings who were investigated for chromosomal instability, 3 were incidentally found to be affected. CONCLUSIONS:: FA is an important cause of AA in Tunisia. Our report is the first study in North Africa that explored cytogenetic and phenotypic findings in FA children. It also showed the importance of mitomycin C sensitivity screening in all FA siblings.Journal of Pediatric Hematology/Oncology 01/2013; · 1.16 Impact Factor -
Article: Differentiation of Fanconi anemia and aplastic anemia using mitomycin C test in Tunisia.
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ABSTRACT: Fanconi anemia (FA) is a recessive chromosomal instability syndrome that is clinically characterized by multiple symptoms. Chromosome breakage hypersensitivity to alkylating agents is the gold standard test for FA diagnosis. In this study, we provide a detailed laboratory protocol for accurate assessment of FA diagnosis based on mitomycin C (MMC) test. Induced chromosomal breakage study was successful in 171 out of 205 aplastic anemia (AA) patients. According to the sensitivity of MMC at 50ng/ml, 38 patients (22.22%) were diagnosed as affected and 132 patients (77.17%) as unaffected. Somatic mosaicism was suspected in an 11-year-old patient with a FA phenotype. Twenty-six siblings of FA patients were also evaluated and five of them (19.23%) were diagnosed as FA. From this study, a standard protocol for diagnosis of FA was developed. It is routinely used as a diagnostic test of FA in Tunisia.Comptes rendus biologies 01/2013; 336(1):29-33. · 1.71 Impact Factor -
Article: High susceptibility for enterovirus infection and virus excretion features in tunisian patients with primary immunodeficiencies.
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ABSTRACT: To estimate the susceptibility to enterovirus infection and the frequency of long-term poliovirus excreters in Tunisian patients with primary immunodeficiencies (PIDs), enteroviruses were assessed in stool specimens of 82 patients with humoral, combined, and other PIDs. Isolated viruses were typed and intratyped by standard molecular techniques, and the whole VP1 region of poliovirus isolates was sequenced. Polioviruses were detected in 6 patients; all isolates were vaccine related. Five patients rapidly stopped excretion; one excreted a poliovirus type 1 isolate for several months, and the isolate accumulated up to 14 mutations in the VP1 region. Nonpolio enteroviruses were identified in 6 patients; 4 of them kept excreting the same strain for more than 6 months. The rate of enterovirus infection was 13.4% of the PID patients and 20.7% of those with an IgG defect; it greatly exceeded the rates generally found in Tunisian supposed-immunocompetent individuals (4.1% during the study period; P = 0.001 and P < 0.0001, respectively). Interestingly, patients with combined immunodeficiencies were at a higher risk for enterovirus infection than those with an exclusively B cell defect. A major histocompatibility complex (MHC) class II antigen expression defect was found in 54% of enterovirus-positive patients and in the unique long-term poliovirus excreter. The study results also suggest that substitutive immunoglobulin therapy may help clearance of a poliovirus infection and that most PID patients have the ability to stop poliovirus excretion within a limited period. However, the high susceptibility of these patients to enterovirus infection reinforces the need for enhanced surveillance of these patients until the use of oral poliovirus vaccine (OPV) is stopped.Clinical and vaccine immunology: CVI 08/2012; 19(10):1684-9. · 2.37 Impact Factor -
Article: Oral HPV infection and MHC class II deficiency (A study of two cases with atypical outcome).
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ABSTRACT: Major 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. Here 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. Viral 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.Clinical and Molecular Allergy 04/2012; 10(1):6. · 1.39 Impact Factor -
Article: Kaposi’s sarcoma in a child with Wiskott-Aldrich syndrome
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ABSTRACT: IntroductionKaposi’s sarcoma (KS) is rare in childhood. It may be favored by acquired immune deficiencies, but the predisposing factors to KS in other children are unclear.DiscussionKS has been reported in only two children and one adult with primary immunodeficiency. We report here a Tunisian child with a Wiskott-Aldrich syndrome who developed KS at the age of 14months.ConclusionThis observation expands the spectrum of primary immunodeficiencies associated with KS in childhood.European Journal of Pediatrics 04/2012; 165(7):453-457. · 1.88 Impact Factor -
Article: Autoimmune polyglandular syndrome type II after bone marrow transplant: real transfer or acceleration of a programmed disease?
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ABSTRACT: We report a case of autoimmune polyglandular syndrome type II that developed in an 11-year-old boy with homozygous sickle cell disease after allogeneic bone marrow transplant; the donor was his father, who was human leukocyte antigen identical and had vitiligo. On day 24 after transplant, the patient developed grade 1 acute graft-versus-host disease, which was controlled over a period of 3 months with corticosteroid-induced immunosuppression. Full donor engraftment was documented on day 31 after transplant, and this was further confirmed on days 59, 231, 321, 472, 549, and 720. Three months after transplant, the recipient developed adrenal insufficiency, and at 13 months, he developed vitiligo. Seventeen months after transplant, autoimmune thyroid disease, positive for thyroid peroxidase and thyroglobulin autoantibodies, was diagnosed. At the same time, we identified adrenal insufficiency in the donor. We analyzed a serum sample from the recipient for autoantibody markers for type 1 autoimmune diabetes mellitus. The sample was positive for antiglutamic acid decarboxylase. Antibody against 21-hydroxylase enzyme was also found (261 U/mL; normal value, < 1 U/mL). We conclude that the recipient developed autoimmune polyglandular syndrome type II after bone marrow transplant from his father, who was probably affected by the same syndrome.Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 02/2012; 10(1):76-80. -
Article: Primary immunodeficiencies in highly consanguineous North African populations.
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ABSTRACT: The study of inbred populations has contributed remarkably to the description of new autosomal recessive primary immunodeficiencies (PIDs). Here, we examine the pattern of PIDs in North African populations and assess the impact of highly prevalent consanguinity. This review reports on the current status of pediatricians' awareness of PIDs in Egypt, Morocco, and Tunisia, where awareness of PIDs is relatively recent. The phenotypic distribution of PIDs is reported and compared among the three countries and with other populations. Data analysis reveals a prevalence of autosomal recessive forms and a peculiar distribution of major PID categories, particularly more combined immunodeficiencies than antibody disorders. In these endogamous communities, molecular diagnosis is critical to developing a genetic-based preventive approach. The organization of diagnosis and care services in these resource-limited settings faces many obstacles. Autosomal recessive PIDs are overrepresented; thus, it is critical to continue investigation of these diseases in order to better understand the underlying mechanisms and to improve patient care.Annals of the New York Academy of Sciences 11/2011; 1238:42-52. · 3.15 Impact Factor -
Article: Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients.
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ABSTRACT: 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.Blood 09/2011; 118(19):5108-18. · 9.90 Impact Factor -
Article: Hypocalcaemia due to hypoparathyroidism in β-thalassemia major. A study of a new case.
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ABSTRACT: To report a new case of hypoparathyroidism in a child with ß-thalassemia major We report a case of a 17-year-old Tunisian girl with transfusion-dependent thalassemia major presented with paresthesia and pubertal delay. Laboratory investigations showed hypocalcaemia and hyperphosphatemia. Parathyroid hormone level was low (2 ng/l, normal range: 12-72 ng/l) than expected for the degree of hypocalcaemia. Serum ferritin concentration was 1770ng/ml. The patient was started on oral daily calcium supplementation, Alfa calciferol and intensive iron chelation therapy. Follow-up after 6 and 12 months revealed normal Calcium and ECG showed QT interval within normal range. Investigating calcium homeostasis at regular intervals and early management of any abnormality can preclude the occurrence of complications.La Tunisie médicale 03/2011; 89(3):302-4. -
Article: Successful treatment of mycophenolate mofetil in a child with refractory Evans syndrome.
Journal of Pediatric Hematology/Oncology 08/2010; 32(6):e244. · 1.16 Impact Factor -
Article: Contribution to the Description of the β‐Thalassemia Spectrum in Tunisia and the Origin of Mutation Diversity
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ABSTRACT: We determined the spectrum of β‐thalassemia (thal) mutations in 118 affected unrelated patients with different forms of β‐thal. Using a combination of reverse dot–blot analysis, denaturing gradient gel electrophoresis (DGGE), polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) and direct nucleotide sequencing, we identified the largest spectrum of β‐thal mutations so far reported in Tunisia, and to the best of our knowledge, within the Mediterranean Basin. A total of 18 distinct alleles were detected at different frequencies, with two alleles [codon 39 (C→T) and IVS‐I‐110 (G→A)] predominating all others. Seven other alleles [frameshift at codon (FSC) 6 (− A), FSC 8 (− AA), codon 30 (G→C), IVS‐I‐1 (G→A), IVS‐I‐2 (T→G), IVS‐I‐6 (T→C), FSC 44 (− C)] were rare, and nine alleles [− 29 (A→G), IVS‐I‐2 (T→C), IVS‐I‐5 (G→C), IVS‐I‐5 (G→T), IVS‐I‐116 (T→G), codon 37 (G→A), IVS‐II‐1 (G→A), IVS‐II‐745 (G→C) and IVS‐II‐849 (A→C)], albeit described elsewhere, are reported here in Tunisia for the first time. The codon 39 and IVS‐I‐110 mutations were the two predominant alleles occurring at frequencies of 43.8% and 10.8%, respectively. They are presumably the earliest mutations introduced into this country. The codon 39 allele could have been introduced in Tunisia during the Roman occupation. Similarly, the IVS‐I‐110 mutation might have been introduced by the Turkish and Phoenician influence. Both gene flow and private mutations may account for the diversity of alleles observed in Tunisia. These data provide the background for implementing prevention programs based on genetic counseling and prenatal diagnosis.08/2009; 28(3):189-195. -
Article: Bone marrow transplantation without conditioning regimen in Omenn syndrome: a case report.
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ABSTRACT: OS is a non-SCID immunodeficiency characterized by a poor outcome even after BMT. We report here a case of BMT without preparative conditioning regimen, and with a successful engraftment in a five-month-old infant with OS. The patient was transplanted with 15 x 10(8) bone marrow mononuclear cells/kg, from his HLA matched brother, without preparative regimen and GVHD prophylaxis. Immunological status was assessed before and after the BMT, and the engraftment was monitored with microchimerism analysis. Six days after BMT, an acute GVHD involving first the skin, then the liver and gut, complicated the post-transplantation course. An excellent engraftment was confirmed by donor chimerism over 95% respectively at day post-transplantation 30, 60, 90, and 150. The cellular immunity of the patient was restored, and infectious complications decreased after BMT. Later the patient experienced chronic GVHD, and he died on day post-transplantation 246 from GVHD. BMT without conditioning regimen for OS is feasible, but there must be a megadose cell transplantation, and appropriate prophylactic immunosuppressive treatment to prevent acute GVHD.Pediatric Transplantation 01/2008; 11(8):922-6. · 1.48 Impact Factor -
Article: Kaposi's sarcoma in a child with Wiskott-Aldrich syndrome.
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ABSTRACT: Kaposi's sarcoma (KS) is rare in childhood. It may be favored by acquired immune deficiencies, but the predisposing factors to KS in other children are unclear. KS has been reported in only two children and one adult with primary immunodeficiency. We report here a Tunisian child with a Wiskott-Aldrich syndrome who developed KS at the age of 14 months. This observation expands the spectrum of primary immunodeficiencies associated with KS in childhood.European Journal of Pediatrics 08/2006; 165(7):453-7. · 1.88 Impact Factor -
Article: X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.
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ABSTRACT: Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.Journal of Experimental Medicine 08/2006; 203(7):1745-59. · 13.85 Impact Factor -
Article: Anti-thrombomodulin antibodies and venous thrombosis.
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ABSTRACT: Thrombomodulin (TM) is a cell surface endothelial glycoprotein having anticoagulant properties. It inhibits thrombin, and activates protein C, leading to the inhibition of activated factors V and VIII. TM autoantibodies could theoretically predispose to thrombosis. We have tested 83 unselected patients with deep venous thrombosis, 36 males and 47 females aged from 1 to 70 years [mean +/- standard deviation (SD), 34.2 +/- 14.5 years] for the presence of IgG anti-TM in their plasmas. Tests were performed by enzyme-linked immunosorbent assay (ELISA) using recombinant human TM kindly provided by PAION GmbH (Aachen, Germany). Results are expressed as the optical density (OD) differences between coated and un-coated wells. Plasmas from 83 normal volunteer donors were used to define the cut-off value as the mean of absorbance of the control group + 3 SDs. The median OD of normal controls group was 0.024 (mean, 0.034; SD, 0.066; range, -0.048 to 0.309). The median OD obtained with plasmas from patients was 0.048 (mean, 0.114; SD, 0.215; range, -0.039 to 1.312) and was significantly higher than that of the control group (P < 0.0001). Choosing a cut-off value of 0.232 (mean OD of the control group + 3 SDs), 11 patients are considered as positive for IgG autoantibodies to TM and three normal controls are weakly positive. Selected plasma with IgG anti-TM and purified IgG were further tested by dot blot using recombinant purified TM and were found positive. Purified IgG of positive plasmas inhibits protein C activation by TM and thrombin, suggesting that anti-TM antibodies have a procoagulant effect. Interestingly, in our study, anti-TM antibodies are found in three of six patients with Budd-Chiari syndrome and four of eight patients with cerebral venous thrombosis. In conclusion, thrombomodulin autoantibodies could be a new interesting marker of thrombophilia easily detected by ELISA.Blood Coagulation and Fibrinolysis 10/2004; 15(7):553-8. · 1.24 Impact Factor -
Article: Contribution to the description of the beta-thalassemia spectrum in Tunisia and the origin of mutation diversity.
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ABSTRACT: We determined the spectrum of beta-thalassemia (thal) mutations in 118 affected unrelated patients with different forms of beta-thal. Using a combination of reverse dot-blot analysis, denaturing gradient gel electrophoresis (DGGE), polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) and direct nucleotide sequencing, we identified the largest spectrum of beta-thal mutations so far reported in Tunisia, and to the best of our knowledge, within the Mediterranean Basin. A total of 18 distinct alleles were detected at different frequencies, with two alleles [codon 39 (C-->T) and IVS-I-110 (G-->A)] predominating all others. Seven other alleles [frameshift at codon (FSC) 6 (-A), FSC 8 (-AA), codon 30 (G-->C), IVS-I-1 (G-->A), IVS-I-2 (T-->G), IVS-I-6 (T-->C), FSC 44 (-C)] were rare, and nine alleles [-29 (A-->G), IVS-I-2 (T-->C), IVS-I-5 (G-->C), IVS-I-5 (G-->T), IVS-I-116 (T-->G), codon 37 (G-->A), IVS-II-1 (G-->A), IVS-II-745 (G-->C) and IVS-II-849 (A-->C)], albeit described elsewhere, are reported here in Tunisia for the first time. The codon 39 and IVS-I-110 mutations were the two predominant alleles occurring at frequencies of 43.8% and 10.8%, respectively. They are presumably the earliest mutations introduced into this country. The codon 39 allele could have been introduced in Tunisia during the Roman occupation. Similarly, the IVS-I-110 mutation might have been introduced by the Turkish and Phoenician influence. Both gene flow and private mutations may account for the diversity of alleles observed in Tunisia. These data provide the background for implementing prevention programs based on genetic counseling and prenatal diagnosis.Hemoglobin 09/2004; 28(3):189-95. · 1.30 Impact Factor -
Article: [The hyper-IgM syndrome: 13 observations].
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ABSTRACT: The hyper-IgM syndrome (HIGM) is a rare hereditary immune deficiency, characterised by a low or nil level of IgG and IgA and a normal or increased level of IgM, predominately affecting boys. Its clinical manifestations are dominated by recurrent infection, notably of the digestive tube, the ears nose and throat and the lungs. We conducted a retrospective study of the medical files of 13 patients with 10 boys and 3 girls from 12 different families. In all the patients, the diagnosis was established on measuring the serum immunoglobulines IgG, IgA and IgM using Mancini's technique. The mean age at the onset of the disease was of 20 months (6 - 42 months). The clinical manifestations were dominated by recurrent and persisting infections, notably digestive (10 cases), respiratory (9 cases), cutaneous (5 cases) and glandular (5 cases). No pulmonary Pneumocystis carinii infection or sclerosing Cryptosporidium cholangitis was observed. Two boys exhibited neurological manifestations, unrelated to an infection. The IgG deficiency was constant and IgA deficieny encountered in 12 patients. Ten patients exhibited a high level of IgM (4.6 - 29,9 g/l) whereas this was normal in the 3 others. The expression of the CD(40) ligand was absent in the 6 boys in whom it was assessed and normal in the only girl studied. Eleven patients exhibited concomitant cellular immune deficiency. Three patients presented moderate neutropenia. Nine patients received replacement therapy with IV immunoglobulines with a residual level of IgG at 8,27 g/l (4 - 14,45 g/l) associated with the regression in the manifestations of infection. One patient died from a Burkitt lymphoma before any treatment was initiated. The primary hyper-IgM syndrome in Tunisia is characterised by a relative frequency of autosomal recessive forms (3 girls), the absence of Pneumocystis carinii pulmonary infections and sclerosing cholangitis and the occurrence of neurological manifestations (2 cases).La Presse Médicale 04/2003; 32(12):544-9. · 0.67 Impact Factor -
Article: Community-acquired poliovirus infection in children with primary immunodeficiencies in Tunisia.
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ABSTRACT: The global polio eradication program recommends the use of massive vaccination campaigns with live vaccine through National Immunization Days (NIDs) to displace the wild virus from the community. Immunodeficient patients may be indirectly infected and become chronic excretors and potential reservoirs of polioviruses, a concern for the posteradication era. This prospective study aimed to assess the risk of community-acquired infection of immunodeficient patients following NIDs, the dynamics of viral excretion and the genetic variation of excreted viruses. Sixteen children with various primary immunodeficiencies, who did not receive the vaccine during the campaign, were investigated. Stool samples were collected weekly, shortly after the NIDs, during at least 3 months, and were processed for viral isolation. Isolates were characterized by three intratypic differentiation methods and partial sequencing of the VP1/2A region. Polioviruses were detected in 4 out of 16 patients (serotype 1 in 3 patients and serotype 3 in 1 patient). Sequencing revealed more than 99% homology with homotypic Sabin strains, suggesting recent infection. Duration of viral excretion ranged from 1 to 7 weeks. Nine out of eleven isolates from the three poliovirus serotype 1-infected patients disclosed a non-Sabin-like phenotype by enzyme-linked immunosorbent assay and had recurrent mutations within or close to the neutralizing antigenic sites. In summary, the risk of secondary infection in immunodeficient patients is within the range previously reported for the general population. Although none of the four infected patients developed prolonged viral excretion, particular viral variants were selected and may be of epidemiological significance.Journal of Clinical Microbiology 04/2003; 41(3):1203-11. · 4.15 Impact Factor
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2006
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Hôpital Universitaire Necker
Paris, Ile-de-France, France
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