Choanal atresia: Diagnosis and management

Objective: Choanal atresia (CA) is a rare congenital malformation caused by the obliteration of the posterior choanae by an atretic plate. The aim of our study is to describe the diagnosis and management modalities of CA and to determine the factors associated with recurrence. Materials and methods: This is a retrospective study based on the medical records of patients with CA managed in our department in the period between 2002 and 2021. We studied the clinical features and management modalities of each patient. For patients who developed a recurrence, we determined the factors associated with recurrence based on a bivariate analysis. Results: We studied the medical records of 26 patients with either a bilateral (n=8) or a unilateral (n=16) form of CA. The median age at surgery was two days for bilateral forms and 5 years and 4 months for unilateral forms. At computed tomography scan, CA was mixed (n=20), bony (n=4) or membranous (n=2). All patients underwent intranasal endoscopic surgical treatment using cold instruments alone in membranous forms and combined to the drilling of the atretic plate in bony and mixed forms. The surgical management included the resection of the posterior part of the vomer bone and the placement of nasal stents in 10 and 16 patients respectively. We recorded 6 cases of recurrence requiring a surgical re-intervention. The presence of associated cranio-facial malformations was the only factor associated with recurrence (p=0,001). Conclusion: Choanal atresia diagnosis was based on nasal endoscopy and CT scan. Surgical treatment using transnasal endoscopic approach was an effective and safe technique. Associated local malformations was a factor associated with re-stenosis

Involvement of the IL23/Th17 Pathway in the Pathogenesis of Tunisian Pemphigus Foliaceus.

Pemphigus foliaceus (PF) is a rare autoimmune skin disease caused by anti-Dsg1 pathogenic autoantibodies. It is considered as a Th2-mediated disease. Likewise, Th17 cells were recently described in the pathogenesis of the disease but their role is still unclear. We aimed to unravel the eventual implication of the IL23/Th17 pathway in the development of PF. A case-control study was conducted on 115 PF patients and 201 healthy controls using PCR-RFLP and AS-PCR methods. SNPs in IL23R, RORγt, IL17A, IL17F, IL17AR, TNFa, and STAT3 genes were genotyped. mRNA expression of IL23R and RORγt was evaluated using Q-PCR. The frequency of circulating Th17 cells was analyzed by flow cytometry. Genetic associations between IL23R>rs11209026, IL17A>rs3748067, IL17F>rs763780, and TNFa>rs1800629 and the susceptibility to PF were reported. Moreover, we revealed a significant increased frequency of circulating CD4+IL17+ cells as well as higher mRNA levels of RORγt and IL23R in PBMCs of patients. However, no significant increase of RORγt and IL23R mRNA expression was observed in lesional skin biopsies. In spite of the little size of specimens, our results provide converging arguments for the contribution of the IL23/Th17 pathway in the pathogenesis of PF.

Is there any relationship between polymorphism of Heat Shock Protein 70 genes and Pemphigus foliaceus?

The human Heat Shock Proteins (HSP70) family plays a key role in up-regulating stress responses. Some studies reported possible associations of single nucleotide polymorphisms in the HSP70 genes with some autoimmune diseases. However, whether HSP70 polymorphisms represent a risk factor for pemphigus foliaceus (PF) is still unkown. We analyzed by PCR-RFLP polymorphisms of HSP70 genes HSA1A, HSPA1B and HSPA1L in 80 Tunisian patients with PF, 160 matched healthy controls and 147 related healthy subjects. There were significant differences between PF patients and controls in the allelic (pc=5.91×10(-12), pc=1.14×10(-5) and pc=0.0089, respectively) and homozygous genotypic frequencies of HSPA1L>T, HSPA1A>C and HSPA1B>G (p=2.617×10(-12), p=1.017×10(-5) and p=0.0058, respectively). Haplotype analysis showed significant differences between PF patients and controls: the CCA, CGA, CCG and CGG haplotypes were significantly over-represented in controls whereas the TCG haplotype was significantly over-represented in patients. However, the significant LD found between the HSP70 and the HLA class II susceptibility alleles together with the multivariant regression analysis data between the two loci could argue against a direct role of the HSP70 polymorphism in the occurrence of PF.

Cytokine gene polymorphisms in Tunisian endemic pemphigus foliaceus: a possible role of il-4 variants.

Polymorphism in the genes of TH2 cytokines and/or theirs receptors can influence serum cytokine levels in and the switch to the pathologic IgG4 auto-antibodies. In order to underline the role of these genes in the aethiopathogenesis of Pemphigus Foliaceus, we conduct a familial and a case control studies including 80 Tunisian patients, 147 related subjects and 160 matched healthy controls. We investigated, by PCR-RFLP technique, seven nucleotide polymorphisms: rs2243250 in promoter region of IL4 gene, rs47877948, rs3024530 and rs30246223 in the IL4R gene, rs1881457and rs205412 SNPs in IL13 gene and rs535036 in IL13RA2 gene. After Bonferroni adjustment, T allele and the TT genotype of IL4-590 were significantly increased in the PF patients group compared to healthy controls. This association was confirmed by the family study. Interestingly, the serum IL-4 levels were significantly increased in patients with the TT genotype compared to CT or CC genotypes. Interestingly, the IL4/IL13:T-A-C haplotype exhibited a significant effect on PF susceptibility. In addition, a significant gene-gene interaction between the IL4/IL4R (TACA) significantly increases in PF patients as compared to controls. These findings assess the role of the IL4/IL4R axis in the aethiopathogenesis of Tunisian endemic PF by the induction of a high transcriptional activity which could enhance the T-cell balance and inducing immunoglobulin isotype switching.

Polymorphisms of HLA microsatellite marker in Tunisian pemphigus foliaceus.

Pemphigus foliaceus (PF) is an autoimmune blistering skin disease that partly results from genetic factors, especially from human leucocyte antigen (HLA) class II genes. Several data have reported the involvement of microsatellite (STR) markers across different regions of the HLA in many auto-immune diseases. To test the hypothesis of the existence of a major HLA haplotype predisposing to PF, we analyzed six polymorphisms of microsatellite loci at 6p21.3-21.4 spanning HLA: D6S291, D6S273, TNFa, MICA, D6S265 and D6S276 in 81 PF patients compared to 123 healthy individuals recruited from the south of Tunisia. In this study, after Bonferroni's correction, 3 STR alleles from the TNFa locus were associated with the disease: the allele TNFa(∗)2 (p(c) = 4.2×10(-6)) and, at a lower level, the TNFa(∗)5 (p(c) = 0.014) as susceptibility alleles and TNFa(∗)6 (p(c) = 0.014) as protective ones. Furthermore, the expression of the TNFa(∗)2/TNFa(∗)5 genotype seem to confer susceptibility to PF (p = 0.00001, OR = 11.25). Interestingly, no significant LD was found between TNFa2/TNFa5 alleles and DRB1(∗)03/DRB1(∗)04 alleles. However, the multivariant regression analysis indicates that both the HLA class II and the TNFa alleles remained significant (p < 0.001). Although, these findings rejected our hypothesis on the existence of HLA susceptibility haplotype, they assessed the role of TNFa loci. Accordingly, TNFa seem to contribute to the aethiopathogenesis of Tunisian endemic PF may be by the induction of a high TNFα production which is known to enhance the autoimmune cascade of the disease.

Biomarkers of oxidative stress in epidermis of Tunisian pemphigus foliaceus patients.

BACKGROUND: Reactive oxygen species play a key role in the development of many dermatological disorders. OBJECTIVE: The purpose of this study is to examine the lipid peroxidation, protein oxidation and antioxidative profile in Tunisian pemphigus foliaceus (PF) patients. METHODS: Malondialdehyde (MDA), conjugated dienes (CD), protein thiol levels, catalase (CAT) and superoxide dismutase (SOD) activities were evaluated in skin biopsies of 13 patients compared to biopsies of 7 healthy controls. RESULTS: Oxidative stress was confirmed in these three types of patient biopsies as compared to controls. Thus, MDA, CD levels and catalase CAT and SOD activities were significantly increased in lesional, perilesional and normal biopsies of PF patients than in those of control subjects. Protein oxidative was confirmed by lower levels of protein thiols in lesional, perilesional and normal biopsies than in control's biopsies. Otherwise, in patients, a significant rise of these biomarkers was observed in lesional and perilesional biopsies compared with normal biopsies. CONCLUSION: This study shows that oxidative stress could be involved in the pathogenesis of PF by the spread of skin lesions and/or by the increase in auto-antibodies' reactivity.

[Antisynthetase syndrome: a report of four cases and literature review]. / Le syndrome des antisynthétases : à propos de quatre observations et revue de la littérature.

The antisynthetase syndrome (ASS) includes inflammatory myopathy (polymyositis or dermatomyositis), interstitial lung disease (ILD), arthritis, Raynaud's phenomenon, and mechanic's hands, associated with antibodies against aminoacyl-tRNA-synthetases, the most well-recognized being the anti-Jo1 antibody (anti-histidyl-tRNAsynthetase). We report four cases of antisynthetase syndrome and review the clinical characteristics and prognosis factors dominated by ILD. We report the cases of four women with a mean age of 42 years (28-62 years). The interstitial lung disease was found in four cases and was objectified by CT-scan in all cases. The pulmonary symptoms were consisted of dyspnea (one case) and respiratory distress (one case). The anti-Jo1 antibodies were present in the four patients. The myopathy was concomitant with pulmonary involvement (two cases), preceded it in 6 months (one case) and in the course of evolution and after 1 month (one case). All patients received corticosteroid treatment. The immunosuppressive treatment was necessary for two patients because of the severity of the pulmonary involvement. The outcome was favorable in two patients, partially favorable in a patient who presented pulmonary fibrosis. However, one patient died after developing brain abscesses.

[Prevalence and diagnostic value of antinuclear antibodies without identified antigenic target: a retrospective study of 90 patients]. / Prévalence et valeur diagnostique des anticorps antinucléaires de spécificité antigénique indéterminée : étude rétrospective à propos d'une série de 90 patients.

PURPOSE: The objective of this study was to determine the clinical relevance and the diagnostic significance of positive antinuclear antibodies (ANA) without identified antigenic target by the usual characterization technique. PATIENTS AND METHODS: Retrospective study conducted in the Laboratory of Immunology of Habib Bourguiba Hospital (Sfax, Tunisia) during 18 months. The inclusion criteria were the presence of an ANA titer greater or equal to 1/320 with negative characterization result. ANA screening was performed by indirect immunofluorescence (IIF) on Hep2 cells. Each positive serum was tested by IIF on Crithidia luciliae (anti-native DNA) and by immunodot (anti-nucleosome, anti-histone, anti-Sm, anti-RNP, anti-SSA, anti-SSB, anti-Scl 70, anti-PM-Scl, anti-Jo1, anti-PCNA and anti-ribosomal protein). Sera of systemic lupus erythematosus (SLE), myositis, and scleroderma patients were tested for anti-Ku, anti-PL7, anti-PL12 and anti-Ro-52 using dot myositis. RESULTS: Sera of 90 patients were studied: 18 men and 72 women (average age: 44 years). Drug-induced ANA was found in eight patients. The most frequent clinical symptoms were joint (56.7%), cutaneous (54.4%) and constitutional symptoms (45.6%). The diagnosis of an autoimmune disease was suspected in 49 patients (54.5%) and confirmed in 30 (33.3%) including 20 cases of connective tissue disease: myositis (n=6), scleroderma (n=5), Sjögren's syndrome (n=3), SLE (n=4), rheumatoid arthritis (n=6) and antiphospholipid syndrome (n=4). Other autoimmune diseases were less frequent. The anti-Ku antibody was detected in the majority of patients with connective tissue disease. The diagnosis of non-autoimmune diseases was established in 25.5% of patients. Eighteen patients (20%) had no diagnosis orientation. CONCLUSION: Our study demonstrated the diagnostic value of the presence of ANA even in the absence of known antigenic target, confirmed the role of the IIF as "gold standard" test for ANA screening, and suggested the usefulness of the addition of Ku antigen in the immunodot classic profile.

Association of the RAVER2 gene with increased susceptibility for ulcerative colitis.

Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE) and autoimmune polyglandular syndromes (APS) are autoimmune diseases (ADs) that may share common susceptibility pathways. We examined ribonucleo-protein, polypyrimidine tract-binding protein (PTB)-binding 2 (RAVER2) loci for these diseases in a cohort of 39 CD cases, 67 UC cases, 93 SLE cases, 60 APS cases and 162 healthy control subjects of Tunisian origin. We genotyped 3 SNPs of RAVER2 (rs2780814, rs1333739 and rs2780889) and evaluated it genetic association with each ADs, using X2-test. For each association, odds ratio (OR) and 95% CI were calculated. We show that rs2780814 is significantly associated with UC (P = 0.00016, P(corr) = 0.00048, OR = 3.66 (1.82; 7.34)). We also observed a trend of possible association to SLE (P = 0.023, P(corr) = 0.69, OR = 2.19 (1.1; 4.36)). None of these RAVER2 SNPs were associated with CD and APS susceptibility. These findings establish RAVER2 as a new UC genetic susceptibility factor and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between ADs suggesting different immunopathological roles of RAVER2 in these diseases.

HLA-DRB1/DQB1 susceptibility for autoimmune polyglandular syndrome type II and III in south of Tunisia.

OBJECTIVES: The aim of our study was to investigate the association of HLA-DRB1 and HLA-DQB1 alleles with autoimmune polyglandular syndromes (APS) type II and III in a southern Tunisian population. PATIENTS AND METHODS: Sixty-two unrelated patients with APSII (n=20) and APSIII (n=42) and 146 healthy controls were genotyped for HLA class II alleles (DRB1*, DQB1*) by PCR-SSP technique. RESULTS: An increased frequencies of HLA-DQB1*03:02 (P=0,02; OR=2.98) in APSII patients, HLA-DRB1*03 (P=310(-6); OR=4.28) and HLA-DQB1*02:01 (P=0.04; OR=1.95) in APSIII patients were found compared to healthy controls. Study of the HLA-DRB1*;DQB1* haplotype frequencies showed a higher occurrence of DRB1*04;DQB1*03:02 and DRB1*03;DQB1*02:01 in APSII patients (P=410(-3); OR=3.31 and P=0.03; OR=2.74 respectively) whereas APSIII was only associated with DRB1*03;DQB1*02:01 (P=7.210(-8), OR=4.71). CONCLUSION: Our data suggest that the variation in class II HLA alleles and haplotypes could be a genetic factor involved in the susceptibility of APS syndrome.

[The myofibroblastic inflammatory tumours: A fortuitous association or an unknown postpartum complication]. / Les tumeurs myofibroblastiques inflammatoires : association fortuite ou complication peu connue du post-partum ?

The inflammatory myofibroblastic tumour has clinical, biological or histological features sometimes misleading with a septic condition. Presenting symptoms are variable and arising circumstances remain obscure. We report three cases occurring in a postpartum context. The first patient, a 28-year-old female, had left psoitis with a sepsis the first day postpartum in relation with an inflammatory myofibroblastic tumour of the meso-ovary. The second patient, a 40-year-old woman, had a hepatic inflammatory myofibroblastic tumour revealed by a ruptured sub-capsular haematoma of the liver in the forth day postpartum. The third patient, a 32-year-old woman, had a pulmonary inflammatory myofibroblastic tumour, diagnosed 5 months after a delivery and which recurred 10 years after surgical treatment. These cases illustrate the difficulty to diagnose inflammatory myofibroblastic tumour, particularly in postpartum.

Spectrum of autoantibodies other than anti-desmoglein in pemphigus patients.

BACKGROUND: Pemphigus is a life-threatening autoimmune blistering disease mediated by autoantibodies against adhesion molecule of the skin. Its concurrence with systemic and organ-specific autoimmune disease was described in case reports. OBJECTIVES: To evaluate the presence of a broad spectrum of organ-specific and non-organ-specific autoantibodies other than anti-desmoglein antibodies in pemphigus patients. PATIENTS AND METHODS: Serum samples were obtained from 105 pemphigus foliaceus (PF) patients, 51 pemphigus vulgaris (PV) patients and 50 controls. Both indirect immunofluorescence assay and ELISA were used to assess the presence of autoantibodies related to connective tissue diseases, autoimmune hepatitis, vasculitis, rheumatoid arthritis, coeliac disease, diabetes and thyroiditis. RESULTS: Significant difference was observed between the three groups for anti-thyroglobulin antibodies in the pemphigus foliaceus group (18% vs. 4%, P=0.03). A significantly higher occurrence of IgM anti-cardiolipin (P=0.03), IgG anti-reticulin (P=0.01) and IgG anti-gliadin antibodies (P=0.008) were observed in the PV group. Cases with more than four autoantibodies were frequently positives for both anti-desmoglein 1 and anti-desmoglein 3. CONCLUSION: Autoantibodies other than anti-desmoglein antibodies are not rare in pemphigus patients. Clinical and serological follow-up of pemphigus patients with positive autoantibodies are needed to clarify their impact in disease evolution.

Atypical clinical appearance and localization of trichilemmoma. a case report.

Trichilemmoma is a benign cutaneous tumor that shows characteristics of differentiation similar to the outer hair sheath. We report the case of a woman presenting with a nodular tender mass of the back that was diagnosed as an isolated trichilemmoma. Several lines of evidence suggest that trichilemmoma should be considered in the differential diagnosis of any indistinct facial papule. This report documents a non-facial example of trichilemmoma. Atypical clinical appearance and localization of this neoplasm in our patient suggest that only histological findings are specific of this tumor.

Tunisian endemic pemphigus foliaceus is associated with the HLA-DR3 gene: anti-desmoglein 1 antibody-positive healthy subjects bear protective alleles.

BACKGROUND: Pemphigus foliaceus is an autoimmune blistering skin disease that partly results from genetic factors, especially human leucocyte antigen (HLA) class II genes. OBJECTIVES: The aim of the study was to determine the HLA DR/DQ markers of susceptibility and protection in the Tunisian endemic form. METHODS: Genomic DNA from 90 patients with pemphigus foliaceus recruited from all parts of the country and matched by age, sex and geographical origin with 270 healthy individuals, was genotyped. RESULTS: Firstly, when the whole patient population was studied, DRB1*03, DQB1*0302 and DRB1*04 alleles were significantly associated with the disease while a significant decrease of, in particular, DRB1*11 and DQB1*0301 was observed in patients compared with controls. DRB1*0301 was the dominant allele in DR3-positive patients and controls, while DRB1*0402 was found in 42% of DR4-positive patients. Secondly, when the HLA DR/DQ allele distribution was studied after dividing patients according to their geographical origin, the southern group, which consisted exclusively of patients with the endemic form of the disease, showed the same associations as the whole pemphigus foliaceus population, particularly with DRB1*03. In the northern group, only the DRB1*04 and DQB1*0301 alleles were found to be associated. Interestingly, anti-desmoglein 1 antibody-positive healthy controls did not carry susceptibility alleles but, in contrast, most carried negatively associated alleles. CONCLUSIONS: These observations indicate that a particular genetic background characterizes the Tunisian endemic form of pemphigus foliaceus and that HLA class II genes control the pathogenic properties of the autoimmune response rather than the initial breakage of B-cell tolerance.

Anti-desmoglein 1 antibodies in healthy related and unrelated subjects and patients with pemphigus foliaceus in endemic and non-endemic areas from Tunisia.

BACKGROUND: Pemphigus foliaceus is an autoimmune blistering skin disease characterized by the production of pathogenic IgG autoantibodies directed against desmoglein 1. AIM: To determine the prevalence of anti-desmoglein 1 antibodies in healthy subjects and their distribution in the different regions of Tunisia and to better identify endemic areas of pemphigus foliaceus. METHODS: We tested, by enzyme-linked immunoserbent assay, sera of 270 normal subjects recruited from different Tunisian areas and 203 related healthy relatives to 90 Tunisian pemphigus foliaceus patients. Results Seventy-six patients (84.4%), 20 healthy controls (7.4%), and 32 relatives (15.76%) had anti-desmoglein 1 antibodies. In southern regions where pemphigus foliaceus is associated with a significant sex ratio imbalance (9 female : 1 male in the south vs. 2.3 : 1 in the north) and a lower mean age of disease onset (33.5 in the south vs. 45 years in the north), a higher prevalence of anti-desmoglein 1 antibodies in healthy controls was observed (9.23% vs. 5.71% in the north). Interestingly, the highest prevalence of anti-desmoglein 1 antibodies in healthy relatives (up to 22%) was observed in the most rural southern localities. More than half anti-desmoglein 1-positive healthy controls were living in rural conditions with farming as occupation, which suggests that this activity may expose the subjects to particular environmental conditions. CONCLUSION: These results show that the endemic features of Tunisian pemphigus foliaceus are focused in these southern areas more than in other areas and that both environmental and genetic factors contribute to the disease.

[Giant insulinoma]. / Un insulinome géant : à propos d'un cas.

Islet-cell tumors are the most common neuroendocrine tumors that arise from the endocrine pancreas. They are typically benign and sporadic. Diagnosis is generally established late because clinical signs lack specificity. The insulinoma is difficult to localize since it is very small in size, often not exceeding 2cm. We report an exceptional case of giant insulinoma initially revealed by a pseudo-polycythemia in an 80-year-old man. He had been treated for hypertension for a few months. Routine biological investigations showed elevated hematocrit and haemoglobin, suggesting Vaquez disease. History taking revealed recent episodes of nocturnal agitation. On admission, he had reddish skin with a suspected enlarged spleen, but total blood volume was normal. Imaging studies showed a voluminous tumor located between the pancreas and the spleen. The presence of an insulinoma was confirmed on the basis of an elevated level of proinsulin at the time of an asymptomatic episode of hypoglycemia. Spleno-pancreatectomy was performed. Histopathological examination revealed a malignant, well-differentiated neuroendocrine malignant tumor.