ATP6V0A2-related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype.

In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibres has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and with elastic fibre anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa.

Two novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11ß hydroxylase deficiency in a Tunisian family.

Steroid 11ß hydroxylase deficiency (11ß-OHD) (OMIM # 202010) is the second most common form of congenital adrenal hyperplasia (CAH), accounting for 5-8% of all cases. It is an autosomal recessive enzyme defect impairing the biosynthesis of cortisol. The CYP11B1 gene encoding this enzyme is located on chromosome 8q22, approximately 40kb from the highly homologous CYP11B2 gene encoding for the aldosterone synthase. Virilization and hypertension are the main clinical characteristics of this disease. In Tunisia, the incidence of 11ß-OHD appears higher due to a high rate of consanguinity (17.5% of congenital adrenal hyperplasia). The identical presentation of genital ambiguity (females) and pseudo-precocious puberty (males) can lead to misdiagnosis with 21 hydroxylase deficiency. The clinical hallmark of 11ß hydroxylase deficiency is variable, and biochemical identification of elevated precursor metabolites is not usually available. In order to clarify the underlying mechanism causing 11ß-OHD, we performed the molecular genetic analysis of the CYP11B1 gene in a female patient diagnosed as classical 11ß-OHD. The nucleotide sequence of the patient's CYP11B1 revealed two novel mutations in exon 4: a missense mutation that converts codon AGT (serine) to ATT (isoleucine) (c.650G>T; p.S217I) combined with an insertion of a thymine at the c.652-653 position (c.652_653insT). This insertion leads to a reading frame shift, multiple incorrect codons, and a premature stop in codon 258, that drastically affects normal protein function leading to a severe phenotype with ambiguous genitalia of congenital adrenal hyperplasia due to 11ß hydroxylase deficiency.

Disseminated BCG infection revealing a severe combined immunodeficiency: A case report.

INTRODUCTION: Bacillus Calmette Guerin (BCG) vaccine, which is administered to all newborns in Tunisia, can lead to serious complications ranging from local disease to disseminated disease in a group of patients with primary immunodeficiency diseases. CASE REPORT: A 3-month-old boy presented with persistent fever, hepato-splenomegaly and multiple osteolytic lesions. He was diagnosed with severe combined immunodeficiency disease and disseminated BCG infection. Despite anti-tubercular therapy combined with intravenous immunoglobulin, the evolution was fatal. CONCLUSION: The case highlights the possible risk of such rare yet lethal complication of BCG vaccine. In suspected cases of primary immunodeficiency disease, inoculation of BCG should be postponed until appropriate screening tests exclude such diagnosis to prevent serious complications.

[Coronary artery aneurysm in Kawasaki disease and its risk factors : a retrospective study about 65 Tunisian children]. / Les complications coronaires de la maladie de Kawasaki et ses facteurs de risque : à propos de 65 cas d'enfants tunisien.

INTRODUCTION: Kawasaki syndrome (KS) is a systemic vasculitis of unknown etiology that affects medium and small blood vessels. The aim of our study is to analyze coronary artery lesions in children with KS and their risk factors. MATERIAL AND METHODS: All children under the age of 15 years-old presenting KS and admitted in the pediatric department of three university hospital (Sahloul hospital, and Farhat Hached hospital of Sousse, Ibn El Jazzar hospital of Kairoun) from January 2000 to December 2018 were included. RESULTS: Sixty-five patients were included in our study. The mean age at diagnosis was of 29.9 months [2-120 months] and the sex ratio was of 1.7. Echocardiography was performed in all patients. It showed coronary dilation in 37% of patients with coronary artery diameter of 4.2 mm on average [3.2-7mm]. The coronary aneurysm was small in 19 cases and medium in 5 cases. No giant aneurysm has been identified. In univariate analysis, the predictors of coronary artery lesions were male sex, atypical form, fever duration more than 10 days, hepatic cytolysis, thrombocytosis and anemia. In multivariate analysis, only the last four parameters were the predictive factors of the coronary artery involvement. CONCLUSION: Several risk factors can be used to determine which children are predisposed to develop coronary dilations. In case of patient with risk factors, intravenous immunoglobulins should be initiated early to avoid these serious complications.

[Idiopathic steroid-resistant nephrotic syndrome in child : study of 20 cases]. / Syndrome néphrotique idiopathique corticorésistant de l'enfant : Etude de 20 cas.

BACKGROUND: Idiopathic steroid-resistant nephrotic syndrome (ISRNS) is rare and represents a significant therapeutic dilemma for paediatricians and paediatric nephrologists. AIM: To analyze characteristics of the ISRNS in the child. METHODS: Retrospective study of 20 cases of ISRNS enrolled in paediatric department of nephrology in Sahloul hospital (Tunisia) between June 1993 and December 2007 (14 years period). RESULTS: There were eight girls and 12 boys (mean age: 5.8± 3.7 years) originating from the center or the south of Tunisia. Eight of them had a minimal-change disease (MCD), 11 a focal and segmental glomerulosclerosis (FSGS) and one a mesangioproliferative glomerulonephritis (MePGN). In this group, no family form could be identified. All patients were treated by cyclosporine associated with low dose of steroid. We noted a complete remission (CR) in nine cases, partial remission (PR) in three cases and no response to cyclosporine in eight cases. Among patients with CR, six presented MCD and three a FSGS. In this group, we observed relapse of nephrotic syndrome in six cases. End stage renal disease (ESRD) was noted in 10 patients of which five not responded to cyclosporine, two initially having presented a RC and three having since the beginning a PR. Among them, two only could be grafted; one relapses on transplant was observed with a single patient initially presenting a secondarily transformed MePGN in FSGS. CONCLUSION: Our study confirms the clinical, histological and evolutive heterogeneity of idiopathic steroid-resistant nephrotic syndrome. Although there is any therapeutic consensus in this domain, cyclosporine remains indicated in first intention in sporadic forms of ISRNS. On the other hand, renal transplantation constitutes the only therapeutic alternate in genetic forms that constantly evolve at ESRD.

Molecular genetic diagnosis of Tunisian Glanzmann thrombasthenia patients reveals a common nonsense mutation in the ITGA2B gene that seems to be specific for the studied population.

: Glanzmann thrombasthenia is an inherited severe bleeding disease. Mutations associated with Glanzmann thrombasthenia are highly heterogeneous and occur across the two genes coding for the platelet αIIbß3 integrin. This study was aimed at identifying Glanzmann thrombasthenia-associated novel mutations in Tunisian patients. Seven unrelated Glanzmann thrombasthenia patients issued from high consanguineous families (86%; 6/7 of the patients) were studied. Glanzmann thrombasthenia diagnoses were based on patients' bleeding histories and platelet aggregation tests. Screening of ITGA2B and ITGB3 genes was performed by denaturing high-performance liquid chromatography (DHPLC) analysis. Amplicons with abnormal elution profiles were subjected to direct sequencing. DHPLC/sequencing analysis identified a pathogenic homozygous mutation in exon 26 at position c.2702C>A, inducing a substitution of a serine to a stop codon (p.S901*) in the ITGA2B gene, in three patients. This mutation was only previously reported in a Glanzmann thrombasthenia patient of a Tunisian origin and not in other populations. We diagnosed a pathogenic Glanzmann thrombasthenia mutation in ITGA2B screened by DHPLC that appears to be specific to individuals of Tunisian heritage and that deserves to be investigated in first intention. As a result, we determined that performing prenatal diagnosis and setting a prevention strategy via counselling for affected heterozygote individuals will be helpful for Tunisian Glanzmann thrombasthenia families where there is still a high rate of consanguinity.

Steroid 21-hydroxylase gene mutational spectrum in 50 Tunisian patients: characterization of three novel polymorphisms.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease of steroid biosynthesis in humans. More than 90% of all CAH cases are caused by mutations of the 21-hydroxylase gene (CYP21A2), and approximately 75% of the defective CYP21A2 genes are generated through an intergenic recombination with the neighboring CYP21A1P pseudogene. In this study, the CYP21A2 gene was genotyped in 50 patients in Tunisia with the clinical diagnosis of 21-hydroxylase deficiency. CYP21A2 mutations were identified in 87% of the alleles. The most common point mutation in our population was the pseudogene specific variant p.Q318X (26%). Three novel single nucleotide polymorphism (SNP) loci were identified in the CYP21A2 gene which seems to be specific for the Tunisian population. The overall concordance between genotype and phenotype was 98%. With this study the molecular basis of CAH has been characterized, providing useful results for clinicians in terms of prediction of disease severity, genetic and prenatal counseling.