Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North-African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi-allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North-African patients. This mutation is estimated to date back at least 1,400-1,750 years ago. The identification of this major allele allowed us to suggest a cost-effective genetic diagnostic strategy in North-African patients with PCD.

Frequent Infections, Hypotonia, and Anemia in a Breastfed Infant.

Vitamin B12 deficiency may be responsible of serious hematologic and neurodevelopmental abnormalities. We report the case of an infant who was hospitalized because of recurrent infections, failure to thrive, hypotonia, and weakness. He was 8 months old and had been exclusively breastfed. Blood cell count showed pancytopenia with megaloblastic bone marrow. The serum IgG concentration was low. Vitamin B12 level was very low and associated with increased urinary methylmalonic acid. Cobalamin deficiency was caused by mother's unrecognized pernicious anemia. Vitamin B12 supply led to rapid clinical and hematologic improvement.

Hemolytic anemia and metabolic acidosis: think about glutathione synthetase deficiency.

Glutathione synthetase deficiency (GSSD) is a rare disorder of glutathione metabolism with varying clinical severity. Patients may present with hemolytic anemia alone or together with acidosis and central nervous system impairment. Diagnosis is made by clinical presentation and detection of elevated concentrations of 5-oxoproline in urine and low glutathione synthetase activity in erythrocytes or cultured skin fibroblasts. The prognosis seems to depend on early diagnosis and treatment. We report a 4 months old Tunisian male infant who presented with severe metabolic acidosis with high anion gap and hemolytic anemia. High level of 5-oxoproline was detected in her urine and diagnosis of GSSD was made. Treatment consists of the correction of acidosis, blood transfusion, and supplementation with antioxidants. He died of severe metabolic acidosis and sepsis at the age of 15 months.

Ataxia-telangiectasia in the south of Tunisia: A study of 11 cases.

BACKGROUND: Ataxia-telangiectasia (A-T) is a multisystem disorder characterized by progressive neurologic impairment, variable immunodeficiency, impaired organ maturation, X-ray hypersensitivity, oculocutaneous telangiectasia, and a predisposition to malignancy. AIM: We performed this study in order to describe clinical, immunological and molecular features of patients with AT followed in the south of Tunisia Methods: we performed a retrospective study (1996-2012) in the south of Tunisia about all cases of A-T in order to describe their clinical, immunological and molecular features. RESULTS: 11 cases of AT were found. The mean age at onset of symptoms was 20 months with extremes varying from 3 months to 4 years. The median time to diagnosis was 3.6 years (range: 0-12 years).The main clinical feature of cerebellar syndrome, ataxia, was present at diagnosis in 8 patients and occurred at mean ages of 2.8 years. Ocular telangiectasia occurred at a mean age of 3.9 years (extremes: 3 months and 7 years). Recurrent sino-pulmonary infections that affected 7 children occurred at the mean age of 4.3 years. The most common humoral immune abnormality was serum IgA deficiency. Lymphopenia was found in 7 cases and lack of CD4 T in 6 cases. Cytogenetic analyses showed chromosomal instability in all children and a translocation (7-14) in two patients. A molecular diagnosis established in 6 patients from 4 families showed 5 different mutations of ATM gene. After an average decline of 5 years and 6 months, 7 patients died of severe pulmonary infection. Among them, 3 were ATM mutated. CONCLUSION: Morbidity and mortality among patients with A- T are associated with ATM genotype.

[Cerebral imaging in epileptic children: study of 140 cases]. / Magerie cérébrale de l'épilepsie de lenfant. Etude de 140 observations.

BACKGROUND: Epilepsy is a chronic disease, often with an onset during childhood and characterized by spontaneous and recurrent seizures. It concerns 0.5-1% of children under 16 years of age. Being much more sensitive than computed tomography, magnetic resonance imaging is the technique of choice to identify an underlying cause. CT scan is used in emergency situations. AIM: To describe cerebral lesions in epilepetic children and to identify predicative factors of abnormal neuroimaging. METHODS: Authors present a retrospective descriptive study of Neuroimaging data of 140 epileptic children evaluated for a period from 2000-2007 in the paediatric departement of Sfax. RESULTS: The mean age at onset of seizures was 3 years. The sex ratio was 1.12. Psychomotor retardation was noted in 75 patients. The seizures were generalized in 75% of case. Neurological examination was abnormal in 73 cases (52%). The main indications for conducting a brain imaging were psychomotor retardation (65 cases) and focal onset seizures (25 cases). Anoxo-ischemic lesions were the most frequent cerebral anomalies followed by brain malformations. Predictors of pathological MRI were an age at onset of seizure <3 years, psychomotor retardation and abnormal neurological examination. CONCLUSION: The morphological imaging is recommended for recent seizures of the child with the exception of idiopathic epilepsies. MRI is the best imaging modality in exploration of epilepsy in this context.

Recent advances in selective allergies to mammalian milk proteins not associated with Cow's Milk Proteins Allergy.

Cow's milk proteins allergy (CMA) is an atypical immune system response to cow's milk and dairy products. It's one of the most common food allergies in children affecting 8% of the total pediatric population pediatric population. This comprehensive review examines recent studies in CMA, especially regarding mammalian milk allergies such as goat's, sheep's, buffalo's, camel's, mare's and donkey's milk allergies in order to increase awareness of these selective allergies and to reduce allergy risks for those who have them. The consumption of other mammalian milk types is not recommended because of the significant homology between milk proteins from cow, sheep, goat and buffalo resulting in clinical cross-reactivity. However, camel's, mare's or donkey's milk may be tolerated by some allergic patients. Selective mammalian milk allergies are unusual and rare disorders characterized by severe symptoms including angio-oedema, urticaria, respiratory manifestations and anaphylaxis. Based on the reported allergic cases, cheese products including Ricotta, Romano, Pecorino and Mozzarella, are considered as the most common source of allergens especially in goat's, sheep's and buffalo's milk allergies, while the major allergens in donkey's and mare's milk seems to be whey proteins including lysozyme, α-lactalbumin and ß-lactogloblin due to the low casein/whey proteins ratio in equine's milk.

Variable Expression of Lung Disease Due to a Novel Homozygous ABCA3 Variant.

Background: Mutations in the ATP-binding cassette transporter A3 (ABCA3) gene are one of the most common surfactant disorders leading to interstitial lung diseases (ILD). The clinical spectrum and severity of lung disease caused by ABCA3 deficiency due to missense variants is variable. Case Presentations: A novel ABCA3 c.3135G>C (p.Gln1045His) mutation was identified at the homozygous state in 3 subjects from 2 unrelated families: one 19-month-old boy with severe ILD and his homozygous pauci-symptomatic mother, and one 10-year-old girl with moderate late-onset ILD. Corticosteroid pulses associated with hydroxychloroquine were beneficial for both children. Conclusion: We illustrate here the huge intra- and interfamilial phenotypic variability associated with the same homozygous missense ABCA3 mutation, and the benefit of identifying the disease for treatment, follow-up, and appropriate genetic counseling.

[Bardet - Biedl syndrome in the child. A study of 11 cases]. / Le syndrome de Bardet - Biedl chez l'enfant. Etude de 11 observations.

BACKGROUND: The syndrome of Bardet-Biedl is definite clinically by the association of obesity, polydactyly, pigmentary retinopathy, hypogonadism and backwardness. AIM: To study the epidemiologic, clinical, biological, genetic, therapeutic and evolutionary characteristic of our patients. METHODS: We carried out a retrospective study concerning 11 hospitalized children and/or follow-ups with the service of pediatry of the CHU Hédi Chaker of Sfax for syndrome of Bardet-Biedl during a period of 21 years (1987-2007). RESULTS: The obesity was constant among all patients, polydactyly was found in 9 cases, the fall of night vision in 7 cases. The hypogonadism was constant among all our boys. The bottom of eye was practised among 9 patients, it showed a pigmentary aspect of retinopathy among 8 patients. The electroretinogram was done in 10 patients, it showed a pigmentary retinopathy in all the cases. The radiological exploration of the urinary tract made it possible to identify morphological anomalies in 3 cases. The genetic study concerned the families of one of our patients and it allowed the identification of a new gene BBS8 at one of the families. Treatment was only symptomatic. After 6 years an average retreat, we noted an aggravation of obesity (9cas) and visual deficit (7cas). Only one patient evolved to the chronic renal insufficiency. CONCLUSION: The syndrome of Bardet-Biedl is a hereditary disease characterized by a genetic heterogeneity. The diversity of the systemic attacks defining this syndrome is a source of several handicaps: blindness, backwardness and obesity. The forecast is conditioned by the renal attack of or the interest of an early tracking and genetic council.

Childhood asthma : factors predicting severity and persistence of symptoms.

BACKGROUND: Asthma is the most common chronic disease in infants. In young children, asthma still raises many questions and many points are still being debated. AIM: The aim of this study is to identifies, in asthmatic children, factors predictors of severity and persistence of symptoms. METHODS: A retrospective study of asthmatic infants<3 years enrolled in the pediatric department of Sfax over a period of 5 years (2007-2011). We were interested to social and environmental factors, the allergic background, clinical severity of the disease, results of allergic skin tests, treatment and respiratory outcome. RESULTS: We collected 180 children with a sex ratio of 2.2. Family history of atopy and exposition to passive tobacco were noted in 45 % and 52% of cases respectively. The mean age of onset of wheezing was 6.6 months. Skin tests were positives in 32% of cases. At the time of diagnosis, asthma was classified intermittent (21%), mild to moderate (55.6%) and severe (22.2%).  Inhaled corticosteroids was initiated in 142 infants (78.8%). Skin tests performed in 84 patients, were positive in 32%. Factors associated with severe asthma were passive smoking, early age of onset, number of hospitalizations for exacerbation and existence of an aggravating factor. Factors predictors of persistence were an early age of onset, caesarean delivery, passive smoking and positive skin tests. CONCLUSION: Factors associated with persistence of asthma at the individual level remains uncertain. However, atopy and passive smoking are major indicators.

Congenital lung malformations : analysis of 27 cases.

INTRODUCTION: Congenital lung malformations (CLM) include a complex range of developmental abnormalities. Currently, most are diagnosed prenatally or during early childhood. OBJECTIVE: to investigate clinical and imaging findings of congenital lung malformations in children. METHODS: Retrospective study of CLM diagnosed between 2000 and 2017 at the pediatric and neonatology department of Hedi Chaker Hospital. Analysis of clinical spectrum, diagnosis tools, and radiological appearances. RESULTS: Twenty seven cases of CLM have been investigated: 8 congenital lobar emphysema, 8 congenital cystic adenomatoid malformation, 8 pulmonary sequestrations, 2 bronchogenic cysts, and 1 hybrid lesion. Five (18,5%) patients were diagnosed antenatally and 22 (81,4%) postnatally. Symptoms occurred at a mean age of 9 months: Respiratory distress (11 cases), wheezing (4 cases), and pneumonia (7 cases). Antenatal ultrasound features include echogenic masses within the chest (2cases), the presence of cysts (2cases), unilateral pleural effusion (1 case) and hydramnios (2cases). A computed tomography scan was performed in all patients with a radio-histological concordance of 96%.

[Positivity of antineutrophil cytoplasmic antibodies in children: prevalence and etiologies]. / Positivité des anticorps anti-cytoplasme des polynucléaires neutrophiles chez l'enfant : prévalence et étiologies.

In adults, anti-neutrophil cytoplasmic antibodies (ANCA) are considered as serological markers of several diseases, especially vasculitis and glomerulonephritis. Since ANCA are rarely positive in children, few data about the clinical relevance of these auto-antibodies in pediatric population have been reported. Therefore, our study aims to describe the spectrum of disorders associated with positive ANCA in Tunisian children. This study had been carried out over a period of 12 years and a half. All patients under the age of 15 for whom ANCA screening was performed in our laboratory were included. Clinical data were collected retrospectively. Indirect immunofluorescence (IFI) technique for ANCA detection was performed using PNN smears fixed with ethanol, formalin and, if necessary, methanol. Positive results were tested using immunodot to characterize the antigenic targets (myeloperoxydase (MPO) and proteinase 3 (PR3)). Our results showed that 410/5,990 (6.8%) laboratory requests for ANCA screening were for children. Forty (9.7%) requests were positive (24 children). Clinical data were available for 19 patients only. Sex-ratio (F/M) was 1.25. The mean age was 9 years and a half (3-15 years). The most frequent IIF patterns were x-ANCA (n=12) and p-ANCA (n=7). In our patients, the most frequent conditions associated to ANCA were treatment with benzylthiouracil for hypothyroidism (n=6), inflammatory bowel disease (n=4) and hemolytic anemia (n=4). In conclusion, the positivity of ANCA in children seems to be a rare event. Associated conditions include clinical disorders specific to the pediatric population. Treatment with benzylthiouracil is an etiology to be taken into consideration.

Clinical and Genetic Characterization of Tunisian Children with Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets.

BACKGROUND: Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder characterized by the early onset of rickets and is caused by mutations in the vitamin D receptor (VDR) gene. Some HVDRR patients also have alopecia. PATIENTS AND METHODS: We retrospectively studied the clinical features, laboratory findings, genetic defects, as well as responses to treatment in a series of children with HVDRR. RESULTS: Eight patients from 7 families met the inclusion criteria. Alopecia was noted in 7 patients. Two different homozygous mutations in the VDR gene were identified in 6 patients: the p.K45E mutation located in the DNA-binding domain (5 patients with alopecia) and a novel p.T415R mutation located in the ligand-binding domain. A p.E143del CYP24A1 mutation, in the gene encoding the 25-hydroxyvitamin D3-24-hydroxylase, was identified in 2 brothers carrying the VDR gene mutation p.K45E. Six patients were treated with intermittent intravenous calcium treatment via the peripheral route with a clear improvement in 5 cases. CONCLUSION: To the best of our knowledge, this is the first major series reporting on HVDRR in Tunisia. The same mutation (p.K45E) was found in 5 apparently unrelated affected individuals. We have also extended the mutation spectrum by studying 1 novel VDR mutation.

Lung manifestations in MPO-ANCA associated vasculitides in children.

OBJECTIVE: To describe lung manifestations in MPO-ANCA associated vasculitides in children. METHODS: We retrospectively reviewed the medical records of patients with MPO-ANCA associated vasculitis, who were followed in two pediatric nephrology departments from January 2000 to December 2010. RESULTS: Twelve patients were identified with MPO-ANCA over the study period. Their median age (IQR) at diagnosis was 10.5 (6.3-12.0) years, and their median duration of follow-up was 4.8 (1.2-7.5) years. Only five of them had pulmonary involvement with diffuse alveolar hemorrhage. Lung involvement was inaugural for four of five children. One child with severe chronic respiratory disease and renal failure died after 6 years of disease progression. Pulmonary function tests were available for 10 children. They were within normal ranges in four of five patients without clinical lung manifestations, and no significant impairment was observed in children with pulmonary complications. CONCLUSIONS: Diffuse alveolar hemorrhage complicates 40% of cases of MPO-ANCA associated vasculitides in children with renal involvement. After an acute potentially severe phase, a complete recovery without significant functional impairment was observed in four of five affected children.