Comorbidity in the Tunisian population.

Genetic diseases in the Tunisian population represent a real problem of public health as their spectrum encompasses more than 400 disorders. Their frequency and distribution in the country have been influenced by demographic, economic and social features especially consanguinity. In this article, we report on genetic disease association referred to as comorbidity and discuss factors influencing their expressivity. Seventy-five disease associations have been reported among Tunisian families. This comorbidity could be individual or familial. In 39 comorbid associations, consanguinity was noted. Twenty-one founder and 11 private mutations are the cause of 34 primary diseases and 13 of associated diseases. As the information dealing with this phenomenon is fragmented, we proposed to centralize it in this report in order to draw both clinicians' and researcher's attention on the occurrence of such disease associations in inbred populations as it makes genetic counseling and prenatal diagnosis challenging even when mutations are known.

Molecular characterization of piebaldism in a Tunisian family.

OBJECTIVE: The present study is aimed at performing the molecular characterization of a Tunisian family with piebaldism. METHODS: As the proband and her mother showed a severe phenotype, we first chose to screen exons 10, 11, 12, 13, 16, 17 and 18 of the KIT proto-oncogene by direct sequencing. RESULTS: Direct sequencing analysis showed a C to T substitution at 1939 in exon 13 (c.1939C>T) in heterozygous state in the patient and her mother. The mutation was not found in their unaffected family members or normal controls. CONCLUSION: Our results provide additional support that mutations in the tyrosine kinase domain of the KIT gene are responsible for the severe form of piebaldism.

Homogénéité mutationnelle de la glycogénose de type Ia en Tunisie.

The glycogen storage disease type Ia (GSD Ia) is a rare inherited disorder, with autosomal recessive determinism. It is characterized by hepatomegaly, short stature and hypoglycemia with lactic acidemia. The confirmation of diagnosis is based on the enzymatic assay performed on liver biopsy. For Tunisians patients, this biochemical test is performed abroad. The aim of our study is the molecular characterization of GSD Ia in Tunisian patients and the development of a molecular diagnosis tool. Our study included 27 patients from 23 unrelated families, mutation analysis revealed that the R83C mutation is the most frequent (65%, 30/46 mutant alleles), followed by the R170Q mutation (30%, 14/46 mutant alleles). The homogeneity of mutation spectrum of GSD Ia in Tunisia allows the development of a cost effective and reliable tool for the confirmation of clinical diagnosis among suspected GSD Ia patients.

[A case of hypernatremic dehydration due to breast-feeding]. / Déshydratation hypernatrémique au cours d'un allaitement maternel.

The authors report an 11-day-old exclusively breast-fed female, with a birth weight of 3 300 g, who had suffered from dehydration stage I, with acute renal failure and metabolic acidosis, with 170 mmol/L of serum sodium. Renal ultrasounds were normal but the rate of sodium in mother's milk was three times higher than controls (87 versus 21 mmol/L). Intravenous rehydration allowed the correction of hydroelectrolytic disorders.

Mutation spectrum of glycogen storage disease type Ia in Tunisia: implication for molecular diagnosis.

Glycogen storage disease type Ia (GSD Ia; OMIM 232200) is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the microsomal glucose-6-phosphatase (G6Pase). It is characterized by short stature, hepatomegaly, hypoglycaemia, hyperuricaemia, and lactic acidaemia. Various mutations have been reported in the G6Pase gene (G6PC). In order to determine the mutation spectrum in Tunisia, we performed mutation analysis in 22 Tunisian type I glycogen storage disease (GSD I) patients belonging to 18 unrelated families. All patients were clinically classified as GSD Ia. The R83C mutation was found to be the major cause of GSD Ia, accounting for 24 of 36 mutant alleles (66.6%), The R170Q mutation was the second most frequent mutation; it accounts for 10 of 36 mutant alleles (27.7%). The R83C and R170Q mutations could be rapidly detected by PCR/RFLP. Since the majority of Tunisian patients carried R83C and/or R170Q mutations, we propose direct screening of these mutations as a rapid, valuable and noninvasive tool for diagnosis of GSD Ia in Tunisian as well as in Northern African populations.

[Biochemical and molecular diagnosis of Gaucher disease in Tunisia]. / Diagnostic biochimique et moléculaire de la maladie de Gaucher en Tunisie.

Our study was carried out at a family from the Sahel (Tunisia). The father (index case) and his two children (son and daughter). The father beta-glucocerebrosidase (GCB) activity showing a deficit. These biochemical analyses are supplemented by molecular studies: enzymatic digestion and the direct sequencing. Two mutations were analysed, the p.Asn 370 Ser and the p.Leu 444 Pro. The DNA sequencing confirmed the presence of the homozygous genotype of this p.Asn 370 Ser in the father DNA and the heterozygous one in the two children DNA. It has no detection of the 55 pb deletion in exon 9 among all the specimens of DNA treated. The mutation p.Asn 370 Ser is associated with Gaucher disease type 1 correlated of a total absence of neurological involvements.

Duodenal Atresia Associated with Apple Peel Atresia and Situs Inversus Abdominus: A Case Report.

Duodenal atresia is rarely associated with situs inversus abdominus. We report a case of duodenal atresia associated with small bowel atresia of apple peel type and situs inversus abdominus.

[Evaluation of the measurement of capillary glucose concentration versus plasma glucose in the newborn]. / Fiabilité de la mesure de la glycémie capillaire par rapport à la glycémie plasmatique chez le nouveau-né.

BACKGROUND: The reliability of blood glucose monitoring in neonatology is not always confirmed. The aim of this study was to evaluate the reliability of blood glucose measurements made with three different devices in newborns. PATIENTS AND METHODS: The study was prospective, conducted in a medical and neonatal intensive care department over a period of 4 months. Capillary glucose level was measured with three different glucometers and compared with venous glucose level determined using the hexokinase method. An ANOVA and Scheffe test were used for the correlation analysis. RESULTS: Three hundred and nine infants were included, with a mean age of 55h and a mean term of 39 weeks of gestation. Mean blood glucose in the laboratory was 0.62±0.15g/L, 0.71±0.17g/L for Accu-Chek(®) Active, 0.80±0.17g/L for Accu-Chek(®) Performa, and 0.83±0.12g/L for Bionime. An ANOVA showed statistically significant differences between the measurements made by glucometers compared to the reference blood glucose levels, and the Scheffé method showed that glucometers overestimated the real plasma glucose levels. CONCLUSION: None of the devices used in this study was satisfactory. However, an estimation of blood glucose taking into consideration this numerical overestimation would allow early detection of hypoglycemia.

[Hypernatremic dehydration in children: retrospective study of 105 cases]. / La déshydratation hypernatrémique chez l'enfant : étude rétrospective de 105 cas.

UNLABELLED: The hypernatremic dehydration defined by a serum sodium concentration> or = to 150 mmol/l, is a particular form of acute dehydration and constitutes a medical emergency requiring a prompt and adequate diagnosis and management. PURPOSE: To precise the epidemiological profile, course, causes and therapeutic particularities of hypernatremic dehydration in children. POPULATION AND METHODS: Retrospective review of 105 children admitted in the general Paediatrics department of the Fattouma Bourguiba university hospital in Monastir (Tunisia), for hypernatremic dehydration between January 1st 1990 and December 31 2002. RESULTS: Hypernatremic dehydration represented 11.51% of all kinds of dehydration. The mean age was 6.5 months with a small male predominance. The socio-economic level of the parents was good in 62.8% of cases. Half of the children were in shock. Severe dehydration was present in 87.6% of cases and neurological signs were observed in 77.14% of cases. The initial mean serum sodium concentration was 159 mmol/L. Acidosis and acute renal failure were associated respectively in 97.2% and 76.2% of cases. Prominent cause of hypernatremic dehydration was diarrhoea (94.3%). Intravenous rehydration with 5% glucose solution at the average of 147 ml/kg/day and containing a mean sodium level of 42 mmol/L was performed in 74% of cases. In most cases (84.1%) serum sodium was normalized within the first 72 hours. Complications were noted in 5.7% of cases and mortality rate was 11.4%. CONCLUSION: Hypernatremic dehydration was common in infant and the prominent cause is still dominated by diarrhoea in our country. The management of hypernatremic dehydration is based on oral or intravenous rehydration and plasma expanding fluids when shock is present or imminent. The serum sodium concentration should be gradually corrected and should not exceed 0.5 mmol/L/h. Prevention is based on the pursuit of breastfeeding and the use of oral rehydration solution in infantile diarrhoeas.

[Neonatal hyperthyroidism and maternal Graves disease]. / Hyperthyroïdie néonatale et maladie de Basedow maternelle.

The onset of Graves disease during pregnancy exposes the neonate to the risk of hyperthyroidism. The newborn must be monitored and treatment modalities known to ensure early treatment of the newborn. We report on the case of an infant born at term of a mother with Graves disease discovered during pregnancy. He was asymptomatic during the first days of life, before declaring the disease. Neonatal hyperthyroidism was confirmed by hormonal assays. Hyperthyroidism was treated with antithyroid drugs and propranolol with a satisfactory clinical and biological course. Neonatal hyperthyroidism should be systematically sought in infants born to a mother with Graves disease. The absence of clinical signs during the first days of life does not exclude the diagnosis. The duration of monitoring should be decided according to the results of the first hormonal balance tests.

Sanjad-Sakati syndrome in a Tunisian child.

Sanjad-Sakati syndrome (SSS) (OMIM 241410) is a rare autosomal recessive disorder characterized by congenital hypoparathyroidism with growth and mental retardation associated with seizures and a characteristic physiognomy. SSS molecular pathology has been shown to be due to mutations in the TBCE gene on chromosome 1q42-q43. All affected patients of Arab origin are homozygous for a 12-bp (155-166del) deletion in exon 3 of this gene. We report on a Tunisian child with SSS who was homozygous for the 155-166del mutation. Our findings provide additional support of the common (155-166del) deletion founder effect in exon 3 of the TBCE gene in Arab patients. It is very likely that this mutation originated in the Middle East and was introduced in Tunisia by the Banu Hilal invaders.

[Initial antibiotic therapy in maternal-fetal infections which include ampicillin even in countries where listeriosis is an incidental disease]. / L'antibiothérapie initiale des infections materno-foetales doit inclure l'ampicilline même dans les pays où la listériose est exceptionnelle.

Neonatal listeriosis is an exceptional disease in Northern Africa. Hence, protocols for maternal-fetal infection treatment include only a third generation cephalosporin and an aminoside. This protocol does not take into account the possibility of Listeria monocytogenes infection. We report a fatal case of neonatal listeriosis in Tunisia. The use of first antibiotics in maternal-foetal infection must be reconsidered when lacking sufficient bacteriological data and include systematically ampicillin in presumptive antibiotic protocols.

[Antiphospholipid antibodies in 146 women with repeated pregnancy losses]. / Anticorps antiphospholipides et pertes foetales: étude rétrospective de 146 cas.

Antiphospholipid antibodies are associated with arterial and venous thrombosis and recurrent abortions. However, the prevalence of these antibodies in repeated miscarriages varies in different reports. To obtain quantitative data with restricted criteria and discuss the origin of the variability on the literature, we investigated the presence of antiphospholipid antibodies in 146 women who had 2 or more consecutive pregnancy losses and in 99 women whose pregnancies were successful. Antiphospholipid antibodies (lupus anti-coagulant or anticardiolipin antibodies of 20 or more IgG units) were found in 45% of women with pregnancy losses and in 9% of controls (p < 0.001). The type of loss was determined according to the trimester of pregnancy and the time of the fetal loss. 68% of patients with antiphospholipid antibodies had at least one fetal loss on the second or third trimester compared with 45% of patients without fetal loss (p < 0.01). Further studies should be conducted using more rigorous definition of clinical and laboratory characteristics in a way to allow better comparison between studies.

[Gaucher's disease in Tunisia (multicenter study)]. / La maladie de Gaucher en Tunisie (étude multicentrique).

UNLABELLED: Gaucher's disease is one of the rare lysosomial disease that could receive substitutive enzymatic treatment which may improve considerably the prognosis of certain forms. The purpose of this work is to study the epidemiology of the disease in Tunisia, to highlight the diagnostic and therapeutic difficulties and also to precise our subsequent needs for substitutive medication. PATIENTS AND METHODS: We have conducted a retrospective survey of the hospital wards that were susceptible to take care of patients having Gaucher's disease. These wards are the paediatric, neonatology, internal medicine, haematology, neurology and cardiology wards. RESULTS: In this study we have observed 27 cases of Gaucher's disease over a period of 18 years (1983-2001). The age at onset ranges from birth to 73 years of age, with an average age of 14.5 years. According to the age at onset and the clinical presentation, we classify our patients into: 20 cases of type 1 (74%), three cases of type 2 (12%), and three cases of type 3 (12%), and one case of unspecified type.Gaucher's disease type 1: The age at onset ranged from 10 months to 73 years with an average of 19 years. The main clinical signs that we have observed were splenomegaly, hepatomegaly, pallor, haemorrhagic appearance and also osteoporosis and bone pain observed in 40% of the cases. The diagnosis was based on histology showing the Gaucher's cells in various tissues while the diagnosis obtained by the dosage of glucocerebrosidase took place only in 50% of the cases. The treatment has always been symptomatic (analgesics, transfusion). A splenectomy was performed in 47% of the cases and none of the patients received a specific treatment. The follow-up period ranged from 1 month to 18 years with an average follow-up of 4 years. Among the 12 patients having a follow-up of at least 1 year, we have noticed an improvement after splenectomy in three cases, a stability in three cases and two worsening cases dealing mainly with bone problems. One patient aged 73 died from respiratory problem and three were lost to follow-up. Gaucher's disease type 2: We have observed three cases of Gaucher's disease type 2 diagnosed at 1 day, 45 days and 3 months of age. The visceral manifestations were serious and the neurological features included seizures, hypertony, ocular-nerve palsies and psychometric decline. The three patients died. Gaucher's disease type 3: Three patients were probably suffering from Gaucher's disease type 3 with visceral manifestations observed at the ages of 9 months, 1 year and 3 years, and also neurological signs observed at respective ages of 2.5 and 3 years. Two patients died and the remaining one was lost to follow-up. CONCLUSION: Gaucher's disease is not exceptional in Tunisia. Type 1 is by far the most common one. We have noticed some insufficiency in the diagnosis as the glucocerebrosidase enzymatic dosage was performed only in 50% of the cases as well as therapeutic insufficiency with no prescription of the specific treatment.

[Genotypic exploration of a hospital neonatal outbreak due to Klebsiella pneumoniae producing extended-spectrum-betalactamase]. / Exploration génotypique d'une bouffée épidémique nosocomiale néonatale à Klebsiella pneumoniae productrice de bêtalactamase à spectre étendu.

BACKGROUND: The aim of the study was to explore nosocomial neonatal outbreak of Klebsiella pneumoniae producing extended-spectrum-betalactamase by macrorestriction genotyping. PATIENTS AND METHODS: Over a 25 days period, a hospital neonatal outbreak due to Klebsiella pneumoniae producing extended-spectrum-betalactamase affected 14 newborn infants admitted to a university hospital in Sousse (Tunisia). We collected 21 strains of Klebsiella pneumoniae producing extended-spectrum-betalactamase. Susceptibility testing to 17 antibiotics was determined. Macrorestriction genotyping of strains was determined by pulsed-field-electrophoresis. Neonatal intensive care unit survey was undertaken. RESULTS: A macrorestriction genotyping subdivided 21 strains into 3 clonally groups. Only cefoxitin, colistin, imipenem, amikacin and quinolons were active on the whole of strains. All infected babies died. The hygiene insufficiency and contamination of transfusion products at the time of their dividing in neonatal intensive care unit were incriminated. Handholding due to work overcharge was the main cause of bacterial diffusion. CONCLUSION: Multiclonal outbreak of Klebsiella pneumoniae producing extended-spectrum-betalactamase appeared following hygiene insufficiency related to work overcharge.

[Neonatal hemorrhagic syndromes]. / Syndromes hémorragiques du nouveau-né.

PURPOSE: The purpose of our study was to clarify the frequency of these causes. PATIENTS AND METHODS: Retrospective study using reports of newborns in the neonatal unit in Sousse (Tunisia) from 1991 to 1996, hospitalized for hemorrhagic syndrome defined by bleeding, exteriorized or not, whatever its importance, severity, causes and the associated clinical and biological disorders. Isolated meningeal hemorrhages, limited cutaneo-mucous hemorrhages (conjunctival hemorrhages, bruises), and genital crises of the newborn, were excluded. RESULTS: One hundred and fifty-five hemorrhagic syndromes were observed from 7,128 newborn infants (2.17% of hospitalization). Sex ratio was 1.42. Prematurity rate was 35.7%. The Apgar score was < 7 at one minute in 40.7% of cases. Disorders associated with hemorrhagic syndromes were observed in 118 newborn infants (76.1%) with a predominance of neonatal infections (35.6%). The etiology of neonatal hemorrhages was specified in 93% of cases: newborn hemorrhagic disease (27.7%), disseminated intravascular coagulation (27.1%), isolated thrombocytopenia (9%), digestive lesions (13.5%), and obstetrical trauma (2.6%). CONCLUSION: The frequency of the newborns hemorrhagic syndromes underlines the need for its systematic prevention by vitamin K in the antenatal period to the mother and after birth to the newborn.

[Prolonged fever in children. Retrospective study of 67 cases]. / Les fièvres prolongées de l'enfant. Etude rétrospective de 67 cas.

BACKGROUND: The first problem to face in prolonged fever is its etiologic diagnosis. Its incidence varies between 0,5 to 3% of all paediatric hospital-stay. Precise diagnosis need an extensive questionnary, complete physical examination and an algorithm of complementary exams. PURPOSE: To precise the epidemiologic profile and causes of prolonged fever in a children. POPULATION AND METHODS: Retrospective review of 67 children between two and 15 years old admitted in the general paediatrics department of the Fattouma Bourguiba university hospital in Monastir (Tunisia), for prolonged fever between 1(st) January 1988 and 31 December 1998. RESULTS: The incidence of prolonged fever was 1,02%. The mean age was seven years with female predominance. The mean fever duration was 30 days. Fever was isolated in 23,9% of cases. Fever was associated to rheumatic or respiratory signs in respectively 26,9% and 20,9% of cases. Hospital-stay was of 11 days in 50% of cases. Prominent causes were dominated by infectious diseases (56,7%) with predominance of localized infections, followed by inflammatory diseases (20,9%) with predominance of rheumatic fever and neoplasms (3%). Fever remained of unknown origin was seen in 19,4% of cases. CONCLUSION: Prolonged fever is still dominated by infectious and inflammatory diseases and depend on local epidemiological particularities. In fact we noted in this study the relative high-frequency of visceral leishmaniasis, complicated pulmonary hydatic cyst and rheumatic fever. The diagnosis approach should be based on complementary exams of first and second stage because of their high number and cost. Prognosis of fever of unknown origin is often favorable.

[Mutational analysis of breast/ovarian cancer hereditary predisposition gene BRCA1 in Tunisian women]. / Analyse mutationnelle du gène BRCA1 de prédisposition héréditaire aux cancers sein/ovaire chez la femme tunisienne.

BRCA1 is a breast cancer susceptibility gene. Germline mutations in BRCA1 gene are found in 5 to 10% of breast cancer. The aim of this study is to screen the tunisian women with familial or sporadic breast cancer for BRCA1 gene mutations. The authors used the Protein Truncation Test (PTT) and DNA sequencing to detect BRCA1 gene mutations in 12 tunisian families with breast cancer and the Allele Specific Oligonucleotide-PCR (ASO-PCR) to detect the 185delAG and 1294del40 mutations in 150 tunisian women with sporadic breast cancer. A nonsens mutation was found, by PTT, in exon 11 of BRCA1 gene in one case of familial breast cancer. No mutation in the rest of exons was found by the DNA sequencing. The BRCA1 1294del40 mutation was found only in a patient with non familial breast cancer. The 185delAG mutation was absent in all cases of breast cancer. These data suggest that the germline mutation of BRCA1 is implicated in breast cancer in Tunisia and that the 185delAG mutation is absent in arab tunisian women.

[Respiratory disorders among late-preterm infants in a neonatal intensive care unit]. / Morbidité respiratoire des prématurés tardifs dans une unité de soins intensifs néonatale.

INTRODUCTION: The rate of infants born at 34-36 weeks of gestation has increased over the last 20 years. These babies are at higher risk of morbidity, particularly respiratory, than full-term infants are. The purpose of this study was to describe the respiratory morbidity of late-preterm infants and identify risk factors. PATIENTS AND METHODS: This was a descriptive, single-center study including 273 late-preterm infants born in a tertiary care hospital between July 2009 and December 2010. RESULTS: Of the mothers who delivered, 53.9% had morbidity. The cesarean-section delivery rate before labor was 20.9%; the main indication was fetal growth restriction (34%). Sixty-four percent of newborns had morbidity during their hospitalization and 23.1% suffered from respiratory distress. Mechanical ventilation was needed in 4.4% of the infants. Respiratory distress was mainly caused by early-onset sepsis or transient tachypnea. Ten infants presented with respiratory distress syndrome, of whom seven received a surfactant. Neonatal respiratory distress risk factors were gestational age, sex, and prelabor cesarean section (P<0.05). CONCLUSION: Late-preterm infants have an increased risk of respiratory disorders requiring ventilation. Elective cesarean should be limited if possible during this period.

Molecular characterization of maple syrup urine disease patients from Tunisia.

Maple syrup urine disease (MSUD) is a rare disorder of branched-chain amino acids (BCAA) metabolism caused by the defective function of branched-chain α-ketoacid dehydrogenase complex (BCKD). The disease causal mutations can occur either in BCKDHA, BCKDHB or DBT genes encoding respectively the E1α, E1ß and E2 subunits of the complex. In this study we report the molecular characterization of 3 Tunisian patients with the classic form of MSUD. Two novel putative mutations have been identified: the alteration c.716A>G (p.Glu239Gly) in BCKDHB and a small deletion (c.1333_1336delAATG; p.Asn445X) detected in DBT gene.