Molecular basis of pyruvate kinase deficiency among Tunisians: description of new mutations affecting coding and noncoding regions in the PKLR gene.

INTRODUCTION: Pyruvate kinase (PK) deficiency is one of the most common hereditary nonspherocytic hemolytic anemias worldwide with clinical manifestations ranging from mild to severe hemolysis. However, investigation of this enzymopathy is lacking in Tunisia. We report here a pioneer investigation of PK deficiency among Tunisian cases referred to our laboratory for biological analysis of unknown cause of hemolytic anemia. METHODS: Two hundred and fifty-three patients with unknown cause of hemolytic anemia have been addressed to our laboratory in order to investigate for red blood cells genetic disorders. Red cell enzyme activities were measured by standard methods, and molecular analysis was performed by DNA sequencing. The interpretation of mutation effect and the molecular modeling were performed by using specific software. RESULTS: Six different PKLR mutations were found (c.966-1G>T; c.965+1G>A; c.721G>T; c.1163C>A; c.1456C>T; c.1537T>A), among which four are described for the first time. Genotype-phenotype correlations for the novel missense mutations were investigated by three-dimensional structure analysis. CONCLUSION: This study provides important data of PK deficiency among Tunisians. It might be followed by a large neonatal screening to determine the spectrum of PK mutations and identify potential deficient patients for an early medical follow-up.

[Central diabetes insipidus: diagnostic difficulties]. / Diabète insipide central: difficultés diagnostiques.

UNLABELLED: Central diabetes insipidus is rare in children. Characteristic features include polyuria and polydipsia due to arginine vasopressin deficiency. The differential diagnosis of polyuric states may be difficult. Etiologic diagnosis of central diabetes insipidus may be an equally difficult task. OBJECTIVE: To specify the difficulties encountered in the diagnosis of central diabetes insipidus and to point out features of the etiologic work-up and of long-term follow-up of children with idiopathic central diabetes insipidus. METHODS: A retrospective study of 12 children admitted with a polyuria/polydipsia syndrome to the pediatric - consultation and emergency unit of the children's hospital of Tunis between 1988 and 2005. Children with acquired nephrogenic central diabetes insipidus were excluded. Fourteen-hour fluid restriction test and/or desmopressin test were used without plasma vasopressin measurement. RESULTS: Eight patients were classified as having central diabetes insipidus, which was severe in seven children and partial in one girl. One patient was classified as having primary polydipsia. The diagnosis remains unclear in three patients. The etiological work-up in eight patients with central diabetes insipidus enabled the identification of Langerhan's-cell histiocytosis in two patients and neurosurgical trauma in one. The cause was considered idiopathic in five patients. The median follow-up of the five patients with idiopathic central diabetes insipidus was five years two months plus or minus six years seven months (range five months, 14.5 years). During this follow-up, neither brain magnetic resonance imaging scans findings nor anterior pituitary function have changed. CONCLUSION: Fluid restriction and desmopressin tests did not enable an accurate distinction between partial diabetes insipidus and primary polydipsia. Regular surveillance is warranted in patients with idiopathic central diabetes insipidus to identify potential etiologies.

[Clinical and etiological features of primary adrenal insufficiencies in children]. / Aspects cliniques et etiologiques de la maladie d'Addison chez l'enfant.

BACKGROUND: The chronic primary adrenal insufficiency or Addison's disease is uncommon in children and belongs generally to a complex syndrome. AIM: Study of the clinical and aetiological features of primary adrenal insufficiencies in children. METHODS: In a retrospective study, we reviewed clinical and diagnostic data of all cases of Addison's disease admitted within a period of 15 years (from january 1991 to December 2006), in a department of paediatrics. Cases due to congenital adrenal hyperplasia were excluded. RESULTS: 6 cases of Addison's disease were diagnosed. Five patients are the product of consanguineous marriage. The age at the diagnosis of adrenal insufficiency varried from 15 months to 9 years 8 months. The adrenal insufficiency was associated to Allgrove syndrome in three cases, to autoimmune polyendocrinopathy type 1 in one patient and to probable peroxisomal disease in another one. The etiological disease was not determined in one patient. A substitutive hormonal therapy was conducted in all patients. During a mean follow-up of 26 months, two adrenal crises were noted. CONCLUSION: Larger studies about Addison's disease are needed to confirm the preponderance of the Allgrove syndrome.

[Cardiotoxicity of n-methyl-glucamine antimoniate (Glucantime). A case report]. / Toxicité cardiaque de l'antimoniate de méglumine (Glucantime). A propos d'une observation.

The pentavalent antimonial meglumine (Glucantime) is the drug of choice in treatment of cutaneous leishmaniasis in Tunisia. It may create severe adverse effects. A ten year-old girl was treated by Glucantime for cutaneous leishmaniasis. On the eighth day of treatment, she developed palpitations and precordialgia. The ECG showed T wave inversion prolongation of corrected QT interval. Drug therapy was stopped. Within a few days, she recovered and her elctrocardiographic changes came back to normal. The cardio toxicity of Glucantime may be severe. Electrocardiographic changes are the primary signs. Long term ECG follow-up is necessary.

[Currarino syndrome a rare cause of recurrent purulent meningitis]. / Syndrome de Currarino cause rare de méningites purulentes récidivantes.

The authors report a case of partial Currarino syndrome in a three and a half year old child with a left hemisacrum agenesis and a presacral mature teratoma. The special aspect of the observation was the apparition of repetitive polymicrobial purulent meningitis (Escherichia coli, Streptococcus B, Haemophilus influenzae) treated several times with non-specific antibiotics without normalization of CSF, particularly the CSF glucose, which remained low, justifying the use of an antimycobacterial treatment, especially since there was no local or general cause explaining the relapse. During a relapse of meningitis after ten months of antituberculosis treatment, the teratoma was discovered by a spine MRI done to detect any cerebrospinal defect. The authors insist on the fact that the Currarino syndrome must be investigated in case of repetitive purulent meningitis after ruling out the usual causes of meningitis.

[Uveitis of children: a report of 18 cases]. / Les uvéites de l'enfant: étude de 18 observations.

UNLABELLED: Childhood uveitis is a rare but serious disease that may causes visual loss. Causes are various and an underlying disease is not always found. PURPOSE: To analyse clinical features and prognosis of uveitis in children. PATIENTS AND METHODS: A retrospective, descriptive study of cases observed in a general pediatric unit over a period of 15 years (1990-2005) at Tunis. RESULTS: We gathered 18 cases of uveitis (girls 55.6% ,boys 44.4%). Mean age at the diagnosis was 8+/-3 years. Diagnosis was made after a decreased of visual acuity in 55.6% of cases. Localization of uveitis was anterior (6 cases), intermediate (1 case), posterior (3 cases) and total (8 cases). An underlying disease was found in only 5 patients: Behçet's disease (3 patients), juvenile chronic arthritis (1 patient), possible dermatopolymyositis (1 patient). The evolution was favorable in 10 cases with local treatment, systemic corticotherapy and/or immunosuppressive agents. Complications occurred in 3 cases. CONCLUSION: Causes of uveitis in childhood remains most often undiagnosed Our study illustrates the pending risk of severe visual impairment and strict ophtalmology follow-up is mandatory.

Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia.

NADPH oxidase, a multi-subunit protein consisting of cytosolic components and the membrane-bound heterodimer, plays an instrumental role in host defence mechanisms of phagocytes. Genetic deficiency of the enzymatic complex results in an inherited disorder, chronic granulomatous disease (CGD), which is characterized by an impaired phagocyte microbicidal activity. X-Linked (XL) CGD results from a mutation in the CYBB gene encoding the gp91phox subunit, while autosomal recessive (AR) CGD is associated with mutations in one of the NCF1, NCF2 and CYBA genes that encode the p47phox, p67phox and p22phox subunits, respectively. In the study reported here, we investigated genetic defects underlying CGD in 15 Tunisian patients from 14 unrelated families. Haplotype analyses and homozygosity mapping with microsatellite markers around known CGD genes assigned the genetic defect to NCF1 in four patients, to NCF2 in four patients and to CYBA in two patients. However, one family with two CGD patients seemed not to link the genetic defect to any known AR-CGD genes. Mutation screening identified two novel mutations in NCF2 and CYBA in addition to the recurrent mutation, DeltaGT, in NCF1 and a splice site mutation previously reported in a North African patient. Our results revealed the genetic and mutational heterogeneity of the AR recessive form of CGD in Tunisia.

[Arabian variant of Kenny syndrome: a familial case in Tunisia]. / Variant arabe du syndrome de Kenny: à propos d'une famille maghrébine.

Kenny syndrome is rare. Clinical feature include severe dwarfism, growth retardation macrocephaly, episodic hypocalcemia, internal cortical thickening and medullary stenosis of tubular bones. Genetic and phenotypic polymorphisms are characteristic. We report the observation of a Tunisian girl with the arabic variant of Kenny syndrome. She had chronic hypoparathyroidism, classic dwarfism, short stature with hormone deficiency, mental retardation and low helper/suppressor ratio. Our patient had two sisters and one brother with the same dysmorphic face and a marked intra-uterine growth retardation. They died from severe infections. Hypoparathyroidism was established in one sister.

[Sydenham's chorea in children]. / Chorée de Sydenham chez l'enfant.

BACKGROUND: Sydenham's chorea was the most common form of acquired chorea in childhood. Its incidence has declined since the use of antibiotics. The aim of our study was to determine the hospital incidence of this disease and to illustrate the clinical characteristics and outcome of this disease in Tunisia. POPULATION: Retrospective study of 15 cases of Sydenham's chorea, seen between 1987 and 1997. RESULTS: Our patients (five boys and ten girls) represented 5.6 per 1000 hospitalized children. Their mean age was 10.5 years. Two patients had a history of rheumatic fever and five had a history of throat infection during the month before chorea. The onset of symptoms was acute in five cases and insidious in ten. Choreic movements were generalized but asymmetrical in 12 cases, and unilateral in three. Psychological disorders were noted in nine cases and hypotonia in six. Rheumatic carditis was found in three patients. No patient had an obvious increase in sedimentation rate, and antistreptolysin were increased in 50% of cases. All patients were given haloperidol and five steroids, 11 were given antibiotics at the attack of chorea and 13 received secondary prevention with benzathine penicillin. Initially, abnormal movements disappeared in all cases after a mean of three months. Three patients relapsed and two among them still show abnormal movements and psychological disorders after a follow-up of 3 and 3.5 years respectively. CONCLUSION: Sydenham's chorea, although less frequent than previously, is not exceptional in Tunisia. Malignant forms are not observed, but two of 15 patients developed a chronic form with sequelae. No correlation is found between outcome and secondary prevention of streptococcal infections.

Failure of immunosuppressive therapy and high-dose intravenous immunoglobulins in four transfusion-dependent, steroid-unresponsive Blackfan-Diamond anemia patients.

Blackfan-Diamond anemia (BDA) is a rare hypoproliferative anemia occurring in infancy or in early childhood. Patients who fail on usual doses of steroids did not achieve remission with other pharmacological agents. Claims that other molecules such as cyclosporin A (CSA) or antithymocyte globulin (ATG) are effective require substantiation. We treated four transfusion-dependent, steroid-unresponsive BDA patients with ATG and methylprednisolone (MP). Only a transient response was obtained in one case. None of these patients responded to high-dose intravenous immunoglobulins (HDIg) or CSA.