SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype.

Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2Leu381Hisfs∗95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2-/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development.

Vitamin D status and VDR gene polymorphisms in patients with growth hormone deficiency: A case control Tunisian study.

Introduction: Growth Hormone Deficiency (GHD) is a rare disease marked by a complete or partial reduction in the production of growth hormone. Vitamin D deficiency is frequent and may be associated with several pathologies. However, the association between GHD and vitamin D deficiency has not been extensively studied. This study aimed to analyse VDR gene polymorphisms related to vitamin D status to ensure better care for patients with GHD. Material and methods: A case-control study was conducted at the Children's Hospital of Tunis in collaboration with the Farhat Hached's Hospital of Sousse, including patients with GHD and healthy subjects. Genetic analysis of the VDR gene polymorphisms was performed using PCR-RFLP technique. Haplotypes were examined with Haploview software, while statistical analyses were carried out using SPSS and R programming language. Results: Our study revealed significant differences in vitamin D (p = 0, 049) and calcium concentrations between patients and healthy subjects, which were lower in the GHD group (p = 0,018). A comparison of allelic and genotypic frequencies of the five polymorphisms indicated an association between the FokI polymorphism and GHD. Furthermore, significant difference was observed between the ApaI genotypes and PTH (p = 0,019) and ALP (p = 0,035). FokI genotypes were associated with phosphorus (p = 0,021). Additionally, One haplotype, CTAGT, exhibited a significant difference between the patients and healthy subjects (p = 0,002). Conclusion: Our study findings indicate that hypovitaminosis D is common among patients with GHD, even when undergoing treatment with rhGH. This underscores the critical importance of vitamin D supplementation during treatment.

Retrospective Analysis of Clinical Characteristics and Disease Outcomes in Children and Adolescents Hospitalized Due to COVID-19 Infection in Tunisia.

Due to low susceptibility of coronavirus disease of 2019 (COVID-19) in children, limited studies are available regarding COVID-19 in the pediatric population in Tunisia. The current study evaluated the incidence, clinical characteristics, and outcomes of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection among children hospitalized at Béchir Hamza Children's Hospital. A retrospective cohort analysis was conducted using the hospital database between March 2020 and February 2022 with children aged ≤15 years with SARS-CoV-2 infection (confirmed by RT-PCR). A total of 327 COVID-19 hospitalized patients with a mean age of 3.3 years were included; the majority were male. Neurological disease (20%) was the most common comorbidity, while fever (95.3%) followed by cough (43.7%) and dyspnea (39.6%) were the most frequent symptoms reported. Severe disease with oxygen requirement occurred in 30% of the patients; 13% were admitted in the Intensive Care Unit. The overall incidence rate of COVID-19 hospitalization (in Tunis governorates) was 77.02 per 100,000 while the inpatient case fatality rate was 5% in the study population. The most prevalent circulating variant during our study period was Delta (48.8%), followed by Omicron (26%). More than 45% of the study population were <6 months and one-fourth (n = 25, 26.5%) had at least one comorbidity. Thus, the study findings highlight the high disease burden of COVID-19 in infants.

Turner syndrome: results of the first Tunisian study group on Turner syndrome (TuSGOT).

OBJECTIVES: Early diagnosis in Turner syndrome is desirable to optimize growth and puberty and yet, it is often made late. Here, we aim to identify age at diagnosis, clinical features at presentation and potential strategies to improve the care of TS girls. METHODS: Retrospective study, including patients from 14 care centers across Tunisia including neonatal and pediatric care units, adult endocrinology and genetics departments. RESULTS: We identified 175 patients with TS, karyotype showing 45, xmonosomy in 83(47.4 %) with mosaicism in 37(20 %). Mean ± SD, median (range) age at diagnosis available in 173 patients was 13 ± 9.2,12 (birth-48) years. The diagnosis was antenatal in 4(2.3 %), from birth-2 years in 14 (8 %)with lymphoedema (8)and dysmorphic features (9),2-12 years in 53 (35.5 %) including 35 with short stature, 13-18 years in 43(28.8 %) with short stature(28) and delayed puberty(14) and 35(23.5 %) after 18 years, related to ovarian insufficiency (20) and short stature (11). The associated malformations were cardiac in 14 (12.8 %), renal in 22 (19.6 %). A total of 56 girls (32 %) had proven gonadal dysgenesis and 13 (7 %) had otological problems. Parental height was available in 71 girls (40 %) of whom 59 were below the lower end of parental target range (LTR) (83 %). CONCLUSIONS: This first Tunisian multicenter study, the first African of its kind, reveals that more than half of Turner syndrome cases are diagnosed after the age of 12 years. Subsequently, national strategies for an earlier TS diagnosis are needed such as measuring and plotting parental heights as well as introducing a systematic height screening at 5 years in Tunisia with a view to carrying out a re-audit in five years' time.

Hyperbaric Oxygen Therapy for Mumps-Associated Outer Retinitis with Frosted Branch Angiitis.

PURPOSE: To describe a case of outer retinitis with frosted branch angiitis associated with mumps infection treated with hyperbaric oxygen (HBO) therapy. METHODS: Observational case report. CASE REPORT: A four-year-old boy with bilateral blindness was diagnosed with necrotizing outer retinitis with frosted branch angiitis associated with serologically confirmed mumps virus infection. He was treated with HBO therapy. Visual acuity subsequently improved to 20/40 in the right eye and to 20/320 in the left eye. Sequential follow-up optical coherence tomography examinations showed progressive recovery of the outer retinal layers in the right eye. CONCLUSION: HBO therapy appears to be a feasible and safe treatment that might improve the anatomical and functional outcome in patients with mumps retinitis.

Prevalence and risk factors of overweight and obesity in elementary schoolchildren in the metropolitan region of Tunis, Tunisia.

BACKGROUND: Local data about prevalence of obesity in emerging countries are rather scarce. Risk factors for obesity, well known in most industrialized countries, are poorly understood in Tunisia. AIMS: To assess prevalence of overweight and obesity and to investigate associations with possible risk factors in a group of 6-12 year- old schoolchildren in Tunis, Tunisia. METHODS: A descriptive transversal study including a sample of 1335 schoolchildren (6-12 years; mean: 9.7 ± 1.5 years) was conducted in Tunis. Personal and parental data were collected by questionnaires completed by parents. Height and weight were measured and body mass index was calculated. Prevalence of overweight and obesity was defined based on international agreed cut-off points. RESULTS: Prevalence of overweight and obesity was 19.7% and 5.7%, respectively. Risk factors associated with overweight were: high degree- educated mother and father: 17.3% vs 11.7% (p=.01) (OR (95%CI): 1.58; 1.09-2.29) and 26% vs 17.4% (p=.002) (OR: 1.66; 1.21-2.29), respectively; mother, father high in occupational hierarchy: 7.2% vs 3.6% (p=0.009) (OR: 2.1; 1.2-3.7) and 14% vs 9% (p=.014) (OR: 1.6; 1.1-2.48), respectively. Overweight children had a significantly higher consumption of bread (p=.044), of snack intake (p=0.046) and of soft drink consumption (p=.035). CONCLUSIONS: Prevalence of overweight and obesity in this cohort are 19.7% and 5.7%, respectively. Substantial differences in food choices in families with the highest socio-economic status are among risk factors contributing to obesity development.

A rare cause of cyanosis: Congenital methemoglobinemia.

Congenital Methemoglobinemia is a rare condition that may mimic congenital heart diseases. There are two types of congenital Methemoglobinemia. The type I is usually benign. The enzyme deficiency is limited to red blood cells. Clinically, the patient presents cyanosis without neurological disorders. Whereas, in type II, cyanosis is associated with severe neurological impairment.

Abdominal tuberculosis in children.

BACKGROUND: Abdominal tuberculosis (TB) includes infection of the gastrointestinal tract, peritoneum, mesentery, abdominal lymph nodes, liver, spleen, and pancreas. The most common forms of abdominal TB in children are adhesive peritonitis and nodal disease. PATIENTS AND METHODS: We report our experience with abdominal TB treated in our hospital from 1995 to 2008. RESULTS: Thirteen patients (3 boys and 10 girls) of mean age 9.8 years were diagnosed as having abdominal TB. Eight patients presented with abdominal distension and abdominal pain. Fever was seen in 4 patients. One patient had surgical abdominal pain and 2 had abdominal mass. Two patients had coexisting pleural effusion and 1 of them had multifocal TB. Abdominal TB involved peritoneum in 9, abdominal lymph nodes in 7, gastrointestinal tract in 3, spleen in 2 patients, and liver in 1. Ascitic fluid analysis of 9 patients showed exudative fluid with predominately lymphocytes. Laparotomy was performed in 3 patients. The diagnosis of abdominal TB was confirmed histopathologically in 5 patients and microbiologically in 3. The remaining patients had been diagnosed by ascitic fluid diagnostic features, abdominal imaging, tuberculin skin test, history of exposure, and a positive response to antituberculous treatment. Twelve patients completed the antituberculous therapy without any complications. One patient with multifocal TB had neurological sequelae. CONCLUSIONS: In the areas with a high prevalence of tuberculosis and confirmatory investigations are inadequately available, treatment may be initiated, based on strong clinical diagnosis and supportive investigations. In such situations, it is the response to therapy that indirectly proves the diagnosis.

Characteristics and etiologies of short stature in children: Experience of an endocrine clinic in a Tunisian tertiary care hospital.

BACKGROUND: Short stature is a common reason for referral to pediatric endocrinology clinics. It may be a manifestation of a pathological condition requiring early treatment. The aim of this study was to describe the characteristics and etiologies of short stature among children referred to the pediatric endocrinology clinic of the main pediatric tertiary care center in Tunisia. METHODS: Retrospective and descriptive study in the endocrinology unit of children referred for short stature between January 2012 and December 2016. Data on the patients' medical history, physical findings, laboratory tests, bone age and chromosomal analysis were collected. RESULTS: 470 children (266 males and 204 females) were referred during that period. 214 (45.5%) had normal height, and 80.8% of them were referred by general practitioners. The other 256 children (54.5%) had a confirmed short stature (mean age :7.2 years, mean height: -2.77 SDS). Endocrinological causes were the most common(43% GHD, 4% hypothyroidism) followed by intrauterine growth retardation IUGR (24%), genetic syndromes (8.4%), chronic pediatric diseases (7.8%), skeletal dysplasia (6.2%), normal variant of short stature (5%), and psychosocial deprivation (1.2%). Among non-endocrine causes, Turner syndrome was the most common genetic syndrome (4.4%), achondroplasia the main skeletal dysplasia (4%) and celiac disease the main chronic disease (3.4%). CONCLUSIONS: ST is largely overestimated in our country. Therefore, it is important to insist on adequate measurement and analysis of growth parameters to avoid unnecessary investigations. GHD and IUGR were the most common causes. Celiac disease, though frequent in Tunisia, is not a common cause of short stature.

Extra-pulmonary tuberculosis in children: a study of 41 cases.

BACKGROUND: Extrapulmonary tuberculosis accounts for up to one third of all cases of tuberculosis and children show a higher predisposition to the development of extra-pulmonary tuberculosis. AIM: To review the clinical features of the extrapulmonary tuberculosis in children. METHODS: forty one children with extrapulmonary tuberculosis followed in the Children Hospital of Tunis between January 1995 and December 2007 were reviewed. RESULTS: Extrapulmonary tuberculosis constitutes 57.9% of all cases of tuberculosis. Male to female ratio was 0.7 and the mean age was 7.5 years. The most commonly involved sites were the peripheral lymphadenitis (14 cases) followed by abdominal (11 cases), central nervous system (7 cases), osteoarticular (5 cases) and multifocal (4 cases). A positive family history of active tuberculosis was detected in 22.5% of the cases. Diagnosis delay was 4.7 months. Sequelae observed during the follow up were: neurosensory in 5 cases, and vertebral deformation in 1 case. CONCLUSION: extrapulmonary tuberculosis represents an important fraction of tuberculosis in our study. The most common form is lymph nodes localization followed by abdominal and central system nervous forms. Neurosensory sequelae were frequent in central system nervous tuberculosis.

Congenital hypothyroidism presenting with reversible renal impairment: an under-recognised problem?

BACKGROUND: Hypothyroidism with impairment of renal function and raised creatinine phosphokinase (CPK) is described in adults and children with acquired hypothyroidism, but not in congenital hypothyroidism. CASE PRESENTATION: A male infant born at term weighing 3390 g was seen aged 2 months with prolonged jaundice. Examination showed somnolence, umbilical hernia, enlarged fontanelles and lower limb edema; length 55 cm (-1.5 SD), weight 5.4 kg (-0.13 SD). Biochemistry showed fT4 < 1 pmol/L, TSH = 1044.36 µUI/mL, creatinine 77 µmol/L(normal <35 µmol/L), estimated glomerular filtration rate (GFR) 26 ml/min/1.73 m2, CPK 3952.5 IU/L (normal<400 IU/L). Ultrasound showed no thyroid tissue in the neck. In view of the renal impairment, peritoneal dialysis was initially contemplated but postponed and the child received levothyroxine 10 µg/kg/day. Two months later thyroid function tests, CPK and renal function had all normalized with creatinine 19 µmol/L and GFR 116 ml/min/1.73m2. DISCUSSION: Reversible renal impairment is attributable to severe congenital hypothyroidism causing decreased myocardial contractility and cardiac output and to a direct effect on the kidneys. Thyroid function should be checked in infants with renal impairment of unknown cause. Cautious fluid management is indicated in hypothyroid infants. Hypothyroidism may also be associated with elevated serum CPK levels but resolves with thyroxin therapy.

Validation of the Arabic and Tunisian Arabic version of the KINDL questionnaires for children with diabetes type 1.

AIM: We aimed to validate the Arabic and Tunisian Arabic versions of diabetes- specific quality of life (QOL) instrument KINDL-R Diabetes Module for Tunisian children population with type 1 diabetes. PATIENTS AND METHODS: This a cross-sectional study to validate Arabic and Tunisian KINDL QOL instrument that we translate in literary and dialectal Arabic. Both forward and backward translations from the German version of KINDL QOL into Arabic version were performed. Our project received a GPED grant in August 2014. After the face validity of the Arabic version was established, it was then pilot-tested. Finally, the validity and reliability of the final version of the Arabic KINDL questionnaire were evaluated. RESULTS: The KINDL-R Diabetes Module (DM) questionnaire of QOL was given to 212 persons : 108 children (aged 3-17 years) with T1DM and 104 parents. The Cronbach's alpha coefficients of the overall items and the main domains was about 0.7. The mean total score of the KINDL-R DM was 69,56  ± 14,01 in children aged 7-13 years, 59.93± 15.17 in children aged 13-17 years and 56.6± 9.9 in parents (higher scores indicate better QOL). The parents reported lower diabetes-specific HRQOL than the children themselves (p < 0.01).Emotional score was correlated to environment (p = 0,03). Self-esteem was reported to environment (p = 0,02) and mother's instruction level's (p = 0,014). CONCLUSIONS: The KINDL-R Diabetes Module (DM) of QOL in literary and dialectal Arabic have sufficient acceptability, reliability and validity so as to be used for the purposes of a comparative in Tunisian and Arabic populations.

Implementation of effective transition from pediatric to adult diabetes care: epidemiological and clinical characteristics-a pioneering experience in North Africa.

AIMS: Type 1 diabetes is increasing in children leading more T1D young adults to adult healthcare settings. This change is experienced as a tear and results in a disengagement from specialist services. This study reports on an implementation of an effective and pioneering program of transition in North Africa. METHODS: A total of 65 teenagers with T1D were recruited for a structured program of transition. They attend transitional meetings involving both pediatric and adult team and were, when ready, welcomed in specialized consultations for adolescents with a special « passport ¼. Here we study their characteristics before and after structured transition and the benefit of this program. RESULTS: 9 transition meetings took place (September 2012-December 2017). Mean age was 16.5 years. Mean age at onset of T1D was 7.5 years with average pediatric follow-up of 9 years.72% of young adults felt satisfied. After the transition meeting, 74% of patients wished to join directly adult unit. They were followed there for 28.4 ± 16.2 months. The glycaemic control improved significantly with a decrease in HbA1C of 0.93 ± 1.69% the first year of follow-up and the number of young adults achieving a HbA1C < 7.5% increased by 8%. CONCLUSION: This program was beneficial for 75% of patients who demonstrated an improvement in their metabolic control the year following transition to adult care service. To our knowledge, this study is the first one in North Africa to report on the outcome of a structured transition program from pediatric to adult diabetes care.

A founder mutation underlies a severe form of phosphoglutamase 3 (PGM3) deficiency in Tunisian patients.

Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Mutations in PGM3 gene have been recently shown to underlie a new congenital disorder of glycosylation often associated to elevated IgE. Herein, we report twelve PGM3 deficient patients. They belong to three highly consanguineous families, originating from a rural district in the west central Tunisia. The patient's clinical phenotype is characterized by severe respiratory and cutaneous infections as well as developmental delay and severe mental retardation. Fourteen patients died in early infancy before diagnosis supporting the severity of the clinical phenotype. Laboratory findings revealed elevated IgE, CD4 lymphopenia and impaired T cell proliferation in most patients. Genetic analysis showed the presence, of a unique homozygous mutation (p.Glu340del) in PGM3 gene leading to reduced PGM3 abundance. Segregating analysis using fifteen polymorphic markers overlapping PGM3 gene showed that all patients inherited a common homozygous haplotype encompassing 10-Mb on chromosome 6. The founder mutational event was estimated to have occurred approximately 100 years ago. To date, (p.Glu340del) mutation represents the first founder mutation identified in PGM3 gene. These findings will facilitate the development of preventive approaches through genetic counselling and prenatal diagnosis in the affected families.

Central system nervous tuberculosis in infants.

The lack of specific symptoms and signs in patients with tuberculous meningitis makes early diagnosis difficult. In this report, we reviewed the clinical features and laboratory findings of 6 infants with central system nervous tuberculosis during a 10-year period. One of the patients had multifocal tuberculosis. The mean time to the diagnosis was 32 +/- 13.4 days. A contact source was identified in only 2 patients. All 6 patients had abnormal cerebrospinal fluid findings, less than 500 cells/microL with lymphocytic predominance. Computerized tomography (CT) and/or magnetic resonance imaging (MRI) revealed hydrocephalus with basal enhancement in 2 patients. One patient developed pontocerebellar and pituitary tuberculomas, which were responsible for compression and diabetes insipidus, 1 year after antituberculous treatment. These localizations are very rare. On the follow-up, 3 patients had hypoacousia and only 1 had severe sequelae, despite a diagnostic delay.