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INTRODUCTION: Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited disease caused by germline variants in the APC gene. It is characterized by the development of hundreds to thousands of adenomatous polyps in colon and rectum. Recently, biallelic germline variants in the base excision repair (BER) gene: MUTYH have been identified in patients with attenuated FAP and/or negative APC result. It can be responsible for an autosomal recessive inherited colorectal cancer syndrome (MAP syndrome: MUTYH-associated polyposis).OBJECTIVE: The aim of this study was to evaluate germline variants of MUTYH gene in Tunisian patients with attenuated FAP.METHODS: thirteen unrelated patients from Tunisia with attenuated FAP were screened for MUTYH germline variants. Direct sequencing was performed to identify point variants in this gene.RESULTS: A Biallelic MUTYH germline variant were found in all patients and showed an attenuated polyposis phenotype almost of them without extra-colic manifestations: The known pathogenic frameshift variant c.1227_1228dupGG (p. Glu410Glyfs) was found, in homozygous state, in 13 index patients.CONCLUSION: Patients with attenuated familial adenomatous polyposis (

Steroid 11β hydroxylase deficiency (11β-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 11β-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 11β hydroxylase deficiency is variable, and biochemical identification of elevated precursor metabolites is not usually available. In order to clarify the underlying mechanism causing 11β-OHD, we performed the molecular genetic analysis of the CYP11B1 gene in a female patient diagnosed as classical 11β-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 11β hydroxylase deficiency.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and muscles and caused by deficiency in the glycogen debranching enzyme, the amylo-1,6-glucosidase (AGL). In this study, we report the clinical, biochemical and genotyping features of five unrelated GSD III patients coming from the same region in Tunisia. The concentration of erythrocyte glycogen and AGL activity were measured by colorimetric and fluorimetric methods, respectively. Four CA/TG microsatellite markers flanking the AGL gene in chromosome 1 were amplified with fluoresceinated primers. The full coding exons and their relevant exon-intron boundaries of the AGL gene were directly sequenced for the patients and their parents. All patients showed a striking increase of erythrocytes glycogen content. No AGL activity was detected in peripheral leukocytes. Sequencing of the AGL gene identified a c.3216_3217delGA (p.Glu1072AspfsX36) mutation in the five patients which leads to a premature termination, abolishing the AGL activity. Haplotype analysis showed that the mutation was associated with a common homozygote haplotype. Our results suggested the existence of a founder effect responsible for GSD III in this region of Tunisia.

Resume Introduction La keratodermie palmoplantaire (KPP) ponctuee de Buschke-Fischer-Brauer (KPP-BFB) est une genodermatose rare a transmission autosomique dominante. Le gene responsable n’a pas encore ete identifie. Deux regions chromosomiques ont ete incriminees, en 15q22 et en 8q24. Nous rapportons les caracteristiques cliniques et genetiques de la KPP-BFB dans une famille tunisienne. Methodes Une enquete familiale a permis d’etudier 17 sujets atteints. Le diagnostic etait pose sur des criteres cliniques et histologiques. Un interrogatoire, un examen clinique, une biopsie cutanee, ainsi que des prelevements sanguins pour etude moleculaire ont ete realises chez chaque patient dans la mesure du possible. Resultats L’âge moyen des patients etait de 59 ans et le sex-ratio H/F de 3,2. L’âge moyen d’apparition de la maladie etait de 28 ans (10 a 65). L’aspect clinique de la KPP variait de quelques lesions papuleuses keratosiques des paumes jusqu’a des plaques diffuses palmaires et plantaires. Des macules hypochromiques, une onychodystrophie et une hyperhydrose etaient associees chez certains patients. L’examen anatomopathologique montrait dans tous les cas un epiderme acanthosique avec une hyperkeratose orthokeratosique compacte surmontant une depression epidermique ponctuee. La detersion mecanique et les keratolytiques amelioraient transitoirement les lesions. Les resultats du genotypage pour les chromosomes 8 et 15 ainsi que le LOD score ont confirme la liaison genetique au locus suspecte sur le chromosome 15 ; la taille du locus concerne etait reduite a 3,26 Megabases. Conclusion L’etude de cette famille a confirme les caracteres classiques de la KPP-BFB et releve en outre quelques manifestations cliniques associees, dont la signification devra etre precisee par des travaux ulterieurs. L’identification du gene mute par sequencage de la region impliquee pourrait permettre de comprendre la physiopathologie de cette affection et de proposer une therapie adequate.

Placental mesenchymal dysplasia (PMD) is a distinct placental disorder that may coexist with a normal fetus. In one-third of cases, the fetus exhibits Beckwith-Wiedemann Syndrome (BWS). In the present study, we report a case of PMD changes associated with an unusual genetic constitution. Pathological examination showed an enlarged placenta with a mixture of normal but also numerous clusters of grape-like fluid-filled vesicles confined to the stem villi without trophoblast proliferation. Some stem villi contained many large vessels filled by partially organized thrombi consistent with PMD. The fetus presented an enlarged liver and cytomegaly in the adrenal glands, hyperplastic islets of Langerhans in the pancreas, and some microcysts with cuboidal epithelium in the kidneys. These findings suggest the Beckwith-Wiedemann syndrome phenotype. DNA genetic markers showed three alleles for three independent markers and two alleles for the 12 others. Fluorescent in situ hybridization (FISH) demonstrated that villous trophoblast and fetal tissues are diploid. The haploid paternal complement found in the androgenetic cells was different from that found in biparental cells, suggesting a double fertilization event. Preferential distribution of the androgenetic cells into the placenta explains the predominance of molar villi with an apparently normal fetus. This represents a well-documented case of androgenic and biparental mixture of cell types in both fetal and placental tissues.

Glycogen storage disease type III (GSD III) is an autosomal recessive inborn error of metabolism caused by mutations in the glycogen debranching enzyme amylo-1,6-glucosidase gene, which is located on chromosome 1p21.2. GSD III is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. The spectrum of AGL gene mutations in GSD III patients depends on ethnic group. The most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands. Here, we present the molecular and biochemical analyses of 22 Tunisian GSD III patients. Molecular analysis revealed three novel mutations: nonsense (Tyr1148X) and two deletions (3033_3036del AATT and 3216_3217del GA) and five known mutations: three nonsense (R864X, W1327X and W255X), a missense (R524H) and an acceptor splice-site mutation (IVS32-12A>G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population.

Objectives Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder which is characterized by a high clinical variability with severe, intermediate, mild and adult forms. These forms are caused, in 95% of cases, by a homozygous deletion of exon 7 of SMN1 gene. Our purpose was the determination of a possible genotype–phenotype correlation between the copy number of SMN2, NAIP, p44, H4F5 and occludin genes localized in the same SMN1 region (5q13) and the severity of the disease in SMA Tunisian patients. Patients and methods Twenty six patients affected by SMA were enrolled in our study. MLPA and QMPSF were used to measure copy numbers of these genes. Results We found that 31.3% of type I patients carried one copy of SMN2 , while all patients of other forms had at least 2 copies. NAIP was absent in 87.5% of type I patients. Furthermore, all SMA type I patients had one copy of H4F5 . No correlation was found for p44 and occludin genes. Conclusion There is a close relationship between SMN2 , NAIP and H4F5 gene copy number and SMA disease severity, which is compatible with the previous reports.

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare disease, characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D(3) (calcitriol) levels. This syndrome involves rickets with bone deformities in childhood and osteomalacia, osteoporosis, articular and para-articular pain, and fatigue in adulthood. It is caused by mutations in a consensus sequence for proteolytic cleavage of the FGF23 protein. Normally, this protein actively regulates phosphate homeostasis. Here we report a Tunisian family in which one parent and three children show clinical and biological features of ADHR. Mutation analysis of the FGF23 gene finds a heterozygous substitution of the C at position 526 by a T (526 C --> T), leading to an amino acid replacement of the FGF23 protein (R176W) at position 176. This causative new mutation is located in the consensus sequence for the proteolytic cleavage domain. These results confirm the importance of this site in FGF23 function and its essential role in ADHR physiopathology.