CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma.

Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.

Clinical and molecular investigation of Buschke-Fischer-Brauer in consanguineous Tunisian families.

BACKGROUND: Punctate palmoplantar keratoderma type I (PPPK-BFB), also called Buschke-Fischer-Brauer disease (MIM 148600) is a rare autosomal dominant disorder of keratinization, characterized by multiple hyperkeratotic lesions on the palms and soles. Recently, PPPK-BFB has been shown to be associated with mutations in the AAGAB gene in several families of European, African, Canadian and Asian origins. OBJECTIVE: To characterize the clinical and genetic features of PPPK-BFB in a broad group of Tunisian patients. METHODS: Epidemiological and clinical data were collected from 18 PPPK-BFB patients belonging to eight Tunisian families. We carried out mutational and structural analysis for families not previously investigated. RESULTS: Sequencing of the remaining families identified a total of three different mutations in AAGAB gene: one founder mutation (c.348_349delAG, p.R116Sfs*1) specific to the inbred Tunisian population, one recurrent mutation and (c.370C>T, p.R124*) one novel variant (c.430C>G, p.E144K). This novel mutation, involving a conserved amino acid, is predicted to be probably damaging to the p34 protein function. Assessment of the phenotypic presentation of this group of Tunisian patients was marked by variable severity and varying age at onset with a possible presence of anticipation noted in five out of eight families (62.5%). There is no apparent genotype-phenotype correlation. Despite the high degree of inbreeding, no homozygous individuals for AAGAB mutations were observed. Homozygous carriers in AAGAB gene are likely non-viable. CONCLUSION: This study contributes to further characterize PPPK-BFB in consanguineous families and to extend the mutational spectrum of AAGAB gene in the Tunisian population.

Severe phenotypes in two Tunisian families with novel XPA mutations: evidence for a correlation between mutation location and disease severity.

Xeroderma pigmentosum (XP) is a rare disorder characterized by a high skin sun-sensitivity predisposing to skin cancers at an early age. Among Tunisian XP patients with an intermediate skin phenotype, 92% presented neurological abnormalities related to XPA gene deficiency. Clinical variability of the XP-A phenotype is associated with a mutational heterogeneity. In the present study, two Tunisian families with severe dermatological and neurological XP phenotypes were investigated in order to determine clinical characteristics and genetic basis. Two Tunisian families with four XP affected children were examined in the Dermatology Department. Clinical features showed severe presentation of the disease. Coding regions of the XPA gene were analysed by direct sequencing. Results showed the presence of a novel mutation, p.E111X, in three patients belonging to the same family and presenting a very severe phenotype i.e. development of skin lesions and neurological signs before 1 year age. For the other patient, we identified a nonsense mutation, p.R207X, already identified in a Palestinian XP-A patient. Identification of novel causing mutations in Tunisian XP-A patients shows the genetic and mutational heterogeneity of the disease in Tunisia. Despite a relatively homogenous mutational spectrum, mutational heterogeneity for rare cases is observed because of the high rate of consanguinity.

[Pemphigoid gestationis: a study of 20 cases]. / Pemphigoïde gravidique: étude de 20 cas.

INTRODUCTION: Pemphigoid gestationis is a bullous autoimmune sub-epidermal dermatosis, occurring during pregnancy and/or postpartum. The objective of our study was to define the epidemio-clinical profile, the histopathological and immunopathological features, the treatment and the course of pemphigoid gestationis in Tunisian patients. PATIENTS AND METHODS: This was a retrospective study concerning the cases of pemphigoid gestationis recorded between 1989 and 2003 in the dermatology department in La Rabta Hospital in Tunis. The patients were included according to clinical, histopathological and immunopathological criteria. RESULTS: We retained 20 patients: 15 multiparae and 5 primiparae. The average age at onset was 29. The first clinical signs appeared in the 3rd trimester in 60 p. 100 of all cases. Clinically, the urticarial patches were noticed in 90 p. 100 of all cases and blisters in 65 p. 100 of the cases. The eruption was located mainly on the trunk and the limbs. The face was affected in 7 cases, the mucous membranes in 3 cases, the palms in 2 cases and the soles in 1 case. Cutaneous histologic examination revealed a sub-epidermal blister in 11 cases and a lymphohistiocyte infiltrate in all cases. Direct immunofluorescence showed a linear deposition of the third component of the complement along the basement membrane zone in all cases. Fetal prognosis was assessed in 13 cases: 1 fetal death, 1 still-born, 3 miscarriages, 1 anencephaly and 2 cases of transit bullous affection in the new-born. DISCUSSION: Our results are similar to those in the literature, but with some particular aspects: the late onset of the pemphigoid gestationis in the course of the 3rd trimester of pregnancy, the frequent involvement of the face and the mucous membranes and the absence of the two main fetal risks: prematurity and hypotrophy. Moreover, we underline the efficiency of topical class I corticosteroids in the treatment of pemphigoid gestationis.