First genetic characterization of Xeroderma pigmentosum in Libya: High frequency of XP-C founder mutation.

BACKGROUND: Xeroderma pigmentosum is an autosomal recessive disease characterized by a high sensitivity to UV radiations. The disease is clinically and genetically heterogeneous, thus making accurate early clinical diagnosis difficult. Although the disease is considered rare worldwide, previous studies have shown that it is more frequent in Maghreb countries. So far, no genetic study has been published on Libyan patients, except three reports limited to clinical descriptions. METHODS: Our study, which represents the first genetic characterization of XP in Libya, was conducted on 14 unrelated families including 23 Libyan XP patients with a consanguinity rate of 93%. Blood samples were collected from 201 individuals including patients and their relatives. Patients were screened for founder mutations already described in Tunisia. RESULTS: The two founder Maghreb XP mutations, XPA p.Arg228* associated with the neurological form and XPC p.Val548Alafs*25 in patients with only cutaneous manifestations, were homozygously identified. The latter was predominant (19 of 23 patients). In addition, another XPC homozygous mutation (p.Arg220*) has been identified in only one patient. For the remaining patient, the absence of founder XPA, XPC, XPD, and XPG mutations suggests mutational heterogeneity of XP in Libya. CONCLUSION: Identification of common mutations with other Maghreb populations is in favor of a common ancestor in North-African populations.

Inflammatory landscape in Xeroderma pigmentosum patients with cutaneous melanoma.

Xeroderma pigmentosum (XP) is a DNA repair disease that predisposes to early skin cancers as cutaneous melanoma. Melanoma microenvironment contains inflammatory mediators, which would be interesting biomarkers for the prognosis or for the identification of novel therapeutic targets. We used a PCR array to evaluate the transcriptional pattern of 84 inflammatory genes in melanoma tumors obtained from XP patients (XP-Mel) and in sporadic melanoma (SP-Mel) compared to healthy skin. Commonly expressed inflammatory genes were further explored via GTEx and GEPIA databases. The differentially expressed inflammatory genes in XP were compared to their expression in skin exposed to UVs, and evaluated on the basis of the overall survival outcomes of patients with melanoma. Monocyte subsets of patients with SP-Mel, XP and healthy donors were also assessed. PCR array data revealed that 34 inflammatory genes were under-expressed in XP-Mel compared to SP-Mel. Differentially expressed genes that were common in XP-Mel and SP-Mel were correlated with the transcriptomic datasets from GEPIA and GTEx and highlighted the implication of KLK1 and IL8 in the tumorigenesis. We showed also that in XP-Mel tumors, there was an overexpression of KLK6 and KLK10 genes, which seems to be associated with a bad survival rate. As for the innate immunity, we observed a decrease of intermediate monocytes in patients with SP-Mel and in XP. We highlight an alteration in the immune response in XP patients. We identified candidate biomarkers involved in the tumorigenesis, and in the survival of patients with melanoma. Intermediate monocyte's in patients at risk could be a prognostic biomarker for melanoma outcome.

Case Report: Identification of Novel Variants in ERCC4 and DDB2 Genes in Two Tunisian Patients With Atypical Xeroderma Pigmentosum Phenotype.

Xeroderma Pigmentosum (XP) is a rare genetic disorder affecting the nucleotide excision repair system (NER). It is characterized by an extreme sensitivity to sunlight that induces cutaneous disorders such as severe sunburn, freckling and cancers. In Tunisia, six complementation groups have been already identified. However, the genetic etiology remains unknown for several patients. In this study, we investigated clinical characteristics and genetic defects in two families with atypical phenotypes originating from the central region in Tunisia. Clinical investigation revealed mild cutaneous features in two patients who develop multiple skin cancers at later ages, with no neurological disorders. Targeted gene sequencing revealed that they carried novel variants. A homozygous variation in the ERCC4 gene c.1762G>T, p.V588F, detected in patient XP21. As for patient XP134, he carried two homozygous mutations in the DDB2 gene c.613T>C, p.C205R and c.618C>A, p.S206R. Structural modeling of the protein predicted the identified ERCC4 variant to mildly affect protein stability without affecting its functional domains. As for the case of DDB2 double mutant, the second variation seems to cause a mild effect on the protein structure unlike the first variation which does not seem to have an effect on it. This study contributes to further characterize the mutation spectrum of XP in Tunisian families. Targeted gene sequencing accelerated the identification of rare unexpected genetic defects for diagnostic testing and genetic counseling.

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder due to a defect in the nucleotide excision repair (NER) DNA repair pathway, characterized by severe sunburn development of freckles, premature skin aging, and susceptibility to develop cancers at an average age of eight. XP is an example of accelerated photo-aging. It is a genetically and clinically heterogeneous disease. Eight complementation groups have been described worldwide. In Tunisia, five groups have been already identified. In this work, we investigated the genetic etiology in a family with an atypically mild XP phenotype. Two Tunisian siblings born from first-degree consanguineous parents underwent clinical examination in the dermatology department of the Charles Nicolle Hospital on the basis of acute sunburn reaction and mild neurological disorders. Blood samples were collected from two affected siblings after written informed consent. As all mutations reported in Tunisia have been excluded using Sanger sequencing, we carried out mutational analysis through a targeted panel of gene sequencing using the Agilent HaloPlex target enrichment system. Our clinical study shows, in both patients, the presence of achromic macula in sun exposed area with dermatological feature suggestive of Xeroderma pigmentosum disease. No developmental and neurological disorders were observed except mild intellectual disability. Genetic investigation shows that both patients were carriers of an homozygous T to C transition at the nucleotide position c.2333, causing the leucine to proline amino acid change at the position 778 (p.Leu778Pro) of the ERCC5 gene, and resulting in an XP-G phenotype. The same variation was previously reported at the heterozygous state in a patient cell line in Europe, for which no clinical data were available and was suggested to confer an XP/CS phenotype based on functional tests. This study contributes to further characterization of the mutation spectrum of XP in consanguineous Tunisian families and is potentially helpful for early diagnosis. It also indicates that the genotype-phenotype correlation is not always coherent for patients with mild clinical features. These data therefore suggest that targeted NGS is a highly informative diagnostic strategy, which can be used for XP molecular etiology determination.

Whole Exome Sequencing allows the identification of two novel groups of Xeroderma pigmentosum in Tunisia, XP-D and XP-E: Impact on molecular diagnosis.

BACKGROUND: Skin cancers (SC) are complex diseases that develop from complex combinations of genetic and environmental risk factors. One of the most severe and rare genetic diseases predisposing to SC is the Xeroderma pigmentosum (XP) syndrome. OBJECTIVES: First, to identify the genetic etiology of XP and to better classify affected patients. Second, to provide early molecular diagnosis for pre-symptomatic patient and finally to offer genetic counseling for related individuals. METHODS: Whole Exome Sequencing (WES) and Run Of Homozygosity (ROH) were performed for two patients belonging to two different multiplex consanguineous families. The identified mutations were confirmed by Sanger sequencing and researched in ten Tunisian families including a total of 25 affected individuals previously suspected as having XP group V (XP-V) form. All patients had mild dermatological manifestations, absence of neurological abnormalities and late onset of skin tumors. RESULTS: Screening for functional variations showed the presence of the ERCC2 p.Arg683Gln in XP14KA-2 patient and a novel mutation, DDB2 p. (Lys381Argfs*2), in XP51-MAH-1 patient. Sanger sequencing and familial segregation showed that the ERCC2 mutation is present at a homozygous state in 10 affected patients belonging to 3 families. The second mutation in DDB2, is present at a homozygous state in 5 affected cases belonging to the same family. These two mutations are absent in the remaining 10 affected patients. The ERCC2 c.2048G > A mutation is present in a medium ROH region (class B) suggesting that it mostly arises from ancient relatedness within individuals. However, the c.1138delG DDB2 mutation is present in a large ROH region (class C) suggesting that it arises from recent relatedness. CONCLUSION: To our knowledge, this is the first study that identifies XP-D and XP-E complementation groups in Tunisia. These two groups are very rare and under-diagnosed in the world and were not reported in North Africa.

Epidemiological trends and clinicopathological features of cutaneous melanoma in sporadic and xeroderma pigmentosum Tunisian patients.

BACKGROUND: Epidemiological features and trends of cutaneous melanoma (CM) in North-African populations remain unclear. Those populations are of particular interest as they belong to a mosaic of various other origins (sub-Saharan, European Ancestry, and North-African Berbers). The aim of this study is to draw epidemiological profile and clinicopathological features of CM in the Tunisian population. METHODS: Incidence analyses were based on data from regional cancer registries. Clinical data were collected from dermatological departments and xeroderma pigmentosum (XP) referral centers and provided CM clinicopathological characteristics and progression. Statistical analyses were achieved using R packages and SPSS 20.0. RESULTS: The incidence of CM in Tunisia is relatively low (0.5-0.7 per 100,000 inhabitants per year). Gender differences were observed regarding anatomical distribution (P = 0.004). Acral lentiginous melanoma (ALM) was the most frequent histological subtype (32.3%); however, nodular melanoma (NM) was the most aggressive and responsible for 54.8% of deaths. CM in XP patients develops at a median age that is 42 years earlier than sporadic cases, with preferential localization on the head and neck (P < 0.001). Finally, male patients exhibited survival disadvantages compared with females (adjusted hazard ratio (HR) = 2.22, 95% CI: 1.05-4.68, P = 0.037). CONCLUSIONS: Cutaneous melanoma features in Tunisia are closer to those of non-Caucasians, even though gender differences that are similar to those observed in Caucasians were uncovered. This study also emphasizes the aggressiveness of NM and its effect on melanoma patient deaths. Xeroderma pigmentosum stands as the major predisposing host factor.

A founder large deletion mutation in Xeroderma pigmentosum-Variant form in Tunisia: implication for molecular diagnosis and therapy.

Xeroderma pigmentosum Variant (XP-V) form is characterized by a late onset of skin symptoms. Our aim is the clinical and genetic investigations of XP-V Tunisian patients in order to develop a simple tool for early diagnosis. We investigated 16 suspected XP patients belonging to ten consanguineous families. Analysis of the POLH gene was performed by linkage analysis, long range PCR, and sequencing. Genetic analysis showed linkage to the POLH gene with a founder haplotype in all affected patients. Long range PCR of exon 9 to exon 11 showed a 3926 bp deletion compared to control individuals. Sequence analysis demonstrates that this deletion has occurred between two Alu-Sq2 repetitive sequences in the same orientation, respectively, in introns 9 and 10. We suggest that this mutation POLH NG_009252.1: g.36847_40771del3925 is caused by an equal crossover event that occurred between two homologous chromosomes at meiosis. These results allowed us to develop a simple test based on a simple PCR in order to screen suspected XP-V patients. In Tunisia, the prevalence of XP-V group seems to be underestimated and clinical diagnosis is usually later. Cascade screening of this founder mutation by PCR in regions with high frequency of XP provides a rapid and cost-effective tool for early diagnosis of XP-V in Tunisia and North Africa.

Further evidence of mutational heterogeneity of the XPC gene in Tunisian families: a spectrum of private and ethnic specific mutations.

Xeroderma Pigmentosum (XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage to XPC gene, genotyping and direct sequencing of XPC gene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in the XPC gene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of the XPC mRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease.

[Basal cell carcinoma of unusual site]. / Carcinome basocellulaire de siège inhabituel.

BACKGROUND: Labial mucosa is an atypical site of basal cell carcinoma. The involvement of the vermilion lip, devoid of hair follicles and sweat glands, contrasts with the concept of its origin from pilar structures. We report a case of basal cell carcinoma developed on the vermilion upper lip. CASE REPORT: A 49-year-old woman, presented with an asymptomatic, 1-cm-diameter, erythematous, telangiectatic and crusted nodule on the upper lip evolving for 9 months and having once interested the vermilion border. There were no cervical lymph nodes. Diagnosis of infiltrative basal cell carcinoma was made by histological study, which showed a tumoral proliferation of epithelial basal cells infiltrating the dermis with perineural and muscular infiltration. DISCUSSION: Our report illustrates a rare but not exceptional site of basal cell carcinoma. The nodule, initially confined to the vermilion border, has then developed onto the mucosal and the cutaneous areas. Histopathological study revealed, as previously reported, infiltarative features. Basal cell carcinoma of the lip should be rapidly managed since its invasion to deeper structures occurs early.

Genetic homogeneity of mutational spectrum of group-A xeroderma pigmentosum in Tunisian patients.

BACKGROUND: Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder characterized by cutaneous and ocular alterations. Eight genes, Xeroderma Pigmentosum group A (XPA) to Xeroderma Pigmentosum group G (XPG) and Xeroderma Pigmentosum group V (XPV), are known to be responsible for the disease and products of these genes are involved in the repair of deoxyribonucleic acid (DNA) lesions generated by UV radiation. Several XP patients suffer from neurological defects, found in the XPA (the most common form), D and G groups. The aim of this study was to investigate the mutational spectrum of XPA in Tunisia, in order to propose a simple tool for molecular diagnosis. METHODS: This study was carried out on six unrelated families with nine Tunisian XPA patients. Clinical features were recorded. As a previous study showed the presence of the R228X mutation in Tunisia, patients were first screened for this mutation by polymerase chain reaction-restriction fragment length polymorphism and then confirmed by direct sequencing. RESULTS: The results showed that all patients carried the XPA R228X mutation. This mutation corresponds to a C to T transition, which creates a premature stop codon at position 228, thus causing a DNA repair defect. CONCLUSIONS: The XPA R228X mutation is common in Tunisian population. This mutation is associated with a relatively moderate phenotype of the XPA. As all explored patients presented the recurrent mutation XPA R228X, a potential founder effect was searched and confirmed by haplotype analysis. Taking into account similar genetic background, investigation of this mutation should allow a cost effective and rapid diagnosis of XPA in north-African populations.

[Adult discoid lupus erythematosus]. / Le lupus erythemateux chronique de l'adulte.

BACKGROUND: Discoid lupus erythematosus is a particular form of systemic lupus in which manifestations are confined to the skin. AIM: Our purpose was to evaluate the epidemiology trends, presenting clinical manifestations, therapeutic features and outcome of patients with discoid lupus erythematosus (DLE). METHODS: It's a retrospective study, done in the dermatology department of Habib Thameur Hospital over an 8 years period. We included only the cases of DLE confirmed by the histology and/or the direct immunofluorescence. RESULTS: We identified 26 patients mean aged 46.19 years. All of them were adults. The lesions were localized on the face for 25 patients, neck (7 patients), scalp (6) and hands (6). Eleven patients presented a generalized DLE. The mean period of follow-up was 3 years raging from 1 month to 20 years. After a 15 year evolution, 1 patient presented degeneration in squamous cell carcinoma of 2 lesions. CONCLUSION: Unfortunately, there is still in our country a long delay before the first consultation, which, added to an absence of adequate photoprotection, can obscure the prognosis of DLE.

[Epidemioclinical aspects of dermatomyositis in the region of Tunis]. / Aspects epidemiocliniques de la dermatomyosite dans la region de Tunis.

BACKGROUND: Dermatomyositis (DM) is a rare but serious disease. The aim was to evaluate the epidemiology, presenting clinical manifestations, therapeutic features and outcome of patients with DM. METHODS: From January 1986 to December 2003, we collected retrospectively cases of DM identified at the dermatology department of Habib Thameur hospital. We included only patients with definitive diagnosis of DM. RESULTS: We included 13 patients, mean aged 32.85 years: 9 adults and 4 children. We identified 9 cases of adult DM among them 2 cases of wiihich were of paraneoplastic DM and 4 cases of juvenile DM among them 1 case of amyopathic DM and 1 case of DM associated with connective tissue disease. The evolution of DM followed the course of the neoplasm for the 2 patients with paraneoplastic DM. All patients received corticotherapy initially. Patients were followed-up for an average of 3 years (2 months to 10 years). We found no serious repercussions on the growth of children with juvenile DM. CONCLUSION: DM is rare in Tunisia. In our study, its frequency is about 0.72 patients per year. Age of onset of DM is markedly smaller than the one reported in the relevant litterature. Our 2 cases of DM associated with cancer are considered like really paraneoplastic. Juvenile DM seems to have a relatively good prognosis.

[Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 49 Tunisian cases]. / Xeroderma pigmentosum: manifestations cutanées, oculaires et neurologiques à partir de 49 patients tunisiens.

This is a retrospective study about 49 cases of xeroderma pigmentosum (XP). The goal was to determine the clinical features of XP in Tunisia. Our study revealed the predominance of a moderate form. Malignant skin tumors showed early. Squamous cell carcinoma (SCC) remainsed the most frequent skin malignancy in all clinical forms. Neurological abnormalities were more frequent in the moderate form. Mental retardation and peripheral neuropathy were the most common signs.

[Necrobiosis lipoidica. Report of 4 cases and review of the literature]. / La necrobiose lipoidique. Etude de 4 cas et revue de la littérature.

Necrobiosis lipoidica belongs to the inflammatory granulomatous skin disorders groups with palisade reaction. The association to diabetes mellitus is classical involving 80% of diabetics in its tibial localization. A retrospective study of all cases of necrobiosis lipoidica conducted in our dermatology department over a-15-year period, found 4 diabetic patients, 3 of whom were women known as diabetic patient with extremities involvement, and 1 man not known as diabetic patient at the time of the diagnosis. Necrobiosis lipoidica appears to be a rare disorder in diabetic people and this association seems to be over estimated.

[Epidemiologic profile of sexually transmitted diseases (STD) through a specialized consultation of STD]. / Profil epidemiologique des infections sexuellement transmissibles (IST) a travers une consultation d'IST specialisee.

INTRODUCTION: A confidential, free and specialised consultation of sexually transmitted diseases (STD) was initiated since 1993 in the department of Dermatology of hospital Charles Nicolle. We present the epidemiological and clinical features of this consultation. PATIENTS AND METHODS: It is a retrospective study including patients consulting during a period of 7 years (1993-1999). 546 patients were included. The mean age of our patients was 29 years and the sex-ratio 9. The diagnosis of urethritis was done for 242 patients. This diagnosis was clinic in the most cases. Urethral swabs was done for 71 patients. Neisseria gonorrhoeae was isolated in 56 cases and Chlamydia trachomatis in 15 cases. 41 patients were directed to our consultation for a positive syphilis serology. Condyloma were diagnosed in 23 cases and scabies in 12 cases. HIV serology was positive in 10 cases. In 3 cases, the diagnosis of HIV infection was done in this consultation. DISCUSSION: The epidemiologic profile showed a frequency of young men, bachelors and having multiple sexual partners. Clinically, urethritis was the principal STD observed.

[Mycosis fungoides. Study of a series of 11 Tunisian cases]. / Le mycosis fongoïde. Etude d'une série Tunisienne de 11 cas.

Mycosis fungoides is an epidermotropic cutaneous T lymphoma. It's a non Hodgkinian lymphoma. We report the results of a retrospective review of 11 mycosis fungoide seen during 22 years. The frequency of MF was about 39.3% among all cutaneous lymphoma. Six patients were male and 5 were female; the mean age was about 56 years. Mean delay between diagnostic and the first manifestation was about 25 months. All patients had the progressive form: 4 had infiltrate plaques and 7 were at the tumoral phase. Lymph nodes and medullar metastases were noted respectively in 1 and 2 cases. Treatment was mono or polychemotherapy associated in 6 cases with topical drug. Three patients died of their diseases According to our experience and after reviewed the literature, we notice that our patients are slightly younger without male predominance. The diagnostic was done tardily and this may explain the pejorative prognostic.

[Erosive buccal lichen planus: nine case reports]. / Le lichen érosif buccal: à propos de 9 cas.

Erosive oral lichen planus (EOLP) is uncommon. We present nine cases of EOLP in patients aged from 39 to 77 years. The aim of our retrospective study was to determine the clinical particularities and the treatment difficulties of this disease.