Psoriatic Arthritis Quality of Life questionnaire: Translation, cultural adaptation and validation into Arabic language.

BACKGROUND: Psoriatic arthritis (PsA) is a multifaceted inflammatory disease that has a strong negative impact on the quality of life (QoL) of patients. The Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire was the first disease-specific patient-derived instrument developed to measure the QoL in patients with PsA. Our objective was to translate the PsAQol into Arabic language and evaluate its reliability and validity in patients with PsA. METHODS: This was a cross-sectional study including patients with PsA. A clinical and biological assessment of the patients was performed at inclusion. The translation of the original PsAQoL into Arabic was performed by a professional bilingual and lay panel. Eight patients were interviewed to assess face and content validity. A separate sample of PsA patients (n = 30) were invited to participate in a test-retest postal study in order to investigate reproducibility and construct validity. One week separated the two administrations. The Arabic version of Health Assessment Questionnaire (HAQ) was used as a comparator instrument for convergent validity. RESULTS: Face and content validity were satisfactory. The Arabic version of the PsAQoL was found to be relevant, understandable and easy to complete in only a few minutes. One item was excluded (item 16). It had no correlation with either the other 19 items or the total score of PsAQol. The Arabic PsAQol had excellent internal consistency (Cronbach's a = 0.926), and test-retest reliability (r = 0.982). There was a positive correlation between the total score of the PsAQoL and the Arabic version of HAQ (Spearman's r = 0.838, p < 10-3 ). Exploratory factor analysis had extracted two factors explaining 55% of the total variance. CONCLUSION: Nineteen items were selected to compose the Arabic version of PsAQoL, which was found to be relevant and understandable and has excellent reliability and construct validity. The new measure will be a valuable new tool for use in routine care for patients' assessment.

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.

Chronic macrocheilia: a clinico-etiological series of 47 cases.

BACKGROUND: Macrocheilia is an inflammatory disfiguring condition responsible for the swelling of the lips. This multi-etiological entity represents a diagnostic and therapeutic challenge. Published data on macrocheilia is scarce, often limited to granulomatous cheilitis. METHODS: We conducted a retrospective study, including all patients presenting with chronic macrocheilia (CM) for nineteen years. CM was defined as a persistent enlargement of one or both lips for at least eight weeks. Both descriptive and analytical analyses were performed. RESULTS: Of the 47 patients identified, 20 (43%) had cutaneous leishmaniasis, 10 (21%) had Miescher's cheilitis, five (11%) had Melkersson-Rosenthal syndrome, five (11%) had sarcoidosis, one (2%) had lepromatous leprosy, one (2%) had systemic amyloidosis, and one (2%) had Crohn's disease. In four cases, the CM was unlabeled. Ulcerations were significantly associated with leishmaniasis (P < 0.05). Histological study showed a granulomatous infiltrate in 72% of cases. Medical treatment was adapted to the etiology of CM. Surgery was performed in two cases. Improvement of CM secondary to leishmaniasis was seen in all cases. In patients with idiopathic orofacial granulomatosis, partial improvement was noted in four cases and a total improvement in one case. Recurrences were noted in three cases after complete regression. CONCLUSIONS: Macrocheilia is a rare and disfiguring condition that requires an etiological investigation, considering that it can reveal a serious underlying systemic disease. We identified several factors that could help recognize the cause of CM, including age, history of intermittent swelling, the extent of lip enlargement, the existence of ulceration, and systemic symptoms.

Intradermal tranexamic acid microinjections: a novel treatment option for erythematotelangiectatic rosacea.

BACKGROUND: Treatment options for erythematotelangiectatic rosacea (ETR) are still scarce. Tranexamic acid (TXA) is an antifibrinolytic drug that was recently used for the treatment of ETR. AIMS: To evaluate the efficacy and safety of intradermal microinjections of TXA for ETR. PATIENTS/METHODS: This was a retrospective study enrolling patients, treated with TXA intradermal microinjections for ETR, from January 2019 to February 2020. Response to treatment was assessed based on subjective symptoms, clinical photographs, and the Investigator Global Assessment of Rosacea Severity Score (IGA-RSS). RESULTS: Six patients were included. The mean number of monthly intradermal TXA microinjections was 5.1 ± 1.3. The mean decrease of IGA-RSS was 2.4 ± 0.5. Local side effects, mainly transient erythema and swelling, were noticed in three cases. No systemic effects were noted. Clinical improvement, in respondent patients, lasted after 3 months of follow-up. CONCLUSION: Intradermal TXA microinjections are a safe and effective treatment option for ETR. The optimal number of monthly sessions has yet to be determined.

Acquired epidermodysplasia verruciformis in renal-transplant recipients.

Acquired epidermodysplasia verruciformis in renal-transplant recipients is associated with a high risk for developing squamous cell carcinoma. An accurate diagnosis and a regular monitoring in this high-risk population must be stressed.

Dermoscopic features of lupus miliaris disseminatus faciei: Distinct aspects depending on disease stage.

Dermoscopy is a useful tool that helps distinguish lupus miliaris disseminatus faciei (LPDF) from sarcoidosis and tuberculosis. Follicular keratotic plugs (FKP) represent the hallmark of LPDF. Dermoscopic aspect of LPDF changes through the course of the disease.

Effectiveness of dermoscopy in the demarcation of surgical margins in slow Mohs surgery.

There is a need for adjuvant imaging techniques that would allow reducing the number of slow Mohs stages. This study aimed to evaluate the use of dermoscopy in the demarcation of basal cell carcinoma (BCC) surgical margins for slow Mohs surgery. This was a retrospective study over 3 years (2016-2019), including patients with BCC excised using slow Mohs surgery. On the basis of the treatment received, the patients were divided into 2 groups: group 1 (28 BCC) and group 2 (26 BCC). In group 2, BCC margins were demarcated using dermoscopy. A total of 54 patients were enrolled in the study. The number of positive lateral margins was significantly lower in the group where BCC margins were demarcated using dermoscopy (19% vs 53%, P = .012). In this group, the number of Mohs stages needed to achieve complete clearance was significantly lower. However, the mean interval between the first Mohs excision and Mohs clearance was not significantly different between the 2 groups (9 ± 4 vs 12 ± 7 days). In conclusion, preoperative dermoscopy is useful for reducing the number of positive lateral margins and the number of slow Mohs stages in treating BCC especially pigmented tumors.

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.

Classification of cysts with follicular germinative differentiation.

BACKGROUND: Cysts are very common in the routine of dermatopathology but follicular germinative (trichoblastic) differentiation in cysts is seen rarely. The presence of follicular germinative differentiation in a cyst alerts to consider the possibility of a basal cell carcinoma (BCC) arising in a cyst. METHODS: Five cystic lesions with zones of follicular germinative differentiation were collected. Hematoxylin and eosin sections were reassessed for architecture, types of follicular differentiation and stromal characteristics; immunohistochemical studies with Ber-EP4 were analyzed. Articles about follicular germinative differentiation in cystic lesions were reviewed. RESULTS: Cystic lesions with follicular germinative differentiation have been described in the literature under various names including trichoblastic infundibular cyst, cystic trichoblastoma, cystic panfolliculoma (CPF), dermoid cyst with basaloid proliferations, folliculosebaceous cystic hamartoma and BCC occurring in infundibular cysts. The lesions presented by us could be classified as three cystic trichoblastomas, one CPF and one cystic hamartoma with follicular germinative differentiation. CONCLUSIONS: Histopathologically, cystic trichoblastomas can be separated from CPFs. Some lesions defy classification and may be regarded as cystic follicular hamartomas. The presence of follicular papillae and bulb-like structures, advanced follicular differentiation like that of inner and outer root sheath exclude the differential diagnosis of BCC arising in a cyst.

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.

Histiocytosis X revealed by diabetes insipidus and skin lesions.

Langerhans cell histiocytosis is part of a larger group of syndromes described as histiocytoses. The disease may involve single or multiple systems including skin and nervous system. Here we report an adult case where Langerhans cell histiocytosis presented with diabetes insipidus and cutaneous ulcers.

Cytokeratin 10-negative nested pattern enables sure distinction of clonal seborrheic keratosis from pagetoid Bowen's disease.

BACKGROUND: The histopathologic pattern of clonal seborrheic keratosis (SK) is quite similar to the nested pattern of pagetoid Bowen's disease [squamous cell carcinoma in situ (SCCIS)], and differentiation between the two can be challenging, especially when only small pieces are available for interpretation. METHODS: Eleven examples of clonal SK and 13 examples of pagetoid SCCIS were examined histopathologically (tabulating necrotic keratinocytes, suprabasal mitoses, infiltrate, parakeratosis housing plump nuclei, crowding of nuclei) and immunohistochemically (using Ki-67, bcl-2, cytokeratin 7 and cytokeratin 10). Sensitivity, specificity, p-values (Fisher's exact test, two-tailed) and positive/negative likelihood ratios (+LR/-LR) were calculated. RESULTS: Significant differences were seen with regard to crowding (p = 0.0009) and mitoses (p = 0.0006); however, only complete absence of necrotic keratinocytes or of crowding appeared to be diagnostically convincing for a diagnosis of clonal SK (-LR < 0.01). Significant differences were also seen with bcl-2 (p = 0.0005) and cytokeratin 10 antibodies (p < 0.00001). Both markers displayed a typical nested pattern in clonal SK, nests being bcl-2-positive and cytokeratin 10-negative. Cytokeratin 10-negative nests were the most convincing criterion for differentiation between clonal SK and pagetoid SCCIS (+LR > 10, -LR < 0.01). CONCLUSIONS: The most reliable marker to distinguish clonal SK from pagetoid SCCIS is cytokeratin 10 when it spares nests. Other criteria that assist in the differential diagnosis are bcl-2 expression, absence of crowding and of mitoses.

[Anhidrotic/hypohidrotic ectodermal dysplasia: ten cases]. / Dysplasie ectodermique hypo/anhidrotique: 10 observations.

BACKGROUND: Ectodermal dysplasias are rare hereditary diseases characterised by congenital absence of ectodermally derived structures and classified according to four symptoms: trichodysplasia, hypodontia, onychodysplasia and hypohidrosis. AIM: The objective of our study is to precise the epidemioclinical characteristics, the diagnostic tools, the evolution and the treatments of this rare disease through a 10-case series of hypohidrotic ectodermal dysplasia (HED). METHODS: The present report is a retrospective study of all cases of an/hypohidrotic ectodermal dysplasia collected from 1977 to 2006. We have specified age, sex, parental consanguinity, similar familial cases, clinical and histological features, dental, oto-rhino-laryngologic, ophthalmologic and respiratory examinations. RESULTS: Ten cases of HED were collected (average age: 14 years, sex ratio 9/1). The mean duration diagnostic period was of 14 years. Parental consanguinity was registered in 3 cases but only one patient had similar familial cases. All patients had facial dysmorphy, hypotrichosis and hypo/anodontia (respectively 8/10 and 2/10). All patients had clinically and histologically documented hypoplastic (6/10) or aplastic sweat glands (4/10). Extra-cutaneous manifestations were noted in 8 patients (recurrent rhinitis 6/10, recurrent pneumopathies 3/10, xerophtalmy 3/10). CONCLUSION: Our series deals with 10 cases of HED, consisting in Chris-Siemens Touraine syndrome. It highlights the delayed diagnosis of this disease (mean: 14 years) with a diagnosis made at an adult age in four patients. Our study confirm the X-linked heredity (9/10) with a possible autosomal transmission (one female-case). HED is rarely life-threatening, but early diagnosis allows a better quality of life to patients and genetic counselling to parents. Our series illustrates the rarity of HED which is also probably due to its underestimation by clinicians.