Absent meibomian glands and cone dystrophy in ADULT syndrome: identification by whole exome sequencing of pathogenic variants in two causal genes TP63 and CNGB3.

BACKGROUND: Ectrodactyly is a rare congenital limb malformation characterized by a deep median cleft of the hand and/or foot due to the absence of central rays. It could be isolated or depicts a part of diverse syndromic forms. Heterozygous pathogenic variants in the TP63 gene are responsible for at least four rare syndromic human disorders associated with ectrodactyly. Among them, ADULT (Acro-Dermato-Ungual-Lacrimal-Tooth) syndrome is characterized by ectodermal dysplasia, excessive freckling, nail dysplasia, and lacrimal duct obstruction, in addition to ectrodactyly and/or syndactyly. Ophthalmic findings are very common in TP63-related disorders, consisting mainly of lacrimal duct hypoplasia. Absent meibomian glands have also been well documented in EEC3 (Ectrodactyly Ectodermal dysplasia Cleft lip/palate) syndrome but not in ADULT syndrome. METHODS: We report a case of syndromic ectrodactyly consistent with ADULT syndrome, with an additional ophthalmic manifestation of agenesis of meibomian glands. The proband, as well as her elder sister, presented with congenital cone dystrophy.The molecular investigation was performed in the proband using Whole Exome Sequencing. Family segregation of the identified variants was confirmed by Sanger sequencing. RESULTS: Two clinically relevant variants were found in the proband: the novel de novo heterozygous missense c.931A > G (p.Ser311Gly) in the TP63 gene classified as pathogenic, and the homozygous nonsense pathogenic c.1810C > T (p.Arg604Ter) in the CNGB3 gene. The same homozygous CNGB3 variation was also found in the sister, explaining the cone dystrophy in both cases. CONCLUSIONS: Whole Exome Sequencing allowed dual molecular diagnoses: de novo TP63-related syndromic ectrodactyly and familial CNGB3-related congenital cone dystrophy.

Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis-Like Autosomal Recessive Congenital Ichthyosis.

Erythrokeratodermia variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3. Genetic heterogeneity of EKV has already been suggested. We investigated at the clinical and genetic level a consanguineous Tunisian family with 2 sisters presenting an autosomal recessive form of EKV to better characterize this disease. Mutational analysis initially screened the connexin genes and Whole-exome sequencing (WES) was performed to identify the molecular aetiology of the particular EKV phenotype in the proband. Migratory shaped erythematous areas are the initial presenting sign followed by relatively stable hyperkeratotic plaques are the two predominates characteristics in both patients. However, remarkable variability of morphological and dominating features of the disease were observed between patients. In particular, the younger sister (proband) exhibited ichthyosiform-like appearance suggesting Autosomal Recessive Congenital Ichthyosis (ARCI) condition. No causative mutations were detected in the GJB3 and GJB4 genes. WES results revealed a novel missense homozygous mutation in NIPAL4 gene (c.835C>G, p.Pro279Ala) in both patients. This variant is predicted to be likely pathogenic. In addition, in silico analysis of the mutated 3D domain structure predicted that this variant would result in NIPA4 protein destabilization and Mg2+ transport perturbation, pointing out the potential role of NIPAL4 gene in the development and maintenance of the barrier function of the epidermis. Taken togheter, these results expand the clinical phenotype associated with NIPAL4 mutation and reinforce our hypothesis of NIPAL4 as the main candidate gene for the EKV-like ARCI phenotype.

H syndrome: Clinical, histological and genetic investigation in Tunisian patients.

H syndrome is a rare autosomal recessive disorder with characteristic dermatological findings consisting of hyperpigmentation and hypertrichosis patches mainly located on the inner thighs and multisystemic involvement including hepatosplenomegaly, hearing loss, heart abnormalities and hypogonadism. The aim of this study was to conduct a clinical and genetic investigation in five unrelated Tunisian patients with suspected H syndrome. Hence, genetic analysis of the SLC29A3 gene was performed for four patients with a clinical diagnosis of H syndrome. We identified a novel frame-shift mutation in the SLC29A3 gene in a female patient with a severe clinical presentation. Furthermore, we report two mutations previously described, the p.R363Q mutation in a male patient and the p.P324L mutation in two patients of different age and sex. This paper extends the mutation spectrum of H syndrome by reporting a novel frame-shift mutation, the p.S15Pfs*86 in exon 2 of SLC29A3 gene and emphasizes the relevance of genetic testing for its considerable implications in early diagnosis and clinical management.

Should we continue to indicate meglumine antimoniate as first-line treatment for cutaneous leishmaniasis in Tunisia.

Meglumine antimoniate compounds have been the mainstay of treatment for cutaneous leishmaniasis (CL) for decades. We propose to evaluate the place of these drugs in this indication in Tunisia. We retrospectively reviewed medical records of 67 patients treated for (CL) using meglumine antimoniate at a dose of 20 mg/kg/day for 15 day from 1998 to 2010. Clinical and laboratory data, tolerance, and outcome were precised. Side effects were recorded in 17 among 67 patients (25%). The average age was 44.4 years (2-86 years). Antimony intolerance events occurred in 11 patients, stibio-intoxication events in nine cases, and the both type of antimony adverse effects were observed in three patients. Fever was the most frequent complication of antimony intolerance (five cases), followed by cough (three cases), rash (two cases), injection site erythema (two cases), musculoskeletal pain (one case), asthenia (one case), and vomiting (one case). Signs of stibio-intoxication were asymptomatic elevation of amylase level (four cases), hepatic cytolysis (three cases), hematologic toxicity (three cases), and acute toxic kidney failure (one case). Meglumine antimoniate was stopped in 13 cases. Systemic administration of pentavalent antimonials in the treatment of CL has been associated with severe adverse effects. CL observed in Tunisia is a self-healing dermatosis that never induces sequela; therefore, other therapies such as topical treatment or cryotherapy should be considered.

[Hyalinosis cutis et mucosae : 5 cases from Tabarka (Tunisia)]. / La hyalinose cutanéo-muqueuse : 5 cas originaires de Tabarka (Tunisie)

BACKGROUND: Hyalinosis cutis et mucosae (HCM), is a rare autosomal recessive genodermatosis. Cutaneous features are characteristic and allow to suspect diagnosis. AIM: To report a series of HCM. METHODS: A retrospective study of all cases of HCM, diagnosed in a dermatology department over a period of 25 years (1983-2007). RESULTS: Over the considered period, 5 new cases of HCM were diagnosed. Patients were aged between 14 and 41 years. They were 3 females and 2 males. All patients were native of Tabarka (northwestern Tunisia). The age of the onset of the disease varied from neonatal period to 5 years. Hoarseness was the first clinical manifestation in all cases. Skin lesions developed between the ages of 3 and 8 years. Vesiculobullous lesions were observed in 2 patients. Moniliform blepharosis was seen in all patients. Warty and hyperkeratotic papules were observed in 3 patients. Diffuse thickening of the skin was seen in 3 patients. Lesions were primarily distributed on the face. All patients presented diffuse scars. Linear palmoplantar keratoderma was seen in one patient. Asymptomatic endocranial calcifications were noted in 4 patients. A pituitary adenoma was noted in one patient. Histopathological examination of a skin lesion revealed a typical pattern of HCM. Two patients were treated with systemic retinoids without improvement. CONCLUSION: We reported five new cases of HCM. All patients were native from Tabarka. We report also one case of linear palmar keratoderma associated with HCM. This association was not reported in the literature. Finally, the association HCM-pituitary adenoma, seen in one patient, may be fortuitous.

[Pruritus in the elderly: an epidemic-clinical study (about 208 cases)]. / Prurit chez le sujet âgé: etude de 208 cas.

BACKGROUND: Pruritus is an unpleasant cutaneous feeling causing the desire to scratch. Few epidemiologic studies were interested in this symptom which relates to the old subject particularly. AIM: To study the epidemiological and clinical features as well as the treatment of pruritus in this age bracket. METHODS: A retrospective study over 10 years and 5 months at the dermatology department of Habib Thameur hospital concerned 208 patients, 65 years old and more presenting a pruritus without specific dermatological lesion. RESULTS: The frequency of pruritus in the old subject was 5.14 per 1000 new consultants. Pruritus had revealed an ignored affection in 36.36% of the cases: an iron deficiency in 10 cases, a type 2 diabetes in 6 cases, a hypereosinophilia over 1000 elements/mm3 in 4 cases, a chronic renal failure in 2 cases, a hepatic cytolysis in 2 cases, a cholestasis in one case, a polycythemia vera in one case and hepatitis B one a case. Skin lubricants and antihistamines associated to topical corticosteroids in 25 cases and UVB therapy in a case were prescribed. These treatments brought an attenuation of pruritus in 62% of the cases. CONCLUSION: Iron deficiency anemia was the principal cause of pruritus in our series, followed by the type 2 diabetes. Our results contrast with the data of the literature considering that the traditional prevalence of the hepatic cholestasis was not noted and that diabetes is not regarded as inductive factor of pruritus.

[Sweet's syndrome: a propos of 8 cases]. / Le syndrome de Sweet: a propos de 8 cas.

BACKGROUND: Sweet's syndrome is a dermatosis classically determined by painful erythematous plaques or nodules associated with fever, neutrophilia and dense neutrophilic dermal infiltrate. In most cases, Sweet's syndrome may occur in the absence of other diseases. However, it can be associated with an inflammatory disease and essentially with malignant conditions in 20% of cases requiring a careful investigation. AIM: We report herein, the epidemiological, clinical, therapeutic and evolutive features of a hospital serie. METHODS: We retrospectively reviewed all the files of patients conforming with the diagnosis of SS, seen at the dermatology departement of Habib Thameur hospital during a 7-year period (from 1997 to 2003). All patients fulfilled at least two major criteria and two minor criteria of Su et Liu's diagnostic criteria modified by Von Den Driesch. RESULTS: 8 cases of .Sweet's syndrome were diagnosed. All patients were females. The mean age was 51.62 years. The lesions occurred on the upper limbs in 7/8 cases. SS was isolated in 6 cases and para-inflammatory in one case corresponding to an associated Sjogren's syndrome. Besides the standard therapy using oral corticosteroids (3 patients), non steroidal inflammatory agents has been efficient in 4 cases. CONCLUSION: In our serie, we report an exclusive female involvement and a lower frequency of associated diseases compared with the relevant literature. Association of SS and Sjogren's syndrome is exceptional. To our knowledge, only 6 cases have already been reported.

Risk factors for erysipelas of the leg in Tunisia: a multicenter case-control study.

BACKGROUND: Risk factors for erysipelas (cellulitis) were rarely evaluated in controlled studies. Regional variations of these risk factors have never be assessed. OBJECTIVE: To assess risk factors for erysipelas of the leg in Tunisia. SUBJECTS AND METHODS: Case-control study in seven hospital centers in Tunisia. Cases were 114 consecutive patients with erysipelas of the leg [sudden onset (<24 h) of a well-demarcated dermo-hypodermatitis with fever or chills]. Two controls were matched to each case for age, sex, and hospital (n = 208). Main outcome measures are local and general suspected risk factors for erysipelas of the leg. RESULTS: In multivariate analysis, disruption of the cutaneous barrier (i.e. traumatic wound, toe-web intertrigo, excoriated leg dermatosis or plantar squamous lesions) and leg edema were independently associated with erysipelas of the leg, with respective odds ratios of 13.6 (95% confidence interval: 6.0-31) and 7.0 (1.3-38). No association was observed with diabetes, alcoholism, or smoking. CONCLUSIONS: We confirmed the major role of local risk factors and the minor role of general risk factors for erysipelas of the leg, in a setting different than the one previously studied. Detecting and treating toe-web intertrigo and traumatic wounds should be considered in the prevention of erysipelas of the leg.

[Angiomatoid fibrous histiocytoma: rare tumor of intermediate malignancy]. / Histiocytome fibreux angiomatoide: une tumeur rare a malignite intermediaire.

Angiomatoid fibrous histiocytoma is a rare tumour affecting young adults. Unlike conventional malignant fibrous histiocytoma, its extension is only local thus giving a good prognosis. We report the cases of a 9 year-old girl and a 16 year-old boy presenting respectively, with an axillary tumour 5 cm of diameter and a paravertebral subcutaneous tumour 1.5 cm of diameter. In both cases, the diagnosis was not initially suspected. The treatment consisted in surgical resection.

[Bullous pemphigoid in children. Report of three cases]. / Pemphigoïde bulleuse de l'enfant. A propos de 3 cas.

Bullous pemphigoïd (BP) is an acquired immunobullous disease that usually affects adults and rarely children. About 60 cases of infant PB have been reported. Diagnosis is based on immunofluorescence investigations. Clinical, histological and immunopathological findings in childhood PB appear to be not different from the adult. Nevertheless, oral mucosal and palm and sole lesions seem to occur more frequently. We report 3 cases of children BP in one girl and 2 boys, aged respectively of 7.2 and 3 years. Palm and sole were affected in 1 case, and no oral mucosal lesion was noted. Recovery was reached in all cases under dapsone. Characteristics of BP in children are discussed with comparison to literature data.