Subject(s)
Anodontia/genetics , Breast/abnormalities , Dermatitis, Exfoliative/genetics , Ectodermal Dysplasia/genetics , Lacrimal Duct Obstruction/genetics , Limb Deformities, Congenital/genetics , Mutation/genetics , Nails, Malformed/genetics , Pigmentation Disorders/genetics , Transcription Factors/genetics , Transglutaminases/genetics , Tumor Suppressor Proteins/genetics , Anodontia/diagnosis , Child , Dermatitis, Exfoliative/diagnosis , Ectodermal Dysplasia/diagnosis , Female , Heterozygote , Humans , Lacrimal Duct Obstruction/diagnosis , Limb Deformities, Congenital/diagnosis , Male , Nails, Malformed/diagnosis , Pigmentation Disorders/diagnosis , Skin Diseases/congenitalABSTRACT
BACKGROUND: Integrin α6ß4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6ß4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). OBJECTIVES: To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. METHODS: DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. RESULTS: We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of ß4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. CONCLUSIONS: The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of ß4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype.
Subject(s)
Epidermolysis Bullosa/genetics , Integrin alpha6beta4/genetics , Mutation/genetics , Adolescent , Adult , Child , Child, Preschool , DNA/analysis , Epidermolysis Bullosa/pathology , Fatal Outcome , Female , Fluorescent Antibody Technique , Genotype , Humans , Infant , Integrin beta4/genetics , Male , Microscopy, Electron , Phenotype , Skin/ultrastructureABSTRACT
Ehlers Danlos type VI is a rare autosomal recessive connective tissue disease involving primarily the skin and joints. The main feature of the condition is neonatal hypotonia and rare complications are ruptures of arteries and the eye globe. A 4 year old girl with a typical clinical presentation and molecular diagnosis of EDS VI is presented. Sequencing of PLOD1 gene revealed a homozygous deletion in exon 13 (c.1362delC), leading to a frameshift and truncation of the lysyl hydroxylase, an enzyme necessary for collagen biosynthesis. Early diagnosis allowed treatment with high doses of ascorbic acid in order to prevent complications, genetic counseling of the family and prenatal diagnosis of an unaffected embryo.
Subject(s)
Ehlers-Danlos Syndrome/diagnosis , Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/genetics , Biopsy , Child, Preschool , Ehlers-Danlos Syndrome/genetics , Female , Humans , Muscle, Skeletal/pathologyABSTRACT
Tinea capitis as a result of Trichophyton rubrum has very rarely been reported in infants. A 3-month-old girl with tinea capitis as a result of T. rubrum is reported. Our patient was treated with a 3-week course of oral fluconazole, which resulted in clearance of the scalp lesion. To our knowledge this case is the first in the literature in which fluconazole was used to treat T. rubrum tinea capitis in children.
Subject(s)
Antifungal Agents/therapeutic use , Fluconazole/therapeutic use , Tinea Capitis/microbiology , Trichophyton/isolation & purification , Administration, Oral , Female , Hair/microbiology , Humans , Infant , Tinea Capitis/drug therapyABSTRACT
Fluconazole has been shown to be effective in the treatment of fungal scalp infections in children; however, there is limited experience of its use in Microsporum scalp infections. We studied 11 children with tinea capitis caused by Microsporum canis who received oral fluconazole at a dose of 5-7.5 mg/kg/day for 6 weeks. Mycological cure was observed in two of the 11 patients at week 4 from the start of therapy, in four patients at week 8 and in three patients at week 16. One of the remaining patients had positive mycology at week 8, but was unavailable for further evaluation. Fluconazole was effective in treating pediatric tinea capitis caused by Microsporum canis and was well tolerated. Clinical and mycological response was achieved in some patients weeks after the cessation of the administration of fluconazole.
Subject(s)
Fluconazole/therapeutic use , Microsporum , Tinea Capitis/drug therapy , Adolescent , Child , Child, Preschool , Female , Fluconazole/pharmacology , Follow-Up Studies , Humans , Male , Microsporum/drug effects , Tinea Capitis/physiopathologyABSTRACT
Junctional epidermolysis bullosa (JEB) associated with pyloric atresia (PA) is a distinct entity which is inherited as an autosomal recessive disorder. We describe five patients with this association; four died in the neonatal period and one is still alive at 4 years of age. The cutaneous lesions in these patients are identical or similar to those in other JEB subtypes. Urinary tract involvement is part of the syndrome and presents a problem for long-term survival. Using the monoclonal antibody GB3 we investigated skin biopsies from three of our patients and showed normal expression in all of them, unrelated to the outcome of their disease. This indicates that the GB3 monoclonal antibody is without prognostic significance in this syndrome. It is clear that JEB with PA is a distinct entity. The molecular basis as yet is unknown.
