Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mecha nobullous disorder that results from loss-of-function mutations in the genes e ncoding the basement membrane component, laminin 5. Typical...Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mecha nobullous disorder that results from loss-of-function mutations in the genes e ncoding the basement membrane component, laminin 5. Typically, there are framesh ift, splice site or nonsense mutations on both alleles of either theLAMA3,LAMB3o rLAMC2genes,withaffectedindividuals inheriting one mutated allele from each pare nt. In this report, we describe a patient with Herlitz JEB in whom DNA analysis revealed homozygosity for the recurrent nonsense mutation R635X in LAMB3, locate d on chromosome 1q32.2. However, screening of parental DNA showed that although the patient’s father was a heterozygous carrier of this mutation, the mother’s DNA showed only wild-type sequence. Subsequent genotype analysis using 13 micr osatellite markers spanning chromosome 1 revealed that the affected child was ho mozygous for the entire seriesofmarkerstestedandthatalloftheallelesoriginatedfro m the father. These results indicate that the Herlitz JEB phenotype in this pati ent is due to complete paternal isodisomy of chromosome 1 and reduction to homoz ygosity of the mutant LAMB3 gene locus. This is the fourth case of uniparental d isomy to be described in Herlitz JEB, but it represents the first example of com plete paternal isodisomy for chromosome 1 with a pathogenic mutation in the LAMB 3 gene. These findings have important implications for mutation screening in JEB and for genetic counselling.展开更多
Transient bullous dermolysis of the newborn (TBDN) is a rare form of dys- trophic epidermolysis bullosa (DEB) that improves markedly during early life or even remits completely.Skin biopsies reveal abnormal intraepide...Transient bullous dermolysis of the newborn (TBDN) is a rare form of dys- trophic epidermolysis bullosa (DEB) that improves markedly during early life or even remits completely.Skin biopsies reveal abnormal intraepidermal accumulation of type VII collagen which results in poorly constructed anchoring fibrils and a sublamina densa plane of blister formation. The reason for the spontaneous clinical improvement is not known,but there is a gradual recovery in type VII collagen secretion from basal keratinocytes to the dermal- epidermal junction, with subsequent improvement or correction of anchoring fibril morphology. In this report, we describe TBDN occurring in three generations of the same family. Blistering occurred only during the first few months after birth, and all affected individual swere found to have a heterozygous glycine substitution mutation in exon 45 of the type VII collagen gene, COL7A1, designated G1522E. This mutation represents the third report of a pathogenic COL7A1 mutation in TBDN.Despite limited understanding of the disease mechanism in TBDN, this distinct form ofDEB is important to recognize as it typically has a benign and self- limiting course. However, not all cases of DEB associated with intraepidermal type VII collagen are ‘ transient’ . Genetic counselling in such patients therefore should be guarded until the pathophysiology of TBDN is better understood.展开更多
We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently...We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently developed skin fragility, progressive plantar keratoderma, nail dystrophy, and alopecia. Skin biopsy revealed widening of intercellular spaces in the epidermis and a reduced number of small, poorly formed desmosomes. Mutation analysis of the plakophilin 1 gene PKP1 revealed a homozygous deletion of C at nucleotide 888 within exon 5. This mutation differs from the PKP1 gene pathology reported in 8 previously published individuals with this rare genodermatosis. However, all cases show similar clinical features, highlighting the importance of functional plakophilin 1 in maintaining desmosomal adhesion in skin, as well as the role of this protein in aspects of ectodermal development.展开更多
The mechanobullous disease Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) results from mutations in the typeVII collagen gene (COL7A1) on chromosome 3p21.31. Typically, there are frameshift, sp...The mechanobullous disease Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) results from mutations in the typeVII collagen gene (COL7A1) on chromosome 3p21.31. Typically, there are frameshift, splice site, or nonsense mutations on both alleles. In this report, we describe a patient with HS-RDEB, who was homozygous for a new frameshift mutation, 345insG, in exon 3 of COL7A1. However, sequencing of parental DNA showed that although the patient’s mother was a heterozygous carrier of this mutation, the father’s DNA contained only wild-type sequence. Microsatellite marker analysis confirmed paternity and genotyping of 28 microsatellites spanning chromosome 3 revealed that the affected child was homozygous for every marker tested with all alleles originating from a single maternal chromosome 3. Thus, the HS-RDEB phenotype in this patient is due to complete maternal isodisomy of chromosome 3 and reduction to homozygosity of the mutant COL7A1 gene locus. To our knowledge, there are no published reports of uniparental disomy (UPD) in HS-RDEB; moreover, this case represents only the third example of UPD of chromosome 3 to be reported. The severity of the HS-RDEB in this case was similar to other affected individuals and no additional phenotypic abnormalitieswere observed, suggesting an absence of maternally imprinted genes on chromosome 3.展开更多
文摘Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mecha nobullous disorder that results from loss-of-function mutations in the genes e ncoding the basement membrane component, laminin 5. Typically, there are framesh ift, splice site or nonsense mutations on both alleles of either theLAMA3,LAMB3o rLAMC2genes,withaffectedindividuals inheriting one mutated allele from each pare nt. In this report, we describe a patient with Herlitz JEB in whom DNA analysis revealed homozygosity for the recurrent nonsense mutation R635X in LAMB3, locate d on chromosome 1q32.2. However, screening of parental DNA showed that although the patient’s father was a heterozygous carrier of this mutation, the mother’s DNA showed only wild-type sequence. Subsequent genotype analysis using 13 micr osatellite markers spanning chromosome 1 revealed that the affected child was ho mozygous for the entire seriesofmarkerstestedandthatalloftheallelesoriginatedfro m the father. These results indicate that the Herlitz JEB phenotype in this pati ent is due to complete paternal isodisomy of chromosome 1 and reduction to homoz ygosity of the mutant LAMB3 gene locus. This is the fourth case of uniparental d isomy to be described in Herlitz JEB, but it represents the first example of com plete paternal isodisomy for chromosome 1 with a pathogenic mutation in the LAMB 3 gene. These findings have important implications for mutation screening in JEB and for genetic counselling.
文摘Transient bullous dermolysis of the newborn (TBDN) is a rare form of dys- trophic epidermolysis bullosa (DEB) that improves markedly during early life or even remits completely.Skin biopsies reveal abnormal intraepidermal accumulation of type VII collagen which results in poorly constructed anchoring fibrils and a sublamina densa plane of blister formation. The reason for the spontaneous clinical improvement is not known,but there is a gradual recovery in type VII collagen secretion from basal keratinocytes to the dermal- epidermal junction, with subsequent improvement or correction of anchoring fibril morphology. In this report, we describe TBDN occurring in three generations of the same family. Blistering occurred only during the first few months after birth, and all affected individual swere found to have a heterozygous glycine substitution mutation in exon 45 of the type VII collagen gene, COL7A1, designated G1522E. This mutation represents the third report of a pathogenic COL7A1 mutation in TBDN.Despite limited understanding of the disease mechanism in TBDN, this distinct form ofDEB is important to recognize as it typically has a benign and self- limiting course. However, not all cases of DEB associated with intraepidermal type VII collagen are ‘ transient’ . Genetic counselling in such patients therefore should be guarded until the pathophysiology of TBDN is better understood.
文摘We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently developed skin fragility, progressive plantar keratoderma, nail dystrophy, and alopecia. Skin biopsy revealed widening of intercellular spaces in the epidermis and a reduced number of small, poorly formed desmosomes. Mutation analysis of the plakophilin 1 gene PKP1 revealed a homozygous deletion of C at nucleotide 888 within exon 5. This mutation differs from the PKP1 gene pathology reported in 8 previously published individuals with this rare genodermatosis. However, all cases show similar clinical features, highlighting the importance of functional plakophilin 1 in maintaining desmosomal adhesion in skin, as well as the role of this protein in aspects of ectodermal development.
文摘The mechanobullous disease Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) results from mutations in the typeVII collagen gene (COL7A1) on chromosome 3p21.31. Typically, there are frameshift, splice site, or nonsense mutations on both alleles. In this report, we describe a patient with HS-RDEB, who was homozygous for a new frameshift mutation, 345insG, in exon 3 of COL7A1. However, sequencing of parental DNA showed that although the patient’s mother was a heterozygous carrier of this mutation, the father’s DNA contained only wild-type sequence. Microsatellite marker analysis confirmed paternity and genotyping of 28 microsatellites spanning chromosome 3 revealed that the affected child was homozygous for every marker tested with all alleles originating from a single maternal chromosome 3. Thus, the HS-RDEB phenotype in this patient is due to complete maternal isodisomy of chromosome 3 and reduction to homozygosity of the mutant COL7A1 gene locus. To our knowledge, there are no published reports of uniparental disomy (UPD) in HS-RDEB; moreover, this case represents only the third example of UPD of chromosome 3 to be reported. The severity of the HS-RDEB in this case was similar to other affected individuals and no additional phenotypic abnormalitieswere observed, suggesting an absence of maternally imprinted genes on chromosome 3.
