We report the clinical and molecular abnormalities in a 19year-old woman with Rapp-Hodgkin ectodermal dysplasia syndrome. The physical features include mid-facial hypoplasia, uncombable hair, cleft palate and bifid uv...We report the clinical and molecular abnormalities in a 19year-old woman with Rapp-Hodgkin ectodermal dysplasia syndrome. The physical features include mid-facial hypoplasia, uncombable hair, cleft palate and bifid uvula, lacrimal duct obstruction and dry skin. Sequencing of the p63 gene reveals a new heterozygous frameshift mutation, 1787delG, in exon 14. The frameshift results in changes to the tail of p63 with the addition of 68 missense amino acids downstream and a delayed termination codon that extends the protein length by 21 amino acids. These changes are predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is overlap between Rapp-Hodgkin syndrome and several other ectodermal dysplasia syndromes, notably Hay-Wells syndrome, and that characterization of the functional consequences of these p63 gene mutations at a molecular and cellular level is likely to provide further insight into the clinical spectrum of these developmental malformation syndromes.展开更多
Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition t hat results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyom...Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition t hat results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papil lary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous m utations in the gene encoding fumarate hydratase have been found to underlie bot h conditions. Fumarate hydratase is an enzyme that catalyses the conversion of f umarate to malate in the Kreb’s cycle and may also function as a tumour suppres sor gene. We report a family with multiple leiomyomas, uterine fibroids and papi llary renal cell cancer. The proband is a 77-year-old Polish woman who develop ed multiple cutaneous leiomyomas on her right upper arm in her thirties and subs equently underwent a hysterectomy for uterine fibroids in her forties. She has f our offspring: her eldest daughter also has skin and uterine leiomyomas with a s imilar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two you ngest daughters are unaffected. DNA sequencing in all the affected individuals d isclosed a heterozygous G ?úC substitution at nucleotide 173 ofthefumaratehydra tasegene,thatconvertsanarginineresidue (CGA) to proline (CCA). This missense mut ation has not been reported previously and is designated R58P. Interestingly, th e clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop sk in leiomyomas in the future but the risk of renal cancer is difficult to predict . Nevertheless, detection of this mutation has important implications for screen ing and genetic counselling in this and other family members.展开更多
Several ectodermal dysplasia syndromes have been shown to result from mutations in the gene that encodes the transcription factor p63. We describe an 11- year-old boy, with clinically normal parents, who had a develop...Several ectodermal dysplasia syndromes have been shown to result from mutations in the gene that encodes the transcription factor p63. We describe an 11- year-old boy, with clinically normal parents, who had a developmental disorder that resembled EEC (ectrodactyly ectodermal dysplasia-clefting) syndrome (OMIM 604292). He had ectrodactyly and missing middle fingers bilaterally, onychodysplasia, hypodontia with missing teeth, hypohidrosis and lacrimal duct obstruction. DNA sequencing disclosed a heterozygous G ?ú .A substitution at nucleotide 893, that converts an arginine residue (CGA) to glutamine (CAA), the mutation being designated R298Q. This mutation occurs within the DNA-binding domain of p63, and is close to many of the published EEC syndrome mutations. However, R298Q has been described once previously in a large German pedigree, not with EEC syndrome, but another ectodermal dysplasia disorder, ADULT (acro-dermato-unguallacrimal-tooth) syndrome (OMIM 103285). Further clinical assessment in our patient revealed that, apart from not having cleft lip and/or palate, he had an exfoliative dermatitis of his hands and feet, and some freckling on his face and shoulders. Collectively, these features support a diagnosis of ADULT syndrome. This study has identified a specific genotype- phenotype correlation in a rare ectodermal dysplasia syndrome and the findings are useful in improving genetic counselling in this family.展开更多
Although the precise aetiology of lichen sclerosus is unknown, evidence for an autoimmune basis to the disorder is emerging. Indeed, circulating IgG autoantibodies to the glycoprotein extracellular matrix protein 1 (E...Although the precise aetiology of lichen sclerosus is unknown, evidence for an autoimmune basis to the disorder is emerging. Indeed, circulating IgG autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been demonstrated in the sera of about 75%of affected individuals. To assess this humoral immune response further, immunoblotting was performed using bacterial recombinant proteins spanning different domains of the ECM1 protein. The aim was to identify autoantibody-reactive sites recognized by 90 lichen sclerosus sera. The subclass distribution of anti-ECM1 IgG autoantibodieswas also determined in 54 lichen sclerosus sera. Immunoblotting showed that the IgG autoantibodies from lichen sclerosus patients recognize multiple antigenic reactive sites on the ECM1 protein within both the amino terminus (50/90, 55.6%) and the protein loop cysteine-rich repeat domains (54/90, 60%), although few sera (7/90, 7.8%) had antibodies to the carboxyl terminus of ECM1. IgG subclass analysis revealed that the anti-ECM1 autoantibodies belong predominantly to the IgG2 subclass (48/54, 88.9%), either IgG2 alone (28/54, 51.9%) or in combination with one or more other IgG subclasses. No correlation was found between the site(s) of the ECM1 epitopes or the anti-ECM1 IgG profile and any specific clinical parameters. Nevertheless, characterization of anti-ECM1 antibodies does provide further insight into humoral immune responses and understanding disease mechanisms in lichen sclerosus.展开更多
Advances in molecular diagnostics have led to the feasibility of DNA-based prenatal testing in families at risk for recurrence of severe forms of both dystrophic and junctional epidermolysis bullosa. In this report, w...Advances in molecular diagnostics have led to the feasibility of DNA-based prenatal testing in families at risk for recurrence of severe forms of both dystrophic and junctional epidermolysis bullosa. In this report, we describe prenatal testing in a woman who previously had a child affected with Herlitz junctional epidermolysis bullosa. However, in her second pregnancy, she was found to have dichorionic diamniotic twins. DNA analysis of a pathogenic mutation and informative intragenic polymorphisms (LAMB3 gene) predicted one fetus to be affected and the other unaffected. Selective termination of the affected fetus was performed, and pregnancy with the unaffected fetus was continued, leading to full term delivery of a healthy girl with no skin blisters. This is the first reported case of DNA analysis in a twin pregnancy at risk of Herlitz junctional epidermolysis bullosa, with successful diagnosis and selective termination of one affected twin.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We report the clinical and molecular abnormalities in a 19year-old woman with Rapp-Hodgkin ectodermal dysplasia syndrome. The physical features include mid-facial hypoplasia, uncombable hair, cleft palate and bifid uvula, lacrimal duct obstruction and dry skin. Sequencing of the p63 gene reveals a new heterozygous frameshift mutation, 1787delG, in exon 14. The frameshift results in changes to the tail of p63 with the addition of 68 missense amino acids downstream and a delayed termination codon that extends the protein length by 21 amino acids. These changes are predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is overlap between Rapp-Hodgkin syndrome and several other ectodermal dysplasia syndromes, notably Hay-Wells syndrome, and that characterization of the functional consequences of these p63 gene mutations at a molecular and cellular level is likely to provide further insight into the clinical spectrum of these developmental malformation syndromes.
文摘Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition t hat results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papil lary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous m utations in the gene encoding fumarate hydratase have been found to underlie bot h conditions. Fumarate hydratase is an enzyme that catalyses the conversion of f umarate to malate in the Kreb’s cycle and may also function as a tumour suppres sor gene. We report a family with multiple leiomyomas, uterine fibroids and papi llary renal cell cancer. The proband is a 77-year-old Polish woman who develop ed multiple cutaneous leiomyomas on her right upper arm in her thirties and subs equently underwent a hysterectomy for uterine fibroids in her forties. She has f our offspring: her eldest daughter also has skin and uterine leiomyomas with a s imilar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two you ngest daughters are unaffected. DNA sequencing in all the affected individuals d isclosed a heterozygous G ?úC substitution at nucleotide 173 ofthefumaratehydra tasegene,thatconvertsanarginineresidue (CGA) to proline (CCA). This missense mut ation has not been reported previously and is designated R58P. Interestingly, th e clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop sk in leiomyomas in the future but the risk of renal cancer is difficult to predict . Nevertheless, detection of this mutation has important implications for screen ing and genetic counselling in this and other family members.
文摘Several ectodermal dysplasia syndromes have been shown to result from mutations in the gene that encodes the transcription factor p63. We describe an 11- year-old boy, with clinically normal parents, who had a developmental disorder that resembled EEC (ectrodactyly ectodermal dysplasia-clefting) syndrome (OMIM 604292). He had ectrodactyly and missing middle fingers bilaterally, onychodysplasia, hypodontia with missing teeth, hypohidrosis and lacrimal duct obstruction. DNA sequencing disclosed a heterozygous G ?ú .A substitution at nucleotide 893, that converts an arginine residue (CGA) to glutamine (CAA), the mutation being designated R298Q. This mutation occurs within the DNA-binding domain of p63, and is close to many of the published EEC syndrome mutations. However, R298Q has been described once previously in a large German pedigree, not with EEC syndrome, but another ectodermal dysplasia disorder, ADULT (acro-dermato-unguallacrimal-tooth) syndrome (OMIM 103285). Further clinical assessment in our patient revealed that, apart from not having cleft lip and/or palate, he had an exfoliative dermatitis of his hands and feet, and some freckling on his face and shoulders. Collectively, these features support a diagnosis of ADULT syndrome. This study has identified a specific genotype- phenotype correlation in a rare ectodermal dysplasia syndrome and the findings are useful in improving genetic counselling in this family.
文摘Although the precise aetiology of lichen sclerosus is unknown, evidence for an autoimmune basis to the disorder is emerging. Indeed, circulating IgG autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been demonstrated in the sera of about 75%of affected individuals. To assess this humoral immune response further, immunoblotting was performed using bacterial recombinant proteins spanning different domains of the ECM1 protein. The aim was to identify autoantibody-reactive sites recognized by 90 lichen sclerosus sera. The subclass distribution of anti-ECM1 IgG autoantibodieswas also determined in 54 lichen sclerosus sera. Immunoblotting showed that the IgG autoantibodies from lichen sclerosus patients recognize multiple antigenic reactive sites on the ECM1 protein within both the amino terminus (50/90, 55.6%) and the protein loop cysteine-rich repeat domains (54/90, 60%), although few sera (7/90, 7.8%) had antibodies to the carboxyl terminus of ECM1. IgG subclass analysis revealed that the anti-ECM1 autoantibodies belong predominantly to the IgG2 subclass (48/54, 88.9%), either IgG2 alone (28/54, 51.9%) or in combination with one or more other IgG subclasses. No correlation was found between the site(s) of the ECM1 epitopes or the anti-ECM1 IgG profile and any specific clinical parameters. Nevertheless, characterization of anti-ECM1 antibodies does provide further insight into humoral immune responses and understanding disease mechanisms in lichen sclerosus.
文摘Advances in molecular diagnostics have led to the feasibility of DNA-based prenatal testing in families at risk for recurrence of severe forms of both dystrophic and junctional epidermolysis bullosa. In this report, we describe prenatal testing in a woman who previously had a child affected with Herlitz junctional epidermolysis bullosa. However, in her second pregnancy, she was found to have dichorionic diamniotic twins. DNA analysis of a pathogenic mutation and informative intragenic polymorphisms (LAMB3 gene) predicted one fetus to be affected and the other unaffected. Selective termination of the affected fetus was performed, and pregnancy with the unaffected fetus was continued, leading to full term delivery of a healthy girl with no skin blisters. This is the first reported case of DNA analysis in a twin pregnancy at risk of Herlitz junctional epidermolysis bullosa, with successful diagnosis and selective termination of one affected twin.
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.
