Biomedical subjects

J E Mellerio

Publications and source records attributed to J E Mellerio.

At least 19 recordsLinked to original sources

PubMed2007

Plectin defects in epidermolysis bullosa simplex with muscular dystrophy.

Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD, MIM 226670) is caused by plectin defects. We performed mutational analysis and immunohistochemistry using EBS-MD (n = 3 cases) and control skeletal muscle to determine pathogenesis. Mutational analysis revealed a novel homozygous plectin-exon32 rod domain mutation (R2465X). All plectin/HD1-121 antibodies stained the control skeletal muscle membrane. However, plectin antibodies stained the cytoplasm of type II control muscle fibers (as confirmed by ATPase staining), whereas HD1-121 stained the cytoplasm of type I fibers. EBS-MD samples lacked membrane (n = 3) but retained cytoplasmic HD1-121 (n = 1) and plectin staining in type II fibers (n = 3). Ultrastructurally, EBS-MD demonstrated widening and vacuolization adjacent to the membrane and disorganization of Z-lines (n = 2 of 3) compared to controls (n = 5). Control muscle immunogold labeling colocalized plectin and desmin to filamentous bridges between Z-lines and the membrane that were disrupted in EBS-MD muscle. We conclude that fiber-specific plectin expression is associated with the desmin-cytoskeleton, Z-lines, and crucially myocyte membrane linkage, analogous to hemidesmosomes in skin.

Adult↗

PubMed2006

The management of general and disease specific ENT problems in children with Epidermolysis Bullosa--a retrospective case note review.

OBJECTIVE: Epidermolysis Bullosa encompasses a group of inherited disorders characterized by excessive susceptibility of the skin and mucosa to separate from underlying tissues following mechanical trauma. Information in the literature and guidance on the management of Ear, Nose and Throat problems in such children is scarce. The aim of this study is to report the experience of an Ear, Nose and Throat department in a tertiary paediatric hospital linked to a national Epidermolysis Bullosa unit, describing how children have presented and the care that has been given including a theatre protocol aimed at reducing shearing forces. METHODS: Retrospective case note review of Epidermolysis Bullosa patients referred to Otolaryngology over an 8-year period. RESULTS: Reviewing notes of 307 EB patients identified 15 that had been referred to the ENT department. Four children with middle ear effusions were effectively treated by watchful waiting or grommets. Three children with otitis externa had some relief from careful microsuction but reinfection from ulcers on other parts of the children's bodies tended to occur. One child with profound sensorineural hearing loss benefited from cochlear implantation but later passed away from unrelated sepsis. One child with intrinsic rhinitis was treated with steroid and then a salt-water nasal spray. Five children had nasal crusting documented, although this was not a specific reason for referral. When severe this had been treated with topical steroids by the dermatology team. One patient with obstructive sleep aponea had tonsillectomy and examination of the post-nasal space. Of the five patients referred with glottic or supraglottic scarring, the management of four included a tracheostomy. When carried out tracheostomy sites healed well in each case. With repeated endoscopic procedures it was subsequently possible to remove the tracheostomy in the two of the children. Using a special theatre protocol no new ulcers were recorded as being precipitated by any of the procedures children underwent. CONCLUSIONS: Optimal management depends on the support of a multidisciplinary team, including otolaryngologists, pediatricians, dermatologists, anaesthetists, and specialist nurses. Adherence to a protocol for theatre management can help avoid intraoperative complications.

Adolescent↗

PubMed2006

Prenatal diagnosis for severe inherited skin disorders: 25 years' experience.

BACKGROUND: Over the last 25 years there have been major advances in methods for prenatal testing of inherited skin disorders. Since 1979, our group at the St John's Institute of Dermatology has performed 269 prenatal diagnoses, using a variety of approaches, including fetal skin biopsy (FSB), chorionic villus sampling (CVS) and preimplantation genetic diagnosis (PGD). OBJECTIVES: This study was designed to review the clinical indications, testing procedures and laboratory analyses for all prenatal tests conducted at St John's over this period. METHODS: FSBs were examined for morphological and, when relevant or feasible, immunohistochemical abnormalities. The DNA-based tests involved screening by nucleotide sequencing, restriction enzyme digests or, in a few cases, by linkage analysis. Results Of the 269 tests, 191 were FSB, 76 were CVS and two were PGD. The major indications for FSB were epidermolysis bullosa (EB) (138 cases, including 88 junctional and 48 dystrophic), ichthyoses (37 cases, including 22 tests for harlequin ichthyosis) and oculocutaneous albinism (12 cases). Of the CVS procedures, 75 were for EB (40 junctional, 35 dystrophic) and one was for the EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome. Both of the PGD procedures were for the skin fragility-ectodermal dysplasia syndrome. All tests provided accurate diagnoses and the fetal loss rate was approximately 1% for both FSB and CVS. CONCLUSIONS: The development of prenatal testing has proved to be of great benefit for individuals or couples at risk of having children with severe inherited skin disorders and, in the absence of a cure, prenatal testing along with appropriate counselling has become an important translational benefit of basic research and an integral part of clinical management.

Biopsy↗

PubMed2006

Bone mineralization in children with epidermolysis bullosa.

BACKGROUND: Various factors may have deleterious effects on bone health in patients with epidermolysis bullosa (EB). OBJECTIVES: In a retrospective notes review, to assess bone mineralization in children with EB and to identify the relative contributions of nutrition, activity and disease severity to low bone mass. METHODS: Thirty-nine children with EB [32 recessive dystrophic EB (RDEB), four Dowling-Meara EB simplex (DMEBS) and three junctional EB (JEB)] had lumbar spine bone mass measured using dual X-ray absorptiometry (GE Lunar Prodigy; GE Healthcare, Chalfont St Giles, U.K.). Seventy-six healthy children were also studied. Weight and height were recorded and mobility was rated. RESULTS: Children with RDEB and JEB, but not those with DMEBS, had lower bone mineral density SD scores than controls; differences remained after adjusting for the smaller body size of the patients. Bone mass was best predicted by mobility rating. CONCLUSIONS: Children with RDEB and JEB have low bone mass after adjusting for their smaller size, which may put them at risk for fragility fractures. Low bone mass was best predicted by the level of mobility, raising the hypothesis that improving activity or bone loading may be a potential preventive intervention in these children. However, as low bone mass may be multifactorial in these children, more detailed investigation of potential aetiological factors is required before interventions are planned.

Absorptiometry, Photon↗

PubMed2006

Target proteins in inherited and acquired blistering skin disorders.

Maintenance of an intact epidermis depends on secure adhesion between adjacent keratinocytes, and between basal keratinocytes and the underlying epidermal basement membrane. The major adhesion units that achieve this are the hemidesmosomes and desmosomes, but when these structures are disrupted, e.g., by gene mutations or autoantibodies, the resilience of the epidermis is lost and blisters develop. Recently, there have been considerable advances in our knowledge of the proteins and glycoproteins that contribute to maintaining keratinocyte adhesion via hemidesmosomes and desmosomes, as well as new insights into the molecular pathogenesis of several inherited and autoimmune blistering skin diseases. These new basic scientific data are clinically relevant, helping to improve patient management and to provide a rationale for developing better and more specific treatments for patients with inherited or acquired blistering skin diseases. In addition, there have also been improvements in our understanding of the organization and assembly of these adhesion structures, and their involvement in signalling pathways, intricately linked to skin development, wound healing and tumour invasion. This review provides an update on the structure and organization of hemidesmosomes and desmosomes, and on the molecular pathology of their various components that result in bullous skin diseases.

Autoimmune Diseases↗

PubMed2006

An unusual patient with Rothmund-Thomson syndrome, porokeratosis and bilateral iris dysgenesis.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis characterized by poikiloderma and the variable presence of other features including skeletal and ocular abnormalities, ectodermal defects, and susceptibility to certain malignancies. We report a 40-year-old woman with known RTS who developed porokeratoses on her limbs in adulthood, an association that has not previously been reported. In addition, she had bilateral iris dysgenesis, which has only been described once before in RTS.

Abnormalities, Multiple↗

PubMed2005

Thalidomide in the management of epidermolysis bullosa pruriginosa.

Epidermolysis bullosa (EB) pruriginosa is a distinctive clinical subtype of dystrophic EB. We report a patient with dominant dystrophic EB pruriginosa, who had an excellent response to systemic thalidomide treatment. The mechanism of action of thalidomide in the management of pruriginous disorders is not yet completely understood. Most recent studies point towards an immunomodulatory action of thalidomide that may suppress excessive production of tumour necrosis factor-alpha and may downregulate certain cell surface adhesion molecules involved in leucocyte migration.

Adolescent↗

PubMed2005

Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa.

Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mechanobullous disorder that results from loss-of-function mutations in the genes encoding the basement membrane component, laminin 5. Typically, there are frameshift, splice site or nonsense mutations on both alleles of either the LAMA3, LAMB3 or LAMC2 genes, with affected individuals inheriting one mutated allele from each parent. In this report, we describe a patient with Herlitz JEB in whom DNA analysis revealed homozygosity for the recurrent nonsense mutation R635X in LAMB3, located 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 microsatellite markers spanning chromosome 1 revealed that the affected child was homozygous for the entire series of markers tested and that all of the alleles originated from the father. These results indicate that the Herlitz JEB phenotype in this patient is due to complete paternal isodisomy of chromosome 1 and reduction to homozygosity of the mutant LAMB3 gene locus. This is the fourth case of uniparental disomy to be described in Herlitz JEB, but it represents the first example of complete paternal isodisomy for chromosome 1 with a pathogenic mutation in the LAMB3 gene. These findings have important implications for mutation screening in JEB and for genetic counselling.

Chromosome Mapping↗

PubMed2005

Multiple dermatofibromas associated with lupus profundus.

We report a 58-year-old Afro-Caribbean woman who presented with more than 20 dermatofibromas on the body particularly on the back, arms and legs. These developed spontaneously over the course of 5 years. She also had a long-standing 5 x 2-cm area of lipoatrophy on the right upper arm and a 2-year history of several inflammatory subcutaneous nodules developing on the upper chest and left breast. These were confirmed histologically as lupus profundus. Apart from a mild arthritis, she had no other markers for systemic lupus erythematosus and was systemically well. Multiple dermatofibromas are rare. There are around 30 reports of multiple dermatofibromas associated with systemic diseases. More than half of these cases were associated with systemic lupus erythematosus, with or without systemic steroid therapy and about one-third were associated with HIV infection. Although the mechanism is unknown, it appears that multiple dermatofibromas are associated with autoimmune diseases or altered immune states. This is the first case of multiple dermatofibromas associated with lupus profundus. The knowledge of such associations may contribute to the understanding of the pathogenesis of dermatofibromas, which is as yet unknown.

Autoimmune Diseases↗

PubMed2005

Prenatal diagnosis of Herlitz junctional epidermolysis bullosa in nonidentical twins.

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.

Adult↗

PubMed2004

ADULT ectodermal dysplasia syndrome resulting from the missense mutation R298Q in the p63 gene.

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-->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-ungual-lacrimal-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.

Base Sequence↗

PubMed2003

Dilemmas in distinguishing between dominant and recessive forms of dystrophic epidermolysis bullosa.

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a heterogeneous inherited blistering skin disorder. The mode of inheritance may be autosomal dominant or recessive but all forms of DEB result from mutations in the gene encoding the anchoring fibril protein, type VII collagen, COL7A1. Consequently, in spite of careful clinical and skin biopsy examination, it may be difficult to distinguish mild recessive cases from de novo dominant disease in families with clinically normal parents and no other affected siblings; this distinction has significant implications for the accuracy of genetic counselling. OBJECTIVES: To assess whether COL7A1 mutation analysis might help determine mode of inheritance in mild to moderate DEB. METHODS: We performed COL7A1 screening using heteroduplex analysis and direct nucleotide sequencing in four individuals with mild to moderate "sporadic" DEB and clinically unaffected parents. RESULTS: In each patient, we identified a heterozygous glycine substitution within the type VII collagen triple helix. However, in two cases these mutations had been inherited in trans with a non-sense mutation on the other allele (i.e. autosomal recessive DEB). In the other two cases, no additional mutation was identified and neither mutation was present in parental DNA (i.e. de novo dominant disease). CONCLUSIONS: This study highlights the usefulness of DNA sequencing in determining the inherited basis of some sporadic cases of DEB. However, delineation of glycine substitutions should prompt comprehensive COL7A1 gene sequencing in the affected individual, as well as clinical assessment of parents and mutation screening in parental DNA, if the true mode of inheritance is to be established correctly.

Adolescent↗

PubMed2001

Alpha 6 beta 4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia.

Junctional epidermolysis bullosa with pyloric atresia (JEB-PA) (MIM 226730) is an autosomal recessive disorder resulting from mutations in the genes encoding alpha 6 beta 4 integrin (ITGA6 and ITGB4). Clinically, it is characterized by mucocutaneous fragility and gastrointestinal atresia, which most commonly affects the pylorus. Additional features of JEB-PA include involvement of the urogenital tract, aplasia cutis and failure to thrive. While most affected individuals have a poor prognosis resulting in death in infancy, others have milder clinical features and a better prognosis. We report two previously undescribed homozygous ITGB4 mutations in two unrelated families, which resulted in severe skin blistering, pyloric atresia and lethality in infancy. Delineation of the mutations was used to undertake DNA-based prenatal diagnosis in subsequent pregnancies at risk for recurrence in both families. We review all previously published ITGA6 and ITGB4 mutation reports to help define genotype--phenotype correlation in this rare genodermatosis.

Antigens, Surface↗

PubMed2001

Three cases of de novo dominant dystrophic epidermolysis bullosa associated with the mutation G2043R in COL7A1.

In the absence of a positive family history, it is often difficult to determine whether a single case of mild-to-moderately severe dystrophic epidermolysis bullosa (DEB) represents autosomal recessive or de novo dominant disease. Recent molecular analyses of the type VII collagen gene, COL7A1, have established that the vast majority of such cases are recessive in nature. Nevertheless, a small number of de novo dominant patients have been documented. In this report, we describe three further examples of de novo dominant disease. In each case the COL7A1 mutation comprised the same glycine substitution, G2043R. This mutation has previously been reported in both dominant DEB pedigrees and as a de novo phenomenon and is the most common COL7A1 mutation in dominant DEB throughout the world. These cases emphasize the importance of molecular analysis in providing accurate genetic counselling in this genodermatosis.

Adolescent↗

PubMed2001

Dominant dystrophic epidermolysis bullosa presenting as familial nail dystrophy.

Nail dystrophy, a well-recognized feature of dystrophic epidermolysis bullosa (EB), is usually accompanied by skin fragility. We present a three-generation family with an autosomal dominant history of dystrophic nails, but without skin fragility or trauma-induced blisters. No specific diagnosis had been made. However, in the fourth generation, an infant presented with nail dystrophy, acral blistering and milia, raising the possibility of dominant dystrophic EB. This was confirmed by mutational analysis of the type VII collagen gene, COL7A1. We identified a glycine substitution mutation, G1776A, in exon 61 of COL7A1, characteristic of dominant dystrophic EB, which segregated with nail dystrophy in this family. A diagnosis of dominant dystrophic EB should be considered in families with autosomal dominant nail dystrophy even when there is no history of blistering.

Collagen↗

PubMed2000

Heterozygous germline missense mutation in the p63 gene underlying EEC syndrome.

Mutations in the p63 gene have recently been delineated as the molecular basis for some cases of the ectrodactyly, ectodermal dysplasia and cleft lip/palate (EEC) syndrome, an autosomal dominant disorder (MIM 129900). In this report, we describe a 35-year-old woman with EEC syndrome and document a heterozygous germline missense mutation, R304W, in exon 8 of the p63 gene. As with most other p63 mutations in EEC syndrome, this mutation has arisen de novo and is located within the core DNA-binding domain of p63. Identification of this mutation has implications for genetic counselling and the feasibility of future DNA-based prenatal diagnosis in this individual.

Abnormalities, Multiple↗

PubMed1999

Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin 1.

We report a 2-year-old boy with an unusual autosomal recessively inherited skin disease comprising trauma-induced skin fragility and congenital ectodermal dysplasia affecting hair, nails and sweat glands. Skin biopsy showed widening of intercellular spaces between keratinocytes and ultrastructural findings of small, poorly formed desmosomes with reduced connections to the keratin filament cytoskeleton. Immunohistochemical analysis revealed a complete absence of staining for the accessory desmosomal plaque protein plakophilin 1 (PKP1; band 6 protein). The affected individual was a compound heterozygote for null mutations on both alleles of the PKP1 gene. Both mutations occurred within the amino terminus of PKP1, the domain which normally binds the cytoskeletal keratin filament network to the cell membrane. Apart from its localization within desmosomal plaques, PKP1 may also be present within the cytoplasm and nucleus and has putative roles in signal transduction and regulation of gene activity. The clinicopathological observations in this patient demonstrate the relevance of PKP1 to desmosome formation, cutaneous cell-cell adhesion and epidermal development and demonstrate the specific manifestations of human functional knockout mutations in this gene.

Base Sequence↗

PubMed1999

Molecular pathology of the cutaneous basement membrane zone.

Recent research has provided considerable information concerning the biology of the cutaneous basement membrane zone (BMZ) in health and disease. In particular, identification of pathogenetic mutations in the genes encoding protein components at the BMZ has done much to increase our understanding of the inherited skin blistering disease, epidermolysis bullosa (EB). As the molecular pathology of different forms of EB is elucidated, correlations between genotype and phenotype become apparent. Determination of specific mutations in patients and families has not only clinical significance, but has also led to the introduction of DNA-based prenatal testing for severe forms of disease, and has laid the foundations for the development of future treatments including gene therapy.

Basement Membrane↗