Showing papers by "John A. McGrath published in 2008"

The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB.

Abstract: BACKGROUND: Since publication in 2000 of the Second International Consensus Report on Diagnosis and Classification of Epidermolysis Bullosa, many advances have been made to our understanding of this group of diseases, both clinically and molecularly. At the same time, new epidermolysis bullosa (EB) subtypes have been described and similarities with some other diseases have been identified. OBJECTIVE: We sought to arrive at a new consensus of the classification of EB subtypes. RESULTS: We now present a revised classification system that takes into account the new advances, as well as encompassing other inherited diseases that should also be included within the EB spectrum, based on the presence of blistering and mechanical fragility. Current recommendations are made on the use of specific diagnostic tests, with updates on the findings known to occur within each of the major EB subtypes. Electronic links are also provided to informational and laboratory resources of particular benefit to clinicians and their patients. LIMITATIONS: As more becomes known about this disease, future modifications may be needed. The classification system has been designed with sufficient flexibility for these modifications. CONCLUSION: This revised classification system should assist clinicians in accurately diagnosing and subclassifying patients with EB.

Anatomy and Organization of Human Skin

Abstract: Human skin consists of a stratified, cellular epidermis and an underlying dermis of connective tissue [1–5]. The dermal–epidermal junction is undulating in section; ridges of the epidermis, known as rete ridges, project into the dermis. The junction provides mechanical support for the epidermis and acts as a partial barrier against exchange of cells and large molecules. Below the dermis is a fatty layer, the panniculus adiposus, usually designated as ‘subcutaneous’. This is separated from the rest of the body by a vestigial layer of striated muscle, the panniculus carnosus. There are two main kinds of human skin. Glabrous skin (non-hairy skin), found on the palms and soles, is grooved on its surface by continuously alternating ridges and sulci, in individually unique configurations known as dermatoglyphics. It is characterized by a thick epidermis divided into several well-marked layers, including a compact stratum corneum, by the presence of encapsulated sense organs within the dermis, and by a lack of hair follicles and sebaceous glands. Hair-bearing skin (Fig. 3.1), on the other hand, has both hair follicles and sebaceous glands but lacks encapsulated sense organs. There is also wide variation between different body sites. For example, the scalp with its large hair follicles may be contrasted with the forehead, which has only small vellus-producing follicles, albeit associated with large sebaceous glands. The axilla is notable because it has apocrine glands in addition to the eccrine sweat glands, which are found throughout the body. Regional variation is further considered below. Chapter 3

Oncostatin M Receptor-β Mutations Underlie Familial Primary Localized Cutaneous Amyloidosis

Abstract: Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1–q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor β (OSMRβ), in three families. OSMRβ is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.

Transformation-specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas

Abstract: Summary Background Patients with recessive dystrophic epidermolysis bullosa (RDEB) have an increased risk of developing rapidly progressive and metastatic cutaneous squamous cell carcinomas (SCC). It is unclear why these SCC behave more aggressively than sporadic SCC. Matrix metalloproteinases (MMP) are a family of endopeptidases that contribute to growth, invasion and metastasis of SCC. The role of MMP in RDEB-associated SCC is not known. Objectives To investigate the expression of MMP-7, MMP-13 and MMP-9 in RDEB-associated SCC in comparison with sporadic SCC and Bowen’s disease. Methods Immunohistochemical analysis of 25 RDEB-associated SCC, 61 sporadic SCC and 28 sporadic lesions of Bowen’s disease was carried out using monoclonal antibodies for MMP-7, MMP-9, MMP-13 and E-cadherin and syndecan-1. Results MMP-7 was detected in all RDEB-associated SCC, in tumour cells within the invasive edge, where E-cadherin and syndecan-1 were markedly diminished or absent. MMP-7 expression was also observed in 98% of sporadic SCC and in 68% of Bowen’s diseases. MMP-7 staining was significantly stronger in RDEB-associated SCC than in sporadic SCC, and was most abundant in poorly differentiated tumours. MMP-13 was detected in tumour cells in 96% of RDEB-associated SCC and in all sporadic cutaneous SCC. MMP-9 was detected in the inflammatory cells in all SCC examined. Conclusions These results identify MMP-7 and MMP-13 as tumour cell-specific markers for SCC progression and as potential therapeutic targets in RDEB-associated SCC. The pattern of immunolabelling suggests that MMP-7 may shed E-cadherin and syndecan-1 from the SCC cell surface.

A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes

Abstract: Missense mutations in the 3' end of the p63 gene are associated with either RHS (Rapp-Hodgkin syndrome) or AEC (Ankyloblepharon Ectodermal defects Cleft lip/palate) syndrome. These mutations give rise to mutant p63alpha protein isoforms with dominant effects towards their wild-type counterparts. Here we report four RHS/AEC-like patients with mutations (p.Gln9fsX23, p.Gln11X, p.Gln16X), that introduce premature termination codons in the N-terminal part of the p63 protein. These mutations appear to be incompatible with the current paradigms of dominant-negative/gain-of-function outcomes for other p63 mutations. Moreover it is difficult to envisage how the remaining small N-terminal polypeptide contributes to a dominant disease mechanism. Primary keratinocytes from a patient containing the p.Gln11X mutation revealed a normal and aberrant p63-related protein that was just slightly smaller than the wild-type p63. We show that the smaller p63 protein is produced by translation re-initiation at the next downstream methionine, causing truncation of a non-canonical transactivation domain in the DeltaN-specific isoforms. Interestingly, this new DeltaDeltaNp63 isoform is also present in the wild-type keratinocytes albeit in small amounts compared with the p.Gln11X patient. These data establish that the p.Gln11X-mutation does not represent a null-allele leading to haploinsufficiency, but instead gives rise to a truncated DeltaNp63 protein with dominant effects. Given the nature of other RHS/AEC-like syndrome mutations, we conclude that these mutations affect only the DeltaNp63alpha isoform and that this disruption is fundamental to explaining the clinical characteristics of these particular ectodermal dysplasia syndromes.

Filaggrin and the great epidermal barrier grief.

Abstract: One of the principal functions of human skin is to form an effective mechanical barrier against the external environment. This involves the maturation and death of epidermal keratinocytes as well as the assembly of a complex network of differentially and spatially expressed proteins, glycoproteins and lipids into the keratinocyte cell membrane and surrounding extracellular space. In 2006, the key role of the granular cell layer protein filaggrin (filament-aggregating protein) in maintaining the skin barrier was determined with the identification of loss-of-function mutations in the profilaggrin gene (FLG). These mutations have been shown to be the cause of ichthyosis vulgaris and a major risk factor for the development of atopic dermatitis, asthma associated with atopic dermatitis as well as systemic allergies. Mutations in the FLG gene are extremely common, occurring in approximately 9% of individuals from European populations. The remarkable discovery of these widespread mutations is expected to have a major impact on the classification and management of many patients with ichthyosis and atopic disease. It is also hoped that the genetic discovery of FLG mutations will lead to the future development of more specific, non-immunosuppressive treatments capable of restoring effective skin barrier function and alleviating or preventing disease in susceptible individuals.

Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco

Abstract: Three siblings from Morocco consanguineous family presented with cutaneous poikiloderma following postnatal ichthyosiform lesions, associated with papillomatous lesions, palmoplantar keratoderma, pachyonychia of toenails, fragile carious teeth, and lachrymal duct obstruction Photosensitivity and blistering improved with age Atrophic scars were prominent on the limbs Neutropenia developed in the first year secondary to dysmyelopoiesis affecting the granulocyte lineage, associated with a polyclonal hypergammaglobulinemia Several broncho-pulmonary infectious episodes complicated the evolution, and cystic fibrosis was first considered on the basis of repeated abnormal sweat chloride tests but not confirmed by molecular analyses This autosomal recessive disorder matches that described originally as poikiloderma with neutropenia-Clericuzio type in Navajo Indians (OMIM 604173) It is discussed within the group of the major hereditary poikiloderma disorders, that is, Rothmund-Thomson syndrome, dyskeratosis congenita, and Kindler syndrome

Desquamative enteropathy and pyloric atresia without skin disease caused by a novel intracellular beta4 integrin mutation.

Abstract: ITGB4 mutation may induce a desquamative enteropathy in infancy without significant skin disease. A history of pyloric atresia is important in infants with severe chronic diarrhoeal disease and should prompt investigation for JEB-PA associated mutations. Acquired immune responses may exacerbate primary genetic disorders of epithelial adhesion and immunomodulatory therapy may be beneficial.

A delay in radical cystectomy of >3 months is not associated with a worse clinical outcome

Abstract: We agree with the authors [1] that delays to definitive treatment for high-risk bladder cancer should be minimized because it is a potentially lethal disease, and management options need to be discussed with colleagues in a multidisciplinary setting as well as with the patient. In addition, reducing delays should help to ease the anxiety and psychological morbidity that patients and their families suffer.

Molecular genetics as a diagnostic and prognostic aid in the assessment of neonates with red, scaly genodermatoses: work still in progress.

Abstract: A LONG DIFFERENTIAL DIAGNOSIS IS A familiar scenario for many dermatologists caring for patients with inherited skin diseases, and no more so than when neonates present with dry, scaly, red, or eroded skin. An ability to make accurate diagnoses in such cases is often vitally important in patient management because the clinical course and prognosis of the conditions may vary widely—a real problem given the often overlapping and indistinguishable early physical signs. For the perplexed clinician, some new diagnostic and prognostic help is at hand. Recent advances in understanding the molecular basis of more than 350 monogenic inherited diseases is now having a direct impact on patient care. The emerging translational benefits from genetics research are multiple: more accurate diagnoses, improved genotype-phenotype correlation, better genetic counseling, greater feasibility of DNA-based prenatal diagnosis, and new ideas about treatment, including gene, protein, and cell therapies.