Fragility Syndrome Research Articles

Síndrome da fragilidade biológica em idosos: revisão sistemática

The aim of this study was to identify the prevalence and assessment strategies of Biological Fragility Syndrome in the Elderly.For the development of this study was it was done a search in electronic databases (Medline/PubMed) and the reference lists of articles identified using the following key words/terms in English: "frailty" and `frail" in conjunction with the terms "elderly", "aging" and "prevalence". These terms/descriptors were combined using the logical operators available in search engines. The initial electronic search resulted in 1 865 manuscripts. The process of analysis of the studies involved reading titles, abstracts and full texts. After all these phases, 35 manuscripts met the inclusion criteria of the review.The results indicated that women, with rage from 7.3 % to 21.6 %, are frailer than men, with percentages ranging from 4 % to 19.2 %.Differences in prevalence rates of prefrailty and frailty should be minimized, with stimulus for standardization for the evaluation of human frailty.

Overexpression of the Flii gene increases dermal–epidermal blistering in an autoimmune ColVII mouse model of epidermolysis bullosa acquisita

Epidermolysis bullosa (EB) is a severe genetic skin fragility syndrome characterized by blister formation. The molecular basis of EB is still largely unknown and wound healing in patients suffering from EB remains a major challenge to their survival. Our previous studies have identified the actin remodelling protein Flightless I (Flii) as an important mediator of wound repair. Here we identify Flii as a novel target involved in skin blistering. Flii expression was significantly elevated in 30 patients with EB, most prominently in patients with recessive dystrophic EB (RDEB) who have defects in production of type VII collagen (ColVII). Using an autoimmune ColVII murine model of EB acquisita (EBA) and an immunocompetent-ColVII-hypomorphic genetic mouse model of RDEB together with murine Flii alleles, we investigated the contribution of Flii to EB. Overexpression of Flii produced severe blistering post-induction of EBA, while decreased Flii reduced blister severity, elevated integrin expression, and improved ColVII production. Flii(+/-) blistered skin showed reduced α-SMA, TGF-β1, and Smad 2/3 expression, suggesting that decreasing Flii may affect fibrosis. In support of this, Flii-deficient fibroblasts from EBA mice were less able to contract collagen gels in vitro; however, addition of TGF-β1 restored collagen contraction, suggesting an interplay between Flii and TGF-β1. Elevated Flii gene and protein expression was further observed in the blisters of ColVII hypomorphic mice, a murine model of RDEB, suggesting that reducing Flii in blistered skin could be a potential new approach for treating patients with EB.

Reducing pain during the removal of adhesive and adherent products

Silicone Medical Adhesive Removers (SMARs) have proved a valuable addition to formularies. In the absence of SMARs, trauma following removal of adhesive dressings, ostomy products, retention tapes and monitoring equipment can lead to skin stripping or extension of existing wounds. Those at increased risk of skin stripping include groups such as older people, premature infants and neonates and those with skin fragility syndromes. Appeel® Sterile Sachet (CliniMed) is a sterile SMAR in liquid form supplied in a single-use sachet. The addition of this sterile product to the existing Appeel range of wipes and aerosols provides an adhesive remover suitable for use on broken skin. Unlike delivery from an aerosol, Appeel Sterile Sachet does not feel cold on application, a sensation which can be confused with pain. This article discusses the value of SMARs and in particular the advantages of using the single-use Appeel Sterile Sachet.

Ectodermal dysplasia-skin fragility syndrome

Ectodermal dysplasia-skin fragility (EDSF) syndrome is a rare and first described inherited disorder of desmosomes. It occurs due to loss-of-function mutations in PKP1 gene resulting in poorly formed desmosomes and loss of desmosomal and epidermal integrity. We report a case of a 2-year-old Indian male child who presented with palmoplantar hyperkeratosis with fissuring, short, sparse, and easily pluckable scalp hair, nail dystrophy, and multiple erosions over the skin. Skin biopsy showed epidermal hyperplasia with widening of intercellular spaces. His developmental milestones were delayed but intelligence was normal. Echocardiography, X-ray chest, and electrocardiogram were normal. Very few cases of this syndrome have been reported in the literature. We consider this as the first case report from India.

A Case of Feline Acquired Skin Fragility Syndrome with Hepatic Lymphoma

推定16歳の去勢雄の雑種猫が食欲および活動性の低下を主訴として来院した。初診時において，本症例では重度の削痩が認められた。脱水の評価を目的として胸背部の皮膚をつまみあげたところ，皮膚が容易に剥離した。剥離した皮膚片の病理組織検査より，表皮の菲薄化，真皮における膠原線維の高度減少，皮膚付属器における高度の萎縮などが認められたことから，猫の後天性皮膚脆弱症候群と診断した。潜在する基礎疾患を同定するため各種検査を実施したところ，Ｘ線検査および超音波検査により胸水の貯留と肝臓における正常構造の消失が認められた。対症療法を実施したが初診日より第16日目に死亡した。死後の剖検ならびに病理組織学的診断により，本症例では肝臓にリンパ腫が認められた。

Osteoporosis Associated With Pulmonary Silicosis in an Equine Bone Fragility Syndrome

California horses incur a bone fragility syndrome manifested by pathologic fractures. This study investigated gross, radiographic, and histologic features of the disorder as well as relationships with silicosis and levels of heavy metals and trace minerals through a postmortem study of 9 affected and 3 unaffected horses. Bones and soft tissues were evaluated grossly and histologically. Bones, lymph nodes, and lung tissue were evaluated radiographically. Tissues were evaluated for silicon levels, intracytoplasmic crystals, heavy metals, and trace minerals. All 9 affected horses had osteoporosis and clinical or subclinical pulmonary disease due to silicosis (8/9) or pneumoconiosis (1/9). All affected horses had radiographic findings consistent with osteopenia and histologic evidence of osteoporosis characterized by osteopenia, numerous resorption cavities, cement lines, and a mosaic lamellar pattern indicative of multiple remodeling events. Silicosis was characterized by widespread pulmonary granuloma formation with fibrosis; variable tracheobronchiolar and mediastinal granulomatous lymphadenitis; intracellular crystals within lung and lymph node macrophages; and pronounced lymph node fibrosis, focal necrosis, and dystrophic calcification. Crystals in lung (6/9) and lymph node (8/9) tissues were identified as cytotoxic silica dioxide polymorphs. Lung and liver tissue from affected horses had elevated levels of elemental silicon. Osteoporosis was highly correlated (r = 0.8, P < .01) with silicosis. No abnormalities in heavy metal or trace minerals were detected. This evaluation indicated that horses with bone fragility disorder have systemic osteoporosis associated with fibrosing pulmonary silicosis. The etiopathogenesis of the bone fragility syndrome is unknown; however, this study provides circumstantial evidence for a silicate associated osteoporosis.

A Nuclear Function for Plakophilin-1 in the DNA Damage Response?

Plakophilins are proteins of the desmosomal plaque. Based on the observation that plakophilins localize not only to desmosomes but also to the cytoplasm and nucleus, additional functions in cell signaling have been proposed. In this issue, Sobolik-Delmaire et al. address the nuclear function of Plakophilin-1. The authors show that Plakophilin-1 interacts with ssDNA in vitro and may have a function in protecting cells from DNA damage.

Pituitary-dependent hyperadrenocorticism and generalised toxoplasmosis in a cat with neurological signs

A 12-year-old female neutered cat presented with acute onset unilateral vestibular syndrome, a spontaneous cutaneous wound, polyuria, polydipsia, and diabetes mellitus. Hyperadrenocorticism was demonstrated by means of hyper-responsiveness to adrenocorticotropic hormone stimulation, elevated urine cortisol-to-creatinine ratio, bilaterally enlarged adrenal glands on abdominal ultrasound, and pituitary enlargement on computed tomography imaging. The cat was euthanased and post-mortem histological examination revealed feline skin fragility syndrome; confirmed a pituitary cromophobe macroadenoma; and generalised toxoplasmosis with tachyzoites in the pancreas, bowel and brain. This report is the first to describe the concurrence of macroadenoma pituitary-dependent hyperadrenocorticism and generalised toxoplasmosis in a cat with central vestibular syndrome.

Ectodermal Dysplasia-Skin Fragility Syndrome

Pathogenic mutations have now been described in ten different desmosomal proteins: plakophilin 1 (PKP1) and 2 (PKP2); desmoplakin; plakoglobin; desmoglein 1, 2, and 4; desmocollin 2, and 3 corneodesmosin. Nevertheless, the first report of an inherited desmosomal gene disorder, published in 1997, involved loss-of-function mutations on both alleles of PKP1, the PKP1 gene. Loss of PKP1 expression in human skin leads to skin erosions and crusting, notably with perioral fissuring as well as palmoplantar hyperkeratosis with painful cracking of the skin. Other more variable features include abnormalities of ectodermal development with growth delay, hypotrichosis or alopecia, hypohidrosis, and nail dystrophy. In contrast to some other inherited disorders of desmosomes, there is no cardiac pathology in individuals with PKP1 mutations since it is not expressed in the heart. The collection of clinical features in individuals with PKP1 mutations has been termed ectodermal dysplasia-skin fragility (ED-SF) syndrome. This genodermatosis is classified as a suprabasal form of epidermolysis bullosa simplex and thus far there have been 10 published cases. Skin biopsy shows acanthosis, acantholysis, and a reduced number of small, poorly formed desmosomes. Loss of PKP1 expression results in an integral weakness within the desmosomal plaque, leading to desmosomal detachment and cell-cell separation. Thus, the clinicopathologic features attest to the significant role of PKP1 in stabilization of desmosome structure and function, predominantly in the spinous layers of the epidermis. This article reviews the clinical, structural, and molecular pathology of this genetic disorder of desmosomes.

The Desmosomal Plaque Proteins of the Plakophilin Family

Three related proteins of the plakophilin family (PKP1_3) have been identified as junctional proteins that are essential for the formation and stabilization of desmosomal cell contacts. Failure of PKP expression can have fatal effects on desmosomal adhesion, leading to abnormal tissue and organ development. Thus, loss of functional PKP 1 in humans leads to ectodermal dysplasia/skin fragility (EDSF) syndrome, a genodermatosis with severe blistering of the epidermis as well as abnormal keratinocytes differentiation. Mutations in the human PKP 2 gene have been linked to severe heart abnormalities that lead to arrhythmogenic right ventricular cardiomyopathy (ARVC). In the past few years it has been shown that junctional adhesion is not the only function of PKPs. These proteins have been implicated in cell signaling, organization of the cytoskeleton, and control of protein biosynthesis under specific cellular circumstances. Clearly, PKPs are more than just cell adhesion proteins. In this paper we will give an overview of our current knowledge on the very distinct roles of plakophilins in the cell.

Acquired Skin Fragility Syndrome with Systemic Amyloidosis in a Cat

推定9歳の短毛雑種猫が臀部皮膚の裂傷を訴え当院を受診。臀部皮膚は菲薄化しており負荷をかけると容易に裂開した。血液検査で貧血と左方移動を伴う好中球の増加が認められた。皮膚病理組織学検査で表皮の菲薄化，角化亢進，真皮の萎縮や，コラーゲン線維の微細化等が認められ，猫の後天性皮膚脆弱症候群と診断した。第54病日に突然死亡し剖検を実施，脂質肺炎および間質性腎炎を伴う全身性アミロイド症が観察された。

Acantholytic ectodermal dysplasia: clinicopathological study of a new desmosomal disorder

We describe two boys with curly hair, palmoplantar keratoderma and skin fragility who presented clinical and histological features similar, but not identical, to those exhibited by patients with ectodermal dysplasia-skin fragility syndrome (McGrath syndrome) and other genetic desmosomal defects such as Carvajal syndrome and Naxos disease. Clinical features included trauma-induced blisters and erosions, palmoplantar keratoderma and hyperkeratotic, fissured plaques with perioral involvement. The patients had abundant curly scalp hair, and normal eyebrows and eyelashes. Sweating was normal. Nails were normal at birth but subsequently showed secondary dystrophy. Histopathological analysis of the skin demonstrated acantholysis and intercellular widening of the spinous and granular layers in involved regions. No involvement of scalp skin was seen. Desmosomes were markedly reduced in number and poorly developed with no clear insertions of the keratin filaments. The latter were clumped around the nuclei. Immunostaining of patient skin with antibodies raised against key desmosomal proteins demonstrated disrupted expression of desmoplakin, plakoglobin and desmoglein 1. Additional studies of the family history and of the desmoplakin, plakoglobin and desmoglein 1 genotype for both patients may help further elucidate the molecular cause of this variation on ectodermal dysplasia-skin fragility syndrome.

Novel truncating mutations inPKP1andDSPcause similar skin phenotypes in two Brazilian families

Inherited mutations in components of desmosomes result in a spectrum of syndromes characterized by variable abnormalities in the skin and its appendages, including blisters and erosions, palmoplantar hyperkeratosis, woolly hair or hypotrichosis and, in some cases, extracutaneous features such as cardiomyopathy. We investigated the molecular basis of two Brazilian patients presenting with clinical features consistent with ectodermal dysplasia-skin fragility syndrome. In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1). This particular mutation has not been reported previously but is similar to the molecular pathology underlying other cases of this syndrome. In patient 2 we found compound heterozygosity for two frameshift mutations, c.2516del4 and c.3971del4, in the DSP gene (encoding desmoplakin). Although there was considerable clinical overlap in the skin and hair abnormalities in these two cases, patient 2 also had early-onset cardiomyopathy. The mutation c.3971del4 occurs in the longer desmoplakin-I isoform (which is the major cardiac transcript) but not in the more ubiquitous desmoplakin-II. In contrast, PKP1 is not expressed in the heart, which accounts for the lack of cardiomyopathy in patient 1. Collectively, these cases represent the first desmosomal genodermatoses to be reported from Brazil and add to genotype-phenotype correlation in this group of inherited disorders. Loss-of-function mutations in the DSP gene can result in a phenotype similar to ectodermal dysplasia-skin fragility syndrome resulting from PKP1 mutations but only DSP pathology is associated with cardiac disease.

Skin fragility syndrome in a cat with feline infectious peritonitis and hepatic lipidosis

A 6‐year‐old spayed female domestic shorthair cat with a 3‐week history of inappetence, weight loss, and hiding was examined. A palpable abdominal fluid wave, dehydration, and a small tear on the left flank were noted during initial examination. When the cat was gently restrained for blood sampling, the skin on the dorsal neck tore, leaving a 15 cm × 7 cm flap of skin. Clinicopathological abnormalities included nonregenerative anaemia, hypoalbuminaemia, increased globulin concentration, and mildly elevated aspartate aminotransferase and alkaline phosphatase activities. Abdominal fluid was viscous and had a total protein of 5.3 g dL−1 with 316 cells µL−1, consistent with a modified transudate. Cytology of the abdominal fluid revealed 86% nondegenerate neutrophils, 13% macrophages, and 1% small lymphocytes. Histopathological evaluation and indirect immunohistochemistry confirmed a diagnosis of feline infectious peritonitis, hepatic lipidosis and feline skin fragility syndrome. Feline skin fragility syndrome has not previously been reported in association with feline infectious peritonitis (FIP). Its inclusion as a clinical sign associated with FIP may facilitate a diagnosis.

Conhecimento dos médicos clínicos do Brasil sobre as estratégias de prevenção e tratamento da osteoporose

OBJETIVOS: investigar o conhecimento de profissionais médicos brasileiros a respeito da osteoporose, estratégias de prevenção e tratamento e o acesso à informação em osteoporose, utilizando-se um questionário desenvolvido para avaliar o conhecimento de profissionais médicos em relação à importância da osteoporose e suas estratégias de tratamento. PACIENTES E MÉTODOS: o questionário foi divulgado a11 mil médicos afiliados à Sociedade Brasileira de Clínica Médica (SBCM). Realizou-se a divulgação da pesquisa e do questionário por meio de anúncios publicados no Jornal do Clínico. Inicialmente, foi disponibilizado na home-page e, em seguida, diretamente enviado via e-mail aos sócios cadastrados da SBCM. RESULTADOS: um total de 329 questionários retornou aos pesquisadores. A maioria dos médicos (55,3%) tinha tempo de graduação superior a 10 anos. Pouco mais que a metade dos profissionais médicos pesquisados (55%) relatou ter fácil acesso à densitometria óssea. A maioria (99%) dos participantes acredita que é importante ou muito importante prevenir a osteoporose. Da mesma forma, 73% dos médicos pesquisados acreditam que a osteoporose possa ser prevenida e 63% deles discutem o assunto com os seus pacientes. Por outro lado, mais da metade dos médicos pesquisados não crê que seus pacientes venham a mudar hábitos de vida e cerca de 50% deles não acreditam que seus pacientes venham a aderir ao tratamento da doença em longo prazo. Apenas 35% dos médicos pesquisados acreditam que os tratamentos para osteoporose sejam efetivos. Cerca de 82% fazem uso da densitometria óssea. Médicos com 10 anos ou mais de graduação utilizam a densitometria óssea mais freqüentemente que seus colegas com menos tempo de graduação. CONCLUSÃO: os autores acreditam que as informações obtidas no presente estudo poderiam ser úteis para o início do desenvolvimento de estratégias educacionais efetivas para a prevenção e o tratamento de pacientes com osteoporose.

The ends of a conundrum?

The existence of differential keratin protein functions is a matter of controversy. Keratin genes display a differential regulation in the various epithelia of the body and inherited mutations affecting keratin genes are responsible for a variety of epithelial fragility syndromes. In recent years,

Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability

Fanconi anemia (FA) is a chromosome fragility syndrome characterized by bone marrow failure and cancer susceptibility. The central FA protein FANCD2 is known to relocate to chromatin upon DNA damage in a poorly understood process. Here, we have induced subnuclear accumulation of DNA damage to prove that histone H2AX is a novel component of the FA/BRCA pathway in response to stalled replication forks. Analyses of cells from H2AX knockout mice or expressing a nonphosphorylable H2AX (H2AX(S136A/S139A)) indicate that phosphorylated H2AX (gammaH2AX) is required for recruiting FANCD2 to chromatin at stalled replication forks. FANCD2 binding to gammaH2AX is BRCA1-dependent and cells deficient or depleted of H2AX show an FA-like phenotype, including an excess of chromatid-type chromosomal aberrations and hypersensitivity to MMC. This MMC hypersensitivity of H2AX-deficient cells is not further increased by depleting FANCD2, indicating that H2AX and FANCD2 function in the same pathway in response to DNA damage-induced replication blockage. Consequently, histone H2AX is functionally connected to the FA/BRCA pathway to resolve stalled replication forks and prevent chromosome instability.

Skin Needs Plakophilin-1

In 1997, McGrath et al. (1997) described a condition called ectodermal dysplasia/skin fragility syndrome and showed that it was caused by mutations of the plakophilin-1 gene, the first mutations to be discovered in a human desmosomal gene. Effectively a plakophilin-1 knockout, the discovery gave novel insights into the function of this protein in desmosomal adhesion and keratin filament attachment to the desmosomal plaque. At birth, the proband suffered from severe blistering of his face, soles and buttocks. Nevertheless he survived and, although small, grew at a normal rate. By 5 years of age, he showed complete absence of hair, widespread crusts and erosions on his skin, marked hyperkeratosis on the palms and soles, and abnormal nails. Wide intercellular spaces, indicative of loss of keratinocyte adhesion, were revealed by histological and ultrastructural examination of the epidermis. Moreover, keratin filaments were withdrawn from the keratinocyte peripheries and aggregated around the nuclei. Desmosomes were small, with widened intercellular spaces and greatly reduced intercellular plaques, suggesting that the syndrome might be due to a desmosomal abnormality. The nature of this was revealed by immunofluorescence with specific desmosomal antibodies. Desmosomal cadherins and plakoglobin were normally distributed, but desmoplakin was diffuse and, crucially, cytoplasmic staining for plakophilin-1 was absent. Mutational analysis of the plakophilin-1 gene revealed distinct mutations in the paternally and maternally inherited alleles, both resulting in premature termination due to the insertion of stop codons and in severe truncation of the polypeptide. A study of this human syndrome had revealed that plakophilin-1 is a key component of the desmosomal plaque, being somehow involved in the location of desmoplakin, and through this, the anchoring of intermediate filaments. Loss of plakophilin function also reduced desmosomal adhesion. Subsequently, plakophilin-1 was localized to the outer dense plaque, to bind to desmoglein, desmocollin, desmoplakin and keratin and to recruit desmosomal proteins to the cell periphery (Smith and Fuchs, 1998; North et al., 1999; Hatzfeld et al., 2000). Furthermore, Grossman et al. (2004), studying plakophilin-2 knockout in mice, confirmed plakophilin’s role in the location of desmoplakin to the desmosomal plaque. Plakophilin-1 is a member of the armadillo gene family and one of three plakophilin isoforms to have been identified. All three are present in the epidermis, and this may account for the nonlethality for the viability of the proband in this case; plakophilins-2 and -3 may compensate for the loss of plakophilin-1. Besides being desmosomal components, plakophilins are widely distributed in the cytoplasm and nuclei of various cells. Their nuclear function is unclear, but a recent study suggests an involvement with RNA-binding proteins and involvement in translation and RNA metabolism (Hofmann et al., 2006). Several other inherited diseases involving desmosomal components have since been discovered. These disorders include a variety of defects in the skin, hair and the heart, and vary in severity from mild to lethal (reviewed in McGrath, 2005). Collectively, such studies have provided a greater understanding of the cellular mechanisms underlying skin biology that may aid the future treatment of skin diseases and how desmosomal components contribute to tissue structure, regulation and function.

C-terminal Truncation Impairs Glycosylation of Transmembrane Collagen XVII and Leads to Intracellular Accumulation

Collagen XVII, a type II transmembrane protein in hemidesmosomes, is involved in the anchorage of stratified epithelia to the underlying mesenchyme. Its functions are regulated by ectodomain shedding, and its genetic defects lead to epidermal detachment in junctional epidermolysis bullosa (JEB), a heritable skin fragility syndrome, but the molecular disease mechanisms remain elusive. Here we used a spontaneously occurring homozygous COL17A1 deletion mutant in JEB to discern glycosylation of collagen XVII. The mutation truncated the distal ectodomain and positioned the only N-glycosylation site 34 amino acids from the newly formed C terminus, which impaired efficient N-glycosylation. Immunofluorescence staining of authentic JEB keratinocytes and of COS-7 cells transfected with the mutant indicated intracellular accumulation of collagen XVII precursor molecules. Cell surface biotinylation and quantification of ectodomain shedding demonstrated that only about 15% of the truncated collagen XVII reached the cell surface. The cell surface-associated molecules were N-glycosylated in a normal manner, in contrast to the molecules retained within the cells, indicating that N-glycosylation of the ectodomain is required for targeting of collagen XVII to the plasma membrane and that reduced accessibility of the N-glycosylation site negatively regulates this process. Functional consequences of the strong reduction of collagen XVII on the cell surface included scattered deposition of cell adhesion molecule laminin 5 into the extracellular environment and, as a consequence of faulty collagen XVII-laminin ligand interactions, aberrant motility of the mutant cells.

Ectodermal dysplasia–skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1

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.