Kindler Syndrome Research Articles

Long nail cuticle in kindler syndrome

Kindler syndrome is a rare autosomal recessive disorder associated with skin fragility. It is characterized by blistering in infancy, photosensitivity, and progressive poikiloderma. The syndrome can also involve mucous membrane, eyes, bones, and rarely nails. We report the case of an adolescent female patient with characteristic features of Kindler syndrome and striking presence of long and thick cuticle of nails, which has been rarely reported.

The kindlin family: functions, signaling properties and implications for human disease.

The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation. Another hallmark of kindlins is their involvement in disease. Mutations in the KINDLIN-1 (also known as FERMT1) gene cause Kindler syndrome (KS)--in which mainly skin and intestine are affected, whereas mutations in the KINDLIN-3 (also known as FERMT3) gene cause leukocyte adhesion deficiency type III (LAD III), which is characterized by impaired extravasation of blood effector cells and severe, spontaneous bleedings. Also, aberrant expression of kindlins in various forms of cancer and in tissue fibrosis has been reported. Although the malfunctioning of integrins represent a major cause leading to kindlin-associated diseases, increasing evidence also point to integrin-independent functions of kindlins that play an important role in the pathogenesis of certain disease aspects. Furthermore, isoform-specific kindlin functions have been discovered, explaining, for example, why loss of kindlins differentially affects tissue stem cell homeostasis or tumor development. This Commentary focuses on new and isoform-specific kindlin functions in different tissues and discusses their potential role in disease development and progression.

Dystrophic epidermolysis bullosa associated with congenital contractures of the upper and lower limbs: literature review

Epidermolysis bullosa (EB) is a rare hereditary disease. Its main feature is vesication and weeping sores (erosions) of the skin and mucous membranes, resulting from a minor injury. Clinical manifestations of the disease may vary from localized vesicles on the hands and feet to a generalized rash of the skin as well as lesions of the mucosa of the inner organs. At present, there are four main groups of EB: simple, intermediate, dystrophic, and Kindler syndrome. Mutations cause changes in the structure of the proteins responsible for the adhesion between layers of the dermis, leading to vesication. Treatment of EB is a challenge because of the lack of opportunities for the direct influence on the disease process, and its main purpose is to correct the existing cutaneous manifestations and prevent the occurrence of new elements. This article describes the main types of EB, methods of current diagnosis, and treatment of the disease as well as a clinical case of a rare combination of two severe disorders: 1) dystrophic EB and 2) arthrogryposis with upper and lower limb involvement.

Kindler syndrome - a rare type of hereditary epidermolysis bullosa

The Kindler syndrome is one of the types of hereditary epidermolysis bullosa with its onset related to mutations of the KIND1 gene. The authors describe a case of a family with three members suffering from this rare disease. All of these patients have typical clinical manifestations of the Kindler syndrome such as the formation of blisters on the skin and mucous membranes right after the birth, scarring with the formation of contractures, pseudosyndactyly, microstomia and ankyloglossia, progressive poikiloderma, photosensibility, affections of the gastrointestinal tract - dysphagia, esophagostenosis, stool disorders, dental pathology, phimosis vaginalis in women.

Using immunofluorescence (antigen) mapping in the diagnosis and classification of epidermolysis bullosa: a first report from Iran.

Immunofluorescence antigen mapping (IFM), is a newly introduced technique for diagnosis and classification of epidermolysis bullosa (EB) disease. The precise level of skin cleavage can be determined using monoclonal antibodies to EB-specific basement membrane zone protein. To apply IFM technique in diagnosis and classification of EB and to identify utility and limitation of this method in our clinical setting. IFM was done according to a described protocol by Pohla-Gubo et al. Monoclonal antibodies used for antigen mapping were against cytokeratin 5, cytokeratin 14, α6 integrin, β4 integrin, laminin 332, Collagen IV, and Collagen VII. IFM was done for 95 referred patients, compromising 49 females and 46 males, aged 5 days to 45 years (mean = 9.5 years). Ninety cases were diagnosed with EB and classified as follows: EB simplex: (n = 13), junctional EB (n = 14), dystrophic EB (n = 62), and Kindler syndrome (n = 1). Diagnosis was not made in five cases as their specimens contained no blister. Confirmatory genetic analysis was done for five junctional cases from two families with clinical features of laryngo-onycho-cutaneous syndrome. Genetic molecular studies showed nonsense mutations in the last codon of exon 39 of the laminin α3a (LAMA3) gene (p.Gln57X) and a donor splice site mutation in LAMA3 (IVS57+5G>A) in the first and second family, respectively. IFM technique is relatively simple to perform, and interpretation of the results is not sophisticated. The proportion of inconclusive results will be decreased if the specimens contain freshly induced blister.

Epidermolysis bullosa and Kindler syndrome - where is the border in oral manifestaions

Epidermolysis bullosa (EB) represents a rare chronic autoimmune subepidermal vesiculobullous disorder that affects the skin and mucosa and is characterized by blistering and mechanical fragility of the skin. The most recent classification recognizes four major EB groups: intraepidermal EB (Simplex), junctional EB, dermolytic EB (Dystrophic), and mixed EB (Kindler syndrome). Kindler syndrome is a rare genodermatosis with clinical features of trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The clinical features of the syndrome have been annotated by different authors but definite criteria to confirm the diagnosis have not yet been generally accepted.

Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm.

Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues.

New associated clinical findings in Kindler syndrome: Case report

New associated clinical findings in Kindler syndrome: Case report

Recently Identified Forms of Epidermolysis Bullosa.

Epidermolysis bullosa (EB) comprises a collection of clinically diverse inherited blistering diseases that affect the skin and, in some subtypes, mucous membranes and other organs. Currently classified into four main subtypes (EB simplex, junctional EB, dystrophic EB, and Kindler syndrome, mainly based on the level of skin cleavage), the spectrum of EB extends to more than 30 clinical subtypes with pathogenic mutations in at least 18 distinct genes. This review focuses on three recent additions to variants of EB: all are autosomal recessive, and result from mutations in either DST-e (coding for epidermal dystonin, also known as the 230 kDa bullous pemphigoid antigen, BP230), EXPH5 (coding for exophilin-5, also known as Slac2-b), or ITGA3 (coding for the integrin alpha-3 subunit). Each of these new forms of EB is reviewed with respect to the initial gene discovery, clinical features, the current mutation database, and skin pathology. Awareness of these recently described forms of EB is helpful in the clinical evaluation of patients with EB and in defining genotype-phenotype correlation for inherited blistering skin diseases.

Nailfold capillaroscopic changes in Kindler syndrome.

Kindler syndrome (KS), the fourth major type of hereditary epidermolysis bullosa (HEB), is a rare, autosomal recessive disorder characterized by skin fragility and blistering at birth followed by development of marked photosensitivity and progressive poikilodermatous skin changes in later years. We reported here the case of a 54-year-old woman, who fulfills the diagnostic criteria of KS type of HEB, putting accent on the nailfold capillaroscopic changes. Using videocapillaroscopy we observed pronounced alterations in finger nail capillaries including reduction in capillary density, features of neoangiogenesis (architectural derangement, elongated loops, extremely tortuous, bushy or branching capillaries, thin, branching and interconnected capillaries), enlarged and giant capillaries. We consider the changes observed as an adaptive mechanism that compensate the loss of capillaries due to chronic periungual trauma. Further studies with larger number of patients are needed to confirm the significance of capillaroscopy findings for patients with HEB.

Immunofluorescence mapping in inherited epidermolysis bullosa: a study of 86 cases from India.

Epidermolysis bullosa (EB) poses diagnostic challenges in infancy. In India, the diagnosis is largely clinical. There were no facilities to perform immunofluorescence mapping (IFM) until recently, and electron microscopy, which requires expertise to interpret, is limited to a few research laboratories. To describe the patterns of IFM staining in the various forms of EB in Indian patients and to correlate these findings with clinical diagnosis. We conducted a cross-sectional study of IFM findings in EB. Antibodies against type IV collagen, cytokeratin 14, laminin 332 and type VII collagen were used. Clinical correlation was performed in all cases, and concordance-discordance rates were calculated. Eighty-six patients with a diagnosis of EB were included in the study. There were 29 with EB simplex (EBS), 18 with junctional EB (JEB) and 15 with dystrophic EB (DEB). The remaining 24 cases included rare variants, cases with overlapping clinical features and cases where the type of EB was not known. On IFM diagnosis, there were 32 cases of EBS, 15 JEB, 17 DEB and two Kindler syndrome. Two cases were not EB and 18 were inconclusive. IFM could establish the type in 12 of 15 cases (80%) that had overlapping clinical features. Most of these cases were under 1year of age. Overall the concordance was 57% and was seen best in cases of EBS. This is the first large study of IFM of the subtypes of EB in Indian patients. The study provides a framework for better understanding of EB in Indian patients and for better diagnosis and management, particularly in infancy.

Oxidative stress and mitochondrial dysfunction in Kindler syndrome.

BackgroundKindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease.MethodsPatient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy.ResultsPatient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state.ConclusionsThis is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0211-8) contains supplementary material, which is available to authorized users.

P-183 Kindlin 1and Kindlin 2 Regulate Adhesion and Migration of Colonic Epithelial Cells

The Intestinal epithelial barrier plays an important role in the pathophysiology of inflammatory bowel disease (IBD). Integrity and barrier properties of the intestinal epithelium are determined by specialized adhesive structures such as intercellular junctions and focal adhesions, which respectively mediate cell-cell and cell-matrix interactions. Disassembly of epithelial junctions and matrix adhesion mediates disruption of the gut barrier during acute inflammation, whereas restoration of these adhesion structures is critical for epithelial restitution. Kindlins are unique cytosolic adaptor proteins that are enriched in both epithelial junctions and matrix adhesions. They have multiple binding partners including major classes of integrins and different cytoskeletal regulators. Importantly, mutations in the kindlin-1 gene result in Kindler syndrome, a genetic disorder associated with severe colitis, and deletion of kindlin-2 gene in mice is embryonically lethal. Despite these dramatic phenotypes caused by kindlin dysfunctions, little is known regarding the role of these adaptor proteins in regulation of the intestinal mucosal barrier disruption and restitution. This study was performed using a well-differentiated clone of HT29 human colonic epithelial cell line (HT29cF8). Transient downregulation of kindlin isoforms was achieved using RNA interference. Stable overexpression of kindlins 1 and 2 was achieved using a lentiviral expression system. Cell lines were cultured either on collagen-coated, permeable polycarbonate filters (0.4 mm pore size), or on 6-well plastic plates, for permeability, adhesion and motility assays. Barrier function of epithelial cell monolayers was determined via transepithelial electrical resistance (TEER) measurements Focal adhesions and cytoskeleton were visualized by immunofluorescence labeling and confocal microscopy. Overexpression of either kindlin 1 and/or kindlin 2 resulted in a significant increase in TEER, while siRNA-mediated knockdown of either isoform caused a substantial increase in paracellular permeability. Interestingly, both overexpression and depletion of kindlin 1 attenuated collective cell migration as determined by wound closure assay. By contrast, downregulation of kindlin 2 expression did not affect cell motility. Analysis of cell adhesion and spreading on a collagen matrix revealed significant attenuation of matrix adhesion and spreading of kindlin 1 and kindlin 2 overexpressing cells. These effects correlate well with a marked reduction of the phosphorylated form of focal adhesion protein, paxillin. Additionally, kindlin 1 overexpression regulated an increased level of non-muscle myosin IIB, which is indicative of increased contractile forces. Our data highlights kindlins as important regulators of barrier properties and restitution of human intestinal epithelium.

FERMT1 promoter mutations in patients with Kindler syndrome

Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity.

Epidemiology of inherited epidermolysis bullosa in Romania and genotype-phenotype correlations in patients with dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) is a rare and so far incurable genetic disease, affecting mainly the skin and mucosal membranes, manifesting with blisters triggered by minor mechanical trauma. Since only few epidemiological data on EB are available, we established a Registry for EB and implemented molecular diagnostic methods. We present epidemiologic data from the EB Registry and genotype-phenotype correlations. In 2006, a registry of patients with EB was initiated in the Department of Dermatology of the University of Medicine, as well as molecular diagnostic tools. The patients were diagnosed on clinical bases, and whenever possible, immunofluorescence mapping and molecular analysis were performed. 89 EB patients were enrolled in the study from 2006 to 2012: 58 patients with dystrophic EB (DEB), 20 with EB simplex, one patient was diagnosed with Kindler syndrome; in 10 patients, the type of EB could not be determined. We have estimated, the total number of EB patients in Romania and we have estimated the incidence and the prevalence of EB. We have also managed to approximate the distribution of EB types in Romania. Moreover, we performed a phenotypic and genotypic characterization in some of the patients included in the EB register.

Kindler Syndrome: A case Report from Iran

Kindler syndrome (KS) is a rare, autosomal recessive genodermatosis characterized by skin blistering and photosensitivity in infancy, progressive poikiloderma, and diffuse cutaneous atrophy. It affects the skin, mucous membranes, and oral cavity and is caused by mutations in the KIND1 gene on 20p12.3. The first case of KS associated with periodontitis was reported in 1996, and have been infrequently reported since. Here we present a case of KS with classic clinical presentations involving skin, mucous membranes, and the periodontium in a patient from Iran.

Diverse functions of kindlin/fermitin proteins during embryonic development in Xenopus laevis

The kindlin/fermitin family includes three proteins involved in regulating integrin ligand-binding activity and adhesion. Loss-of-function mutations in kindlins1 and 3 have been implicated in Kindler Syndrome and Leukocyte Adhesion Deficiency III (LAD-III) respectively, whereas kindlin2 null mice are embryonic lethal. Post translational regulation of cell–cell and cell-ECM adhesion has long been presumed to be important for morphogenesis, however, few specific examples of activation-dependent changes in adhesion molecule function in normal development have been reported. In this study, antisense morpholinos were used to reduce expression of individual kindlins in Xenopus laevis embryos in order to investigate their roles in early development. Kindlin1 knockdown resulted in developmental delays, gross malformations of the gut and eventual lethality by tadpole stages. Kindlin2 morphant embryos displayed late stage defects in vascular maintenance and angiogenic branching consistent with kindlin2 loss of function in the mouse. Antisense morpholinos were also used to deplete maternal kindlin2 protein in oocytes and eggs. Embryos lacking maternal kindlin2 arrested at early cleavage stages due to failures in cytokinesis. Kindlin3 morphant phenotypes included defects in epidermal ciliary beating and partial paralysis at tailbud stages but these embryos recovered eventually as morpholino levels decayed. These results indicate a remarkably diverse range of kindlin functions in vertebrate development.

RhoA activation by CNFy restores cell–cell adhesion in kindlin‐2‐deficient keratinocytes

Kindlins are a family of integrin adapter and cell-matrix adhesion proteins causally linked to human genetic disorders. Kindlin-2 is a ubiquitously expressed protein with manifold functions and interactions. The contribution of kindlin-2 to integrin-based cell-matrix adhesions has been extensively explored, while other integrin-independent roles emerge. Because of the early involvement of kindlin-2 in development, no viable animal models with its constitutional knockout are available to study its physiological functions in adult skin. Here, we uncovered a critical physiological role of kindlin-2 in the epidermis by using a skin-equivalent model with shRNA-mediated knock-down of kindlin-2 in keratinocytes. Kindlin-2-deficient keratinocytes built stratified epidermal layers, but displayed impaired dermal-epidermal and intra-epidermal adhesion and barrier function. Co-immunoprecipitation studies demonstrated that kindlin-2 interacts with both integrin- and cadherin-based adhesions. In kindlin-2-deficient keratinocytes, reduced cell-cell adhesion was associated with abnormal cytoplasmic distribution of adherens junctions and desmosomal proteins, which was dependent on RhoA activation. Direct activation of RhoA with recombinant bacterial cytotoxic necrotizing factor y (CNFy) reverted the abnormal phenotype and barrier function of kindlin-2-deficient keratinocytes and skin equivalents. These findings have physiological and pathological significance, since kindlin-2 expression modulates the phenotype in Kindler syndrome, a skin fragility disorder caused by kindlin-1 deficiency. Our results suggest that pharmacological regulation of RhoGTPase activity may represent a therapeutic option for skin fragility.

Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation.

Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene lead to Kindler Syndrome in man, which is characterized by skin blistering, premature skin ageing and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler Syndrome, and in addition produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting αvβ6 integrin-mediated TGFβ activation and by inhibiting Wnt-β-catenin signaling through an integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the novel and essential task to control cutaneous epithelial stem cell homeostasis by balancing TGFβ mediated growth inhibitory and Wnt-β-catenin mediated growth-promoting signals.

Kindler syndrome with severe mucosal involvement in childhood

Kindler syndrome (KS) is an inherited dermatosis linked to the FERMT1 gene, and is characterized clinically by trauma-induced acral skin blisters in infancy and childhood, photosensitivity, and progressive poikiloderma. We report a case of KS in a 7-year-old Indian girl with severe mucosal involvement of the oral cavity and genitourinary tract. Mutation analysis in the girl showed a homozygous FERMT1 mutation, c.862C>T, p.R288*. The clinical manifestations in patients with KS show significant inter individual variation, even with the same type of mutations and within members of the same family. Our case highlights the role of environmental modifiers in regulating the clinical features of KS.