A novel PLEC nonsense homozygous mutation (c.7159G > T; p.Glu2387*) causes epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia: a case report.

BACKGROUND: Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM #226670) is an autosomal recessive disease, characterized mainly by skin blistering at birth or shortly thereafter, progressive muscle weakness, and rarely by alopecia. EBS-MD is caused by mutations in the PLEC gene (OMIM *601282), which encodes plectin, a structural protein expressed in several tissues, including epithelia and muscle. We describe a patient affected with EBS-MD and diffuse alopecia in which we identified a novel pathogenic mutation by PCR amplification of all coding exons and exon-intron boundaries of PLEC gene, followed by bidirectional Sanger sequencing. CASE PRESENTATION: The patient, a 28-year-old female and only child of consanguineous healthy parents, was born after uneventful pregnancy. At 2 days of age, she developed skin and oral mucosal blistering, accompanied by voice hoarseness. On physical examination as an adult, we observed diffuse non-scarring alopecia on the scalp, onychodystrophy (pachyonychia) in all 20 nails, dental decay, mild dysphonia, and severe muscle atrophy mainly affecting the extremities. Neurological examination showed profoundly diminished reflexes. Mutation analysis revealed the patient to be homozygous for the novel PLEC nonsense mutation - c.7159G > T (p.Glu2387*) - located in exon 31. Thismutation predicts the lack of expression of the full-length plectin isoform. CONCLUSION: The present case appears to be the second association of EBS-MD with diffuse alopecia, both cases having different mutations involving PLEC exon 31. It remains to be elucidated whether diffuse alopecia results from PLEC mutations and/or from environmental factors.

Kallin syndrome associated with vitiligo.

Kallin syndrome (KS) is a variant of epidermolysis bullosa simplex (EBS), which, in addition to the classic features of EBS, also presents with deafness, alopecia, hypodontia and nail dystrophy. We report the case of a 17-year-old boy who presented to our clinic with trauma-induced skin blistering, alopecia, deafness, dental caries, nail dystrophy and vitiliginous areas. The skin blisters had been appearing since birth, and healed without scarring. The vitiliginous areas were unrelated to the sites of the blisters. Electron microscopy of the skin blisters was diagnostic of EBS, and the depigmented lesions were similar to those of vitiligo. An association of vitiligo with EBS has not been reported previously. Multiple genetic findings have confirmed a role for keratin in regulating skin pigmentation. Apoptosis of melanosome-bearing keratinocytes may participate in the reduction of melanin density and result in depigmentation. Further studies on the defective proteins in KS may clarify the mechanism underlying the association with vitiligo.

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

BACKGROUND: 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. OBJECTIVE: We present epidemiologic data from the EB Registry and genotype-phenotype correlations. METHODS: 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. RESULTS: 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. DISCUSSION AND CONCLUSION: 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.

A fixed denture for a child with epidermolysis bullosa simplex.

AIM: To report the caries treatment and delivery of a fixed denture for a 3-year-old girl with epidermolysis bullosa simplex (EBS). CASE REPORT: EBS is manifested on the skin or mucous membranes where skin separation is easily induced by trauma. Full- mouth rehabilitation under in-patient general anaesthesia was performed to the patient in conjunction with proper pre- and postoperative care. A fixed denture was fabricated and installed to replace the extracted teeth without later causing irritation on the mucosa. The prosthesis restored aesthetics and provided comfort without imposing the burden of compliance on the patient. CONCLUSION: Aided by meticulous pre- and postoperative care and oral hygiene reinforcement, comprehensive dental treatment coupled with fixed denture delivery can greatly improve the life quality and aesthetics for children with EBS.

Otorhinolaryngological and esophageal manifestations of epidermolysis bullosa.

UNLABELLED: Epidermolysis bullosa (EB) is a group of skin diseases with different clinical manifestations and varied inheritance patterns. Blisters may appear spontaneously or following minimal trauma to the skin or mucosa. AIM: this paper aims to describe the otorhinolaryngological manifestations and esophageal complications related to EB, and the experience in treating patients with esophageal stenosis secondary to this disease. MATERIALS AND METHOD: this descriptive study enrolled 60 patients with EB seen from June 1999 to December 2006 at the Head and Neck Surgery Service of X Hospital, a reference center for EB. RESULTS: the patients' mean age was 14.5 years. Twenty-eight (46.6%) were females and 32 (53.4%) were males. Eight (13.4%) were diagnosed with epidermolysis bullosa simplex, while 51 (85%) had epidermolysis bullosa dystrophica; one (1.6%) patient had one acquired EB. Lips, mouth, tongue and ears were the most frequently involved sites (32 patients - 53.3%). Dysphagia was found in 28 patients (46.6%). After esophageal dilatation the symptoms subsided. CONCLUSION: EB is a rare disease and patients must be sent for treatment at reference centers. Physicians treating patients for EB must be aware of the measures required to improve the quality of the treatment provided without putting the patients in harm's way.

Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.

BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.

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

BACKGROUND: 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. OBJECTIVE: To apply IFM technique in diagnosis and classification of EB and to identify utility and limitation of this method in our clinical setting. METHODS: 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, ß4 integrin, laminin 332, Collagen IV, and Collagen VII. RESULTS: 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. CONCLUSION: 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.

Dominance and homozygosity.

Because of the high consanguinity rates in many communities in Israel we had the opportunity to study homozygosity for some dominant disorders. This experience and a review confirmed that in most cases homozygotes of dominant disorders are more severely affected than heterozygotes. In some cases molecular analysis allowed an understanding of the mechanisms involved. While heterozygosity for point mutations or deletions of PAX3 lead to similar manifestations (Waardenburg syndrome), in homozygotes the phenotype is much more severe, probably in direct relation to the loss of function. Charcot-Marie-Tooth 1A is caused by a duplication of PMP22 and further over-expression lead to a more severe disorder. In diseases in which the mutation leads to an abnormal structural protein, the homozygote may be as severely affected as the heterozygote (epidermolysis bullosa simplex) or more severely (achondroplasia, Marfan syndrome). The polyglutamine tract is translated in disorders caused by CAG triplet expansions. In homozygotes for Machado-Joseph disease the onset is earlier and the symptoms are more severe than in heterozygotes, while in Huntington disease homozygotes are affected like heterozygotes.

Development defects of enamel in humans with hereditary epidermolysis bullosa.

Developmental defects of enamel are often reported as a feature of the more severe forms of epidermolysis bullosa (EB). The purpose of this investigation was to determine the prevalence and character of enamel defects in each of the major hereditary EB types. Clinical evaluations were made on 237 individuals representing all of the major EB types and 58 unaffected individuals. All EB cases were categorized by phenotype, mode of inheritance and skin biopsy. The frequency of individuals having developmental enamel defects ranged from 8.6% in recessive dystrophic EB to 100% in junctional EB; 27.5% of the control population had these defects. Generalized hypoplasia characterized by either severe pitting and/or thin enamel was seen in all junctional EB cases but not in any other EB type. There was a tendency for the severe Herlitz form of junctional EB to have thin enamel while non-Herlitz junctional EB cases had less severe pitting and generally no reduction in enamel thickness. The prevalence of individuals with hypoplastic enamel bands was greater in the EB population (9.7%) than controls (1.9%). Thus individuals with simplex and dominant dystrophic EB typically have enamel defects that are similar in frequency and distribution to those of unaffected individuals. Developmental defects of enamel are a consistent feature of junctional EB, although the clinical expression is highly variable.

Epidermolysis bullosa: a case report.

The term epidermolysis bullosa describes a group of rare genetic mechanicobullous disorders. The disease has several modes of inheritance with various degrees of severity and expression. A patient with simplex epidermolysis bullosa had typical cutaneous lesions and dental involvement. The teeth were severely affected by hypoplasia. Dental therapy consisted of placement of amalgam restorations and topical applications of fluoride. The need for, and advantages of, early preventive and restorative dental care are illustrated by the case presented.

Dental caries risk in hereditary epidermolysis bullosa.

Epidermolysis bullosa (EB) is a clinically diverse group of conditions characterized by skin fragility and, in certain types, marked dental involvement. The purpose of this study was to determine the prevalence of dental caries in EB and control populations. Healthy individuals and participants from the Southern Clinical Center of the National EB Registry were examined with artificial light and a #23 dental explorer. Caries levels were evaluated by chi-square analysis, regression analyses, and ANOVA (P < 0.05 being significant). The study included 252 individuals with EB, aged 2.3-71 years, and 57 similarly aged controls. The prevalence of dental caries, scored as DMFS (decayed, missing, filled surfaces), was significantly higher in the junctional (mean = 58.6) and recessive dystrophic (mean = 37.6) EB types than controls (mean = 23.2). The simplex (mean = 25.6) and dominant dystrophic (mean = 21.6) EB groups had DMFS levels similar to the control group. Individuals with recessive dystrophic EB had the most severe oral blistering and scarring and did not have generalized enamel hypoplasia. In contrast, junctional EB always was associated with generalized enamel hypoplasia yet the intraoral blistering rarely involved scarring. This study shows that dental caries is increased in dystrophic and junctional EB compared with unaffected individuals or other EB types. While rampant caries appears related to the soft tissue and enamel involvement in these two EB types, other as yet unclear cofactors also must be involved.

Epidermolysis bullosa: case report of appropriate classification of subtype because of an early dental exam.

Epidermolysis bullosa is a unique group of disorders that have blister formation as the common feature. Although there are many variants of this disorder, the subtypes are classified into three groups based upon the level of tissue separation that occurs after mechanical trauma is sustained by the skin. Specific subtypes of EB may have substantial involvement of extracutaneous areas such as the oral cavity and dentition. This case report demonstrates the importance of a dental examination at an early age in order to facilitate the correct subtyping of EB. For the very young patient, correct classification of the subtype of EB may be very important in identifying the severity of clinical features associated with the disorder, and with this information the patient and family may become better aware of potential complications of the disorder such as the dental defects described in this report.

[Syndromes 13. Epidermolysis bullosa]. / Syndromen 13. Epidermolysis bullosa.

Epidermolysis Bullosa is characterised by blister formation of skin and mucous membranes. Three major varieties of epidermolysis bullosa (EB) are reviewed including their dental and oral aspects: EB simplex, junctional EB and dystrophic EB. Marked oral involvement of the soft and hard tissues can produce potentially devastating alterations in anatomy and function. Oral debilitation is limited primarily to the recessive dystrophic EB type due to soft tissue scarring following blister formation. Microstomia, ankyloglossia and obliteration of the oral vestibule are typical features of dystrophic EB. In other cases enamel hypoplasia and cementum disorders can be present. Epidermolysis bullosa has considerable impact on oral health and dental care.

Localized epidermolysis bullosa simplex with generalized enamel hypoplasia in a child.

Epidermolysis bullosa is an uncommon disease characterized by the formation of blisters following minor trauma. The three major types are simplex, junctional, and dystrophic. Generalized enamel hypoplasia is accepted as a feature of the junctional type. Teeth with enamel hypoplasia are liable to destruction in the form of caries and/or gingivitis. In this report, a patient with epidermolysis bullosa simplex and severe enamel hypoplasia is described and the importance of early dental consultation for all children with this disease is stressed.

Epidermolysis bullosa. A case report.

Epidermolysis bullosa is a group of rare genetic-related skin disorders. It is characterized by bullae and vesicles on the skin and mucosa, that result from friction, trauma, or heat. This article reports a case of Epidermolysis bullosa. With proper diagnosis, the dentist can treat a patient with this type of disorder without causing bullae as a result of treatment.

Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature.

BACKGROUND: Epidermolysis bullosa simplex associated with muscular dystrophy (EBS-MD; OMIM# 226670) is an autosomal recessive disorder caused by genetic defects in the plectin gene. Because EBS-MD is relatively rare, and gene defects have been elucidated only in a limited number of patients, the precise phenotype-genotype correlations have not yet been fully elucidated. OBJECTIVE: The purpose of this study was to define clinical features of EBS-MD and to clarify its phenotype-genotype correlations. METHODS: Clinical, ultrastructural, immunohistochemical, and molecular features of 4 unrelated Japanese patients with EBS-MD were recorded. In addition, 6 cases with defined plectin gene mutations reported in the literature were reviewed. RESULTS: In skin of the EBS-MD patients, the blister formation always occurs just above the hemidesmosomes, and expression of plectin is absent or markedly reduced in all cases examined. All 10 patients, including 6 cases in the literature, showed generalized blistering at birth or soon thereafter, and experienced nail deformities. In addition, decayed teeth (5 cases), urethral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respiratory complications (2), alopecia (1), and laryngeal webs (1) were present. All 8 patients who were older than 9 years demonstrated considerable muscle weakness, and the majority of them ended up being wheelchair bound. Among the 10 patients, 7 were products of consanguineous marriage, 9 have premature termination codon (PTC) mutations in both alleles of the plectin gene, and 7 cases were homozygous for the mutation. One patient who is homozygous for a 2719del9 in-frame deletion mutation that resulted in elimination of 3 amino acids, QEA, could still walk at the age of 46 and showed milder clinical severity. CONCLUSION: EBS-MD reveals clinical features not only characteristic of EBS and MD, but also other manifestations including urethral, dental, and respiratory complications. The majority of patients are products of consanguineous marriage and have homozygous plectin gene mutations. Whereas patients with PTC mutations in both alleles typically showed severe clinical features of EBS-MD and ended up being wheelchair bound, a homozygous patient for an in-frame deletion mutation showed positive, yet attenuated, plectin expression and milder clinical phenotype. Thus plectin immunofluorescence, combined with identification of the underlying plectin mutations, is of value in predicting the severity of the muscle involvement that occurs later in life of patients with EBS-MD.

Plasticin, a type III neuronal intermediate filament protein, assembles as an obligate heteropolymer: implications for axonal flexibility.

The assembly characteristics of the neuronal intermediate filament protein plasticin were studied in SW13 cells in the presence and absence of a cytoplasmic filament network. Full-length plasticin cannot polymerize into homopolymers in filament-less SW13c1.2Vim(-) cells but efficiently coassembles with vimentin in SW13c1.1Vim(-) cells. By cotransfecting plasticin and vimentin in SW13c1.1Vim(-) cells, we show that plasticin assembly requires vimentin in noncatalytic amounts. Differing effects on assembly were seen with point mutations of plasticin monomers that were analogous to the keratin mutations that cause epidermolysis bullosa simplex (EBS). In particular, plasticin monomers with point mutations analogous to those in EBS do not uniformly inhibit neurofilament (NF) network formation. A point mutation in the helix termination sequence resulted in complete filament aggregation when coexpressed with vimentin but showed limited coassembly with low- and medium-molecular-weight NF proteins (NF-L and NF-M, respectively). In transfected SW13c1.1Vim(+) cells, a point mutation in the first heptad of the alpha-helical coil region formed equal amounts of filaments, aggregates, and a mixture of filaments and aggregates. Furthermore, coexpression of this point mutation with NF-L and NF-M was associated with a shift toward increased numbers of aggregates. These results suggest that there are important structural differences in assembly properties between homologous fish and mammalian intermediate filament proteins. These structural differences may contribute to the distinctive growth characteristics of the teleost visual pathway.

Manifestações otorrinolaringológicas e esofágicas da epidermólise bolhosa / Otorhinolaryngological and esophageal manifestations of epidermolysis bullosa

Epidermólise bolhosa (EB) é um conjunto de afecções bolhosas, de caráter hereditário, com diferentes quadros clínicos e diferentes modos de transmissão genética. Os indivíduos evoluem com bolhas na pele e mucosas, que surgem espontaneamente ou após mínimos traumatismos. OBJETIVO: Descrever as manifestações otorrinolaringológicas, as complicações esofágicas relacionadas à EB e a experiência na conduta de pacientes com estenose esofágica decorrente da EB. CASUÍSTICA E MÉTODO: Estudo descritivo de 60 pacientes com EB, atendidos de 1999 a 2006, no serviço de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço do Hospital X, centro de referência para EB. RESULTADOS: Dos 60 pacientes com idade média de 14,5 anos, 28 (46,6 por cento) eram mulheres e 32 (53,4 por cento) homens. Oito (13,4 por cento) tinham o diagnóstico de EB simples, 51 (85 por cento) EB distrófica e um (1,6 por cento) caso de EB adquirida. Lábios, boca, língua e pavilhão auricular foram os locais mais acometidos (32 pacientes - 53,3 por cento). Disfagia foi encontrada em 28 pacientes (46,6 por cento). Após dilatação do esôfago todos apresentaram remissão do sintoma. CONCLUSÃO: EB é uma doença rara e os pacientes devem ser encaminhados para tratamento em centros de referência. Portanto, é fundamental que os médicos envolvidos com os cuidados de pacientes com EB conheçam as condutas necessárias para melhorar a qualidade do tratamento sem prejuízos adicionais.

Epidermolysis bullosa (EB) is a group of skin diseases with different clinical manifestations and varied inheritance patterns. Blisters may appear spontaneously or following minimal trauma to the skin or mucosa. AIM: this paper aims to describe the otorhinolaryngological manifestations and esophageal complications related to EB, and the experience in treating patients with esophageal stenosis secondary to this disease. MATERIALS AND METHOD: this descriptive study enrolled 60 patients with EB seen from June 1999 to December 2006 at the Head and Neck Surgery Service of X Hospital, a reference center for EB. RESULTS: the patients' mean age was 14.5 years. Twenty-eight (46.6 percent) were females and 32 (53.4 percent) were males. Eight (13.4 percent) were diagnosed with epidermolysis bullosa simplex, while 51 (85 percent) had epidermolysis bullosa dystrophica; one (1.6 percent) patient had one acquired EB. Lips, mouth, tongue and ears were the most frequently involved sites (32 patients - 53.3 percent). Dysphagia was found in 28 patients (46.6 percent). After esophageal dilatation the symptoms subsided. CONCLUSION: EB is a rare disease and patients must be sent for treatment at reference centers. Physicians treating patients for EB must be aware of the measures required to improve the quality of the treatment provided without putting the patients in harm's way.