3 Epidermolysis bullosa Inherited epidermolysis bullosa (EB) is a group of genetically transmitted skin disorders characterized by spontaneous blistering or blistering caused by minor trauma. There are three classic types of inherited EB (simplex, junctional and dystrophic). They are differentiated by the level of blister cleavage and subdivided according to the pattern of genetic inheritance, morphology/topography of lesions and genetic mutation involved. After the Third International Consensus on Diagnosis and Classification of Inherited EB, there was the addition of a fourth entity to the group of inherited EB - Kindler syndrome (KS) previously considered a photosensitive poikiloderma. Currently, over 30 phenotypiccally and genetically distinct nosological entities have been described illustrates the key molecules involved in the pathogenesis of EB. Despite their rarity, inherited EB cause a huge impact on the lives of patients and their families, due to physical pain, emotional suffering or economic repercussions. EB is an inherited disease, which means that you have inherited one or two EB genes. In autosomal dominant EB, only one abnormal gene is needed to express the disease. This means only one parent needs to carry the EB gene. On the other hand, autosomal recessive inherited EB requires you to have two EB genes (one from each parent) to have the disease. If a person has one recessive EB gene paired with a normal gene they are called a carrier and do not have the disease. The clinical presentation of inherited EB varies according to the type of disease, and diagnosis can only be reached by skin biopsy and immunofluorescence or electron microscopy, the latter being considered the gold standard
8 CLASSIFICATION I. Epidermolysis bullosa simplex Epidermolysis bullosa simplex (EBS) is characterized by a disorder of keratinocytes, intraepidermal blistering and little systemic involvement. Nail dystrophy, alopecia and mucosal lesions may occur in more severe forms of the disease. Skin lesions usually disappear without scarring. Blistering decreases with age. Inheritance is typically autosomal dominant, although rare cases of autosomal recessive inheritance have been documented.The intraepidermal cleavage observed in EBS is the result of mutations in the K5 and K14 genes, which encode the production of keratin and type I and II intermediate filament proteins, expressed in keratinocytes of the basal layer of the epidermis and epithelial-related complexes.EBS is subdivided as follows: localized EBS (Weber-Cockaine subtype), generalized EBS (Köebner subtype), and EBS herpetiformis (Dowling-Meara subtype). The milder forms of EBS present with blisters that are usually caused by an identifiable traumatic event. The Weber-Cockaine subtype (EBS-WC) is characterized by mild to severe blistering and palmoplantar topography, and patients may concomitantly show hyperhidrosis. In its severe forms, hands, feet and limbs are also commonly involved, although in these cases blisters generally develop soon after birth. Palmoplantar hyperkeratosis and erosions occur mainly in the Köebner subtype. In the Dowling-Meara subtype (EBS-DM) there is involvement of the oral mucosa and formation of herpetiform blisters.Variable blistering, followed by muscular dystrophy in adulthood, can be seen in EBS with muscular dystrophy, a defect in the expression of plectin. Late myopathy is due to the fact that there is plectin in the composition of the cytoskeleton of skeletal muscles. The severity of skin lesions does not necessarily correlate with the degree of muscular dystrophy. Some patients may also present dental abnormalities.As its name suggests, EBS with pyloric atresia presents with pyloric atresia at birth and, usually, blistering is widespread. In most patients, even with correction of pyloric atresia, prognosis is unfavorable, given the extent of systemic involvement. Although the disease is described as precociously fatal, some individuals with milder symptoms can survive during childhoo
12 Schematic of desmosomes Schematic of desmosomes. Components in red characters are target proteins of suprabasal EBS
13 Schematic of the skin basement membrane zone Schematic of the skin basement membrane zone. Components in red characters are target proteins of basal EBS.
14 Epidermolysis bullosa simplex Mutations in genes encoding keratinocyte components involved in the organization of the cytoskeleton or cell-cell junctions are responsible for EBS. EBS can be subclassified into basal and suprabasal according to the level of skin split .Basal EBS is caused by defects in skin basement membrane (BMZ) proteins. diagrams the skin BMZ. Among the BMZ components, keratin 5/14 and plectin are the main targets in EBS . A few EBS cases have been reported to have mutations in ITGB4 and COL17, which encode β4 integrin and type XVII collagen, respectively . Recently, BPAG1-e was added to the list of basal EBS target proteins .In contrast, suprabasal EBS is associated with abnormalities in desmosomal proteins . So far, plakophilin-1, plakoglobin and desmoplakin are known to be the target proteins of suprabasal EBS
15 Epidermolysis bullosa simplex Target proteins in basal EBS3.1. KERATIN 5/14Keratin is one of the most abundant components of the epithelial cytoskeleton . Typically, type I and type II keratins form heteropolymers that function in cells . Keratin 5 (K5) and keratin 14 (K14) are specifically expressed in epidermal basal cells . In the 1980’s, disorganization of those keratins was recognized in the basal keratinocytes of EBS patients . From those findings, it had been hypothesized that EBS patients have mutations in KRT5 or KRT14, which encodes K5 or K14, respectively. In the early 1990’s, transgenic mice overexpressing mutated K14 were reported to have severe skin fragility . Soon after this discovery, two groups of researchers identified EBS cases with heterozygosity for KRT14 misense mutations , which were followed by the identification of the first EBS family with a heterozygous KRT5 mutation . Since then, several hundreds of EBS patients have been described as having KRT5 or KRT14 mutationsThere are several subtypes of keratin-associated EBS,]. Classical and common EBS subtypes, in which traits are autosomal-dominantly inherited, are Dowling-Meara type EBS (EBS-DM), non Dowling-Meara type (EBS-gen-non-DM) and localized type (EBS-loc), from the severest to the mildest. Ultrastructurally, basal keratinocytes of EBS-DM are characterized by keratin aggregates . Hot spots of the mutations in KRT5 or KRT14 are located within the helix-boundary motifs of each keratin . A misense mutation in one allele of those regions (which leads to an amino acid alteration) typically exerts a dominant-negative effect on keratin organization. The severity of the clinical manifestations among EBS-DM, EBS-gen-non-DM and EBS-loc is generally determined by the site of the mutations and the difference between the original and the mutated amino acids . However, it is not always easy to predict the phenotype from the underlying mutations and, in some cases, two different amino acid substitutions at the same codon result in different clinical manifestations . As a single amino-acid alteration does not necessarily cause a pathological change, in vitro and in silico systems to validate mutational effects have been proposed where keratin organization is visualized in cells transfected with mutated or wild-type keratins ..Therapeutic interventions for EBS have been confined to palliative modalities. However, recent innovations in RNA interference have led to therapeutic strategies for dominant-negative disorders including keratin-associated EBS, where aberrant mutated keratin is knocked down while normal keratin synthesis on another allele is left intact . This RNAi strategy is promising and will be further validated in clinical trials.
16 Epidermolysis bullosa simplex 3.2. PLECTINPlectin is a cross-linking protein between the cytoskeleton and membranous proteins including hemidesmosomal components . Plectin has been known to have many transcript isoforms that differ from each other in N-terminal sequences at the protein level . Among the many transcript isoforms, plectin 1a is the one that is mainly expressed in epidermal keratinocytes . In addition to 5’ transcript complexity, plectin has a rodless splicing variant. There are several EBS subtypes that are caused by plectin deficiencies .In the mid-1990’s, mutations in the gene encoding plectin (PLEC) were discovered in patients with EBS with muscular dystrophy (EBS-MD) . Since then, many PLEC mutations, mostly located in the region encoding the rod domain of plectin, have been reported in EBS-MD patientsIn 2005, two groups independently reported a new EBS subtype with PLEC mutations: EBS with pyloric atresia (EBS-PA) . EB with pyloric atresia (PA) had been known in patients withITGA6 or ITGB4 mutations . However, skin specimens from those patients with integrin mutations show skin-split at the level of the lamina lucida, leading to the diagnosis of junctional EB (JEB). In contrast, EBS-PA cases with PLEC mutations were characterized by skin-split within epidermal basal cells .The reason PLEC mutations lead to two distinct subtypes of EBS was clarified only recently. The development of monoclonal antibodies against several portions of plectin allowed us to understand the plectin expression patterns that distinguish between EBS-MD and EBS-PA . EBS-MD skin typically shows the expression of rodless plectin without that of full-length plectin, whereas neither rodless nor full-length plectin is present in EBS-PA skin .The next big question was whether EBS-MD and EBS-PA can occur simultaneously in a single patient or those two distinct EBS subtypes are mutually exclusive. Recently, one case was reported to have the phenotype of both EBS-MD and EBS-PA (EBS-MD-PA) . The patient had truncation mutations at the last exon of PLEC, which resulted in the expression of diminished and shortened full-length and rodless plectin without the intermediate filament binding domain .Apart from autosomal recessive EBS subtypes associated with PLEC mutations (EBS-MD, EBS-MD and EBS-MD-PA), there is one distinct autosomal dominant EBS with a PLEC mutation: EBS, Ogna (EBS-Og). EBS-Og is caused by a heterogeneous mutation of p. Arg2000Trp and is characterized by mild blister formation without MD or PA phenotype . To date, 5 unrelated families of EBS-Og have been reported to have the same mutation .
17 Epidermolysis bullosa simplex . BPAG1-EDystonin, encoded by DST, has various isoforms in neural, muscle and epithelial tissue. BPAG1-e, also called BP230, is a major skin isoform of dystonin and a component of hemidesmosomes . BPAG1-e is known to be an autoantigen in bullous pemphigoid as well as type XVII collagen (C17) . Since COL17, which encodes C17, was identified as a causative gene for non-Herlitz JEB , DST, which encodes BPAG1-e, had also been hypothesized for decades to be a target gene in other EB subtypes. However, it was only recently that mutations in DST were identified in autosomal recessive EBS patients . Those two patients typically had a mild acral blistering phenotype and had truncation mutations in the coiled-coil rod domain of BPAG1-e. Electron microscopy observation revealed loss of the inner plaque of hemidesmosomes in both cases . Dst-null mice show neural degeneration and mild skin fragility upon mechanical stress
18 Epidermolysis bullosa simplex . Target proteins in suprabasal EBS4.1. DESMOPLAKINDesmoplakin is a plakin family protein located in desmosome . Two isoforms (desmoplakins I and II) are generated through alternative splicing . Desmoplakin I is mainly expressed in the heart, whereas desmoplakin II is abundant in the skin . In the early 1990’s, desmoplakin was determined as a major autoantigen in paraneoplastic pemphigus . Mutations in the gene encoding desmoplakin, DSP, have been reported in several genodermatoses, mostly with cardiac manifestations In 2005, a very severe EB case, referred to as lethal acantholytic epidermolysis bullosa (LAEB), was reported to have a homozygous deletion mutation in DSP . The patient showed severe skin blistering and early demise. There have been only three reports on LAEB with DSP mutations . Skin specimens in all the cases revealed acantholytic features in histopathology. From the correlation of clinical manifestations and mutational sites, it seems that complete or almost complete loss of desmoplakin might lead to LAEB . However, at least one full-length desmoplakin (either isoform I or II) may be enough to prevent the development of LAEB .4.2. PLAKOPHILIN-1Plakophilin-deficient EBS is listed in the newest classification of EB . This entity has also been called ectodermal dysplasia-skin fragility syndrome (ED-SF). An excellent review on this EBS subtype was published recently . The first case of ED-SF and the mutations in the gene encoding plakophilin-1, PKP1, were reported in Since then, many cases of ED-SF with PKP1mutations have been published. The clinical manifestations of ED-SF include skin fragility, perioral cracking, alopecia and palmoplantar keratoderma .The desmosomal expression of plakophilin-1 accounts for skin fragility and histological features of skin specimens characterized by widening of spaces between keratinocytes. However, the phenotype of ectodermal dysplasia may not be explained solely by desmosomal proteins. Recently, plakophilin-1 has been identified as a regulator of protein synthesis and proliferation through a pathway associated with eIF4A1 . It is speculated that the role of plakophilin-1 in translation and proliferation is involved in abnormalities in skin appendages of ED-SF patients .4.3. PLAKOGLOBINJUP, which encodes plakoglobin, was not listed as a causative gene of EB in the report of the Third International Consensus Meeting on Diagnosis and Classification of EB . It was only recently that a homozygous nonsense mutation of this gene, leading to complete loss of plakoglobin, was revealed to be responsible for one subtype of suprabasal EBS . Lethal congenital EB (LCEB), named by the authors, has manifestations similar to those of LAEB, which is caused by DSP mutations . This similarity is accounted for by the expression pattern of plakoglobin and desmoplakin in desmosomes .
23 II. Junctional epidermolysis bullosa Junctional epidermolysis bullosa (JEB) is an autosomal recessive disorder characterized by separation of the lamina lucida in the dermo-epidermal junction. A mutation in the LAMB3 gene, which encodes laminin-5, occurs in more than half of patients with JEB. Mutations in the genes encoding collagen XVII and integrin α6β4 are also seen.ClassificationJunctional epidermolysis bullosa with pyloric atresiaJunctional epidermolysis bullosa with pyloric atresia is a rare autosomal recessive form of junctional epidermolysis bullosa that presents at birth with severe mucocutaneous fragility and gastric outlet obstruction. It can be associated with ITGB4 or ITGA6.Herlitz typeJunctional epidermolysis bullosa gravis (also known as "Herlitz disease," "Herlitz syndrome," and "Lethal junctional epidermolysis bullosa") is the most lethal type of epidermolysis bullosa, a skin condition in which most patients do not survive infancy, characterized by blistering at birth with severe and clinically distinctive perorificial granulation tissue.JEB-H is generally caused by mutations in one of the three laminin-332 coding genes: LAMA3 (18q11.2), LAMB3 (1q32) and LAMC2 (1q25-q31).Non-Herlitz typeThese include:@ Generalized atrophic benign epidermolysis bullosa is a skin condition that is characterized by onset at birth, generalized blisters and atrophy, mucosal involvement, and thickened, dystrophic, or absent nails.@ Mitis junctional epidermolysis bullosa (also known as "Nonlethal junctional epidermolysis bullosa") is a skin condition characterized by scalp and nail lesions, also associated with periorificial nonhealing erosions. Mitis junctional epidermolysis bullosa is most commonly seen in children between the ages of 4 and 10 years old.@ Cicatricial junctional epidermolysis bullosa is a skin condition characterized by blisters that heal with scarringPathophysiologyα6β4 integrin is a transmembrane protein found in hemidesmosomes. As a heterodimer molecule containing two polypeptide chains its extracellular domain enters the basal lamina and interacts with type IV collagen suprastructure containing laminins (laminin-5), entactin/nidongen or the perlecan. on the extracellular surface of the hemidesmosome, laminin-5 molecules form threadlike anchoring filaments that extend from the integrin molecules to the structure of the basement membrane of epithelial adhesion. Mutation of the genes encoding laminin-5 chains results in junctional epidermolysis bullosa.
24 Appearance of lesions in patients with junctional epidermolysis bullosa
25 Herlitz type of junctional EB In the patient's case, the clinical presentation was suggestive of the Herlitz type of junctional EB — the most severe of all types and with poor prognosis. The differential diagnoses included dystrophic recessive type. The demonstration of the lamina densa in the floor of the blister by means of immunoperoxidase staining with antibody to collagen type IV clearly identifies this lesion as one of the junctional types of EB. Clinical features make it most likely Herlitz type. This child has been found to have related abnormalities, including pyloric atresia, and areas of aplasia cutis congenita features occasionally seen in this subtype . Most patients in this group will have involvement of skin and multiple mucous membranes, most prominently in the upper respiratory and gastrointestinal tracts. Epithelial erosions are followed by formation of large masses of granulation tissue, which can cause airway obstruction and GI obstruction, among other things. These unfortunate patients rarely survive more than one year.H&E PAS stain
26 Herlitz type of junctional EB (continue) Collagen IV immunoperoxidase
30 Rather profound enamel pitting in a patient with JEB Junctional epidermolysis bullosaEB - enamel pittingRather profound enamel pitting in a patient with JEB
31 Exuberant granulation tissue arising on the nape of the neck of a child with Herlitz JEB.
32 Non-Herlitz JEB 39 year old patient with (a) enamel hypoplasia and severe caries; (b) chronic erosions and atrophic scarring on the lower legs; (c) periodically recurring erosions and blistering on the back of the patient; (d) complete toe nail dystrophy
33 PYLORIC ATRESIA in JEB ULTRASOUND Dilated esophagus. Dilated stomach (± a thick wall) (3).Marked gastric peristalsis (due to impairment of gastric filling and emptying).Polyhydramnios.Color Doppler has been used to detect biphasic flow during breathing movement suggesting gastroesophageal reflux (2).The lower intestines in pyloric atresia appear normal because of the passage of bile
38 III. Dystrophic epidermolysis bullosa Dystrophic epidermolysis bullosa (DEB) is due to mutations in the gene encoding type VII collagen, resulting in defective anchoring fibrils and consequent separation of the sub-basal lamina. When healed, blisters give way to dystrophic lesions . Millium formation occurs due to damage in the hair follicles. DEB may be associated with autosomal recessive or dominant inheritance. In the dominant subtype (DDEB) clinical manifestations usually occur at birth or during childhood, with generalized blistering. With increasing age, blisters tend to be more localized. A common variable described as Cockayne-Touraine has acral distribution and minimal oral/dental involvement. In another variant, described by Pasini, there is also involvement of the oral mucosa and teeth, but blistering is more extensive and similar to papules on the trunk (albopapuloid lesions). Dystrophy or anonychia are common to both forms of DDEB.The recessive subtype (RDEB) may have a mild to severe clinical presentation. The mild/localized form is called RDEB mitis, usually with acral and nail involvement, but little involvement of the mucous membranes. It usually shows clinical manifestations similar to those of other inherited forms of dystrophic EB. The severe form, described by Hallopeau and Siemens (RDEB-HS) usually shows generalized blistering, predominantly in acral surface, which can lead to pseudosyndactyly of the hands ("boxing glove hands") and feet. Flexural contractures of the extremities are common and intensify with age. Nails and teeth are usually affected, and inner mucosal involvement can lead to esophageal obstruction, urethral and anal stenosis, phimosis, and corneal lesions. Malabsorption often leads to iron-deficiency anemia, and protein-calorie malnutrition causes deficit in global development. Patients with severe RDEB who survive
39 Appearance of lesions in patients with dystrophic epidermolysis bullosa
43 Atrophic scarring and postinflammatory hypopigmentation on the extremity of a patient with DDEB.
44 Hypertrophic scarring in a patient with generalized DDEB.
45 Clinical features of dystrophic epidermolysis bullosa Clinical features of dystrophic epidermolysis bullosa. Notes: (A) Nail dystrophy of the toenails in dominant dystrophic epidermolysis bullosa. (B) Mitten deformity of the right hand of a patient with recessiv
46 Dystrophy of all twenty nails in a patient with DDEB.
47 Partial mitten deformity of the hand of a child with severe generalized RDEB.
48 Complete mutilating deformities of the hands of a young adult with severe generalized RDEB.
50 IV. KINDLER SYNDROMEKindler syndrome (KS) is an autosomal recessive genodermatosis that can clinically simulate all three classic types of inherited EB. It is a rare dermatosis characterized by acral blistering, fusion of fingers/toes, and generalized progressive poikiloderma. Other clinical findings include trauma-induced blistering (common to all inherited EB), dry and atrophic skin, lichenification and photosensitivity of proximal surfaces. Generally, KS is associated with disruption of the basement membrane and abnormal deposition of type VII collagen both in regions with active lesions and in lesion-free areas. Immunohistochemical examination shows that blistering occurs in the lamina lucida. Recently, it was shown that this entity results from mutation in the gene encoding Kindlin-1, a focal component of contact between basal keratinocytes. As opposed to other mechano-bullous diseases, there are multiple cleavage planes (intradermal, junctional or sub-lamina densa) and other dermatological findings such as poikiloderma and photosensitivity also differentiate KS from all other forms of inherited EB.
51 Scanning electron microscopy of a blister roof in dystrophic epidermolysis bullosa An. Bras. Dermatol. 88 no.6 Rio de Janeiro , 2013The basement membrane is an important structure involved in dermal-epidermal adherence. In Dystrophic Epidermolysis Bullosa (DEB), a welldefined subset of EB, the epidermal loss includes the basement membrane, which remains attached to the blister roof. This level of cleavage can be easily demonstrated with monoclonal antibodies against collagen IV (the basement membrane), in so-called immunomapping. DBE is secondary to inherited dysfunction of collagen VII, the protein that forms the anchoring fibrils, which adhere the basement membrane to the dermal collagenScanning electron microscopy (SEM) of an inverted blister from a case of DBE in order to examine the basement membrane, which is normally found in the blister roof. The diagnosis was confirmed with immunomapping and DNA sequencing. The first showed collagen IV in the roof of the blister. It was also positive for collagen VII, ruling out recessive DEB. DNA sequencing identified in exon 75 of COL7A1 gene a pathologic mutation: c.6235G>A (p.Gly2079Arg), establishing the diagnosis of dominant DEB,Scanning electron microscopy – A. lower magnification with identification of the stratum corneum (x 300); B. Detail of a net attached to the blister roof
52 Scanning electron microscopy of a blister roof in dystrophic epidermolysis bullosa An. Bras. Dermatol. 88 no.6 Rio de Janeiro , 2013Scanning electron microscopy – A. Projections from the cell membrane (asterisks), (x 2.000). B. Adherence of the net to the cell membrane,
53 IV. Kindler syndromeKindler syndrome is inherited as an autosomal recessive disorder. This means that an abnormal gene must be inherited from each parent. On average, one-in-four children in a family are affected, and the familial nature of the disorder may be unnoticed.clinical features of Kindler syndromeBlistering and photosensitivity beginning in infancy or early childhoodGradual poikiloderma (altered pigmentation) and cutaneous atrophy (wasting)Trauma related blistering on hands and feetCan also develop mucosal involvement, ophthalmic and dental abnormalitiesEarly development of actinic keratoses
54 KINDLER SYNDROMEClinical features of Kindler syndrome. a, b Poikiloderma with hyperpigmentation and hypopigmentation on the face, neck, trunk, and extremities. c Large, irregular, ulcerated tumor present on the patient's left knee. d Ectropion and dental loss (e)
55 Kindler syndromeKindler syndrome was first described in 1954 by Theresa Kindler. Kindler syndrome is a rare autosomal recessive genodermatosis characterized by congenital acral skin blistering, photosensitivity, progressive poikiloderma, and diffuse cutaneous atrophy. The syndrome is a combination of features of inherited blistering skin disorders (eg, dystrophic epidermolysis bullosa) and congenital poikilodermas (eg, Rothmund-Thompson syndrome).Images show the progression of lesions. A and B: At birth, acral blisters and erosions are present. C and D: At age 5 years, atrophy and reticulated erythema with dyschromic patches are noted. E and F: At age 7 years, progressive poikilodermatous changes with reticulated erythema and telangiectasia occur. G and H: At age 10 and 15 years, poikiloderma with telangiectasia and depigmentation are observed. Excoriations are due to pruritus. J Am Acad Dermatol 2002 ; 46(3): 447.
58 clinical features of epidermolysis bullosa Epidermolysis bullosa simplex (EBS) EBS SubtypesFeaturesLocalised EBS Previously known as Weber-CockayneMost common and localised form of EBSBlisters develop on hands and feet in response to frictionUsually presents in infancy as child is starting to crawl and walkWounds heal without scarring but there may be thickening of the skin on soles and palmsGeneralised EBS Previously known as KoebnerGeneralised EBS where blisters develop all over the body but commonly on hands, feet and extremitiesPresents at birth or early in infancyMay be mild involvement of mucous membranes and nailsThickening of skin and plaques develop on palms and solesGeneralised severe EBS Previously known as Dowling MearaGeneralised and severe form of EBSPresent at birth with blistering on the face, trunk and limbsThickened skin may cause calluses that limit or interfere with joint movementNails often affectedMay involve other organs including inside the mouth, gastrointestinal and respiratory tractWidespread involvement may cause death in infancy but usually there is significant improvement with age
59 Junctional epidermolysis bullosa (JEB) JEB SubtypesFeaturesGeneralised severe JEB Previously known as HerlitzGeneralised and most severe form of JEB where blisters appear all over the body and often involve mucous membranes and internal organsMay only present at birth with small single blister but becoming more widespread soon afterHoarse cry or cough is indicative of internal organ involvementComplications such as infection, malnutrition and dehydration usually lead to early death in infancyMost cases are lethal within the first 12–24 months of lifeGeneralised intermediate JEB Previously known as Non-HerlitzGeneralised blistering and mucosal involvement present at birth or soon afterScalp, nails and teeth more involvedComplications such as infection, malnutrition and dehydration may cause death in infancy but those who survive clinically improve with increasing age
60 Dystrophic epidermolysis bullosa (DEB) DEB SubtypesFeaturesDominant generalised DEBGeneralised blistering present at birthBlistering becomes localised to hands, feet, elbow or knees as child grows older and in response to frictionSmall white spots called milia are often present at healed but scarred sitesBart syndrome: aplasia cutis, lesions in the mouth, and abnormal nails due to abnormal type 7 collagen in anchoring fibrilsMay also get blistering of the oesophagusGeneralised severe recessive (R) DEB Previously known as Hallopeau-Siemens; and; Generalised intermediate RDEB (previously Non-Hallopeau-Siemens)May present with severe blistering (generalised severe RDEB) or mild disease (generalised intermediate RDEB)Generalised severe blistering is more common and involves large areas of skin and mucous membranesBlisters heal but with scarring and deformity causing limited movement as fingers and toes may be fused together (mitten hands)Complications such as infection, malnutrition and dehydration may cause death in infancyThose that survive are at great risk of developing squamous cell carcinoma (SCC) within chronic EB wounds. SCC look and behave differently in EB than in unaffected individuals, thus a low threshold for review by a specialist dermatologist should be considered.
61 Kindler syndrome Kindler syndrome Kindler syndrome Features Blistering and photosensitivity beginning in infancy or early childhoodGradual poikiloderma (altered pigmentation) and cutaneous atrophy (wasting)Trauma related blistering on hands and feetCan also develop mucosal involvement, ophthalmic and dental abnormalitiesEarly development of actinic keratosesThere are many other subtypes of EB. The presentation and severity of EB is affected by the specific genetic changes and can at times be difficult to classify.
62 CLINICAL MANIFESTATIONS Besides the typical blistering and erosions secondary to the mechanical fragility of the skin, inherited EB may lead to the formation of millium, nail dystrophy or anonychia. Exuberant granulation tissue (periorificial, in the axillary, occipital, lumbosacral, and periungual regions or at fingertips) and palmoplantar keratoderma (localized or confluent) may be present. Other less common and nonspecific findings include reduced or absent hair, recurrent albopapuloid lesions on the lower trunk, hypo-or hyperhidrosis.Alopecia. Even in the recessive form of DEB, patients show no specific alopecia. In the presence of anemia, reversible telogen effluvium may occur. Complete absence of hair, eyelashes and eyebrows is a distinct finding that occurs in lethal acantholytic EB. Localized or diffuse alopecia can be observed in Herlitz JEB. In some patients, alopecia presents a typical androgenetic pattern. The degree of capillary involvement varies considerably between individuals with deficient type XVII collagen. There is gradual alopecia in areas of frictional trauma and blistering in patients with DEB. Kindler syndrome is not associated with alopecia.Gastrointestinal Tract. In theory, any portion of the gastrointestinal tract, except the gallbladder, pancreas and liver, may be affected in patients with Herlitz JEB, occurring more intensely in RDEB. The most severe complication is stenosis of the esophagus because it compromises swallowing. Malabsorptive syndrome may be secondary to denudation of the small bowel mucosa. As previously mentioned, patients with EBS and JEB may have pyloric atresia at birth.Anemia. Herlitz JEB patients may present with severe anemia caused by multiple factors, especially those with JEB and generalized RDEB. Anemia can be partially improved with iron supplementation and blood transfusions.Wound healing. This process is compromised by multiple factors including foreign bodies, bacteria, deficiency of nutritional factors and tissue hypoxia. Exogenous agents such as glucocorticoids and penicillamine contribute to impaired wound healing. Optimization of healing occurs with control of these factors. Patents with Herlitz JEB heal slowly, probably due to deficiency of laminin-5.
63 CLINICAL MANIFESTATIONS Infections. Extensive areas of bare skin show loss of stratum corneum barrier and allow microbial penetration. The accumulation of lymph and moisture in the surface increases bacterial growth. Severe subtypes of Herlitz JEB correlate with immunological abnormalities, including reduced production of lymphocytes. Along with poor nutritional status, there is decreased resistance to infections. Staphylococcus aureus and Streptococcus pyogenes are often the etiological agents, although infections with gram-negative bacteria may also occur. Patients usually show greater susceptibility to develop sepsis, with a high risk of death in early childhood.Prevention of infection is the preferred strategy. With extensive bare areas or areas of crusting, strict care must be taken. This regimen includes the use of topical antibiotics. Self-adhesive dressing is a good choice to keep the areas covered.Genitourinary Tract. The formation of recurring vesicles along the urethra, in the ureterovesical junction and ureters can generate obstructive processes culminating with hydronephrosis. There may be chronic renal failure secondary to hydronephrosis, streptococcal glomerulonephritis, mesangial IgA disease and amyloidosis. They are the most common complications in RDEB, causing the death of around 12% of these patients.Eyes. They may be affected by recurring erosions or blisters, with greater frequency in JEB and RDEB. Both can occur in childhood, causing scarring and progressive visual impairment, if not treated.Ears, nose and throat. The most significant complication is partial or complete occlusion of the airways, usually resulting from stenosis of the vocal cords, which can quickly lead to death. It is seen almost exclusively in some subtypes of JEB and can occur in the first year of life.Dental manifestations. Tissues of the oral mucosa may be affected in RDEB and JEB. Enamel hypoplasia, which facilitates the formation of cavities and tooth loss, is a pathognomonic characteristic of all types of JEB, while microstomia and ankyloglossia are typical of RDEB. Aggressive dental intervention can increase functionality and contribute to increased nutrient uptake.27Musculoskeletal system. Progressive contracture of the hands and feet (mitten deformities) may develop in the first year of life and is seen primarily in the Hallopeau-Siemenes subtype of RDEB. Surgical intervention may improve hand functionality, although repeated procedures are necessary to maintain this functionality. Osteopenia and osteoporosis are common in RDEB. Muscular dystrophy beginning in adulthood is typical of EBS with muscular dystrophy.Cardiomyopathies. Although uncommon in patients with RDEB-HS, there may be dilated cardiomyopathy, possibly fatal, especially when there is associated renal failure. The cause may be multifactorial, including micronutrient deficiencies (selenium and carnitine), transfusion-related iron loss and viral myocarditis.
64 CLINICAL MANIFESTATIONS Skin tumors. Squamous cell carcinoma (SCC) usually occurs in multiple primary sites of chronic lesions, particularly in patients with DEB, especially in RDEB/RDEB-HS. In cases of DEB, there is no predilection for photoexposed areas. The peak of incidence of SCC increases dramatically in the second and third decades of life. These lesions may recur frequently even with aggressive surgical excision. Recent studies on the pathogenesis of SCC in patients with RDEB suggest that cancer occurs due to decreased expression of type VII collagen in the NC1 domain. Type VII collagen is required for Ras activation in epidermal tumorigenesis.About 80-90% of patients with HS-RDEB between 45 and 55 years of age have or have already had SCC. This high risk shows that early detection and treatment of SCC has great importance in the management of adults with RDEB, considering the development of severe and recurrent lesions or chronic skin ulcerations and erosions. However, the presence of scar tissue in patients with chronic Herlitz JEB cannot explain this phenomenon alone, because SCC that affect scar tissue are not usually as aggressive as those involving patients with RDEB, suggesting that other factors may be involved in its pathogenesis.EBS-DM patients have a substantial risk of developing basal cell carcinoma (BCC). Possibly, repeated injury to keratinocytes promotes tumorigenesis. The risk of BCC is low in other subtypes of EBS. The risk of melanoma and BCC in other subtypes is comparable to that of the general population.
65 CLINICAL MANIFESTATIONS Fifty-five percent of patients with Herlitz JEB show significant disease impact on quality of life. There is also a correlation between the Dermatology Life Quality Index - DLQI -and intensity of the psychological disorders presented by these patients. Psychiatric symptoms are observed in all types of Herlitz JEB. Family is a major influence, with love and affection being important to improve the quality of life of Herlitz JEB patients, regardless of financial status, difficulties, emotional factors or time.The coexistence of symptoms such as depression, anxiety and behavioral disorders should be taken into consideration, as they may compromise treatment strategies and worsen symptoms.DIAGNOSISThe diagnosis of Herlitz JEB is based on clinical and laboratory findings. As genetic differentiation is not available in most Brazilian cities, subtypes are usually distinguished by immunological and ultra-structural analysis. Subclassification is important in determining prognosis (risk of mucosal involvement, development of malignancies and premature death), as well as in providing subsidies for genetic counseling.Electron microscopy (EM) is still the gold standard in the diagnosis of Herlitz JEB, even though it has some limitations. Improper handling or problems in skin tissue sample fixation can result in misdiagnosis. These limitations can be overcome with the concomitant use of immunofluorescence to map the basement membrane in frozen tissue sections with a variety of antibodies, including laminin-1 and 5, collagen V, VII and XVII, bullous pemphigoid antigen, integrin α6β4 and plectin. EM is a relatively expensive method and one that is not yet routinely performed. Immunohistochemical study uses a limited number of antibodies and can be a useful alternativeDEB, dystrophic epidermolysis bullosa, EB, epidermolysis bullosa; EBS, epidermolysis bullosa simplex; JEB, junctional epidermolysis bullosa, JEB-H, Herlitz-type junctional epidermolysis bullosaIn the dominant subtypes of EB, where an informative family tree is known, it is often acceptable for a clinical diagnosis (based on the presenting signs) to be made by a specialist dermatologist.Diagnostic tests are also available in some countries and include skin biopsy of a newly induced blister which undergoes immunofluorescence antigen mapping (IFM) and/or transmission electron microscopy (EM). Mutational analysis (blood testing of genes), although not currently considered the first-line diagnostic test, is also available in some countries...
68 Immunofluorescence antigen mapping for hereditary epidermolysis bullosa
69 Photomicrograph showing normal expression of laminin 332 in the control skin and complete absence of staining in JEB-H (a and b, respectively) and normal expression of type VII in the control skin and complete absence of staining in RDEB (c and d, respectively)
78 THERAPEUTIC MANAGEMENT There is no cure for EB. However, significant research, including gene therapy and cell-based therapy, continue in the aim to improve quality of life.Most current treatment is symptomatic. The primary aim is to protect the skin and stop blister formation, promote healing, and prevent complications.Because EB can affect so many different parts of the body, a team of medical specialists is usually required for overall care. When necessary, treatment with oral and topical medications may be prescribed by your doctor to assist healing or prevent complications.The following are some general measures used in caring for a patient with EB.@ Avoidance of activities that induce friction on the skin. This includes the handling of infants and children – alternative handling techniques are easily learnt from a trained health care professional.@ Maintain a cool environment and avoid overheating@ Use foam padding or sheepskins to help reduce friction on furniture such as beds, chairs and infant car seats@ Choose clothing (including nappies) and footwear that is light, has no irritating seams or detail eg zips and tight elastic.@ Pierce, drain and dress blisters to promote healing (this should be done only by people whom have received training on wound care)@ Many traditional adhesive tapes and dressings may be unsuitable for people with EB — especially those with the more severe forms (eg RDEB) — as their removal can cause additional trauma to the skin. Use of advanced wound care products such as low-adherent silicone tapes and dressings is recommended. However, resourcefulness by using items readily available, such as applying additional lubrication (eg Vaseline/paraffin oil) to some traditional wound dressings, is helpful.@ When EB affects other parts of the body, various cares and treatments are adopted. For example, a soft diet when the oesophagus is involved, or using stool softeners for constipation, or if patient has anal blisters.
82 THERAPEUTIC MANAGEMENT There is no specific therapy for any form of Herlitz JEB. First, an inventory of the affected body surface area and the type of skin involvement (intact blisters, erosions and chronic lesions) should be made.@ Infants require greater care and control of the environment around them to prevent trauma. This includes gentle manipulation techniques by their caregivers, use of foam to cover bony prominences and zinc oxide anti-adherent diapers. In older children, the use of special shoes and foam in the knee to prevent blistering is recommended.@ With respect to the treatment of lesions, blister puncturing to prevent dissemination and use of sterile dressings are recommended. The skin should be left in place, functioning as a biological dressing and preventing bacterial colonization. Firm and easily torn crusts require debridement to prevent maintenance of the inflammatory process.The basic principle underlying the care of patients with Herlitz JEB is to prevent blistering with meticulous skin protection and prevention of infections through wound care. This is done with the use of non-adhesive synthetic hydrocolloid dressing. Treatment decision should consider the location of the lesions, need for extra cushioning and protection, use of special dressings and clothing. Lesions should be cleaned with solutions of low toxicity, such as saline solution and water.The antiadherent and absorbent characteristics of dressings were crucial in the choice of materials, for this is a disease that evolves with bullous lesions, extensive exulcerated wounds, high chances of infection and scarification. Dressings should also be protective - considering the development of lesions after minimal trauma - and durable enough for the exchanges to occur with the minimum possible frequency.@ Silicone foam is the most complete and effective type of coverage in the healing process, offering protection, fluid absorption, hydration of the lesions, and antimicrobial properties when combined with additives such as silver. For drier wounds, foam continues to be the coverage with the broadest action. Hydrogel dressings, contact layers and biosynthetic cellulose can also be used. For scarified wounds, hydrogel dressings, biosynthetic cellulose and hydrocolloid are the best choices, given their debriding action..
83 THERAPEUTIC MANAGEMENT @ Nutritional support plays a critical role in the resolution of wounds. Some patients require a gastrostomy tube for optimal nutritional status. It is also important to monitor and maintain hemoglobin levels above 8mg/dl. Iron supplementation (oral or intravenous) may be required in some patients. In symptomatic cases, even blood transfusion may be needed.@ Topical or systemic antibiotics may be used for short periods following established criteria to avoid bacterial resistance and sensitization. More than three of the following characteristics recommend the use of topical antibiotics: wound that does not heal, increased exudate, erythema, presence of friable tissue, presence of dead tissue and stench. Occurrence of at least three of the following characteristics indicates the use of systemic antibiotics: increased wound size, temperature difference greater than 5.4 º C in relation of degradation, erythema or swelling at the border of the lesion, excessive exudation and stench.@ Avoiding trauma is essential to manage pain. Analgesic drugs should be prescribed according to pain severity, with the use of acetaminophen, NSAIDs, and even morphine in case of severe pain. @ Patients with Herlitz JEB subtypes showing a well-known risk of extra-cutaneous complications require careful monitoring and appropriate intervention (medical, surgical, dental, nutritional and psychological) before the tissues involved become severely injured. Signs and symptoms suggestive of early disease activity in the cornea require a quick assessment by an ophthalmologist to avoid permanent scarring and visual impairment. Patients with esophageal stenosis must undergo dilation to maintain an adequate intake of nutrients orally. Children unable to ingest food orally should receive supplementation via gastrostomy.@ Hand deformities should be prevented with appropriate dressings involving all fingers at night. The "boxing glove hands" can be temporarily improved with surgical procedures. SCC, which may develop early in these patients, should be treated by wide surgical excision, and the patient should be monitored to prevent recurrences.3 Patients with generalized forms of JEB and RDEB should be monitored for prevention and/or early detection of osteoporosis and osteopenia.
87 NUTRITIONAL COMPROMISE AND REQUIREMENTS IN EB An. Bras. Dermatol. 90 no.2 Rio de Janeiro . 2015 The nutritional impairment in patients with EB is directly related to the severity of associated problems, i.e., the more severe the EB type, the more extensive the nutritional impairment. Children and adolescents with junctional or recessive dystrophic EB, as well as Dowling-Meara, a subtype of EB simplex, have a significant risk of nutritional deficits. This is due to numerous complications such as blisters and oral ulcerations, compromised esophageal mobility, esophageal stenosis, dysphagia, dental problems, digestive and absorptive disorders, anal erosions and fissures and rectal constriction. These events result in chronic constipation, blood and protein loss through the blisters, hypermetabolism secondary to the increase in thermogenesis and protein turnover, especially in the presence of infection. These issues have the greatest significance in children and adolescents due to their immense nutritional requirements to achieve proper growth. The interactions between these and other factors are a challenge to the establishment of the best conduct and it becomes very difficult to determine which interventions are priorities
88 Cause-effect correlation of inadequate nutritional intake in patients with severe types of EB An. Bras. Dermatol. 90 no.2 Rio de Janeiro . 2015Malnutrition in EB patients, being the result of a combination of decreased food intake and increased nutrient demand, leads to failure to thrive , delayed puberty, anemia and a cascade of clinical and biological events that, together, culminate with the interruption or retardation of wound healing. Nutritional depletion and protein-energy malnutrition can result in alteration of immunocompetence, and secondary bacterial infections have been reported in EB patients.The nutritional needs of children and adolescents with minimal blisters and little or no gastrointestinal involvement are unlikely to be higher than those of their healthy peers with matching age and sex. In severe forms of EB, however, it is difficult to quantify the nutritional needs due to a number of factors, such as: 1- the multisystemic, inflammatory and infectious nature of the disease; 2-variable nutritional requirements reflecting the age, extent of blisters, presence of infection, need for catch-up growth, among others; 3-difficulties associated with desirable weight gain estimates, since height is also affected by chronic inflammation, pain, osteoporosis and articular contractures and 4-difficulty in conducting clinical trials due to the limited number of patients.
89 Energy requirement estimate for patients with EB An. Bras. Dermatol Energy requirement estimate for patients with EB An. Bras. Dermatol. 90 no.2 Rio de Janeiro . 2015
90 Epidermolysis Bullosa (EB) — The Worst Disease You've Never heard of