Thick-walled blisters on hands and feet

Introduction One of the manifestations of blistering or bullous polymorphic exudative erythema. Polymorphic erythema, also known as exudative polymorphous erythema, is an acute inflammatory skin disease with a complex cause. The rash is pleomorphic, often accompanied by mucosal damage, and its characteristic lesion is iris-like erythema. The disease is prone to spring and autumn and is prone to recurrence. The highest incidence rate is 10-30 years old.

Cause

(1) Causes of the disease

Bullous epidermolysis can be divided into three categories according to the level of blister formation under transmission electron microscopy. Mutations in different genes encoding proteins in the dermal-epidermal junction provide a molecular basis for different clinically distinct subtypes. The level of epidermal release of simple bullous epidermolysis is in the basal cell layer and is the result of basal keratin protein KRT5 and KRT14 mutations. The tissue release of the borderline bullous epidermolysis occurs at the level of the zona pellucida of the basal membrane of the dermis, and the ultrastructure shows an abnormality of the hemidesmosome anchor filament complex, which encodes the anchor fibronectin laminin 5 ( The genes of the three polypeptides 3, 3 and 2 of 1aminin are specifically mutated. In addition, gene mutations encoding hemidesmosome components were found in subtypes of borderline bullous epidermolysis, including mutations encoding the 64 integrin 4 subunit gene and bullous pemphigoid antigen encoding 18OkDa. BPAG2, also known as a mutation in the type VII collagen gene. The tissue release of dystrophic bullous epidermolysis occurs at the level of anchor fibrils in the dense zone, and only the VII collagen gene (COL7A1) mutation has been found.

(two) pathogenesis

Molecular pathophysiology of the disease; there is a close relationship between the mutation site of keratin polypeptide and the severity of simple bullous epidermolysis. The DM-type keratin mutation is located at the amino (1A) or hydroxyl (2B) end of the central apron region of the polypeptide. The position of the K-type mutation is more likely to be in the central portion of the rod region, and the position of the wc-type mutation is often or in the non-helical junction of the rod region. (L12) zone, or the front end of bit K5.

1. Epidermolysis bullosa simplex (EBS) genetics based on the analysis of keratin K5 and K14 genes in patients with simple bullous epidermolysis, found three major subtypes of keratin mutation. Functional studies have shown that these mutations cause disease. The disease gene is located on chromosomes 12qll to q13 or 17q12 to q21, and keratin proteins K5 and K14 are located at two sites, respectively. Therefore, simple bullous epidermolysis is caused by a defect in the specific basic keratin gene. Point mutations in the coding region of the two keratin genes are present in most of the cases reported. However, genetic defects may also be located outside of the K5 and K14 genes. It has recently been found that simple bullous epidermolysis with muscle nutrition is associated with a prectin mutation. Because keratin genes and transcript lengths (1.8 to 2.1 kDa) are small, screening for keratin mutations in patients with simple bullous epidermolysis is mostly performed by DNA sequencing. Especially when skin biopsy, keratinocyte culture and mRNA extraction are available. If an antibody is used for diagnosis and analysis, the generation of a panel of antibodies directed against a critical region of the keratin polypeptide may be useful for future diagnosis. In addition, with the introduction of methods such as morphological-sensitive gel electrophoresis (CSGE), rapid detection of changes in single bases of DNA can be made. Screening for keratin gene mutations can also be made easier. This method is especially useful when screening a large number of patient specimens. It also eliminates the need for sequencing of the entire genomic or transcriptional gene.

2. Malnutrition The dystrophic genetic basis is based on normal skin. Type VII collagen forms a reverse dimer and is joined by overlapping carboxy termini. This linkage is reinforced by disulfide bonds within the chain. This stable type VII collagen molecule aggregates laterally to form anchor fibrils. Thus, after synthesis of collagen type VII, it is further assembled into anchor fibrils. Thus, mutations that affect the synthesis of collagen type VII at the transcriptional or translational level or interfere with the assembly of the supramolecular assembly into anchor fibrils can be manifested as dystrophic bullous epidermolysis.

For HS-RDEB, it has been found that the mutated gene of the early stop codon (PTC) of the two alleles of type VII collagen has low level expression, but the translated protein is truncated at its carboxy terminus and cannot be assembled into anchor fibrils. . This is consistent with the complete lack of anchor fibrils in the HS-RIDEB ultrastructure, which also explains the nature of this type of skin is extremely fragile. In light RDEB, the allele can encode a full-length collagen type VII polypeptide, but often missense mutations alter the spatial conformation of the protein, thus affecting anchor fibril assembly.

Mutations in which dominant hereditary bullous epidermolysis is currently detected are glycine residue substitutions that occur within the collagen molecule as a domain characterized by repeated Gly-XY amino acid sequences. Glycine replacement destabilizes the collagen tricyclic structure, interferes with its secretion, and makes it susceptible to extracellular degradation. Therefore, the role of glycine substitution is at the post-translational level. Since type VII collagen is a homodimer composed of three identical 1(VII) polypeptides, 1/8 of the tricyclic molecule is normal. Thus the mouth can form some normal anchor fibrils, which is consistent with the relatively mild clinical manifestations of fine anchor fibrils and DDEB observed in ultrastructure. In addition to the classic DDEB type, glycine substitution mutations were present in two clinical subtypes (pre- dystrophic bullous epidermolysis and Bart syndrome).

3. The genetic basis of the junctional bullous epidermolysis (JEB) is different from the homozygosity observed in the first two types of bullous epidermolysis. The borderline bullous epidermolysis is very high. The degree of genetic heterozygosity is currently thought to be related to at least six different genes. In borderline bullous epidermolysis (JEB), blisters occur in the basement membrane at the junction of the dermal epithelium, ie, the zona pellucida or overlapping hemidesmosome levels. Under the electron microscope, an abnormality was observed in the area of the semi-bridged anchor wire complex. A study of a large number of patients with lethal and non-sexual borderline bullous epidermolysis found that the three genes encoding the three constituent polypeptides 3, 3 and 2 of anchor fibroin-laminin 5 were specifically mutated. Recently, mutations in genes encoding other components of hemidesmosomes have been detected in some subtypes of borderline bullous epidermolysis. For example, a mutation in a subunit 4 encoding epidermal cell-specific integrin 6, 4 was detected in a patient with bullous epidermolysis and pyloric atresia. In borderline bullous epidermolysis, patients with milder systemic dystrophic benign bullous epidermolysis showed bullous pemphigoid antigen 2 (BPAG2, also known as 180kDa). Mutation of the XVII type collagen). A recent understanding of the molecular basis of borderline bullous epidermolysis has emphasized the complexity of the hemidesmosome-anchored filament complex and its role in pathogenesis.

Herlitz type borderline bullous epidermolysis, mutation detection showed that each gene of laminin 5 has mutations (LAMA3, LAMB3 and LAMC3, three genes encoding 3, 3 and 2 chains, respectively). Most of the mutations were found to occur in the LAMB3 gene, and there are two hotspots that cause mutations, namely R42x and R635x. At the same time, all mutations currently found lead to the early termination of codon production, thereby reducing the corresponding mRNA transcription to a very low level by antisense-mediated mRNA degradation mechanism. Non-Herlitz type borderline bullous epidermolysis also has a mutation in the laminin 5 gene. In some cases, mutations in one of the laminin 5 genes are early termination codes. However, other genetic mutations are missense mutations or exon skip mutations within the framework, and two regional gene mutations were found in these cases. These studies show that full-length polypeptides with intact carboxy termini can assemble into three-dimensional molecules. Three-dimensional structural molecules have a role in anchor filaments.

In some patients, bullous plaques occur within the hemidesmosome and are similar and are classified as "false border type" according to the classification of the ultrastructure of the tissue and the severity of the clinical condition. The main components of hemidesmosome (HD) are mainly polypeptides named HD1 to HD5. These multiple abnormalities are likely to be the cause of these subtypes of borderline bullous epidermolysis. According to the ultrastructural changes, patients with bullous epidermolysis with blistering at the level of hemidesmosome can be classified into at least three categories. Its clinical manifestations are different from any of the classic bullous epidermolysis. They are systemic dystrophic benign bullous epidermolysis (GABEB), bullous epidermolysis with pyloric atresia (PA-JEB), and muscular dystrophy bullous epidermolysis (EB/ MD). In the special subtype of nonfatal bullous epidermolysis, systemic dystrophic benign bullous epidermolysis, the BPAG2 gene was found to be mutated. Another rare subtype of nonfatal borderline bullous epidermolysis is characterized by pyloric stenosis and skin blistering as its first symptom, which is the result of mutations in beta integrin.

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Viral infection immunoassay blood test

1. Simple bullous epidermolysis (EBS) is a group of hereditary skin diseases characterized by vesicles in the epidermis, mainly caused by keratin mutations, invading a population of 1/4 million. Further subtypes are divided according to clinical severity. The simple bullous epidermolysis family has a high penetrance rate, and its most severe subtype, the disease manifests itself at birth. There are at least 11 subtypes of simple bullous epidermolysis, of which 7 are autosomal dominant. The three most common subtypes are autosomal dominant, including generalized bullous epidermolysis (Koebnet), localized bullous epidermolysis (Weber Cockayne), and herpes-like bullous epidermium Dowling Meata (Table 2). The blister can be significantly reduced with age, and sometimes it can be blistered for a few months. It may be that as the patient grows older, the epidermis is fully stretched and the mechanical tension is naturally reduced.

(1) Generalized bullous epidermolysis: starting from the newborn to the early stage of the baby, more common in the hands, feet and limbs. It can also be seen that the palmar hyperkeratosis and desquamation. Do not involve nails, teeth and oral mucosa.

(2) Localized bullous epidermolysis: It is the most common type that begins in childhood or later. It can also appear in adults, which is characterized by thick blistering of the hands and feet after high-intensity exercise. Common hands and feet sweating. The blister on the foot is often infected.

(3) herpes-like bullous epidermolysis: can be seen at birth, is the most serious type, vesicles spread throughout the body, can affect the oral mucosa. Significant inflammation and miliary rash can occur in infancy, and blistering is not scarred in early childhood. The trunk and the proximal extremities can be white hair or "herpes-like" blisters because the blister fissures are located in the epidermis and no scars are left behind. Finger nails may be lost, but are usually regenerable. Unlike the first two types, the blister does not become heavier after the heat. At the age of 6 or 7 years, there may be excessive keratosis. Although some patients have very serious blisters, they are rarely life-threatening. Because of the loss of localized skin barrier function, it is easy to secondary infection. Simple bullous epidermolysis with muscular dystrophy is the only non-keratin mutation in simple bullous epidermolysis, similar to the Koeber type, but with muscular dystrophy in adulthood.

2. Malnutrition Bullous epidermolysis is often accompanied by the formation of scars and miliary rash after blister formation. Subepidermal blisters due to mutation of collagen type VII collagen. It mainly includes four subtypes, namely Cockayne Touraine dominant hereditary type, Pasini white papular-like dominant hereditary type, localized recessive hereditary type and generalized recessive hereditary type. In addition, there are some rare subtypes. Such as Bart syndrome, neonatal temporary bullous epidermolysis and so on.

(1) Dominant hereditary type: Cockayne Touraine. In the disease, blisters are more common in the lower extremities, and there is a malnutrition, which begins in infants or early childhood. After healing, scars and malignant rashes form due to hyperplasia. Oral damage is uncommon and the teeth are normal. Pasini type begins at birth, with blisters dense with atrophic scars and miliary rash. In the absence of obvious trauma. Skin color and scar-like papules spontaneously appear under the body and are called white albopapuloid lesions. Late blisters are mainly confined to the limbs and occasionally. Common malnutrition or nail loss. The mucosal surface and teeth are slightly involved.

(2) Recessive hereditary type: various clinical manifestations. The less severe limitation is called mitis (light) type. It is found at birth, often involving the extremities, with atrophic scars and nail dystrophy on the joint surface, but the mucosa is rarely involved. Limitations of milder limitations are not easily distinguishable from localized dominant hereditary types. Severe damage is disabling and is called the Hallopeau-Siemens (HS-RDEB) type. A wide range of blisters at birth, which continue to expand during infancy, result in significant scarring. Acquired and often caused "boxing gloves"-like deformities in the hands and feet. The scar develops from the proximal end, which in turn affects the entire limb and forms a curved contracture. May involve nails, teeth and scalp. Most mucosal surfaces continue to be involved, with recurrent blisters and erosions, leading to esophageal stricture and degeneration, urethral and anal stenosis, phimosis and corneal scarring. Often combined with malnutrition, growth retardation, and chronic mixed anemia, the most serious complication of HS-RDEB is the development of squamous cell carcinoma in areas of chronic erosion. More than 50% of HS-RDEB patients develop this cancer at around age 30, and many die from cancer metastasis.

(3) Bart syndrome: a clinical subtype of DDEB, which is autosomal dominant, first reported by Bart et al., characterized by congenital localized skin defects, mechanical blisters and nail deformities, with a good prognosis. .

(4) New bulls temporary bullous epidermolysis: In 1985, Hashimoto et al reported that after each minor injury, blisters appeared on the skin, separation under the basement membrane, collagen and anchor wire degeneration. Healed quickly by 4 months. There is no damage to the nail, and no scar is formed after the skin lesion is cured. It is generally believed that the disease has the following characteristics: 1 blistering and bullous rash at birth or friction. 2 After a few months, you can recover on your own. 3 no trophous scars. 4 Epidermis is initiated in the dermal papilla layer. 5 The anchor wire of collagen dissolution and destruction was observed by electron microscopy. 6 There is a stellate of keratinocytes in the crude endoplasmic reticulum.

3. Junctional bullous epidermolysis (JEB) There are at least 6 clinical and subtypes, the most common of which are type 3, Herlitz, mitis and generalized benign dystrophy (GABEB).

(1) Herlitz type: also known as lethal type and gravis type, often can not survive in infancy, more than 40% died within 1 year after birth. It is the most serious type of all bullous epidermolysis. A generalized blisters can be seen at birth with severe perioral granulation tissue. A is often lost in the early stage, and it is manifested as a malnutrition during regeneration. The tooth is malnourished due to enamel deficiency, and most mucosal surfaces have chronic erosion. Severe scalp damage is often seen in the erosion of chronic non-healing with proliferative granulation tissue. Systemic damage includes the entire epithelial blister with respiratory, gastrointestinal and genitourinary involvement. Often combined with tracheal blisters, stenosis or obstruction, hoarseness is a sign of early infant deterioration. Significant growth retardation and intractable mixed anemia make treatment more difficult. Children often die from sepsis, multiple organ failure, and malnutrition. Rare clinical manifestations include pyloric and duodenal atresia, and skin mucosal fragility is extremely high due to integrin gene mutations. Most of the pyloric atresia combined with abnormalities of the urinary system such as hydronephrosis and nephritis.

(2) Mitis (light) type: also known as non-lethal type, some children show moderate borderline damage at birth, or can survive in infancy due to serious damage, and alleviate with age . The hoarseness is lighter or less. The damage of the scalp and nail is more obvious, and the damage of non-healing around the mouth is more common in children 4 to 10 years old. Rare manifestations include borderline blisters in the extremities or wrinkles.

(3) GABEB: a non-lethal subtype with systemic skin involvement at birth. Blisters of varying sizes are found mainly in the limbs, and the trunk, scalp and face can also be involved. Sustained to adult, with serous or bloody blisters and chronic damage to the limbs, trunk and scalp. The blister increases as the temperature increases. Atrophic healing of vesicles is a unique manifestation of this type. A can cause severe malnutrition. Common with or without scarring hair loss. There may be mild oral mucosal involvement and tooth malnutrition due to enamel deficiency. Blisters improve with age, but abnormal tooth and atrophic scar damage can persist to adults. Growth is normal and anemia is rare.

1. In order to correctly diagnose simple bullous epidermolysis, skin biopsy is required. Ultrastructural analysis of skin biopsies can identify the location of fissures in the skin, thus distinguishing simple bullous epidermolysis from other types of EBs. It can further distinguish other vesicular skin diseases, such as epidermal hyperkeratosis (EH), which is pathologically similar to simple bullous epidermolysis, but invades the epithelial basal cell rather than the basal cell layer. . In a few cases, this method is also used for prenatal diagnosis. The current understanding of the genetic basis of simple bullous epidermolysis has made prenatal genetic counseling possible, and it can be performed early in pregnancy, with less risk to the fetus than skin biopsy.

2. The application of mutation analysis in the prenatal diagnosis of bullous epidermolysis is based on genetic counseling, prenatal diagnosis based on DNA and gene therapy to accurately understand the causes of different subtypes of dystrophic bullous epidermolysis. Diseased mutant genes can be used to explain some of the problems.

(1) The more direct relationship with patients is the prenatal diagnosis of DNA, which can be examined by chorionic villus sampling at 10 weeks of gestation, or by abdominal wall amniocentesis at 12-15 weeks. For severe dystrophic bullous epidermolysis, prenatal DNA diagnosis can be performed by direct mutation analysis or genetic linkage analysis. No other methods have been found to demonstrate gene heterozygosity. The above approach has been used for prenatal diagnosis of DNA in more than 30 families with severe disabling RDEB. These genetic knowledge will also provide the basis for the development of pre-implantation diagnosis through blastomere analysis, which avoids the need to terminate a pregnancy when a sick fetus is discovered.

(2) Diagnosis and genetic counseling: dystrophic bullous epidermolysis can be inherited in an autosomal dominant and autosomal recessive manner. The diagnosis of a typical HS-RDEB patient with severe disabling scars is usually not difficult to diagnose even if their parents are not clinically ill. Similarly, vertical hereditary blistering tendencies and relatively light scar phenotypes have been affected by multiple family members in several generations, at which point the diagnosis of dominant genetic dystrophic bullous epidermolysis is undoubted. Clinically, it is more difficult to diagnose and determine the genetic type when parents are normal and patients are less likely to perform. Ultrastructural observations revealed that the skin of these patients had anchor fibrils, but the amount was small. Often diagnosed as dominant dystrophic bullous epidermolysis. It is considered to be a new dominant mutation or a chimeric mosaic of the parental lineage. This diagnosis is obviously important for the Keegan consultation of individual patients. If their disease is really a new dominant mutation, the incidence of their offspring is 1/2. Conversely, the risk of late generation of recessive hereditary diseases is about as low as that of the general population, except for close relatives. For the lighter performance, ultrastructural detection of fibrils, and the careful identification of gene mutations and phenotypes in several patients with positive immunofluorescence staining of type VII collagen suggest that many of them are homozygous and heterozygous for heterozygous or recessive inheritance. mutation. For example, the first evidence that mild dystrophic bullous epidermolysis is a type VII collagen abnormality reveals a homozygous missense mutation, ie, lysine at the carboxy terminus of the molecule replaces methionine (M2798K). Similarly, in other cases, missense mutations in one allele, including H-amino acid substitutions in the collagen domain and mutations in the early allele of the other allele, can cause light RDEB. Finally, a survey of more than 100 families found significant COL7Al mutations, with only a few showing de noco dominant mutations, and at least one from their maternal lineage. Based on the above considerations, it is more appropriate to consider each new case as recessive in heredity, unless it is a dominant mutation by molecular genetic analysis. The reclassification of dystrophic bullous epidermolysis by disease-causing mutations is clearly beneficial to estimate the likelihood of involvement of the offspring of the affected individual.

(3) Accurate understanding of mutations that cause borderline bullous epidermolysis is significant in genetic counseling, DNA-based prenatal diagnosis, and gene therapy. Prenatal diagnosis can be performed by chorionic villus sampling at 10 weeks of gestation, or by abdominal wall amniocentesis at 12 to 15 weeks. Because there are many combinations of heterozygous genes that cause borderline bullous epidermolysis, and because at least 7 different genes can cause genetic changes in different types of borderline bullous epidermolysis, hot spots are observed. Mutations are updated, so prenatal diagnosis must be based on direct evidence of the absence or presence of two mutations. These methods have been used for prenatal diagnosis of DNA in many families at risk of Herzitz-type borderline bullous epidermolysis.

(4) Chinese medicine pathogenesis and syndrome differentiation Chinese medicine believes that this disease is mostly due to congenital loss, fetal element deficiency, endowment is not sufficient, spleen and kidney yang deficiency; or because of the sputum in the cell, the heat, the legacy, and the external friction . TCM syndrome differentiation: 1 spleen deficiency and wetness type general health condition is acceptable, blister size is not equal, tension is full, the content is serous, no inflammation around, easy to lick. The tongue is light, the body is fat and has tooth marks, the white or white greasy moss, and the pulse is slow. Dialectical syndrome: spleen and dampness, water and wet overflow. 2 spleen and kidney yang deficiency type more common in infants and children, children with thin body, thin hair, soft or hair loss, poor teeth development, soft or falling nails, hands and feet are not warm, or often cyanosis, often have more diarrhea, The skin has bullae or blister, the tongue is light or the tongue is fat, the white is white or less, and the pulse is fine. This type is more common in dominant dystrophy. Dialectical: kidney yang deficiency, lack of blood.

Differential diagnosis

1. Neonatal impetigo is highly contagious and can be epidemic.

The blister is easily broken, and the content quickly becomes purulent. Staphylococcus or streptococcus can be found, and the inflammation is remarkable and easy to cure.

2. Skin porphyria blister is more common in the exposed parts of the back, face, ears, etc., sensitive to light. Visible hairy, often accompanied by liver damage. Increased urinary porphyrin and coproporphyrin in urine and feces.

3. Children with linear IgA bullous skin disease is not limited to the friction site, no genetic history, no atrophic scar after the recovery. Direct immunofluorescence showed that IgA was linearly deposited along the basement membrane zone.

4. Neonatal pemphigus often spreads throughout the body, the blister wall is loose, and can be quickly controlled with antibiotics.

5. Bullous papular urticaria is often accompanied by obvious itching and edematous papules.

6. Acquired bullous epidermolysis can be caused by drugs, infections, porphyria, amyloidosis, etc., often accompanied by other manifestations of related diseases.

In addition, during puberty, the blister of the foot should be differentiated from athlete's foot and porphyria.

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