Epidermolysis bullosa

Introduction to bullous epidermis release "epidermolysisbullosa" (EB) was first proposed by Koebner in the late 19th century to depict a blistering skin disease without scarring, which was subsequently used to describe a group of skin and mucous membranes that are susceptible to mechanical damage. A multi-gene hereditary skin disease characterized by the formation of bullae, a group of typical diseases that invade the basement membrane area of the skin, and internal organs can also be involved. Clinically, the condition shows great variability. At the same time, gene heterozygosity is also obvious, with autosomal dominant and recessive inheritance, abnormal wound repair can lead to chronic damage and scarring, metastatic cancer is also common. At present, significant progress has been made in the study of this disease. The main research method is to encode some key protein-based networks that maintain the integrity of the skin's hierarchical structure through molecular cloning. The disease also belongs to the category of "pemphigus" of Chinese medicine. basic knowledge The proportion of illness: 0.006% Susceptible people: no specific people Mode of infection: non-infectious Complications: malnutrition, anemia, squamous cell carcinoma

Bullous epidermolysis

(1) Causes of the disease

Bullous epidermolysis can be divided into three categories according to the level of blister formation under transmission electron microscopy (see Table 1). Different gene mutations encoding proteins in the dermal-epidermal junction provide different clinical subtypes. Molecular basis, the level of epidermal release of simple bullous epidermolysis is in the basal cell layer, the result of basal cell keratin protein KRT5 and KRTl4 mutations, tissue loosening of borderline bullous epidermolysis At the level of the zona pellucida of the dermal epithelial basement membrane, the ultrastructure shows an abnormality of the hemidesmosome anchor filament complex, which encodes the genes of the three polypeptides 3, 3 and 2 of the anchor fibronectin-laminin 5 (1aminin). Specific mutations, in addition, mutations in the subtype of borderline bullous epidermolysis that are found to encode hemidesmosome components, including mutations encoding the 64 integrin 4 subunit gene and bullous sex days encoding 18OkDa The herpes antigen BPAG2, also known as the mutation of type VII collagen gene, the tissue release of dystrophic bullous epidermolysis occurs at the level of anchor fibrils under the dense zone. Currently only type VII collagen gene (COL7) is found. A1) Mutation.

(two) pathogenesis

The molecular pathophysiology of the disease; the mutation site of the keratin polypeptide is closely related to the severity of simple bullous epidermolysis, and the DM-type keratin mutation is located in the amino (1A) or hydroxyl group of the central apron region of the polypeptide. At the (2B) end, the position of the K-type mutation is more prone to the central portion of the rod region, and the wc-type mutation position is often located either in the non-helical junction (L12) region of the rod region or at the front end of the position 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 lead to disease, the disease gene is located on chromosome 12qll ~ q13 or 17q12 ~ q21, keratin K5 and K14 are located at two sites, therefore, simple bullous epidermolysis is Due to defects in specific basic keratin genes, point mutations in the coding region of these two keratin genes have been reported in most cases. However, gene defects may also be located outside the K5 and K14 genes, and recently found to be accompanied by muscle nutrition. Simple bullous epidermolysis is associated with a prectin mutation, because the keratin gene and transcript length (1.8 to 2.1 kDa) is small, simple bullous epidermolysis Screening for keratin mutations in patients 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 against key regions of keratin polypeptides can be useful for future diagnosis. In addition, with the introduction of methods such as morphological-sensitive gel electrophoresis (CSGE), rapid detection of changes in individual DNA bases can be performed. Screening for mutations in keratin genes can also be made easier, and this method is especially useful when screening a large number of patient specimens, which also eliminates the need for sequencing of the entire motif or transcript.

2. Malnutrition The dystrophic genetic basis is based on normal skin. Type VII collagen forms a reverse dimer, which is joined by overlapping carboxy termini. Enhanced by sulfur bonds, this solid type VII collagen molecule aggregates laterally to form anchor fibrils, so that type VII collagen is further assembled into anchor fibrils after synthesis, thus affecting the synthesis or interference of type VII collagen at the transcriptional or translational level. Mutations in which 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 characteristics of this type of skin is extremely fragile. In light RDEB, alleles can encode full-length collagen type VII, but The missense mutation often occurs to alter the spatial conformation of the protein, thus affecting the anchor fibril assembly.

Mutations in the dominant hereditary bullous epidermolysis are detected by glycine residues in the collagen molecule that are characterized by repeated Gly-XY amino acid sequences. Glycine substitutions destabilize the collagen tricyclic structure. Interfering with its secretion and making 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, The 1/8 tricyclic molecule is normal, so 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, except for the classic DDEB type. There are two clinical subtypes (pre-temporal dystrophic bullous epidermolysis and Bart syndrome) with glycine substitution mutations.

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. Degree of genetic heterozygosity, at least six different genes are currently thought to be involved in its pathogenesis. In borderline bullous epidermolysis (JEB), blisters occur in the basement membrane at the junction of the dermal epithelium, ie, zona pellucida or overlapping At the level of hemidesmosome, under electron microscope, abnormalities were observed in the hemellosus-anchored anchorage complex, and studies on a large number of patients with fatal and non-induced borderline bullous epidermolysis found that the anchor filament protein-layer The three genes of the three constituent polypeptides of adhesion protein 5, 3, 3 and 2, are specifically mutated. Recently, mutations in genes encoding other components of hemidesmosome were detected in some subtypes of borderline bullous epidermolysis. For example, in a bullous epidermolysis with pyloric atresia, a gene mutation encoding the epithelial-specific integrin 6, 4 subunit 4, in borderline bullous epidermolysis, clinical manifestations Lighter body Patients with sexual dystrophic benign bullous epidermolysis showed gene mutations encoding the 180kDa bullous pemphigoid antigen 2 (BPAG2, also known as type XVII collagen), and recently the borderline bullous epidermone The understanding of the molecular basis of the disease emphasizes the complexity of the hemidesmosome-anchored filament complex and its role in the pathogenesis.

Herlitz type borderline bullous epidermolysis, mutation detection showed that each gene of laminin 5 has mutations (LAMA3, LAMB3 and LAMC3, three genes encode 3, 3 and 2 chains, respectively), and most of the mutations were found to occur. In the LAMB3 gene, there are two hotspots that cause mutations, namely R42x and R635x, and all mutations found at present also lead to the early termination of codon production, thereby translating the corresponding mRNA by antisense-mediated mRNA degradation mechanism. To a very low level, non-Herlitz-type borderline bullous epidermolysis also has a laminin 5 gene mutation. In some cases, mutation of one of the laminin 5 genes is an early termination password, however, other The gene mutation is a missense mutation or a framework exon skip mutation. In these cases, two regional gene mutations were found. These studies show that the full-length polypeptide with the complete carboxy terminus can be assembled into a three-dimensional molecule, and the three-dimensional structural molecule is in the anchor filament. Has a role in it.

In some patients, bullous plaques occur in hemidesmosomes and their peripheralities and are classified as "false border type" according to the classification of their ultrastructure and the severity of clinical conditions. The main components of hemidesmosome (HD) are mainly It is a polypeptide named HD1~HD5. These abnormalities are probably the cause of these subtypes of borderline bullous epidermolysis. According to the ultrastructural changes, bullae blistering at the hemidesmosome level Patients with scleroderma can be classified into at least three categories, and their clinical manifestations are different from any other type of classic bullous epidermolysis, which is systemic dystrophic benign bullous epidermolysis (GABEB). Pyloric occlusion of bullous epidermolysis (PA-JEB) and dystrophic bullous epidermolysis (EB/MD), a special subtype of nonfatal bullous epidermolysis In the systemic dystrophic benign bullous epidermolysis, the BPAG2 gene is found to be mutated. Another rare subtype of nonfatal borderline bullous epidermolysis is characterized by pyloric stenosis and skin blisters. First symptom, it is the result of mutation of integrin .

Bullous epidermal release prevention It is very important to maintain a good attitude, to maintain a good mood, to have an optimistic, open-minded spirit, and to be confident in the fight against disease.

Bullous epidermolysis complications Complications, malnutrition, anemia, squamous cell carcinoma

1. The recessive inheritance of dystrophic bullous epidermolysis, the most serious complication of severe type (ITS-RDEB) is the development of squamous cell carcinoma in the area of chronic erosion, more than 50% of TTS-RDEB Patients develop this cancer at around the age of 30, and many die from cancer metastasis.

2. The Herlitz type of borderline bullous epidermolysis (JEB), often associated with tracheal blisters, stenosis or obstruction, hoarseness is a sign of early infant deterioration, significant growth retardation and intractable mixed anemia make treatment even more Difficulties, children often die from sepsis, multiple organ failure and malnutrition.

Bullous epidermolysis symptoms Common symptoms Septic squamous cell carcinoma, malnutrition, intestinal atresia, herpes simplex (with purulent fluid), full-thickness of the epidermis and... spleen and kidney yang

1. Simple bullous epidermolysis (EBS)

It is characterized by a blister in the epidermis, a group of hereditary skin diseases caused by keratin mutations, invading a population of 1/4 million, further divided into different subtypes according to clinical severity, simple bullous epidermolysis The family's penetrance is high, and its most serious subtype, the disease manifests itself at birth.

There are at least 11 subtypes of simple bullous epidermolysis, of which 7 are autosomal dominant, and the 3 most common subtypes are autosomal dominant, including generalized bullous epidermium Koebnet, Weber Cockayne and Dowling Meata (Table 2), can significantly reduce blistering with age, sometimes No blistering for a month, it may be that as the patient grows older, the epidermis is fully stretched and the mechanical tension it receives is naturally reduced.

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

(2) Localized bullous epidermolysis: It is the most common type that occurs in childhood or later. It can also appear in adults. It appears as a hand after high-intensity exercise, and the foot is thick. Blister, common hands and feet sweating, blister on the feet often secondary infection.

(3) herpes-like bullous epidermolysis: can be seen at birth, is the most serious type, vesicles are generalized, can involve the oral mucosa, infancy can have obvious inflammation with miliary rash, early childhood blisters Mostly, the trunk and the proximal extremities can be white hair or "herplike" blisters, because the blister fissures are located in the epidermis, leaving no scars after the healing, and the nails may be lost, but they are usually regenerable.

Unlike the first two types, the blister does not become heavier after the heat, and there may be excessive keratosis at the age of 6, 7 years. Although some patients have very serious blister, they are rarely life-threatening because of the loss of localized skin barrier function. 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. Malnourished bullous epidermolysis

Healing after blister formation is often accompanied by the formation of scars and miliary rash. The blister of the epidermis is caused by the mutation of collagen type VII, mainly including four subtypes, namely Cockayne Touraine dominant hereditary type, Pasini white papular-like dominant hereditary type. Localized recessive hereditary and generalized recessive hereditary, in addition, there are some rare subtypes, such as Bart syndrome, neonatal temporary bullous epidermolysis.

(1) dominant hereditary type: Cockayne Touraine, in the disease, blisters are more common in the lower extremities, there is a malnutrition, starting in the early stage of infants or children, after healing, scars and malignant rashes are formed due to hyperplasia, oral damage is not common, teeth are more Normal, Pasini type begins at birth, blister dense with atrophic scar and miliary rash. In the absence of obvious trauma, skin color and scar-like papules spontaneously appear under the body, called white albopapuloid lesions. Late blisters are mainly confined to the extremities, occasionally the whole body, common malnutrition or nail loss, mild adhesion of the mucosal surface and teeth.

(2) Recessive hereditary type: The clinical manifestations are diverse, and the severe lesions are called mitis (light) type. They are often found at birth, often involving the extremities, with atrophic scars and nail dystrophy on the joint surface, but the mucosa is rarely involved. The lesser-performing lesions are indistinguishable from the localized dominant hereditary types. The severe lesions are disabling, called the Hallopeau-Siemens (HS-RDEB) type, which is widely blistered at birth and continues to expand during infancy. Obvious scar formation, acquired and often lead to "boxing gloves"-like deformities in the hands and feet, scars develop from the proximal end, and thus affect the entire limb, forming a curved contracture, which can affect nails, teeth and scalp, most mucosal surfaces continue to be involved, With recurrent blistering and erosion, leading to esophageal stricture and stenosis, urethral and anal stenosis, phimosis and corneal scar, often combined with malnutrition, growth retardation and chronic mixed anemia HS-RDEB the most serious complication is in the development of chronic erosion For squamous cell carcinoma, 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, a blisters appeared on the skin, separation under the basement membrane, collagen and anchor wire degeneration, When it is 4 months old, it will heal quickly. There is no damage to the nail, and no scar is formed after the skin lesion is recovered. It is generally believed that the disease has the following characteristics:

1 at birth or friction-induced blisters, bullous rash,

2 After a few months, you can recover by yourself.

3 no trophous scars,

4 The epidermis is starting from the dermal papilla.

5 Electron microscopy observed the anchor wire of collagen dissolution and destruction,

6 There is a stellate of keratinocytes in the crude endoplasmic reticulum.

3. Junctional bullous epidermolysis (JEB)

There are at least six clinical, subtypes, the most common of which are type 3, Herlitz type, mitis type 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, is the most serious type of all bullous epidermolysis, at birth Visible blisters can be seen with severe perioral granulation tissue. A is often lost at an early stage. It is characterized by malnutrition during regeneration. The tooth is malnourished due to enamel deficiency. Most mucosal surfaces have chronic erosion, and scalp damage is often seen. Chronic non-healing erosion with proliferative granulation tissue, systemic damage including whole epithelial blister, with respiratory, gastrointestinal and genitourinary involvement, often associated with tracheal blisters, stenosis or obstruction, hoarseness is a sign of early infant deterioration, significant Growth retardation and refractory mixed anemia make treatment more difficult. Children often die from sepsis, multiple organ failure and malnutrition. Rare clinical manifestations include pyloric and duodenal atresia, skin mucosal fragility due to integrin gene mutations. Very high, pyloric atresia combined with urinary system abnormalities 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 scalp and nail damage are more obvious, and the damage of the non-union of the mouth is more common in children 4 to 10 years old, and rare manifestations include borderline blisters in the extremities or wrinkles.

(3) GABEB: a non-lethal subtype with gross skin involvement at birth, mainly in the presence of blisters of varying sizes in the limbs, trunk, scalp and face can also be affected, sustainable to adults, with limbs, torso and Serous or bloody vesicles and chronic damage in the scalp, the blister increases when the temperature rises, and the blister atrophic healing is a unique manifestation of this type. A can develop severe malnutrition, with or without scarring hair loss. Mild oral mucosa and tooth malnutrition due to enamel deficiency, blister improved with age, but abnormal teeth and atrophic scar damage can continue to adults, normal growth, anemia is rare.

Examination of bullous epidermis release

Molecular pathophysiology of simple bullous epidermolysis: There is a close relationship between the mutation site of keratin polypeptide and the severity of simple bullous epidermolysis. The DM keratin mutation is located in the central acrole of the polypeptide. At the amino (1A) or hydroxyl (2B) end of the region, the position of the K-type mutation is more prone to the central portion of the rod region, and the WC-type mutation position is often located either in the non-helical junction (L12) region of the rod region or at the front end of the K5 region. .

Diagnosis and identification of bullous epidermis

Diagnostic criteria

1. In order to correctly diagnose simple bullous epidermolysis, skin biopsy is needed. Ultrastructural analysis of skin biopsy can identify the location of fissures in the skin, so simple bullous epidermolysis is associated with other types. EB distinguishes, it can further distinguish other vesicular skin diseases.

2. Mutation analysis in the prenatal diagnosis of bullous epidermolysis is genetic counseling, based on DNA prenatal diagnosis and gene therapy, to accurately understand the 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 sampled at the earliest stage of pregnancy at 10 weeks of gestation, or by abdominal wall amniocentesis at 12 to 15 weeks, for severe dystrophy. Bullous epidermolysis, which can be used for prenatal DNA diagnosis by direct mutation analysis or genetic linkage analysis. No other methods have been found to prove gene heterozygosity. The above methods have been used to cause severe disabling RDEB. The DNA prenatal diagnosis of more than 30 families, these genetics will also provide the basis for the development of pre-implantation diagnosis through blastomere analysis, which can avoid termination of 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, and is a diagnosis of typical HS-RDEB patients with severe disabling scars. Even if the parents are not diagnosed in the clinic, it is usually not difficult to diagnose. Similarly, the vertical hereditary blistering tends to be relatively light scar phenotype. In several generations, several family members are involved. At this time, the diagnosis of dominant genetic malnutrition Bullous epidermolysis is undoubted.

(3) Accurate understanding of mutations that cause borderline bullous epidermolysis is meaningful in genetic counseling, DNA-based prenatal diagnosis and gene therapy, and prenatal diagnosis can be sampled at the earliest stage at 10 weeks of gestation Examination, or by abdominal wall amniocentesis at 12-15 weeks, because there are many combinations of heterozygous genes that cause borderline bullous epidermolysis, and because at least 7 different genes can cause different types of junctions. Gene changes in bullous epidermolysis, and the detection of hotspot mutations are observed, so prenatal diagnosis must be based on the discovery of direct evidence of the absence or presence of two mutations. These methods have been used for many Herlitz-type junctions. Prenatal diagnosis of DNA in a dangerous family with bullous epidermolysis.

(4) Chinese medicine pathogenesis and syndrome differentiation Chinese medicine believes that the disease is mostly due to congenital loss, fetal element deficiency, endowment is not enough, 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 wetness general health condition is acceptable, blister size is not equal, tension is full, the content is serous, no inflammation around, loose stools, pale tongue, body fat with scallops, white or white greasy, slow pulse .

Dialectical: 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 blisters, 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: very contagious, 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 disease: blisters are 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: the disease is not limited to the friction site, no genetic history, no atrophic scar after the recovery, direct immunofluorescence examination shows IgA along the basement membrane band is linear deposition.

4. Neonatal pemphigus: often spread the body, the blister wall is loose, can be quickly controlled with antibiotics.

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

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

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

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