Alternative titles; symbols
SNOMEDCT: 400140006, 79855003; ICD10CM: Q81.1; ORPHA: 79404; DO: 0060737;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q32.2 | Epidermolysis bullosa, junctional 1B, severe | 226700 | Autosomal recessive | 3 | LAMB3 | 150310 |
A number sign (#) is used with this entry because of evidence that severe junctional epidermolysis bullosa 1B (JEB1B) is caused by homozygous or compound heterozygous mutation in the LAMB3 gene (150310) on chromosome 1q32.
See also the non-Herlitz type of junctional epidermolysis bullosa (JEB1A; 226650), an allelic disorder with a much less severe phenotype.
Severe junctional epidermolysis bullosa 1B (JEB1B) is an autosomal recessive skin blistering disorder characterized by extreme fragility of the skin and epithelia of various extracutaneous tissues. Blisters and erosions are present at birth. Blister formation occurs within the dermal-epidermal basement membrane zone. Patients usually die before 1 year of age (summary by Takizawa et al., 1998).
For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (226650).
Reviews
Pulkkinen and Uitto (1999) reviewed the pathophysiology and phenotypic and genetic heterogeneity of the various forms of epidermolysis bullosa.
Junctional epidermolysis bullosa is an autosomal recessive skin disorder in which blisters occur at the level of the lamina lucida in the skin basement membrane. Fine et al. (2000, 2008) proposed classification of the different types of JEB into 'Herlitz' and 'non-Herlitz' types based on severity; the Herlitz type is more severe and often results in early death. Fine et al. (2000, 2008) also eliminated the term 'hemidesmosomal,' which had previously been proposed for some forms of JEB (Uitto et al., 1997).
Roberts et al. (1960) described 3 cases in branches of a large consanguineous French Canadian family from Nova Scotia in which infants were born with bullous lesions and died at 20, 24, and 42 days, respectively, despite meticulous nursing care, antibiotics, corticosteroids, and increased dietary protein. Loss of serum protein and electrolytes and dermal sepsis seemed to have been responsible for death. The disorder was referred to as epidermolysis bullosa letalis.
Cross et al. (1968) studied an extensively involved kindred with the letalis form of EB and noted that the consistently lethal outcome suggested that the disorder was distinct from dystrophic EB (see, e.g., 226600). A congenital absence of skin in localized areas likely resulted from intrauterine trauma and bullae. Hands and feet were relatively spared.
Pearson et al. (1974) characterized the clinical features of the Herlitz form of JEB and noted that some patients may survive into the teens. Syndactyly does not develop and the hands are relatively spared. At the age of about 6 months, peculiar and pathognomonic perinasal or perioral nonhealing crusted lesions may appear.
Pulkkinen et al. (1994) studied a male infant of German ancestry with Herlitz JEB and mutation in the LAMB3 gene. At the age of 2 weeks he presented with extensive blisters and erosions that had been noted at birth. He had an unaffected older brother, and the parents were unaffected.
Muhle et al. (2005) studied 12 patients with Herlitz JEB, 9 of whom had mutation in the LAMB3 gene. Six of these died before 1 year of age; the other 3 died between 14 and 30 months of life. In the 3 patients who survived past 1 year, disease progression, quantified by the percentage of affected body surface, occurred relatively slowly during the first months of life. One patient, who died at 5 months of age, had been born with a large skin defect and remained hospitalized because of severe chronic wound infection and failure to thrive. Two patients were treated with artificial skin equivalents and 1 with skin grafts.
Takizawa et al. (1998) described the probands of 2 unrelated Japanese families with Herlitz JEB and mutation in the LAMB3 gene. Both presented with extensive erosions and blistering at birth; one died at 3 months of age and the other at 8 months. Electron microscopy revealed tissue separation at or within the lamina lucida. Immunofluorescence showed absence of laminin-5.
Gache et al. (2001) described a 7-year-old Caucasian girl born with severe JEB and mutation in the LAMB3 gene who experienced spontaneous and remarkable amelioration with age. Shortly after birth, she developed extensive skin blistering and erosions at sites exposed to friction, involving oral mucosa by the first months of life. Tissue separation was at the basal cell/lamina lucida interface. There was ulceration of the cornea, as well as nail dystrophy and loss of all nails by 9 months of age. Skin involvement then decreased progressively, with excellent general state and normal growth rate being attained by age 4 years. Sporadic blistering affecting the groin and the acral areas submitted to friction, corneal erosions, and teeth with pitted enamel were observed.
The transmission pattern of JEB1B in the family studied by Pulkkinen et al. (1994) was consistent with autosomal recessive inheritance.
Sybert (2010) pointed out that intermediate JEB (see 226650), severe JEB, severe epidermolysis bullosa simplex (EBS) Koebner (see 131900) or Dowling-Meara (see 131760), and recessive dystrophic epidermolysis bullosa (RDEB; 226600) can appear with identical clinical features at birth. Of intermediate versus severe JEB, she noted 'The diagnostic discriminator is time.'
Sybert (2010) stated that in survivors of severe JEB, the presence of granulation tissue around the nose may serve to distinguish their disorder from intermediate JEB.
Prenatal Diagnosis
Anton-Lamprecht (1981) showed that this disorder can be diagnosed or excluded prenatally by electron microscopic examination of fetal skin biopsy. Hausser and Anton-Lamprecht (1990) demonstrated that amnion membranes can also be used for prenatal diagnosis of this disorder.
Hashimoto et al. (1976) found that skin biopsies from patients with the Herlitz form of JEB showed hypoplasia of the hemidesmosomes and a mild decrease of the tonofibrils. There was also focal widening of the lamina lucida, suggesting that early blistering occurs exclusively in the areas devoid of hemidesmosomes. Cleavage always occurs in the plane of lamina lucida, i.e., the mode of blistering is junctional. Among the observed alterations, structural defects of hemidesmosomes were considered to play the most important role in the pathogenesis of junctional blisters.
Fine et al. (1991) commented that exuberant granulation tissue is a hallmark cutaneous feature of the Herlitz variety of junctional EB. The level of skin cleavage is the lamina lucida ('intralamina lucida').
Carter et al. (1991) characterized a human keratinocyte extracellular matrix (ECM) glycoprotein complex termed epiligrin, also known as laminin-5, which is the major component of the keratinocyte ECM. Epiligrin serves as a preferred ligand for the integrin receptors alpha-3/beta-1 in plasma membranes of basal keratinocytes and focal adhesions, and colocalizes with the integrin receptor alpha-6/beta-4 in hemidesmosomes. In human skin, epiligrin is found in the lamina lucida subregion of the epidermal basement membrane (BM), and plays a key role in the attachment of the epidermis to BM. Domloge-Hultsch et al. (1992) identified epiligrin as containing the BM600 or GB3 antigen that is absent from the skin of patients with lethal junctional epidermolysis bullosa. The authors also identified 3 patients with an acquired autoimmune disorder characterized by separation of the epidermis from the BM resulting from circulating autoantibodies to epiligrin. Skin from a fetus with lethal junctional epidermolysis bullosa showed no evidence of reactivity to the acquired patients' antiepiligrin autoantibodies or to a murine monoclonal antiepiligrin antibody. The findings indicated that epiligrin, or laminin-5, is absent or disrupted in patients with Herlitz JEB.
Baudoin et al. (1994) presented evidence of the involvement of different subunits of the heterotrimeric glycoprotein nicein, alternatively known as kalinin, laminin-5, and epiligrin, in Herlitz JEB. Immunohistochemistry, Northern blot, and protein analysis showed defective synthesis of various nicein subunits in 6 patients from 5 different consanguineous families. In 2 patients, the disease correlated with an impaired synthesis of the nicein B2 chain (LAMC2), in 3 others with that of the B1 chain (LAMB3), and in a sixth patient with that of the heavy A chain (LAMA3). The findings suggested genetic heterogeneity underlying Herlitz junctional epidermolysis bullosa.
Hirsch et al. (2017) demonstrated that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a 7-year-old child suffering from a devastating, life-threatening form of JEB caused by a homozygous splice site mutation in LAMB3 (150310). The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, called holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes.
Pulkkinen et al. (1994) demonstrated homozygosity for a nonsense mutation in the LAMB3 gene (R635X; 150310.0001) in an infant with Herlitz JEB. Ultrastructural and immunofluorescence antigenic mapping studies demonstrated tissue separation within or just above the level of the lamina lucida, findings consistent with the diagnosis. Both unaffected parents were shown to be heterozygous carriers.
Among 12 British patients with lethal Herlitz junctional EB, Ashton et al. (1997) identified the R635X mutation in the LAMB3 gene in 7 of 24 (29%) mutant alleles, confirming its relative frequency within the British gene pool. In addition, haplotype analysis using intragenic polymorphisms showed that the mutation arose on at least 4 different haplotype backgrounds, suggesting that it represents a mutation hotspot rather than propagation of a common British ancestral allele.
Among 14 European families with Herlitz junctional EB, Pulkkinen et al. (1997) found that LAMB3 mutations accounted for 22 (79%) of 28 junctional EB alleles, and that 14 (64%) of 22 LAMB3 alleles harbored the R635X mutation.
Nakano et al. (2000) examined the LAMB3 gene for mutations in 22 Herlitz junctional epidermolysis bullosa families and identified 15 distinct mutations, 8 of them novel, bringing the total number of distinct Herlitz junctional epidermolysis bullosa mutations in LAMB3 to 35. Examination of the LAMB3 mutations in all cases revealed 8 recurrent mutations, 6 of which had previously been reported. The authors noted that the comprehensive Herlitz JEB database consisted of a total of 152 mutant alleles in 80 cases, including a set of 111 previously reported alleles from 58 families. R635X and R42X (150310.0003) were present in 45.4% and 5.9% of the mutant LAMB3 alleles, respectively.
In affected infants with JEB1B from 2 apparently unrelated Japanese families, Takizawa et al. (1998) identified compound heterozygosity for LAMB3 mutations. One of the mutations, gln166 to ter (Q166X; 150310.0007), was found in the maternal allele of family 1 and the paternal allele of family 2. Conversely, the other mutation, trp610 to ter (W610X; 150310.0008), was found in the paternal allele of family 1 and the maternal allele of family 2. Haplotype analyses with intragenic LAMB3 polymorphisms suggested that both mutations had arisen independently in these 2 families.
In a patient who had severe JEB at birth which ameliorated with age, Gache et al. (2001) identified compound heterozygous mutations in the LAMB3 gene (see 150310.0011).
In a study of 12 patients with Herlitz junctional EB, Muhle et al. (2005) observed that the 4 patients who survived longer than 6 months were females who were homozygous for the R635X mutation of the LAMB3 gene (150310.0001). In these 4 patients, disease progression as quantified by the percentage of affected body surface occurred relatively slowly during the first months of life, and they had better initial development and weight gain. The 1 male patient who was also homozygous for R635X presented with a large skin defect at birth and remained hospitalized because of severe chronic wound infections and failure to thrive until his death at 5 months of age. Muhle et al. (2005) concluded that modifying factors may lead to significant variability in the clinical course of the disease and that other diagnostic means such as immunofluorescence and mRNA analysis should be taken into account when assessing the prognosis of an individual patient.
In a study involving 265 cases of junctional or hemidesmosomal EB, Varki et al. (2006) reviewed the clinical and molecular heterogeneity of these subtypes of EB, discussed exceptions to the general rules on genotype-phenotype correlations, and noted unusual phenotypes and genetics observed in patients and families with EB.
Nakano et al. (2000) calculated the carrier frequency of Herlitz type junctional EB and all forms of junctional EB from the incidence data presented by Fine et al. (1999). In the general U.S. population, the carrier risk was 1 in 113 for any type of EB mutation, 1 in 350 for junctional EB, and 1 in 781 for Herlitz type junctional EB.
Klunker (1963) thought that the dystrophic and lethal forms of epidermolysis bullosa were the same entity. Davison (1965) reported 'lethal' and 'dystrophic' cases in the same sibship. Dystrophic EB (see, e.g., 226600) is now considered to be a distinct disorder with skin cleavage at the level of the sublamina densa.
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