Epidermolysis Bullosa, Junctional, Herlitz Type

A number sign (#) is used with this entry because of evidence that the Herlitz type of junctional epidermolysis bullosa (JEB) is caused by mutations in any 1 of the 3 genes encoding the subunits of laminin-5: alpha-3 (LAMA3; 600805), beta-3 (LAMB3; 150310), and gamma-2 (LAMC2; 150292).

See also the non-Herlitz type of junctional epidermolysis bullosa (226650), an allelic disorder with a much less severe phenotype.

Description

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).

Pulkkinen and Uitto (1999) reviewed the pathophysiology and phenotypic and genetic heterogeneity of the various forms of epidermolysis bullosa.

Clinical Features

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.

McGrath et al. (1995) reported a child with Herlitz JEB who was born of consanguineous Pakistani parents. The patient presented at birth with extensive blisters and erosions. Electron microscopy of the skin revealed scanty, rudimentary hemidesmosome-anchoring filament complexes and tissue separation within the lamina lucida. Immunofluorescence staining of the basement membrane zone with an anti-laminin-5 antibody revealed absent labeling.

Diagnosis

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.

Pathogenesis

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.

Clinical Management

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.

Molecular Genetics

Mutations in the LAMA3 Gene

In a patient with Herlitz JEB, Vidal et al. (1995) identified a homozygous mutation in the LAMA3 gene (600805.0001). The patient's parents were related as first cousins. Skin biopsies showed showed drastically reduced immunoreactivity to antibodies directed against the alpha-3 chain of laminin-5 and impaired expression of the corresponding mRNA transcripts.

In a boy with the lethal Herlitz form of junctional epidermolysis bullosa, Kivirikko et al. (1995) identified a homozygous nonsense mutation in the LAMA3 gene (R650X; 600805.0002). The infant was born of consanguineous Asian parents and died in early infancy. McGrath et al. (1995) identified a homozygous R650X mutation in the LAMA3 gene in a Pakistani infant with Herlitz JEB.

Mutations in the LAMB3 Gene

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.

Mutations in the LAMC2 Gene

In a patient with Herlitz junctional epidermolysis bullosa, Pulkkinen et al. (1994) identified a homozygous mutation in the LAMC2 gene (150292.0001).

In a Caucasian male with Herlitz JEB who died at the age of 4 months with generalized blistering and abnormal nails, Nakano et al. (2002) found a homozygous mutation in the LAMC2 gene (150292.0005).

Genotype/Phenotype Correlations

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.

Population Genetics

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.

Animal Model

Ryan et al. (1999) observed that mice with targeted disruption of the murine Lama3 gene, had profound epithelial abnormalities resulting in neonatal lethality. The Lama3-null animals developed junctional blisters in the skin caused by a separation at the dermal-epidermal junction, similar to that observed in human Herlitz junctional epidermolysis bullosa.

History

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.