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EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED

Alternative titles; symbols

EBS, GENERALIZED
EPIDERMOLYSIS BULLOSA SIMPLEX, KOEBNER TYPE

Phenotype-Gene Relationships

Location Phenotype
12q13.13 Epidermolysis bullosa simplex, Koebner type
17q21.2 Epidermolysis bullosa simplex, Koebner type

Clinical Synopsis

TEXT
A number sign (#) is used with this entry because generalized epidermolysis bullosa simplex (EBS)
can be caused by heterozygous mutation in either the keratin-5 gene (KRT5; 148040) on
chromosome 12 or the keratin-14 gene (KRT14; 148066) on chromosome 17.

Description
Epidermolysis bullosa simplex (EBS) is a clinically and genetically heterogeneous skin disorder
characterized by recurrent blistering of the skin following minor physical trauma as a result of
cytolysis within basal epidermal cells. Most forms show autosomal dominant inheritance. The 3
main types include the generalized Koebner form, the more severe generalized Dowling-Meara
form (131760), and the localized, mild Weber-Cockayne form (131800) (Fine et al., 2008). All 3
forms can be caused by mutation in the KRT5 or the KRT14 gene. See 601001 for a rare autosomal
recessive form caused by mutation in the KRT14 gene.

Davison (1965) referred to generalized distribution of bullous vesicles as epidermolysis simplex

bullosa. The condition in which bullae were limited to the hands and feet was referred to as the
Cockayne type of epidermolysis bullosa (131800).

On the basis of an extensive study in Norway and review of the literature, Gedde-Dahl
(1971) arrived at a classification of epidermolysis bullosa. EB simplex in this classification
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encompassed disorders characterized by bulla formation within the epidermis, basal cell
vacuolization, and dissolution of tonofibrils on electron microscopy. The generalized Koebner form
and the localized Weber-Cockayne type were believed to be allelic. Gedde-Dahl (1981) recognized
at least 16 varieties of epidermolysis bullosa and suggested that dominant EB simplex can be
clinically and genetically divided into at least 4 types: the generalized Koebner type, the localized
Weber-Cockayne type, the mild Ogna type with fragile skin (131950), and a form with mottled
pigmentation (131960).

Fine et al. (1991) provided a revised classification of the subtypes of inherited epidermolysis
bullosa based on clinical and laboratory criteria.

Clinical Features
Passarge (1965) observed 21 affected persons in 4 generations of a family with generalized
epidermolysis bullosa simplex. The inheritance pattern was autosomal dominant.

Hacham-Zadeh et al. (1988) described a large Arab family originating from Jerusalem in which 38
affected individuals spanning 4 generations had EBS. Onset occurred between birth and 2 weeks of
age. The main clinical features were bullae, generalized, solitary, and in groups, with predilection to
the skin of the palms and soles. Mild to moderate patchy hyperkeratosis of the palms and soles was
found in 5 affected members of the family. Blisters in oral mucous membranes were noted and found
in summer and in periods of fever. Hair, teeth, and nails were normal. Improvement was noted by
progression of age from 5 to 23 years, and by some in summer and by others in winter.
Ultrastructural studies from a fresh blister disclosed intraepidermal blister via cytolysis of basal cell
cytoplasm. The pedigree indicated transmission of an autosomal dominant gene. However, in 1
instance, affected first cousins were married and all 6 of their offspring were affected. There was
marked intrafamilial variability. Although the family was originally thought to have the Dowling-
Meara form of EBS, Stephens et al. (1995)reclassified the phenotype as the Koebner type based on the
lack of keratin filament clumping on electron microscopy.

Mapping
Epstein (1991) cited evidence that linkage to the keratin gene cluster on chromosome 12 had been
demonstrated in at least 1 family with generalized epidermolysis bullosa simplex.

In a large family with 14 affected members in 3 generations with generalized EBS, Ryynanen et al.
(1991) found linkage to DNA marker D12S17, which is located on 12q (maximum lod score of 4.65
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at theta = 0.0). In the full report (Ryynanen et al., 1991), the maximum lod score for linkage to
D12S17 was given as 5.55 at theta = 0.0.

Molecular Genetics
In a family with the generalized form of epidermolysis bullosa simplex, Bonifas et al.
(1991) found linkage to markers on chromosome 17 and identified a point mutation in the
KRT14 gene (L384P; 148066.0001).

In affected members of a large Irish family with generalized EBS, Humphries et al.
(1993) identified a heterozygous mutation in the KRT14 gene (M272R; 148066.0007).

In affected members of a large Finnish family with the generalized Koebner type of EBS in
which Ryynanen et al. (1991) found linkage to 12q, Dong et al. (1993) identified a heterozygous
mutation in the KRT5 gene (L463P;148040.0002).

In affected members of a family with autosomal dominant epidermolysis bullosa

simplex, Stephens et al. (1995)identified a heterozygous mutation in the KRT5 gene
(K173N; 148040.0006). One family member was homozygous for the K173N allele, having
inherited it from each of her affected first-cousin parents. However, this patient showed no
significant differences in either the clinical severity or the ultrastructural organization of the
homozygous keratin intermediate filament cytoskeleton. These data demonstrated that the
K173N mutation behaves as a fully dominant allele.

Among 18 families with various forms of EBS, Pfendner et al. (2005) identified KRT5
mutations in 7 probands and KRT14 mutations in 11 probands, indicating that mutations in
either gene can result in EBS at approximately equal frequencies. A large number (15 of 18)
were de novo mutations. The clinical spectrum was highly variable.

Genotype/Phenotype Correlations
Livingston et al. (2001) reported a patient who presented at 3 to 4 days of age with widespread
generalized blistering. Painful hyperkeratosis of the palms and soles developed in his teen years,
whereas blistering improved somewhat with age. As an adult, he continued to get occasional
blisters in the mouth and cutaneous blisters with increased heat and/or activity. His skin
examination was striking for severe palmoplantar keratosis, underlying erythema in a 'glove and
moccasin' distribution, and limited range of motion in the fingers. There was no scarring and no
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significant nail changes. Clinical, histologic, and ultrastructural features were consistent with a
diagnosis of generalized EBS (Koebner subtype). Genetic analysis identified a heterozygous
nonsense mutation in the KRT5 gene (K472X; 148040.0016), predicting the synthesis of a truncated
keratin-5, missing the entire tail domain and a highly conserved motif in the central rod.
Ultrastructural analysis of the patient's nonhyperkeratotic skin was remarkable for basal
keratinocytes with dense and irregular keratin filaments proximal to the basement membrane. The
occurrence of severe palmoplantar hyperkeratosis suggested that the keratin-5 tail domain may
have important functions in palmoplantar tissues.

History
In skin fibroblast cultures of 3 patients from 3 kindreds with generalized EBS, Sanchez et al.
(1983) found a 7-fold decrease in gelatin-specific neutral metalloprotease. Cultures from
several other forms of epidermolysis bullosa showed no deficiency of this enzyme. Study of
gelatinase activity from 13 cases of localized EBS found that 6 had low levels of the enzyme
and 7 had normal levels. However, Winberg and Gedde-Dahl (1986) found that reduced
production of gelatinase from dermal fibroblasts was not a uniform finding in the Koebner
form of EBS. None of 6 patients tested showed this trait.

Mulley et al. (1984) found that both the Koebner and the Weber-Cockayne types of EBS had
suggestive linkage to Duffy blood group (Fy) on chromosome 1 (maximum lod score 1.5 at
theta = 0.2). In 3 generations of an Irish kindred with the Koebner variety of epidermolysis
bullosa, Humphries et al. (1990) and Ryynanen et al. (1991)found positive lod scores for 5
markers on 1q. In multilocus analysis, a lod score of 3 was obtained, with a maximum in the
region of AT3 (107300) on 1q23. In 3 generations of a Finnish family with EBS, Ryynanen et al.
(1991) found only low positive lod scores for 1q markers. EBS2 was the designation for the
putative locus on chromosome 1 (Ryynanen et al., 1991).

Hoyheim et al. (1991) excluded EBS from chromosome 1 by demonstration of negative scores
in a region up to 0.10 on each side of F13B (134580), which is located at 1q31-
q32.1. Humphries et al. (1990) excluded EBS from a region of more than 10 cM on each side of
the nidogen gene (NID; 131390), located at 1q43. Epstein (1991) suggested that the linkage to
chromosome 1 markers may have been in error.

In reviewing the molecular genetics of epidermolysis bullosa, Epstein (1992) suggested that a
defect in keratin intermediate filament proteins should have been suspected in EBS. Anton-
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Lamprecht and Schnyder (1982)described clumping of keratin intermediate filaments as the

characteristic abnormality demonstrable by electron microscopy in the more severe Dowling-
Meara subtype of EBS (131760). They also pointed to the family reported bySutherland and
Hinton (1981) in which a fragile site at 12q13 was associated with EBS.

See Also:
Bonifas et al. (1991); Bonifas et al. (1991); Humphries et al. (1990)

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Contributors: Cassandra L. Kniffin - updated : 11/3/2009

Creation Date: Victor A. McKusick : 6/4/1986

Edit History: ckniffin : 11/19/2010