Epidermolysis Bullosa Dystrophic Dominant, Pruriginosa

DISEASE CARD

Disease group Epithelial adhesion disorders
DISEASE NAME EPIDERMOLYSIS BULLOSA DYSTROPHIC, DOMINANT, PRURIGINOSA
Synonymous None
Estimated prevalence Unknown
OMIM 604129
Inheritance Autosomal dominant, Autsomal recessive
Gene (s) COL7A1 (120120)

Definition

The term epidermolysis bullosa (EB) describes a clinically and genetically heterogeneous spectrum of rare inherited conditions that are characterized by a marked mechanical fragility of epithelial tissues with blistering and erosions occurring after minor trauma. There are four major types of EB: EB simplex (EBS), dystrophic EB (DEB), junctional EB (JEB), and Kindler-syndrome. Except for Kindler-syndrome, each major EB-type is further subclassified [1]. EB is based on mutations involving at least 15 structural genes expressed within the epidermis and the basement membrane zone (BMZ) [2, 3] (Figure 1). Besides the structural genes, MMP1 (collagenase-1) has been identified as a modifier of severity in dystrophic EB [4, 5]. In addition to the skin involvement, many EB forms present as a multisystemic disease associated with numerous extracutaneous manifestations. Secondary complications like chronic inflammation, chronic wound healing and scarring can result in severe impairments like pseudosyndactyly and mitten formation as well as life threatening forms of cancer, like squamous cell carcinoma in DEB [6].

Dystrophic or dermolytic epidermolysis bullosa (DEB) is characterized by tissue separation within the upper papillary dermis. The cleft formation occurs at the sub-lamina densa level, where collagen VII forms the anchoring fibrils (AF). DEB is divided into two major categories, the dominant (DDEB) and recessive (RDEB) forms, according to the mode of inheritance. Further subclassifications are made by clinical phenotype and severity of disease [1]. DDEB is subdivided into six subtypes (Table 1) with the generalized subtype (DDEB-gen) representing the prototype of DDEB [2]. All forms of DEB are caused by mutations in the COL7A1 gene (3p.21.31).

Dominant DEB pruriginosa (DDEB-Pr) is a more generalized subtype of DDEB, which is characterized by severe pruritus [2]. Approximately 100 families have been reported to date and the transmission is autosomal dominant or autosomal recessive [1].

Table 1: DDEB subtypes.

Subtype Gene
DDEB, generalized DDEB-gen COL7A1
DDEB, acral DDEB-ac
DDEB, pretibial DDEB-Pt
DDEB, pruriginosa DDEB-Pr
DDEB, nails only DDEB-na
DDEB, bullous dermolysis of newborn DDEB-BDN

Figure 1: Schematic representation of EB-causing components.
© graphic design by R. Hametner

Schematic of the basement membrane zone (BMZ). Intermediate filaments composed of keratin 5 and 14 insert on the keratin (cytoskeletal) linker proteins plectin and BPAG1 (BP230) at the superior aspect of the BMZ. Plectin and BPAG1 interact with transmembrane α6β4 integrin and type XVII collagen (BP180/BPAG2), forming hemidesmosomes that attach basal keratinocytes to the underlying basement membrane. Anchoring filaments reach out below the hemidesmosome and include laminin-332 and laminin-311 that associate with type XVII collagen and α6β4 integrin, but also laminin-511, type IV collagen and nidogen, thereby forming the lamina densa. Anchoring fibrils extend as banded projections from the lamina densa and contain type VII collagen molecules. Type VII collagen triple helices attach the lamina densa to papillary dermis and are critical for the integrity of the epidermal-dermal junction through their ability to bind laminin-332.

Clinical Description

Dominant DEB presents with a generally milder phenotype compared to recessive DEB or junctional EB. Blistering starts at birth or soon thereafter, ranging from mainly acral involvement to disseminated lesions. Milia and atrophic scars develop from healing blisters, mainly on the elbows, knees and the back of the hands. Nail dystrophy is always present. Mucosal involvement (oral cavity, esophagus) is rare, but if present can cause strictures. Teeth are normal. Disease activity commonly diminishes with advancing age [1, 2].

In DDEB-Pr, skin fragility and blistering starts at infancy and heals with milia formation and atrophic scarring. The onset of pruritus is delayed and often does not appear until adolescence or adulthood. With the onset of pruritus the clinical picture worsens with development of nodular prurigo-like lesions and in some cases albopapuloid lesions on the trunk. Scratching due to pruritus may generate large areas of disease on the shins and forarms. Nail dystrophy is almost always present [7].

Pathogenesis

More than 600 distinct mutations in the COL7A1 gene have been disclosed in DEB that interfere with the structural and functional integrity of its proteinaceous product, the type VII collagen [7, 8]. The latter polymerizes to form anchoring fibrils (AF) that anchor the epidermal basement membrane with the dermis. Collagen VII in normal tissues is restricted to stratified squamous epithelia, with blistering affecting the skin, mucous membranes and upper third of the esophagus. Secondary systemic manifestations of DEB, such as anemia, renal failure and squamous cell carcinomas are downstream complications due to blood loss, infections and chronic inflammation. In DEB skin, collagen VII is either reduced or absent. Ultrastructurally, electron microscopy reveals paucity, rudimentary structure, or complete lack of AF.

In DDEB, heterozygous glycine substitution mutations in the Gly-X-Y repeat triplet sequence within the collagenous domain of the pro-a-chain of the type VII collagen homotrimer interfere in a dominant-negative manner with collagen synthesis and impair its secretion or the fibrillogenesis of anchoring fibrils [9]. Since the defective as well as the wildtype alleles are expressed, some anchoring fibrils are functionally intact, accounting for the relatively mild course of DDEB. Life expectancy in DDEB is normal.

Diagnosis

Clinically, severe or even intractable pruritus is the main characteristic of DDEB-Pr besides the more generalized appearance of DDEB-like skin lesions. DNA sequencing of the COL7A1 gene confirms the diagnosis on the molecular level.

Treatment

Currently no causative therapy is available for neither form of DEB and treatment is primarily preventive. In everyday life, blister formation has to be avoided by protective padding of the skin. Wound care management is paramount in order to prevent secondary infections and to reduce scarring. In rare cases of tracheolaryngeal complications, esophageal strictures can be treated by balloon dilatation. Special diet may be necessary.

Treatment of DDEB-Pr with emollients, topical steroids or antihistamines has not shown to provide a sustainable long-term effect so far, but may help to control pruritus for a short period of time.

References

1
Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, McGrath JA, Mellerio JE, Murrell DF, Shimizu H, Uitto J, Vahlquist A, Woodley D, Zambruno G. (2008) The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 58:931-50.

2
Fine JD. (2010) Inherited epidermolysis bullosa. Orphanet J Rare Dis 5:12.

3
Pigors M, Kiritsi D, Krümpelmann S, Wagner N, He Y, Podda M, Kohlhase J, Hausser I, Bruckner-Tuderman L, Has C. (2011) Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity. Hum Mol Genet 20:1811-1819.

4
Titeux M, Pendaries V, Tonasso L, Décha A, Bodemer C, Hovnanian A. (2008) A frequent functional SNP in the MMP1 promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa. Hum Mutat 29:267-276.

5
Kern JS, Grüninger G, Imsak R, Müller ML, Schumann H, Kiritsi D, Emmert S, Borozdin W, Kohlhase J, Bruckner-Tuderman L, Has C. (2009) Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort. Br J Dermatol 161:1089-97.

6
Fine JD, Hintner H. (2008) Life with Epidermolysis Bullosa. Springer, Vienna.

7

McGrath JA, Schofield OM, Eady RA. (1994) Epidermolysis bullosa pruriginosa: dystrophic epidermolysis bullosa with distinctive clinicopathological features. Br J Dermatol 130(5):617-25.

8
Bruckner-Tuderman L. (2010) Dystrophic epidermolysis bullosa: pathogenesis and clinical features. Dermatol Clin 28(1):107-14.

9
Van den Akker PC, Jonkman MF, Rengaw T, et al. (2011) The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations. Hum Mutat 32:1100.

10
Varki R, Sadowski S, Uitto J, Pfendner E. (2007) Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet 44(3):181-92.