Epidermolysis Bullosa Recessive Dystrophic, generalized intermediate

DISEASE CARD

Disease group Epithelial adhesion disorders
DISEASE NAME EPIDERMOLYSIS BULLOSA RECESSIVE DYSTROPHIC, GENERALIZED INTERMEDIATE
Synonymous None
Estimated prevalence Unknown
OMIM 226600
Inheritance Autosomal 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]. RDEB is subdivided into seven subtypes with RDEB severe generalized (RDEB-sev gen) being the most severe form of DEB (Table 1). RDEB-generalized intermeidate is a more common subtype of RDEB. It is similar to, but less severe as, RDEB-sev gen [2]. All forms of DEB are caused by mutations in the COL7A1 gene (3p.21.31).

Table 1: RDEB subtypes.

Subtype Gene
RDEB, generalized severe RDEB-sev gen COL7A1
RDEB, generalized intermediate RDEB-gen intermediate
RDEB, inversa RDEB-I
RDEB, pretibial RDEB-Pt
RDEB, pruriginosa RDEB-Pr
RDEB, centripetalis RDEB-Ce
RDEB, bullous dermolysis of newborn RDEB-BDN

Figure1. 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

In RDEB generalized intermediate, blistering is less severe compared to RDEB-sev gen and mutilating deformities do not develop. The clinical picture is variable, with some patients displaying widespread disease, while in others blisters are limited primarily to the extremities. Skin lesions heal invariably with scars and milia. Oral, dental, nail and hair manifestations are similar to RDEB-sev gen, but less extensive. Onset of disease is at birth. Life expectancy of RDEB generalized intermediate is normal, but the risk of squamous cell carcinomas is elevated [2].

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 RDEB, compound heterozygosity for COL7A1 mutations is common. A functionally and/or structurally residual protein expression accounts for a generally milder phenotype [9]. Different mutations and allelic combinations, however, generate a continuum of biological phenotypes. They often are family specific in each individual patient (“private mutations”). This makes phenotype-genotype correlations possible to provide the basis for more accurate genetic counseling and prenatal diagnosis for at-risk families [10].

The genetic background of RDEB generalized intermediate is more heterogeneous compared to RDEB-sev gen [11 - 15]. Combinations of a premature termination mutation with more subtle missense or splice site mutations, accompanied by a defective collagen VII synthesis and structurally abnormal AF, can result in a milder autosomal recessive form of DEB. Moreover, promoter mutations, gene rearrangements following homologous unequal crossing over, recurrent mutations and somatic reversion, referring to the correction of an inherited disease-causing mutation by means of a second genetic event with complete or partial restoration of gene function, have been documented in RDEB.

Diagnosis

Diagnosis by clinical examination can be confirmed by antigen mapping of punch biopsies. Electron microscopy shows cleavage area sub-lamina densa. Genetic testing 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 and appropriate clothing. Wound care management is paramount in order to prevent secondary infections and to reduce scarring. Tracheolaryngeal complications (esophageal strictures) can be treated by balloon dilatation. Special diet is always necessary. SCCs are treated surgically.

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

8
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.

9
Christiano AM, Greenspan DS, Hoffman GG, et al. ( 1993) A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa. Nat Genet 4:62.

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):181-192.

11
Dang N, Murrell DF. (2008) Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa. Exp Dermatol 17(7):553-568.

12
Chiaverini C, Charlesworth AV, Youssef M, Cuny JF, Rabia SH, Lacour JP, Meneguzzi G. (2010) Inversa dystrophic epidermolysis bullosa is caused by missense mutations at specific positions of the collagenic domain of collagen type VII. J Invest Dermatol 130(10):2508-2511.

13
Gardella R, Barlati S, Zoppi N, Tadini G, Colombi M. (2000) A-96C-->T mutation in the promotor of the collagen type VII gene (COL7A1) abolishing transcription in a patient affected by recessive dystrophic epidermolysis bullosa. Hum Mutat 16(3):275.

14
Cuadrado-Corrales N, Sánchez-Jimeno C, Garcia M, Escámez MJ, Illera N, Hernández-Martin A, Trujillo-Tiebas MJ, Ayuso C, Del Rio M. (2010) A prevalent mutation with founder effect in Spanish Recessive Dystrophic Epidermolysis Bullosa families. BMC Med Genet 11:139.

15
Pasmooij AM, Garcia M, Escámez MJ, Nijenhuis AM, Azon A, cuadrado-Corrales N, Jonkman MF, Del Rio M. (2010) Revertant mosaicism due to a second-site mutation in COL7A1 in a patient with recessive dystrophic epidermolysis bullosa. J Invest Dermatol 130(10):2407-2411.