On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.80 no.5 Rio de Janeiro Sept./Oct. 2005
Recessive dystrophic epidermolysis bullosa mitis - Case report*
Thaiz Gava Rigoni GürtlerI; Lucia Martins DinizII; João Basilio de Souza FilhoIII
IDermatology specialist at Escola
de Medicina da Santa Casa de Misericórdia de Vitória (EMESCAM) Dermatology Service
- Vitória (ES), Brasil; Specialist at Sociedade Brasileira de Dermatologia
IIAssociate Professor at Escola de Medicina da Santa Casa de Misericórdia de Vitória (EMESCAM) Dermatology Service - Vitória (ES), Brazil
IIIFull Professor at Escola de Medicina da Santa Casa de Misericórdia de Vitória (EMESCAM) Graduate Studies in Dermatology - Vitória (ES), Brazil
Epidermolysis bullosa are congenital bullous dermatoses that lead to spontaneous or post-traumatic formation of blisters. There are three recognized disease groups, according to the second international consensus: simplex, junctional and dystrophic. The genetic defect of the dystrophic forms is due to a mutation in the COL7A1 gene, which is responsible for codifying collagen VII, the main representative of anchoring fibrils, which participate in the adherence of the "lamina densa" to the dermis. The authors describe a case of a 15 year-old female patient who presented ulcers on her legs, serous blisters and atrophic scars on her arms and body. Dystrophic ungual and dental abnormalities had also been observed since her birth. Blister histopathological examination was compatible with epidermolysis bullosa, which, in association with clinical data, allowed the classification of recessive distrophic epidermolysis bullosa.
Keywords: Collagen type VII; Epidermolysis bullosa; Epidermolysis bullosa dystrophica.
Epidermolysis bullosa (EB) forms a group of hereditary bullous disorders in which blisters form either spontaneously or they are triggered by trauma, having this denomination been suggested by Köebner in 1886.1,2
Basal keratinocytes connect to the dermis through the basal membrane area (dermoepidermical junction), as evidenced by SPA (Schiff's periodic acid) under optic microscopy as a fine, homogenous linear region. Under electron microscopy, two regions are observed: lamina lucida, which is electron-sparse, below basal keratinocytes, and another, lamina densa or basalis, above the dermal area that binds to the upper portion of the latter by anchoring fibrils, which are electron dense filaments.1
Under optical microscopy, EBs present with blisters in the sudepidermal region and, observing this region under electron microscopy, over 16 subtypes were observed and gathered in three main groups.1,3
1. Epidermolysis bullosa simplex - there is an intraepidermal cleavage at the lower portion, owing to cytolytic alterations of basal keratinocytes with defects in cytokeratines 5 (KRT5 gene) and 14 (KRT14 gene).4 Subtypes: Köebner, Weber-Cockaine, Dowling-Meara and Ogna's variant.
2. Epidermolysis bullosa junctionalis - cleavage occurs at lamina lucida or at the central region of the basal membrane area, the ceiling being represented by epidermis and the floor by lamina densa. It is owed to alterations in laminin-5 (LAMA3, LAMB3, LAMC2 genes), integrin-a6b4 (ITGA6 and ITGB4 genes) and transmembrane collagen XVII (COL17A1 gene), being the same as bullous pemphigoid antigen.4 Subtypes: Herlitz, non-Herlitz e benign generalized atrophic.
3. Epidermolysis bullosa dystrophica - cleavage ocurrs at sublamina densa. Epidermis and lamina lucida represent the ceiling of the blister and dermis represents the floor. Alteration is exclusively in COL7A1 gene.4 Subtypes: Cockaine-Touraine, Pasini, Hallopeau- Siemens and the recessive mitis dystrophic form.5-7
Acquired epidermolysis bullosa is na auto-antibody-mediated disease, in which these antibodies deposit on lamina and sublamina densa, emerge in adulthood, with formation of blisters in areas submitted to trauma, which heal with atrophic scars and milium. In this type of EB there is no mutation, however, immunogenetic studies have demonstrated a connection with HLA DR2.
Chart 1 describes in detail clinical differences, inheritance pattern and prognosis of the subtypes of epidermolysis bullosa.
Hallopeau-Siemens' dystrophic epidermolysis bullosa corresponds to a severe form, usually lethal in childhood. It presents with hands and feet synechia, esophageal stenosis, anemia, growth retardation, dysplastic teeth and atrophic scars on the scalp. Mitis subtype is characterized by more discrete alterations, which may vary according to genetic inheritance.4-7
In EB, both dominant and recessive inheritance patterns are found, up to this date with no association with histocompatibility antigens (HLA).5-7
According to epidemiological data from the United States of America, epidermolysis bullosa occurs in 50 cases out of 1,000,000 born alive, 92% of them with simple EB, 5% with dystrophic EB, 1% with junctional EB and 2% non-classified.8 Data from North Ireland have shown that during a period of 23 years (1962-1984), 48 cases of EB were identified, with the following distribution: 31 cases of simple EB (65%), one case of junctional EB (2%), 12 cases of dystrophic EB (25%) and four cases of the acquired form (8%).9 In Brazil, there are no epidemiological data.
White, female, 15 year-old patient, student and residing in the rural area of Afonso Cláudio, ES. Sought medical assistance due to the presence of well-outlined, extense and confluent exulcerations in the leg, covered by an exuberant granulation tissue, without exudation or inflammatory signs (Figure 1), some serous blisters and brown atrophic lesions in the extensor surface of upper limbs, back and abdomen, denouncing preexisting blisters.
Upon dermatological examination, no epidermal cysts, white papulloid lesions, milia and palmary-plantar hyperkeratosis were observed. Hair and body hair were normal, and nails presented the following alterations (Figure 2):
Anonychia in the first and fifth left toes and ungueal hypekeratosis in the third left toe;
Hyponychia of the right toes;
A total prosthesis of the upper dental arcade was also observed, and had been used since 12 years of age, and lower teeth were irregularly implanted, fractured and brown-yellowish colored.
Previous history indicated that the patient had been born with serous blisters on the scalp and fingers, due to delivery trauma. Blisters would burst, leaving superficial ulcerations and later atrophic hyperchromic lesions. Nails were fragile, brownish and easily detached by trauma, teeth erupted normally, yet, developed with darkening, cavities and fragility (Figure 3).
No similar cases were observed in the family.
After the elaboration of the diagnostic hypothesis of epidermolysis bullosa, biopsies of two leg blisters were carried out. Histopathological examination revealed a low cleavage area, in the dermoepidermal junction, along with vascular congestion, diffuse edema and slight perivascular infiltration of lymphocytes and mononuclear cells in the dermis (Figure 4).
All other laboratory tests - complete blood count, clotting tests, biochemistry, seric proteins and stool for parasites - were normal.
Initial therapy consisted on systemic steroid therapy with prednisone 40 mg/day, systemic antibiotic (erythromycin 2 g/day) and bandages with neomycin cream on exulcerated lesions for 10 days. Steroid therapy was maintained up to this period, with a graded dose reduction until complete suspension (Figure 5).
EB diagnosis relies on history, physical examination and blister biopsy, which allows differentiation, under optic microscopy, from other bulloses, such as phemphigi. Electron microscopy or direct immunofluorescence evidenced blister cleavage level in the subepidermal region, thus allowing differential diagnosis among EB subtypes.10
As shown in chart 1, clinical distinction among EB subtypes is also possible. In the case here described, the patient presents features of the recessive dystrophic form, albeit with more discrete alterations: lesions located in areas more often submitted to trauma, such as knees and extremities, hypertrophic granulation tissue in the ulcerations, dental and nail abnormalities, leading to classification as mitis form.
Due to the patient's financial difficulties, electron microscopy and immunofluorescence were not performed, since they are not available in our service.
Other forms of EB were excluded due to clinical signs which were present:
Simple EB: there are no scars, neither ungueal or dental alterations;
Junctional EB: it is usually fatal, anemia, synechiae, growth retardation, disproteinemia, scaring alopecia, palmary-plantar hyperkeratosis also occur;
Dominant dystrophic EB: presence of white papulloid lesions, milia, hypertrophic scars and normal teeth;
Hallopeau-Siemens' recessive dystrophic EB: severe form in which the child usually does not reach adulthood. Presents with hands and feet synechia with functional inutility, esophageal stenosis, anemia, growth retardation, dysplastic teeth and atrophic scars on the scalp. Mitis form is characterized by more discrete alterations.4-7
In dystrophic EB, the degree of genetic defect varies from a subtle alteration to a complete absence of type VII collagen. In recessive forms, mutation of COL7A1 gene causes an early interruption of codons, thereby resulting in an absence of collagen VII in the tissues. Mutations that do not cause such early interruption produce less severe forms, such as mitis.3
Mitis form is referred to as being of moderate severity, and is a consequence of a mutation on COL7A1 gene, due to a replacement of glycine (most frequent mutation),5 leading to alterations of type VII collagen,3 which is the major component of anchoring fibrils. These collagen alterations can be either quantitative or qualitative, hence the phenotype variation.5,11
EB annual incidence in the United States of America is of 50 cases/1,000,000 born alive, 5% of them being dystrophic,6 and moderate severity forms are admitted to be undernotified. Among these is the mitis form, which is why only few publications about it were found in the litearture.5
Steroid therapy is controversial for epidermolysis bullosa: Sampaio & Rivitti suggest the systemic use of corticosteroids, hydantoin (which has an inhibitory action on collagenase) and vitamin complementation, whereas Marinkovich et al.3 refer that, because these are genetic disorders, no drug is capable of correcting the molecular defect, which would thus contraindicate prolonged steroid use, mainly because of side effects.
Treatment generally consists of local care (ulcerations, infections, surgical management) and of other organs (support with mushy diet, laxatives, vitamin E) and screening for Spinocellular Carcinoma (SCC), in the dystrophic forms.12
Recent studies have identified specific proteins and genetic abnormalities for the majority of EB subtypes, advances that have been contributing, in molecular research, for the development of novel gene and protein therapies.12
Ortiz-Urda et al. (2003) have published a study with intradermal fybroblast injection, expressing type VII collagen in integer skin of patients with recessive dystrophic EB and observed that these cells locally restored the expression of type VII collagen in vivo and normalized clinical aspects of the disease, including subepidermal blisters and anchoring fibril defects.13
The patient was being treated with prednisone 40 mg/day with improvement of the cutaneous picture. A graded reduction of the steroid was employed until total suspension, and general measures, such as trauma prevention and local antibiotic drugs, were adopted, resulting in good clinical control.
The patient is currently being followed up, with visits every 6 months, due to the risk of carcinomatous transformation of skin lesions. Incidence of these tumors has been increasing as a consequence of better management and increased survival rates of these patients.14
Unlike ultra violet radiation-induced SCCs, these develop in extremities, sites of chronic blister formation, and have been reported as complication of chronic infection, since the latter, along with tissue repairing, is responsible for tissue alterations that allow tumor formation. Moreover, exposure to repetitive trauma can lead to a rapid uncontrolled epidermal growth, with consequent differentiation and transformation of keratinocytes.14 SCCs are well differentiated, and yet have worse prognosis and high mortality rate.15 Treatment for such cases is surgical, which reinforces the importance of early dignosis and intervention.14
The authors emphasize referral to a medical genetics service, for orientation about inheritance patterns and probability of transmission to descendants.8 q
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13. Ortiz-Urda S, Lin Q, Green CL, Keene DR, Marinkovich MP, Khavari PA. Injection of genetically engineered fibroblasts corrects regenerated human epidermolysis bullosa skin tissue. J Clin Invest. 2003; 111: 251-5. [ Links ]
14. Bosch RJ, Gallardo MA, Ruiz del Portal G, Sanchez P, Arce MF, Herrera E. Squamous cell carcinoma secondary to recessive dystrophic epidermolysis bullosa: report of eight tumours in four patients. J Eur Acad Dermatol Venereol. 1999; 13: 198-204. [ Links ]
15. Webr F, Bauer JW, Sepp N, Högler W, Salmhofer W, Hintner H, et al. Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa. Acta Derm Venereol. 2001; 81:189-92. [ Links ]
Thaiz Gava Rigoni Gürtler
Av. Nossa Senhora dos Navegantes, 451
Ed. Petro Tower - conj 809-811
Clinica AngioDerm - Enseada do Suá
29050-335 - Vitória - Espérito Santo
Tel.: (27) 2123-1020
Received on April 07, 2003.
Approved by the Consultive Council and accepted for publication on April 15, 2005.
* Work done at Escola de Medicina da Santa Casa de Misericórdia de Vitória - EMESCAM - Vitória (ES), Brazil.