Generalized morphea in a child with harlequin ichthyosis: a rare association

Maria F.A. Giacomin Camila M.P. França Zilda N.P. Oliveira Maria C.R. Machado Adriana M.E. Sallum Clovis A. Silva About the authors

Resumo

Introdução

Ictiose arlequim é uma doença cutânea congênita grave, autossômica e rara, caracterizada por ressecamento excessivo da pele e hiperqueratose. A associação de ictiose com esclerose sistêmica foi descrita em apenas três crianças. Ainda não foi descrito nenhum paciente com morfeia generalizada (MG) associada à ictiose arlequim.

Relato de caso:

Menina de quatro anos e seis meses de idade com diagnóstico de ictiose arlequim baseado em espessamento cutâneo difuso, com fissuras, descamação, eritema e sangramento da lesão desde as primeiras horas de vida. A paciente foi tratada com acitretina (1,0 mg/kg/dia) e creme emoliente. Aos três anos e nove meses, desenvolveu contraturas musculares com dor à movimentação e limitação nos cotovelos e joelhos e placas esclerodérmicas difusas no abdômen, nas costas, na região suprapúbica e nas extremidades inferiores. A biópsia de pele mostrou epiderme retificada e hiperqueratose leve, derme reticular com linfócitos, infiltrado mononuclear perivascular e perianexial e esclerose da derme reticular e glândula sudorípara rodeada por um tecido colágeno denso, compatível com esclerodermia. A paciente preencheu os critérios para o subtipo MG. Metotrexato e prednisona foram introduzidos. Aos quatro anos e três meses, apresentou novas lesões esclerodérmicas, associando-se azatioprina à terapêutica anterior, sem resposta após dois meses.

Discussão:

Um caso de ictiose arlequim associada à MG foi descrito. O tratamento dessas duas condições é um desafio e requer uma equipe multidisciplinar.

Palavras-chave
Ictiose arlequim; Crianças; Morfeia; Esclerodermia

Abstract

Introduction:

Harlequin ichthyosis (HI) is a severe and rare hereditary congenital skin disorder characterized by excessive dryness, ectropion and eclabion. The association of ichthyosis with systemic sclerosis has been described in only three children. No patient with generalized morphea (GM) associated with harlequin ichthyosis was described.

Case report:

A 4-years and 6-months girl, diagnosed with harlequin ichthyosis based on diffuse cutaneous thickening, scaling, erythema, ectropion and eclabium since the first hours of birth was described. She was treated with acitretin (1.0 mg/kg/day) and emollient cream. At 3 years and 9 months, she developed muscle contractures with pain on motion and limitation in elbows and knees, and diffuse sclerodermic plaques on the abdomen, back, suprapubic area and lower limbs. Skin biopsy showed rectified epidermis and mild hyperorthokeratosis, reticular dermis with perivascular and periadnexal infiltrates of lymphocytes and mononuclear cells, and reticular dermis and sweat gland sclerosis surrounded by a dense collagen tissue, compatible with scleroderma. The patient fulfilled the GM subtype criteria. Methotrexate and prednisone were introduced. At 4 years and 3 months, new scleroderma lesions occurred and azathioprine was associated with previous therapy, with no apparent changes after two months.

Discussion:

A case of harlequin ichthyosis associated with a GM was reported. The treatment of these two conditions is a challenge and requires a multidisciplinary team.

Keywords
Harlequin ichthyosis; Children; Morphea; Scleroderma

Introduction

Juvenile cutaneous scleroderma is a rare condition in pediatric patients characterized by the involvement of the skin and/or subcutaneous tissue.11 Hedrich CM, Fiebig B, Hahn Suttorp M, Gahr M. Presentations and treatment of childhood scleroderma: localized scleroderma, eosinophilic fasciitis, systemic sclerosis, and graft-versus-host disease. Clin Pediatr (Phila). 2011, 04-614.,22 Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin N Am. 2008;34:239-55. Generalized morphea (GM) is an uncommon subtype of localized scleroderma and occurs in 7% of the patients.22 Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin N Am. 2008;34:239-55. The association of GM with other cutaneous diseases was rarely reported in the literature, especially with ichthyosiform diseases.

Of note, ichthyosis comprehends a heterogeneous group of skin diseases characterized by cutaneous hyperkeratinization and may be congenital or acquired.33 Tlacuilo-Parra JA, Guevara-Gutiérrez E, Salazar-Páramo M. Acquired ichthyosis associated with systemic lupus erythematosus. Lupus. 2004;13:270-3. Harlequin ichthyosis is a congenital form, transmitted in an autosomal recessive mode. It is the most severe and often fatal form of ichthyosis.44 Vahlquist A. Pleomorphic ichthyosis: proposed name for a heterogeneous group of congenital ichthyosis with phenotypic shifting and mild residual scaling. Acta Derm Venereol. 2010;90:454-60.

The association of ichthyosis with scleroderma has been described in only four patients. Three of them had juvenile systemic sclerosis, and one of them had localized scleroderma. Two of the juvenile systemic sclerosis patients were associated with ichthyotic-appearing lesions,55 Oji V,Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:289-97. and one of them with acquired ichthyosis.66 Williams CM, Storm CA, Burns C, Rigby WDinulos JG. Ichthyotic-Appearing skin changes associated with childhood morphea, systemic sclerosis, and systemic lupus erythematosus/scleroderma overlap. Pediatric Dermatology. 2010;27:170-3. The localized scleroderma patient was associated with ichthyotic-appearing lesions.55 Oji V,Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:289-97. However, to our knowledge, no patient with GM scleroderma associated with the harlequim subtype of ichthyosis was reported. This case is described herein.

Case report

A 4-years and 6-months girl was diagnosed with harlequin ichthyosis at neonatal period, based on diffuse cutaneous thickening, diffuse plate-like scales, erythema, fissures, bleeding lesions, bilateral ectropion and eclabium since the first hours of life. No history of parental consanguinity and harlequin ichthyosis were observed. She was a term newborn after cesarean delivery. Her birth weight and height were 2.650 gm and 43 cm, respectively. Microcephaly, auricular pinna and nasal abnormalities, alopecia and flexion contracture were not evidenced. She was treated with acitretin (1.0 mg/kg/day) and emollient cream. During the first 3 months of life, she had been hospitalized three times due to skin infections, with improvement after antibiotic treatment. At 3 years, she presented growth retardation with height of 84 cm, with delayed motor development. Skin biopsy of abdominal epidermis showing hyperkeratosis paraketatotic, agranulose, regular epidermal acanthosis and thickening of the dermis with proliferation of vessels with mild lymphocytic inflammatory infiltrate and psoriasiform dermatitis (Fig. 1) confirmed diagnosis of ichthyosis.77 Lee H, Anh S, Choi J, Chang SE, Choi JH, Moon KC, et al. Acquired ichthyosis associated with an overlap syndrome of systemic sclerosis and systemic lupus erythematosus. Journal of Dermatology. 2006;1:52-4. After 9 months, she developed painful flexion muscle contractures, with pain on motion and limitation affecting elbows and knees, associated with generalized ichthyosis lesions, with diffuse pain upon palpation, bilateral ectropion and diffuse scleroderm plaques without distribution pattern on: abdomen (11 lesions ranged from 0.5 × 0.5 cm to 3.3 × 3.0 cm), back (13 lesions ranged from 1.0 × 1.0 cm to 2.8 × 3.0 cm), supra-pubic area (3 lesions varied from 0.8 × 1.4 cm to 3.5 × 2.0 cm) and proximal aspects of thighs (2 lesions ranged from 1.0 × 1.0 cm to 3.0 × 2.5 cm). Skin biopsy showed rectified epidermis and mild hyperorthokeratosis, reticular dermis with lymphocyte and mononuclear cells that infiltrate perivascular and periadnexal, and sclerosis of reticular dermis and sweat gland surrounded by a dense collagen tissue, compatible with scleroderma. Hemoglobin, leukocyte and platelet counts, renal function and urinalysis were normal. The C-reactive protein was 14.4 mg/dL (reference value <5). The rheumatoid factor, antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA), anti-Sm, anti-RNP, anti-Ro and anti-La antibodies were negative. Thoracic computer tomography, echocardiography, barium meal examination and slit-lamp examination were normal. The nailfold capillaroscopy was performed without being able to visualize capillaries due to crusts periungual. Therefore, the patient fulfilled the juvenile localized scleroderma criteria (GM subtype)88 Chakraborti C, Tripathi PBandopadhyay G, Mazumder DB. Congenital bilateral ectropion in lamellar ichthyosis. Oman J Ophthalmol. 2011;4:35-6. and methotrexate (0.5 mg/kg/week) and prednisone (1.0 mg/kg/day) were introduced at the age of 3 years 11 months. At 4 years and 1 month, methotrexate dosage was increased to 1.0 mg/kg/week. At 4 years and 3 months, she presented generalized ichthyosis lesions with new scleroderma lesions in abdomen (Fig. 2), lower limbs, back and supra-pubic areas and azathioprine (3.0 mg/kg/day) was introduced along with prednisone and methotrexate with no improvement after two months of therapy. Topical corticosteroid was not used. At present, her follow-up is composed of a multidisciplinary team with a rheumatologist, dermatologist, ophthalmologist, geneticist, physiotherapist and occupational therapist.

Fig. 1
Hyperkeratosis paraketatotic, agranulose, regular epidermal acanthosis and thickening of the dermis with proliferation of vessels with mild lymphocytic inflammatory infiltrate and psoriasiform dermatitis.
Fig. 2
Diffuse cutaneous thickening, cracking, scaling, erythema, bleeding and ichthyosiform lesions, and diffuse scleroderm plaques (arrow) on the abdomen.

Discussion

To our knowledge, we describe herein the first case of harlequin ichthyosis associated to GM diagnosis. This congenital disease occurred previously to the scleroderma diagnosis, not in agreement with the rare cases of acquired ichthyosis and scleroderma reported in the literature.55 Oji V,Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:289-97.,66 Williams CM, Storm CA, Burns C, Rigby WDinulos JG. Ichthyotic-Appearing skin changes associated with childhood morphea, systemic sclerosis, and systemic lupus erythematosus/scleroderma overlap. Pediatric Dermatology. 2010;27:170-3.

According to the new classification criteria, localized scleroderma has four different subtypes: plaque morphea, GM, linear scleroderma and deep morphea.88 Chakraborti C, Tripathi PBandopadhyay G, Mazumder DB. Congenital bilateral ectropion in lamellar ichthyosis. Oman J Ophthalmol. 2011;4:35-6.1010 Zulian F, Martini G. Preliminary classification criteria for juvenile systemic sclerosis. In: Zulian F and Ruperto N, editors. Proceedings of the II Workshop on nomenclature and diagnostic criteria for juvenile Scleroderma Syndromes. 2005:5-16. The GM is defined by the presence of four or more plaques, with individual plaques greater than 3 cm and involving at least two out of seven anatomic sites,22 Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin N Am. 2008;34:239-55. as evidenced in our patient that presented lesions occurring in upper and lower limbs, and trunk.

Furthermore, ichthyosis is composed of cutaneous keratinization diseases that can be inherited or acquired.33 Tlacuilo-Parra JA, Guevara-Gutiérrez E, Salazar-Páramo M. Acquired ichthyosis associated with systemic lupus erythematosus. Lupus. 2004;13:270-3. Congenital ichthyosis is often associated with a variety of typical neonatal phenotypes with scaling and erythema. The main subtypes are congenital ichthyosiform erythroderma, lamellar and harlequin ichthyosis, including overlapping phenotypes. The mild subtype is congenital ichthyosiform erythroderma with fine and white scaling, and different degrees of erythema. Coarse and brown/dark scaling are observed in lamellar ichthyosis, generally with collodion membrane and ectropion. The harlequin ichthyosis is a more severe subtype associated with very scaling erythroderma, collodion membrane and pronounced ectropion.55 Oji V,Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:289-97.,1111 Zannin ME, Martini G, Athreya BH, Russo R, Higgins G, Vittadello F, et al. Ocular involvement in children with localized scleroderma: a multi-centre study. Br J Ophtalmol. 2007;91:1311-4. Of note, a collodion baby is defined by erythroderma, shiny and tight skin, like parchment, covering the entire body at birth. It is an initial presentation of several genetic conditions, including congenital ichthyosis,1212 Prado R, Ellis LR, Gamble R, Funk T, Arbuckle HA, Bruckner AL. Collodion baby: An update with a focus on practical management. J Am Acad Dermatol. 2012;67:1362-74. as observed in our case.

The disease course is generally severe with multiple joint contractures.1313 Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis. Pediatric Dermatology. 2003;20:421-6.,1414 Beazley JC, Ho K, Ilchyshyn A, Foguet P.Total hip replacement in an adolescent patient with harlequin ichthyosis; a case report. Hip Int. 2011;21:487-9. Our patient presented contractures mainly in elbows and knees, possibly due to association with GM.

One limitation of the present case was the absence of electronic microscopy in the skin biopsy and genetic evaluations, since this is an autosomal recessive congenital disease.55 Oji V,Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:289-97. ABCA12 mutation analysis showed that 52% of survivors had heterozygous mutations, and all deaths were associated with homozygous mutations, while missense mutations are usually related with milder phenotypes.55 Oji V,Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:289-97.,1515 Rajpopat S, Moss C, Mellerio J, Vahlquist A, Gánemo A, Hellstrom-Pigg M, et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol. 2011;147:681-6.,1616 Walsh DM, Shah SH, Simpson MA, Morgan NV, Khaliq S, Trembath RC, et al. A Novel ABCA12 Mutation in Two Families with Congenital Ichthyosis. Scientifica (Cairo). 2012;2012:649090, http://dx.doi.org/10.6064/2012/649090 [Epub 2012 Dec 31].
https://doi.org/10.6064/2012/649090...
The association between harlequin ichthyosis and scleroderma, an autoimmune disease, is probably coincidental.

Of note, acquired ichthyosis with systemic sclerosis has been described in four patients after this autoimmune diagnosis,66 Williams CM, Storm CA, Burns C, Rigby WDinulos JG. Ichthyotic-Appearing skin changes associated with childhood morphea, systemic sclerosis, and systemic lupus erythematosus/scleroderma overlap. Pediatric Dermatology. 2010;27:170-3.,77 Lee H, Anh S, Choi J, Chang SE, Choi JH, Moon KC, et al. Acquired ichthyosis associated with an overlap syndrome of systemic sclerosis and systemic lupus erythematosus. Journal of Dermatology. 2006;1:52-4. however the rare subtype of harlequin had not been previously reported. Other associations between harlequin ichthyosis and autoimmune chronic disorders have been rarely described without a clear relationship with pathogenesis of autoimmunity, such as hypothyroidism,1313 Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis. Pediatric Dermatology. 2003;20:421-6. celiac disease1717 Nenna R, D'Eufemia P, Celli M, Mennini M, Petrarca L, Zambrano A, et al. Celiac disease and lamellar ichthyosis. Case study analysis and review of the literature. Acta Dermatovenerol Croat. 2011;19:268-70. and juvenile idiopathic arthritis.1313 Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis. Pediatric Dermatology. 2003;20:421-6.,1414 Beazley JC, Ho K, Ilchyshyn A, Foguet P.Total hip replacement in an adolescent patient with harlequin ichthyosis; a case report. Hip Int. 2011;21:487-9.

The ichthyosis treatment is based on the severity of the disease and included topical formulations and oral retinoids,1818 Bassoti A, Moreno S, Criado E. Successful Treatment with topical N-acetylcysteine in urea in five children with congenital lamellar ichthyosis. Pediatric Dermatology. 2011;28:451-5. as indicated in our patient with unsatisfactory response. Moreover, the cutaneous juvenile scleroderma includes pharmacological (glucocorticosteroids and methotrexate) and non-pharmacological (physical exercises and early physiotherapy) therapies.1919 Macedo PA, Shinjo SK, Goldenstein-Schainberg C. Esclerodermia juvenile. Acta Reumatol Port. 2008;33:289-97. Azathioprine may also be administered in refractory cases,2020 Zulian F, Athreya BH, Laxer R, Nelson AM, Feitosa de Oliveira SK, Punaro MG, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatol. 2006;45:614-20. as used in the present case. The difficulty of the treatment concomitantly of these two severe and rare conditions should have contributed to the poor response therapy in our case.

The outcome of harlequin ichthyosis is generally related to stillbirth or first weeks of life death due to prematurity, renal failure, respiratory insufficiency and infection.2121 Akiyama M. Severe congenital ichthyosis of the neonate. Int J Dermatol. 1993;37:722-8. To our knowledge, only eight cases with isolated harlequin ichthyosis or associated with juvenile rheumatoid arthritis survived the neonatal period, with a median of current age of 4 years (ranged from 6 months to 14 years).1313 Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis. Pediatric Dermatology. 2003;20:421-6.

In conclusion, we reported the first case of harlequin ichthyosis associated with a rare type of juvenile scleroderma. The treatment of these two simultaneous illnesses is very challenging indeed and requires a multidisciplinary team.

References

  • 1
    Hedrich CM, Fiebig B, Hahn Suttorp M, Gahr M. Presentations and treatment of childhood scleroderma: localized scleroderma, eosinophilic fasciitis, systemic sclerosis, and graft-versus-host disease. Clin Pediatr (Phila). 2011, 04-614.
  • 2
    Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin N Am. 2008;34:239-55.
  • 3
    Tlacuilo-Parra JA, Guevara-Gutiérrez E, Salazar-Páramo M. Acquired ichthyosis associated with systemic lupus erythematosus. Lupus. 2004;13:270-3.
  • 4
    Vahlquist A. Pleomorphic ichthyosis: proposed name for a heterogeneous group of congenital ichthyosis with phenotypic shifting and mild residual scaling. Acta Derm Venereol. 2010;90:454-60.
  • 5
    Oji V,Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:289-97.
  • 6
    Williams CM, Storm CA, Burns C, Rigby WDinulos JG. Ichthyotic-Appearing skin changes associated with childhood morphea, systemic sclerosis, and systemic lupus erythematosus/scleroderma overlap. Pediatric Dermatology. 2010;27:170-3.
  • 7
    Lee H, Anh S, Choi J, Chang SE, Choi JH, Moon KC, et al. Acquired ichthyosis associated with an overlap syndrome of systemic sclerosis and systemic lupus erythematosus. Journal of Dermatology. 2006;1:52-4.
  • 8
    Chakraborti C, Tripathi PBandopadhyay G, Mazumder DB. Congenital bilateral ectropion in lamellar ichthyosis. Oman J Ophthalmol. 2011;4:35-6.
  • 9
    Zulian F.Woo P Athreya BH, Laxer RM, MedsgerTA Jr, Lehman TJ, et al. The Pediatric Rheumatology European Society/American College of Rheumatology/European League Against Rheumatism Provisional Classification Criteria for Juvenile Systemic Sclerosis. Arthritis Rheum. 2007;57:203-12.
  • 10
    Zulian F, Martini G. Preliminary classification criteria for juvenile systemic sclerosis. In: Zulian F and Ruperto N, editors. Proceedings of the II Workshop on nomenclature and diagnostic criteria for juvenile Scleroderma Syndromes. 2005:5-16.
  • 11
    Zannin ME, Martini G, Athreya BH, Russo R, Higgins G, Vittadello F, et al. Ocular involvement in children with localized scleroderma: a multi-centre study. Br J Ophtalmol. 2007;91:1311-4.
  • 12
    Prado R, Ellis LR, Gamble R, Funk T, Arbuckle HA, Bruckner AL. Collodion baby: An update with a focus on practical management. J Am Acad Dermatol. 2012;67:1362-74.
  • 13
    Chan YC, Tay YK, Tan LK, Happle R, Giam YC. Harlequin ichthyosis in association with hypothyroidism and juvenile rheumatoid arthritis. Pediatric Dermatology. 2003;20:421-6.
  • 14
    Beazley JC, Ho K, Ilchyshyn A, Foguet P.Total hip replacement in an adolescent patient with harlequin ichthyosis; a case report. Hip Int. 2011;21:487-9.
  • 15
    Rajpopat S, Moss C, Mellerio J, Vahlquist A, Gánemo A, Hellstrom-Pigg M, et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol. 2011;147:681-6.
  • 16
    Walsh DM, Shah SH, Simpson MA, Morgan NV, Khaliq S, Trembath RC, et al. A Novel ABCA12 Mutation in Two Families with Congenital Ichthyosis. Scientifica (Cairo). 2012;2012:649090, http://dx.doi.org/10.6064/2012/649090 [Epub 2012 Dec 31].
    » https://doi.org/10.6064/2012/649090
  • 17
    Nenna R, D'Eufemia P, Celli M, Mennini M, Petrarca L, Zambrano A, et al. Celiac disease and lamellar ichthyosis. Case study analysis and review of the literature. Acta Dermatovenerol Croat. 2011;19:268-70.
  • 18
    Bassoti A, Moreno S, Criado E. Successful Treatment with topical N-acetylcysteine in urea in five children with congenital lamellar ichthyosis. Pediatric Dermatology. 2011;28:451-5.
  • 19
    Macedo PA, Shinjo SK, Goldenstein-Schainberg C. Esclerodermia juvenile. Acta Reumatol Port. 2008;33:289-97.
  • 20
    Zulian F, Athreya BH, Laxer R, Nelson AM, Feitosa de Oliveira SK, Punaro MG, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatol. 2006;45:614-20.
  • 21
    Akiyama M. Severe congenital ichthyosis of the neonate. Int J Dermatol. 1993;37:722-8.

Publication Dates

  • Publication in this collection
    Jan-Feb 2016

History

  • Received
    24 Oct 2013
  • Accepted
    21 May 2014
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