Pediatric Dermatology Vol. 23 No. 2 132–135, 2006
Endemic Pemphigus Foliaceus in Venezuela: Report of Two Children
Blackwell Publishing Inc
Francisco González, M.D., Ana Maria Sáenz, M.D., Antonietta Cirocco, M.D., Inés Maria Tacaronte, M.D., Javier Enrique Fajardo, M.D., and Adriana Calebotta, M.D. Department of Dermatology, Hospital Universitario de Caracas, “Luis Razetti” School of Medicine, Central University of Venezuela, Caracas, Venezuela
Abstract: Two native Yanomami children from the Venezuelan Amazonia with erythroderma were hospitalized on our service. Clinical, histologic, and immunofluorescence studies diagnosed endemic pemphigus foliaceous. Human leukocyte antigen class II showed DRB1*04 subtype *0411, which has not been previously associated with this disease. However, it shares a common epitope with all the human leukocyte antigen DRB1 alleles that have been involved in this disease among Brazilian populations. Although this condition is endemic in Brazil, our patients are the first two reported in Venezuela.
Endemic pemphigus foliaceous (EPF) has been described since the beginning of the century in certain states of Brazil (1), and shares clinical, histologic, and immunopathologic features with nonendemic pemphigus foliaceous (PF). This autoimmune skin disease is characterized by the onset of subcorneal acantholytic vesicles and IgG autoantibodies to desmoglein 1. It is endemic in certain regions of Brazil (Goias, Mato Grosso do Sul, Parana, São Paulo, and Minas Gerais), where more than 15,000 occurrences have been registered (2). It has also been reported in Colombia (3), Tunisia (4,5), and El Salvador (6), each with specific epidemiologic characteristics. We describe, to the best of our knowledge, the first two children with this disease in our country.
CASE REPORTS Patient 1 A 16-year-old girl who belongs to the Yanomami people of Mavaca in Amazonas State, was referred to our service
with a 5-month history of continuous eruptions of erythematous papules and plaques on her trunk. Over the same period, she developed erythroderma. She received prednisone at 20 mg/day without response. Folk medicine consisting of topical applications of a mixture of leaves worsened her condition, and she was therefore referred to our hospital. She had a history of several malaria infections, as well as intestinal parasite infestation. Physical examination found erythroderma with sparing of the palms and soles, ectropion, and eclabium (Fig. 1). Mucous membranes were not involved. Complete alopecia of the scalp, onychodystrophy, and hepatosplenomegaly were also present. Laboratory tests showed microcytic hypochromic anemia. Hepatic and renal function test results were normal. Hepatitis B and C virus seriologies were positive. Serial thick and thin blood smears were negative, as were antinuclear antibodies, anti-DNA, anti-Ro, and anti-La titers. Abdominal ultrasound revealed hepatomegaly and diffuse changes of the hepatic parenchyma, as well as
Address correspondence to Ana Maria Sáenz, M.D., CCS 6140, 4440 NW 73rd Ave., Miami, Florida 33166, or e-mail:
[email protected].
Address correspondence to Ana Maria Sáenz, M.D., CCS 6140, 4440 NW 73rd Ave., Miami, Florida 33166, or e-mail:
[email protected].
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© 2006 The Authors. Journal compilation © 2006 Blackwell Publishing, Inc.
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Figure 1. Widespread erythroderma with sparing of palms and soles, ectropion, and eclabium (patient 1).
splenomegaly. Chronic liver disease was diagnosed, probably as a result of malaria. Ophthalmologic evaluation showed two infiltrative lesions affecting the right eye, diagnosed as keratitis. Histologic examination of a skin biopsy specimen found an intraepidermal blister at the level of the stratum granulosum. Acantholytic cells were seen in the blister. In the dermis, a moderate inflammatory infiltrate with a predominance of eosinophils was seen. Direct immunofluorescence examination showed deposits of IgA and IgG in an intercellular pattern throughout the epidermis. Indirect immunofluorescence and immunoblotting of human epidermal extracts could not be performed; nevertheless, a diagnosis of EPF was made. Human leukocyte antigen class II determination showed DRB1*0411, *0402, and DQB1*0303. Prednisone was administered at 1 mg/kg/day and chloroquine at 400 mg/day with a good response, and complete clearing of the lesions. She was sent back to her community, and follow-up was difficult. She died 5 years later of an unknown cause.
Figure 2. Widespread crusted erythema with flaccid blisters. Absence of eyebrows, scarce eyelashes, and alopecia of the scalp are also seen (patient 2).
Patient 2 A 10-year-old boy form the Yanomami people presented with a one and a half year history of widespread vesicles and crusted erosions. He was treated with prednisone without response, and thus was referred to our center. He had a personal history of several episodes of malaria. On cutaneous examination, he had widespread erythema with crusted, flaccid blisters. Absence of eyebrows as well as scarce eyelashes, and complete alopecia of the scalp were also observed (Fig. 2). Initial laboratory tests showed microcytic anemia. Hepatic and renal function test results were normal. Hepatitis B and C virus serologies were positive. Serial thick and thin blood smears were negative, as were immunorheumatologic tests. Histopathologic study of a skin biopsy specimen found laminar hyperkeratosis, irregular acanthosis, and acantholytic cells in the granular layer, and a moderate inflammatory infiltrate with a predominance of mononuclear cells at the papillary dermis, changes suggestive of PF.
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Direct immunofluorescence examination showed deposits of IgA and IgG in an intercellular pattern throughout the epidermis. Indirect immunofluorescence and immunoblotting of human epidermal extracts could not be performed. Human leukocyte antigen class II determination showed DRB1*0411, *0402 homozygous. The boy received oral triamcinolone without therapeutic response, then was changed to prednisone at 1 mg/ kg/day and chloroquine 200 mg/day, with complete resolution of lesions. He was also sent back to his community, and, unfortunately, follow-up was not possible. Both patients were diagnosed as having endemic pemphigus foliaceus, taking into account their epidemiologic, clinical, histologic, and immunopathologic characteristics. DISCUSSION The epidemiology of pemphigus foliaceus is unique. It affects the rural population of the endemic states of Brazil, and has been described in regions with an altitude between 500 and 800 m, being rare in regions below 400 m or above 1000 m (7). New instances of PF in the endemic areas seem to occur in clusters, increasing during the rainy season and diminishing during the dry season (7,8). The disease primarily affects children, adolescents, and young adults, with an equal sex ratio (9). Familial occurrences are frequently seen (10). Although the study of adults with PF is necessary to determine the epidemiology of this disease in our country, we can affirm that it shares certain characteristics with the findings in those affected in Brazil, especially the geographic characteristics of the endemic area. Our patients come from an area called Mouth Mavaca, located in the Venezuelan Amazonia, with the coordinates: 65°13′00″W longitude; 03°32′00″N latitude, 363.64 meters above sea level. It is humid tropical forest, with two seasons, dry (November to April) and rainy (May to November), with the greatest rainfall occurring between July and August. The average annual temperature is 27 to 28 °C. Although the etiology of PF remains unclear, it has been reported that particular HLA alleles confer increased risk of the disease. Previous studies among Brazilian Amerindian patients have described a statistically significant association of a specific DRB1 epitope (residues 67–74) present in DRB1*0404, *1402, and *1406 alleles, and susceptibility to PF (10). It is interesting to note that our patients carried a DRB1*04 subtype: *0411, which shares seven of the eight amino acids of the LLEQRRAA motif described by Moraes et al (10). This was seen as responsible for susceptibility to the disease among three Brazilian populations. However, all the DRB1 alleles mentioned before share residues 67 to 74, suggesting that
this epitope could be the one responsible for susceptibility to the disease, instead of that postulated by Moraes et al. A recent study of Italian patients showed findings similar to those in the studies of Brazilian patients, demonstrating a highly significant association between PF and DRB1*1401. However, no association was detected between any allele of the DR4 group and PF (11). Further investigations are needed to confirm the association of PF with the DRB1 allele *0411 described in our patients. Genetic predisposition is not by itself sufficient to explain the pathogenesis of PF (11). Susceptibility to autoimmune diseases is multifactorial; individuals with a proven susceptible genotype will develop the disease only when additional factors are present (12). The epidemiology of PF has suggested that transmission of the disease may occur through a flying vector (7–9). Correlational studies that have considered geographic distribution and seasonal variation of PF have implicated black flies of the family Simuliidae as a possible vector for this disease (7,13,14). Other factors have been considered in the pathogenesis of pemphigus in susceptible individuals, such as certain compounds found in food and water, i.e., tannins (12). These compounds contain manioc or yucca, which constitutes a very important food in the diet of the Amerindians of the area. Also, tannins are in high quantities in the water of wild rivers, because of the decomposition of leaves and vegetable matter, a process enriched by the humid, warm climate of the tropical forest. Seasonal variations in the incidence of PF coincide with seasonal variations in the concentrations of tannin in water, which increases during the rainy season when the rivers overflow and engulf larger quantities of vegetation (12). These facts suggest that tannins could be involved as a factor in the incidence of PF in Brazil and Venezeula. Systemic corticosteroids are the first line of therapy for all forms of PF. Immunosuppressive agents such as azathioprine, cyclophosphamide, and hydroxychloroquine have been used in combination with corticosteroids with good results, as a steroid-sparing drug with the antiinflammatory effects of inhibition of complement, interference with interleukin secretion, decrease in total T-cell counts, inhibition of NK cytotoxicity and chemotaxis of PMN, macrophages and eosinophils, and other miscellaneous effects (15). For our two patients, this was an adjuvant therapy supplied by the public health programs in the endemic malaria area from which they came. In conclusion, our patients had clinical, histologic, and immunologic features of EPF, as well as the geographic and climate characteristics vary similar to those of the endemic areas of Brazil. However, further studies will be necessary to identify new occurrences and risk factors
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associated with the disease and to define a probably new endemic area in the Venezuelan Amazonia. ACKNOWLEDGMENT We thank Zulay Layrisse, Ph.Sc., Centro de Medicina Experimental, Instituto Venezolano de Investigaciones Cientificas (IVIC), chief of the Immunogenetics Laboratory for her kind help determining HLA class II alleles. REFERENCES 1. Diaz LA, Sampaio SA, Rivitti EA et al. Endemic pemphigus foliaceus (fogo selvagem): I. Clinical features and immunopathology. J Am Acad Dermatol 1989;20:657–669. 2. Giuli Santi C, Sotto M. Immunopathologic characterization of the tissue response in endemic pemphigus foliaceus (fogo selvagem). J Am Acad Dermatol 2001;44:446– 450. 3. Robledo MA, Prada S, Jaramillo D et al. South American pemphigus foliaceus: study of an epidemic in El Bagre and Nechi, Columbia 1982–86. Br J Dermatol 1988;118:737– 744. 4. Morini JP, Jomaa B, Gorgy Y et al. Pemphigus foliaceus in young women. An endemic focus in Sousse area of Tunisia. Arch Dermatol 1993;129:69–73. 5. Bastuji-Garin S, Souissi R, Blum L et al. Comparative epidemiology of pemphigus in Tunisia and France. Incidence of foliaceus pemphigus in young Tunisian women. Ann Dermatol Venereol 1996;123:337–342. 6. Hernendez-Perez J. Pemphigus in El Salvador. Int J Dermatol 1979;18:645–648.
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