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Mibelli revisited: A case of type 2 segmental porokeratosis from 1893
CASE
REPORTS
Mibelli revisited: A case of type 2 segmental porokeratosis from 1893 Rudolf Happle, MD Marburg, Germany In autosomal dominant skin disorders, a pronounced mosaic involvement may sometimes be found to be superimposed on the ordinary nonsegmental lesions. Such ‘‘type 2 segmental manifestation’’ reflects loss of heterozygosity occurring at an early developmental stage, giving rise to a cell clone that lacks the corresponding wild-type allele. Here, this genetic concept is applied to an unusual case of plaque-type porokeratosis of Mibelli (PM) as published in 1893 by Vittorio Mibelli in the International Atlas of Rare Skin Diseases. The right forearm and hand of the 21-year-old patient showed a pronounced linear porokeratosis that had developed since the age of 2 years. Moreover, nonsegmental lesions of PM involved both hands and forearms as well as the face and the neck, having first been noticed at the age of 7 years. Two siblings and the father were likewise affected with PM. Hence, Mibelli’s case from 1893 meets all of the criteria of a type 2 segmental manifestation of an autosomal dominant skin disorder. Recognizing such cases of superimposed segmental involvement may help elucidate the molecular basis of PM. ( J Am Acad Dermatol 2010;62:136-8.)
I
n 1893 Vittorio Mibelli described a new skin disorder for which he coined the term ‘‘porokeratosis’’ because he erroneously believed that the cornoid lamellae, representing the histopathological hallmark of the disease, were related to the sweat pores.1,2 The designation porokeratosis is now firmly entrenched in our terminology and has eternalized Mibelli’s name.3 Today we distinguish different types such as the plaque type of Mibelli (PM), disseminated superficial actinic porokeratosis (DSAP), porokeratosis palmaris, plantaris et disseminata (PPPD), and porokeratosis punctata palmaris et plantaris (PPPP).4 Linear porokeratosis is traditionally categorized as an additional separate type, although there is today convincing evidence that this cutaneous anomaly does not represent a distinct entity but rather a mosaic manifestation of one of the other types of porokeratosis.5,6 An impressive case published by Mibelli in 1893, in both Italian1 and in German, English, and French in the International Atlas of Rare Skin Diseases,2 has thus far been taken as a classical example of PM. However, when looking at the fine illustrations
From the Department of Dermatology, Philipp University of Marburg. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Rudolf Happle, MD, Deutschhaus-Str 9, 35033, Marburg, Germany. E-mail: [email protected]. Published online July 27, 2009. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.12.049
136
recently reproduced in the comprehensive biographical work ‘‘Pantheon der Dermatologie’’,7 it suddenly occurred to me that this was not simply the ‘Mibelli type’ of porokeratosis. Remarkably, the disorder was superimposed by a rather pronounced segmental involvement. Hence, this case can be taken as an early example of type 2 segmental manifestation of an autosomal dominant skin disorder.
THE CASE REPORT BY VITTORIO MIBELLI The report is presented in a German, English, and French version and describes a young man, ‘‘age 21, unmarried, of a well-to-do family of Parma’’. Mibelli gives a detailed description of the patient’s porokeratosis. The ailment shows a pronounced unilateral involvement and, in addition, less severe bilateral disseminated lesions. Documentation of pronounced unilateral involvement The plate shows a large linear area of conspicuously intense involvement of the right arm, extending from the olecranon to the hand (Fig 1): ‘‘On the back of the right hand is seen a wide space prolonged upwards in the form of a broad band. . .This zone of skin bears singular likeness to a geographical map, for it is sharply limited by a line standing out in relief in the form of a dike, sinuous and irregular. . .This border is itself the most remarkable feature of the lesion. . ., for the area which it encloses is, over the greater part of its surface, only slightly smoother than the healthy skin and it is destitute of hairs. . .Nevertheless, there are to be seen in the space referred to small conical
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Fig 2. Left hand of same patient, showing disseminated lesions of plaque-type porokeratosis.2
Fig 1. ‘‘An uncommon form of keratodermia: Porokeratosis’’ as published in 1893 by Vittorio Mibelli. Note conspicuous linear involvement of right forearm and hand, superimposed on disseminated patchy lesions.2
elevations, whitish in colour, acuminated and hard like pin’s points; elsewhere conical elevations with truncated summits and measuring about 2 mm. in diameter; in other places, especially above, there are in the large spaces larger islets very varied in form marked out by a thin peripheral collaret of a dirty white colour.’’2 This lesion can be categorized as an unusually pronounced segmental manifestation of PM. Documentation of nonsegmental lesions of PM Another figure of the same plate depicts the back of the patient’s left hand showing approximately 11 plaque-like lesions of porokeratosis (Fig 2). Similar lesions involved the right hand, the extensor surface of the forearms, the forehead, and the neck. On the face the lesions were ‘‘of the size of a hemp seed or a lentil, visible only owing to their being of a browner shade. . .but easily felt on account of their sharply circumscribed roughness’’. These facial lesions would
be compatible with a diagnosis of DSAP,8 but the size of the other lesions is more suggestive of PM.9 This diagnosis is supported by the fact that ‘‘the same skin affection’’ was present in an older brother since the age of 8 years and in a younger sister since the age of 10 years, which virtually excludes DSAP.9 In the father ‘‘the disease had begun only towards the age of 60.’’2 Evaluation of this report in the light of present knowledge In this historical case, a pronounced unilateral involvement was superimposed on bilateral disseminated lesions characteristic of PM. The bilateral disorder was inherited as an autosomal dominant trait, thus reflecting heterozygosity for the underlying mutation, whereas the pronounced segmental involvement of the right arm would have originated from loss of heterozygosity that occurred at an early developmental stage.6,10 (It should be noted that the nonsegmental PM lesions of this patient, who carried the germline mutation in all of his cells, most probably do likewise reflect loss of heterozygosity, but these additional mutational events occurred later in life, which is why the plaques are disseminated rather than segmentally arranged.) As a rule, type 2 segmental involvement of an autosomal dominant skin disorder tends to appear
138 Case reports
J AM ACAD DERMATOL JANUARY 2010
at a rather young age, thus preceding the onset of nonsegmental lesions by years.11 Indeed, the segmental porokeratosis of Mibelli’s patient developed by the age of 2 years and ‘‘within a period of three years came to occupy all the part of the back of the hand and forearm which it occupies at present’’.2 At the age of about 7 years, nonsegmental lesions were noted on both hands ‘‘without any of them showing a tendency to spread like the primary patch on the right hand’’, and during puberty additional lesions began to involve the face and the neck. Hence, this case fulfills all of the clinical criteria of a type 2 segmental manifestation of an autosomal dominant skin disorder.10 This concept has previously been proposed for many other diseases such as DSAP, Darier disease, neurofibromatosis 1, epidermolytic hyperkeratosis of Brocq, glomangiomatosis, cutaneous leiomyomatosis, and acanthosis nigricans.6,12 Molecular proof of this theory has been provided in Hailey-Hailey disease and Cowden syndrome.13,14 Mibelli’s historical case provides further evidence that the concept is of broad significance because it helps in understanding mosaic skin disorders that otherwise would remain unexplained. The clinical appearance of the segmental involvement was reminiscent of giant porokeratosis and thus distinctly different from type 2 segmental DSAP.5,11,15 DSAP occurs far more frequently than PM, and it shows a remarkable proclivity for development of a type 2 segmental involvement.6 In fact, most cases of linear porokeratosis can today be categorized as examples of type 2 segmental DSAP.15-20 On the other hand, it seems likely that at least some cases of ‘‘giant porokeratosis’’21,22 in fact represent a type 2 segmental manifestation of PM. In conclusion, Mibelli’s case from 1893 can today be categorized as an early example of type 2 segmental manifestation of PM. Recognizing such cases may help elucidate the molecular basis of PM. I want to thank Professor Gerd Plewig (Munich, Germany) who kindly provided a copy of Mibelli’s report as published in the International Atlas of Rare Skin Diseases (1893). REFERENCES 1. Mibelli V. Contributo allo studio della ipercheratosi dei canali sudoriferi (porokeratosi). G It Mal Vener Pelle 1893;28:313-55. 2. Mibelli V. An uncommon form of keratodermia: ‘‘porokeratosis’’. In: Unna PG, Morris M, Leloir H, Duhring LA, eds. Internationaler Atlas seltener Hautkrankheiten. International Atlas of Rare Skin Diseases. Atlas international des maladies rares de la peau. Fascicle IX, edited on 28 October 1893, pp 5-10, plate XXVII. Hamburg: Voss; 1893.
3. Allegra F. Vittorio Mibelli and the tale of « porokeratosis ». Am J Dermatopathol 1986;8:169-72. 4. Schamroth JM, Zlotogorski A, Gilead L. Porokeratosis of Mibelli: overview and review of the literature. Acta Derm Venereol 1997;77:207-13. 5. Happle R. Somatic recombination may explain linear porokeratosis associated with disseminated superficial actinic porokeratosis. Am J Med Genet 1991;39:237. 6. Happle R. Dohi Memorial Lecture: New aspects of cutaneous mosaicism. J Dermatol 2002;29:681-92. 7. Rech G, Arieti S, Iorizzo M, Tosti A. Vittorio Mibelli (1860-1910). In: Lo¨ser C, Plewig G. Pantheon der Dermatologie. Heidelberg: Springer Medizin Verlag; 2008. pp. 688-93. 8. Chernosky ME, Freeman RG. Disseminated superficial actinic porokeratosis (DSAP). Arch Dermatol 1967;96:611-24. 9. Mibelli V. Ueber einen Fall von Porokeratosis mit Localisation im Munde und an der Glans. Arch Dermatol Syph (Vienna) 1899;47:231-43. 10. Happle R. A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity. Arch Dermatol 1997;133:1505-9. 11. Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol 1999;41:143-61. 12. Happle R. Type 2 segmental acanthosis nigricans: a historical case explained by a new concept. Arch Dermatol 2008;144: 1637. 13. Poblete-Gutie´rrez P, Wiederholt T, Ko¨nig A, Jugert FK, Marquardt Y, Ru¨bben A, et al. Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest 2004;114: 1467-74. 14. Happle R. Type 2 segmental Cowden disease vs. Proteus syndrome. Br J Dermatol 2007;156:1089-90. 15. Freyschmidt-Paul P, Hoffmann R, Ko¨nig A, Happle R. Linear porokeratosis superimposed on disseminated superficial actinic porokeratosis: report of two cases exemplifying the concept of type 2 segmental manifestation of autosomal dominant skin disorders. J Am Acad Dermatol 1999;41: 644-7. 16. Bloom D, Abramowitz EW. Porokeratosis Mibelli: report of three cases in one family; histologic studies. Arch Dermatol Syph 1943;47:1-15. 17. MacMillan AL, Roberts SOB. Porokeratosis of Mibelli after renal transplantation. Br J Dermatol 1974;90:45-51. 18. Pearson IC, Cliff S. Case 6: Linear porokeratosis with disseminated superficial porokeratosis erupting in pregnancy. Clin Exp Dermatol 2003;28:345-6. 19. Goebeler M, Bro¨cker EB, Hamm H. Keratotic plaques on the left trunk area and all extremities: porokeratosis with clinical manifestations of both linear porokeratosis (LP) and disseminated superficial actinic porokeratosis (DSAP). Arch Dermatol 2006;142:60-1, 63-4. 20. Sua´rez-Amor O, Pereiro-Ferreiro´s M, Ginarte M, Peteiro C, Toribio J. Coexistence of linear porokeratosis and disseminated superficial actinic porokeratosis: a type 2 segmental manifestation. Acta Derm Venereol 2007;87:363-4. 21. Hanumanthayya K, Magavi S, Tophakhane R, Rathod R. Coexistence of disseminated superficial and giant porokeratosis of Mibelli with squamous cell carcinoma. Indian J Dermatol Venereol Leprol 2003;69:296-7. 22. Bozdag˘ KE, Bıc¸akc¸ı H, Ermete M. Giant porokeratosis. Int J Dermatol 2004;43:518-20.
REPORTS
Mibelli revisited: A case of type 2 segmental porokeratosis from 1893 Rudolf Happle, MD Marburg, Germany In autosomal dominant skin disorders, a pronounced mosaic involvement may sometimes be found to be superimposed on the ordinary nonsegmental lesions. Such ‘‘type 2 segmental manifestation’’ reflects loss of heterozygosity occurring at an early developmental stage, giving rise to a cell clone that lacks the corresponding wild-type allele. Here, this genetic concept is applied to an unusual case of plaque-type porokeratosis of Mibelli (PM) as published in 1893 by Vittorio Mibelli in the International Atlas of Rare Skin Diseases. The right forearm and hand of the 21-year-old patient showed a pronounced linear porokeratosis that had developed since the age of 2 years. Moreover, nonsegmental lesions of PM involved both hands and forearms as well as the face and the neck, having first been noticed at the age of 7 years. Two siblings and the father were likewise affected with PM. Hence, Mibelli’s case from 1893 meets all of the criteria of a type 2 segmental manifestation of an autosomal dominant skin disorder. Recognizing such cases of superimposed segmental involvement may help elucidate the molecular basis of PM. ( J Am Acad Dermatol 2010;62:136-8.)
I
n 1893 Vittorio Mibelli described a new skin disorder for which he coined the term ‘‘porokeratosis’’ because he erroneously believed that the cornoid lamellae, representing the histopathological hallmark of the disease, were related to the sweat pores.1,2 The designation porokeratosis is now firmly entrenched in our terminology and has eternalized Mibelli’s name.3 Today we distinguish different types such as the plaque type of Mibelli (PM), disseminated superficial actinic porokeratosis (DSAP), porokeratosis palmaris, plantaris et disseminata (PPPD), and porokeratosis punctata palmaris et plantaris (PPPP).4 Linear porokeratosis is traditionally categorized as an additional separate type, although there is today convincing evidence that this cutaneous anomaly does not represent a distinct entity but rather a mosaic manifestation of one of the other types of porokeratosis.5,6 An impressive case published by Mibelli in 1893, in both Italian1 and in German, English, and French in the International Atlas of Rare Skin Diseases,2 has thus far been taken as a classical example of PM. However, when looking at the fine illustrations
From the Department of Dermatology, Philipp University of Marburg. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Rudolf Happle, MD, Deutschhaus-Str 9, 35033, Marburg, Germany. E-mail: [email protected]. Published online July 27, 2009. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.12.049
136
recently reproduced in the comprehensive biographical work ‘‘Pantheon der Dermatologie’’,7 it suddenly occurred to me that this was not simply the ‘Mibelli type’ of porokeratosis. Remarkably, the disorder was superimposed by a rather pronounced segmental involvement. Hence, this case can be taken as an early example of type 2 segmental manifestation of an autosomal dominant skin disorder.
THE CASE REPORT BY VITTORIO MIBELLI The report is presented in a German, English, and French version and describes a young man, ‘‘age 21, unmarried, of a well-to-do family of Parma’’. Mibelli gives a detailed description of the patient’s porokeratosis. The ailment shows a pronounced unilateral involvement and, in addition, less severe bilateral disseminated lesions. Documentation of pronounced unilateral involvement The plate shows a large linear area of conspicuously intense involvement of the right arm, extending from the olecranon to the hand (Fig 1): ‘‘On the back of the right hand is seen a wide space prolonged upwards in the form of a broad band. . .This zone of skin bears singular likeness to a geographical map, for it is sharply limited by a line standing out in relief in the form of a dike, sinuous and irregular. . .This border is itself the most remarkable feature of the lesion. . ., for the area which it encloses is, over the greater part of its surface, only slightly smoother than the healthy skin and it is destitute of hairs. . .Nevertheless, there are to be seen in the space referred to small conical
J AM ACAD DERMATOL
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VOLUME 62, NUMBER 1
Fig 2. Left hand of same patient, showing disseminated lesions of plaque-type porokeratosis.2
Fig 1. ‘‘An uncommon form of keratodermia: Porokeratosis’’ as published in 1893 by Vittorio Mibelli. Note conspicuous linear involvement of right forearm and hand, superimposed on disseminated patchy lesions.2
elevations, whitish in colour, acuminated and hard like pin’s points; elsewhere conical elevations with truncated summits and measuring about 2 mm. in diameter; in other places, especially above, there are in the large spaces larger islets very varied in form marked out by a thin peripheral collaret of a dirty white colour.’’2 This lesion can be categorized as an unusually pronounced segmental manifestation of PM. Documentation of nonsegmental lesions of PM Another figure of the same plate depicts the back of the patient’s left hand showing approximately 11 plaque-like lesions of porokeratosis (Fig 2). Similar lesions involved the right hand, the extensor surface of the forearms, the forehead, and the neck. On the face the lesions were ‘‘of the size of a hemp seed or a lentil, visible only owing to their being of a browner shade. . .but easily felt on account of their sharply circumscribed roughness’’. These facial lesions would
be compatible with a diagnosis of DSAP,8 but the size of the other lesions is more suggestive of PM.9 This diagnosis is supported by the fact that ‘‘the same skin affection’’ was present in an older brother since the age of 8 years and in a younger sister since the age of 10 years, which virtually excludes DSAP.9 In the father ‘‘the disease had begun only towards the age of 60.’’2 Evaluation of this report in the light of present knowledge In this historical case, a pronounced unilateral involvement was superimposed on bilateral disseminated lesions characteristic of PM. The bilateral disorder was inherited as an autosomal dominant trait, thus reflecting heterozygosity for the underlying mutation, whereas the pronounced segmental involvement of the right arm would have originated from loss of heterozygosity that occurred at an early developmental stage.6,10 (It should be noted that the nonsegmental PM lesions of this patient, who carried the germline mutation in all of his cells, most probably do likewise reflect loss of heterozygosity, but these additional mutational events occurred later in life, which is why the plaques are disseminated rather than segmentally arranged.) As a rule, type 2 segmental involvement of an autosomal dominant skin disorder tends to appear
138 Case reports
J AM ACAD DERMATOL JANUARY 2010
at a rather young age, thus preceding the onset of nonsegmental lesions by years.11 Indeed, the segmental porokeratosis of Mibelli’s patient developed by the age of 2 years and ‘‘within a period of three years came to occupy all the part of the back of the hand and forearm which it occupies at present’’.2 At the age of about 7 years, nonsegmental lesions were noted on both hands ‘‘without any of them showing a tendency to spread like the primary patch on the right hand’’, and during puberty additional lesions began to involve the face and the neck. Hence, this case fulfills all of the clinical criteria of a type 2 segmental manifestation of an autosomal dominant skin disorder.10 This concept has previously been proposed for many other diseases such as DSAP, Darier disease, neurofibromatosis 1, epidermolytic hyperkeratosis of Brocq, glomangiomatosis, cutaneous leiomyomatosis, and acanthosis nigricans.6,12 Molecular proof of this theory has been provided in Hailey-Hailey disease and Cowden syndrome.13,14 Mibelli’s historical case provides further evidence that the concept is of broad significance because it helps in understanding mosaic skin disorders that otherwise would remain unexplained. The clinical appearance of the segmental involvement was reminiscent of giant porokeratosis and thus distinctly different from type 2 segmental DSAP.5,11,15 DSAP occurs far more frequently than PM, and it shows a remarkable proclivity for development of a type 2 segmental involvement.6 In fact, most cases of linear porokeratosis can today be categorized as examples of type 2 segmental DSAP.15-20 On the other hand, it seems likely that at least some cases of ‘‘giant porokeratosis’’21,22 in fact represent a type 2 segmental manifestation of PM. In conclusion, Mibelli’s case from 1893 can today be categorized as an early example of type 2 segmental manifestation of PM. Recognizing such cases may help elucidate the molecular basis of PM. I want to thank Professor Gerd Plewig (Munich, Germany) who kindly provided a copy of Mibelli’s report as published in the International Atlas of Rare Skin Diseases (1893). REFERENCES 1. Mibelli V. Contributo allo studio della ipercheratosi dei canali sudoriferi (porokeratosi). G It Mal Vener Pelle 1893;28:313-55. 2. Mibelli V. An uncommon form of keratodermia: ‘‘porokeratosis’’. In: Unna PG, Morris M, Leloir H, Duhring LA, eds. Internationaler Atlas seltener Hautkrankheiten. International Atlas of Rare Skin Diseases. Atlas international des maladies rares de la peau. Fascicle IX, edited on 28 October 1893, pp 5-10, plate XXVII. Hamburg: Voss; 1893.
3. Allegra F. Vittorio Mibelli and the tale of « porokeratosis ». Am J Dermatopathol 1986;8:169-72. 4. Schamroth JM, Zlotogorski A, Gilead L. Porokeratosis of Mibelli: overview and review of the literature. Acta Derm Venereol 1997;77:207-13. 5. Happle R. Somatic recombination may explain linear porokeratosis associated with disseminated superficial actinic porokeratosis. Am J Med Genet 1991;39:237. 6. Happle R. Dohi Memorial Lecture: New aspects of cutaneous mosaicism. J Dermatol 2002;29:681-92. 7. Rech G, Arieti S, Iorizzo M, Tosti A. Vittorio Mibelli (1860-1910). In: Lo¨ser C, Plewig G. Pantheon der Dermatologie. Heidelberg: Springer Medizin Verlag; 2008. pp. 688-93. 8. Chernosky ME, Freeman RG. Disseminated superficial actinic porokeratosis (DSAP). Arch Dermatol 1967;96:611-24. 9. Mibelli V. Ueber einen Fall von Porokeratosis mit Localisation im Munde und an der Glans. Arch Dermatol Syph (Vienna) 1899;47:231-43. 10. Happle R. A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity. Arch Dermatol 1997;133:1505-9. 11. Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol 1999;41:143-61. 12. Happle R. Type 2 segmental acanthosis nigricans: a historical case explained by a new concept. Arch Dermatol 2008;144: 1637. 13. Poblete-Gutie´rrez P, Wiederholt T, Ko¨nig A, Jugert FK, Marquardt Y, Ru¨bben A, et al. Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest 2004;114: 1467-74. 14. Happle R. Type 2 segmental Cowden disease vs. Proteus syndrome. Br J Dermatol 2007;156:1089-90. 15. Freyschmidt-Paul P, Hoffmann R, Ko¨nig A, Happle R. Linear porokeratosis superimposed on disseminated superficial actinic porokeratosis: report of two cases exemplifying the concept of type 2 segmental manifestation of autosomal dominant skin disorders. J Am Acad Dermatol 1999;41: 644-7. 16. Bloom D, Abramowitz EW. Porokeratosis Mibelli: report of three cases in one family; histologic studies. Arch Dermatol Syph 1943;47:1-15. 17. MacMillan AL, Roberts SOB. Porokeratosis of Mibelli after renal transplantation. Br J Dermatol 1974;90:45-51. 18. Pearson IC, Cliff S. Case 6: Linear porokeratosis with disseminated superficial porokeratosis erupting in pregnancy. Clin Exp Dermatol 2003;28:345-6. 19. Goebeler M, Bro¨cker EB, Hamm H. Keratotic plaques on the left trunk area and all extremities: porokeratosis with clinical manifestations of both linear porokeratosis (LP) and disseminated superficial actinic porokeratosis (DSAP). Arch Dermatol 2006;142:60-1, 63-4. 20. Sua´rez-Amor O, Pereiro-Ferreiro´s M, Ginarte M, Peteiro C, Toribio J. Coexistence of linear porokeratosis and disseminated superficial actinic porokeratosis: a type 2 segmental manifestation. Acta Derm Venereol 2007;87:363-4. 21. Hanumanthayya K, Magavi S, Tophakhane R, Rathod R. Coexistence of disseminated superficial and giant porokeratosis of Mibelli with squamous cell carcinoma. Indian J Dermatol Venereol Leprol 2003;69:296-7. 22. Bozdag˘ KE, Bıc¸akc¸ı H, Ermete M. Giant porokeratosis. Int J Dermatol 2004;43:518-20.