MSB Review
SULZBERGER ON INCONTINENTIA PIGMENTI J. E. jELINEK, M.D.
Erom the Department of Dermatology, New York University School of Medicine, New York, New York
Initial Description In 1925, at a session of the Swiss dermatological society, Bruno Bloch reported a patient with a peculiar pigmentation, apparently never previously described.1 Because of the singular features of this pigmentation, Sulzberger, an associate of Bloch's, published a detailed discussion of the case in 1928, citing other reports of this entity. In this article,^ the clinical and histopathologic aspects, with emphasis on the role of pigment in this disease, were described. A iy2-year-old girl, had had brown spots on her body at birth, as well as moist, red lesions on the thighs which subsequently healed with brown pigmentation. Abnormal changes of the skin consisted of peculiar hyperpigmented areas involving the trunk and right lower extremities, bizarre both in their shape and arrangement. Some looked like brown mortar spray with irregular outer contours, others extended from a large central spot in linear, spindle-shaped branches which dissolved or joined with adjoining streaks to form net-like figures. Thus an irregular, arbitrary arrangement was formed reminiscent of a marmonized or sprayed wall. The pigmentation did not follow vessel, nerve or metameric distribution. The effloresAddress for reprints: |. E. lelinek, M.D., 15 W. 12th Street, New York, NY 10011.
cences were macular, and the color was brown with shades of slate gray. In the 2 years which had passed since first observation, the eruption had undergone a distinct but slow involution. In addition, there were, in the parietal region of the scalp, a number of completely bald, atrophie, depigmented patches, covering an area the size of a palm. The right eye had been enucleated when she was 1, because of a "retrobulbar glioma." The child was otherwise normal. Histologically, the epidermis was normal except for areas interrupted at irregular intervals by basal cells of pathologic character; these cells were vacuolated, irregularly shaped and elongated, often penetrating into the cutis, and most numerous above those papillae richest in pigment. The greatest amount of pigment was found in massive accumulations of chromotophores in the cutis and papillary bodies with corresponding slight or absent pigment content of the epidermis above. This dermal pigment was dopa negative. In addition, a variable, mostly perivascular inflammatory reaction was seen, consisting of broken connective tis365
366
INTERNATIONAL JOURNAL OF DERMATOLOGY
sue, lymphocytes and plasma cells. Dense cell accumulations which filled the papillae and eliminated the dermoepidermal border were also noted. From the clinical and histologic evidence, Sulzberger hypothesized (1) that the abnormal staining of the skin, the main feature of the case, was due to the presence of pigment in the corium, and (2) that the primary lesion was probably in the epidermal basal melanoblasts, and (3) that the melanotic dermal accumulation was due to the flowing downward of the epidermal pigment. He speculated further that the functional anomaly of the basal cells, resulting in increased delivery of melanin to the dermis, was due to a cell membrane permeability caused by intrauterine inflammation. Because of this abnormal flow of melanin downward into the cutis, instead of the usual upward one, Bloch and Sulzberger named the condition incontinentia pigmenti. Additional Reports In 1933, Levin, at a dermatologic meeting in New York, reported a 3-year-old girl with the diagnosis of nervus reticularis et pigmentosus.'^ The patient had marble-like pigmentation of the face, trunk and extremities. A biopsy was interpreted as plexiform lymphangiectasia. Sulzberger, in his discussion, had no doubt that the disease was a pigmentary nevoid anomaly exactly fitting incontinentia pigmenti. A further case was reported in detail by Sulzberger and others in 1938.'" The patient was a 19-year-old woman with unilateral, bizarre jagged-edged lightbrown to slate-colored lesions which had been present since birth. The histology of the pigmented areas was identical to that of the original patient. In addition to the cutaneous findings, the patient had other congenital defects of the eyes (blind in left eye since birth), hair (sparse.
June 1977
Vol. 16
with a sharply circumscribed alopecic area of the scalp), nails (longitudinal and horizontal ridging, some short, friable and slightly discolored with concave or flat surfaces) teeth (only 10 had erupted and 8 had fallen out) and bones (small skull and hands, shallow large sella turcica). The patient's mother, her sister, and this sister's daughter all suffered various degrees of the same congenital, chiefly ectodermal anomalies. The patient's father, brothers and nephew were all normal. This remarkable limitation of defects to the females of the family was emphasized in the paper. The authors stressed that the combination of typical pigmentary skin lesions with ocular, dental, nail and hair defects was probably part of the same syndrome and that the transmission was both familial and apparently sex-bound. They believed that this case strengthened the original idea of a traumatic, inflammatory or other prenatal change causing defects in the epidermal basal cells, allowing pigmentary incontinence and accumulation of melanin in the dermal chromatophores. The first patient, the child reported by Bloch and Sulzberger, was seen later in adult life by Franceschetti and Jadassohn.^ By that time the pigmented lesions had cleared completely, the remaining eye was normal and the patient was otherwise well. Today, over 50 years since Bloch reported the case, some aspects of incontinentia pigmenti are more clearly defined by more than 650 reports in the world literature.'' Many fundamental questions, including the primary cause, certainly of genetic transmission, and explanation of the peculiar patterning remain to be answered. Priority of original description of the condition, although it was called by other names, belongs to earlier physicians.7'
No. 5
INCONTINENTIA PIGMENTI
Diagnosis The disease is, as before, diagnosed largely on clinical grounds. We now recognize 4 stages of its development'"' >': 1. Erythemata and linear vesicles appearing at, or shortly after birth, 2. Verrucous lesions within a few weeks or months, spontaneously resolving leaving normal, atrophic depigmented areas, 3. The characteristic marble-cake, irregular hyperpigmentation, distributed asymetrically on the torso and to a lesser extent on the extremities, usually evolving in infancy and early childhood, 4. Resolution of pigmentation in late childhood or early adulthood. Associated abnormalities, some of which were noted in Sulzberger's early cases, have been found in 80% of patients; these affect the hair (alopecia, scarring), nails (dystrophy), teeth (partial or complete adontia, conical pegging), eyes (blindness, strabismus, nystagmus), central nervous system (motor abnormalities, mental retardation, convulsions) and bone. The familial tendency of the disease has been found in 55.4%,'' and the female preponderance (593 out of 609 reported cases) emphasized by Sulzberger has been substantiated. The most likely explanation of the sex distribution is that the abnormality is transmitted as an X-linked dominant gene, prenatally lethal to most males.'2 The histologic appearance of the hyperpigmented stage is essentially as that first described. Eosinophilia in the early spongiotic, vesicular lesions^-^ as well as in the peripheral blood''' is now recognized. The electron microscope shows qualitative similarities between inflam-
jelinek
367
matory and nevoid pigmentation'^ and the first 3 stages have dyskeratosis and transient pigmentary discharge."^ Increased chromosomal aberrations in cultured peripheral lymphocytes and fibroblasts of incontinentia pigmenti patients have been described.''' If this finding is seen to be consistent, it should assist in diagnosis, particularly in cases where pigmentation has been minimal or absent but where other defects suggest the disorder. Phenotypic marble-cake pigmentation in affected females might be consistent with random X-chromosome inactivation, as explained in the Lyon hypothesis, according to McKusick.'^ However, this explanation is difficult to accept in the few male patients, and in the similar, albeit reverse, hypopigmented patterning in hypomelanosis of Ito (incontinentia pigmenti achromians) in which the sexes are affected almost equally and where X-chromosome inactivation in the male does not apply.'^ The primary cause is still unknown. Theories, none of them later substantiated, have implicated viruses, especially herpes simpIex,20' 21 dermatitis herpetiformis,22 and nevoid causes.2-' There is no specific therapy for incontinentia pigmenti. Significant advances in genetic counseling have been made. A patient with incontinentia pigmenti has a 25% chance of miscarriage and 50% chance of bearing an affected daughter who is likely to be more severely affected than herself. A normal woman who has had a child with incontinentia pigmenti and is pregnant can have an aminocentesis test to determine fetal sex. If it is male, pregnancy can continue, for there is the strong likelihood of either a normal son or a spontaneous abortion. If it is female, because of a 50% chance of the fetus being affected and a 40% chance of multiple, serious associated
368
INTERNATIONAL JOURNAL OF DERMATOLOGY
problems, a therapeutic abortion could be done. Conclusion
.
Sulzberger made fundamental contributions to the delineation of incontinenti pigmenti. He clearly described its clinical and histoiogic appearance and together with Bloch coined the name, which although challenged by others, has remained as the most widely acceptable one, pending clarification of the true cause. Sulzberger also was the first to emphasize the wide constellation of associated congenital epidermal defects, the family aggregation and the limitation, in most cases, to the female sex. In view of their contributions, while lacking historical precedence, the eponym of Bloch and Sulzberger seems reasonably linked to the mysterious and fascinating entity of incontinentia pigmenti. References 1. Bloch, B.: Eigentumliche, bisher nicht beschreibene Pigmentaffektion (Incontinentia Pigmenti). Schvi/eiz. Med. Wochenschr. 56:404, 1926. 2. Sulzberger, M. B.: Uber eine bisher nicht beschreibene Pigmentaffektion (Incontinentia Pigmenti). Arch. Dermatol. Syphilol. 154:19, 1928. 3. Levin, O.: Nevus reticularis et pigmentosus. Arch. Dermatol. Syphilol. 27:141, 1933. 4. Sulzberger, M. B., Fraser, J. F., and Hutner, L.: Incontinentia pigmenti (Bloch-Sulzberger). Report of an additional case, with comment on possible relationship to a new syndrome of familial and congenital anomalies. Arch. Dermatol. Syphilol. 38:57, 1938. 5. Franceschetti, P. A., and Jadassohn, W.: A propos de 1 "Incontinentia Pigmenti," Delimitation de deux syndromes differents figurants sons le meme terme. Dermatologica 108:1, 1954. 6. Carney, R. G.: Incontinentia pigmenti. A world statistical analysis. Arch. Dermatol. 112:535, 1976.
June 1977
Vol. 16
7. Garrod, A. E.: Peculiar pigmentation of the skin in an infant. Trans. Clin. Soc. London 39:216, 1906. 8. Bardach, M.: Systematisierte Naevusbildungen bei einem eineilgen Zwillingspaar. Z. Kinderheilk 39:542, 1925. 9. Lechleutner, ??: Uber eine seltene systematisierte Dermatose. Inaug. Diss., Munich, 1925. 10. Carney, R. G.: Incontinentia pigmenti: A report of five cases and review of the literature. Arch. Dermatol. Syphilol. 64:126, 1951. 11. Oldfelt, V.: Incontinentia pigmenti. J. Pediatr. 54:446, 1959. 12. Lenz, W.: Zur Genetik der Incontinentia Pigmenti. Ann. Paediatr. 196:146, 1961. 13. Asboe-Hansen, G.: Bullous keratogenous and pigmentary dermatitis with blood eosinophilia in newborn girls: Report of four cases. Arch. Dermatol. Syphilol. 67:152, 1953. 14. Epstein, S., Vedder, J. S., and Pinkus, H.: Bullous variety of incontinentia pigmenti. (Bloch-Sulzberger). Arch. Dermatol. Syphilol. 65:557, 1952. 15. Schamburg-Lever, G., and Lever, W. F.: Electron microscopy of incontinenti pigmenti. Inv. Dermatol. 61:151, 1973. 16. Caputo, R., Gianotti, F., and Innocenti, M.: Ultrastructural findings in incontinentia pigmenti. Int. J. Dermatol. 14:46, 1975. 17. Kelly, T. E., Rary, J. M., and Young, L.: Incontinentia pigmenti: A chromosomal breakage syndrome. Heredit. 67:171, 1976. 18. McKusick, V. A.: Mendelian inheritance in man. Catalogs of autosomal dominant, recessive and X-linked phenotypes. Baltimore, Johns Hopkins University Press, 1976, p. 635. 19. Jelinek, J. E., Bart, R. S., and Schiff, G. W.: Hypomelanosis of Ito (Incontinentia pigmenti achromians) Arch. Dermatol. 107:596, 1973. 20. Haber, H.: The Bloch-Sulzberger syndrome (incontinentia pigmenti). Br. J. Dermatol. 64: 129, 1952. 21.
Palmgren, B.: The relationship of dermatitis herpetiformis to incontinentia pigmenti in in newborn infants. Pediatrics 29:295, 1962. 22. Werner, A.: Kongenitale dermatitis herpetiformis Duhring. Am. Paediatr. 182:176, 1964. 23. Findlay, G. H.: On the pathogenesis of incontinentia pigmenti with observations on an associated eye disturbance resembling retrolental fibroplasia. Br. J. Dermatol. 4:141, 1952.
SULZBERGER ON INCONTINENTIA PIGMENTI J. E. jELINEK, M.D.
Erom the Department of Dermatology, New York University School of Medicine, New York, New York
Initial Description In 1925, at a session of the Swiss dermatological society, Bruno Bloch reported a patient with a peculiar pigmentation, apparently never previously described.1 Because of the singular features of this pigmentation, Sulzberger, an associate of Bloch's, published a detailed discussion of the case in 1928, citing other reports of this entity. In this article,^ the clinical and histopathologic aspects, with emphasis on the role of pigment in this disease, were described. A iy2-year-old girl, had had brown spots on her body at birth, as well as moist, red lesions on the thighs which subsequently healed with brown pigmentation. Abnormal changes of the skin consisted of peculiar hyperpigmented areas involving the trunk and right lower extremities, bizarre both in their shape and arrangement. Some looked like brown mortar spray with irregular outer contours, others extended from a large central spot in linear, spindle-shaped branches which dissolved or joined with adjoining streaks to form net-like figures. Thus an irregular, arbitrary arrangement was formed reminiscent of a marmonized or sprayed wall. The pigmentation did not follow vessel, nerve or metameric distribution. The effloresAddress for reprints: |. E. lelinek, M.D., 15 W. 12th Street, New York, NY 10011.
cences were macular, and the color was brown with shades of slate gray. In the 2 years which had passed since first observation, the eruption had undergone a distinct but slow involution. In addition, there were, in the parietal region of the scalp, a number of completely bald, atrophie, depigmented patches, covering an area the size of a palm. The right eye had been enucleated when she was 1, because of a "retrobulbar glioma." The child was otherwise normal. Histologically, the epidermis was normal except for areas interrupted at irregular intervals by basal cells of pathologic character; these cells were vacuolated, irregularly shaped and elongated, often penetrating into the cutis, and most numerous above those papillae richest in pigment. The greatest amount of pigment was found in massive accumulations of chromotophores in the cutis and papillary bodies with corresponding slight or absent pigment content of the epidermis above. This dermal pigment was dopa negative. In addition, a variable, mostly perivascular inflammatory reaction was seen, consisting of broken connective tis365
366
INTERNATIONAL JOURNAL OF DERMATOLOGY
sue, lymphocytes and plasma cells. Dense cell accumulations which filled the papillae and eliminated the dermoepidermal border were also noted. From the clinical and histologic evidence, Sulzberger hypothesized (1) that the abnormal staining of the skin, the main feature of the case, was due to the presence of pigment in the corium, and (2) that the primary lesion was probably in the epidermal basal melanoblasts, and (3) that the melanotic dermal accumulation was due to the flowing downward of the epidermal pigment. He speculated further that the functional anomaly of the basal cells, resulting in increased delivery of melanin to the dermis, was due to a cell membrane permeability caused by intrauterine inflammation. Because of this abnormal flow of melanin downward into the cutis, instead of the usual upward one, Bloch and Sulzberger named the condition incontinentia pigmenti. Additional Reports In 1933, Levin, at a dermatologic meeting in New York, reported a 3-year-old girl with the diagnosis of nervus reticularis et pigmentosus.'^ The patient had marble-like pigmentation of the face, trunk and extremities. A biopsy was interpreted as plexiform lymphangiectasia. Sulzberger, in his discussion, had no doubt that the disease was a pigmentary nevoid anomaly exactly fitting incontinentia pigmenti. A further case was reported in detail by Sulzberger and others in 1938.'" The patient was a 19-year-old woman with unilateral, bizarre jagged-edged lightbrown to slate-colored lesions which had been present since birth. The histology of the pigmented areas was identical to that of the original patient. In addition to the cutaneous findings, the patient had other congenital defects of the eyes (blind in left eye since birth), hair (sparse.
June 1977
Vol. 16
with a sharply circumscribed alopecic area of the scalp), nails (longitudinal and horizontal ridging, some short, friable and slightly discolored with concave or flat surfaces) teeth (only 10 had erupted and 8 had fallen out) and bones (small skull and hands, shallow large sella turcica). The patient's mother, her sister, and this sister's daughter all suffered various degrees of the same congenital, chiefly ectodermal anomalies. The patient's father, brothers and nephew were all normal. This remarkable limitation of defects to the females of the family was emphasized in the paper. The authors stressed that the combination of typical pigmentary skin lesions with ocular, dental, nail and hair defects was probably part of the same syndrome and that the transmission was both familial and apparently sex-bound. They believed that this case strengthened the original idea of a traumatic, inflammatory or other prenatal change causing defects in the epidermal basal cells, allowing pigmentary incontinence and accumulation of melanin in the dermal chromatophores. The first patient, the child reported by Bloch and Sulzberger, was seen later in adult life by Franceschetti and Jadassohn.^ By that time the pigmented lesions had cleared completely, the remaining eye was normal and the patient was otherwise well. Today, over 50 years since Bloch reported the case, some aspects of incontinentia pigmenti are more clearly defined by more than 650 reports in the world literature.'' Many fundamental questions, including the primary cause, certainly of genetic transmission, and explanation of the peculiar patterning remain to be answered. Priority of original description of the condition, although it was called by other names, belongs to earlier physicians.7'
No. 5
INCONTINENTIA PIGMENTI
Diagnosis The disease is, as before, diagnosed largely on clinical grounds. We now recognize 4 stages of its development'"' >': 1. Erythemata and linear vesicles appearing at, or shortly after birth, 2. Verrucous lesions within a few weeks or months, spontaneously resolving leaving normal, atrophic depigmented areas, 3. The characteristic marble-cake, irregular hyperpigmentation, distributed asymetrically on the torso and to a lesser extent on the extremities, usually evolving in infancy and early childhood, 4. Resolution of pigmentation in late childhood or early adulthood. Associated abnormalities, some of which were noted in Sulzberger's early cases, have been found in 80% of patients; these affect the hair (alopecia, scarring), nails (dystrophy), teeth (partial or complete adontia, conical pegging), eyes (blindness, strabismus, nystagmus), central nervous system (motor abnormalities, mental retardation, convulsions) and bone. The familial tendency of the disease has been found in 55.4%,'' and the female preponderance (593 out of 609 reported cases) emphasized by Sulzberger has been substantiated. The most likely explanation of the sex distribution is that the abnormality is transmitted as an X-linked dominant gene, prenatally lethal to most males.'2 The histologic appearance of the hyperpigmented stage is essentially as that first described. Eosinophilia in the early spongiotic, vesicular lesions^-^ as well as in the peripheral blood''' is now recognized. The electron microscope shows qualitative similarities between inflam-
jelinek
367
matory and nevoid pigmentation'^ and the first 3 stages have dyskeratosis and transient pigmentary discharge."^ Increased chromosomal aberrations in cultured peripheral lymphocytes and fibroblasts of incontinentia pigmenti patients have been described.''' If this finding is seen to be consistent, it should assist in diagnosis, particularly in cases where pigmentation has been minimal or absent but where other defects suggest the disorder. Phenotypic marble-cake pigmentation in affected females might be consistent with random X-chromosome inactivation, as explained in the Lyon hypothesis, according to McKusick.'^ However, this explanation is difficult to accept in the few male patients, and in the similar, albeit reverse, hypopigmented patterning in hypomelanosis of Ito (incontinentia pigmenti achromians) in which the sexes are affected almost equally and where X-chromosome inactivation in the male does not apply.'^ The primary cause is still unknown. Theories, none of them later substantiated, have implicated viruses, especially herpes simpIex,20' 21 dermatitis herpetiformis,22 and nevoid causes.2-' There is no specific therapy for incontinentia pigmenti. Significant advances in genetic counseling have been made. A patient with incontinentia pigmenti has a 25% chance of miscarriage and 50% chance of bearing an affected daughter who is likely to be more severely affected than herself. A normal woman who has had a child with incontinentia pigmenti and is pregnant can have an aminocentesis test to determine fetal sex. If it is male, pregnancy can continue, for there is the strong likelihood of either a normal son or a spontaneous abortion. If it is female, because of a 50% chance of the fetus being affected and a 40% chance of multiple, serious associated
368
INTERNATIONAL JOURNAL OF DERMATOLOGY
problems, a therapeutic abortion could be done. Conclusion
.
Sulzberger made fundamental contributions to the delineation of incontinenti pigmenti. He clearly described its clinical and histoiogic appearance and together with Bloch coined the name, which although challenged by others, has remained as the most widely acceptable one, pending clarification of the true cause. Sulzberger also was the first to emphasize the wide constellation of associated congenital epidermal defects, the family aggregation and the limitation, in most cases, to the female sex. In view of their contributions, while lacking historical precedence, the eponym of Bloch and Sulzberger seems reasonably linked to the mysterious and fascinating entity of incontinentia pigmenti. References 1. Bloch, B.: Eigentumliche, bisher nicht beschreibene Pigmentaffektion (Incontinentia Pigmenti). Schvi/eiz. Med. Wochenschr. 56:404, 1926. 2. Sulzberger, M. B.: Uber eine bisher nicht beschreibene Pigmentaffektion (Incontinentia Pigmenti). Arch. Dermatol. Syphilol. 154:19, 1928. 3. Levin, O.: Nevus reticularis et pigmentosus. Arch. Dermatol. Syphilol. 27:141, 1933. 4. Sulzberger, M. B., Fraser, J. F., and Hutner, L.: Incontinentia pigmenti (Bloch-Sulzberger). Report of an additional case, with comment on possible relationship to a new syndrome of familial and congenital anomalies. Arch. Dermatol. Syphilol. 38:57, 1938. 5. Franceschetti, P. A., and Jadassohn, W.: A propos de 1 "Incontinentia Pigmenti," Delimitation de deux syndromes differents figurants sons le meme terme. Dermatologica 108:1, 1954. 6. Carney, R. G.: Incontinentia pigmenti. A world statistical analysis. Arch. Dermatol. 112:535, 1976.
June 1977
Vol. 16
7. Garrod, A. E.: Peculiar pigmentation of the skin in an infant. Trans. Clin. Soc. London 39:216, 1906. 8. Bardach, M.: Systematisierte Naevusbildungen bei einem eineilgen Zwillingspaar. Z. Kinderheilk 39:542, 1925. 9. Lechleutner, ??: Uber eine seltene systematisierte Dermatose. Inaug. Diss., Munich, 1925. 10. Carney, R. G.: Incontinentia pigmenti: A report of five cases and review of the literature. Arch. Dermatol. Syphilol. 64:126, 1951. 11. Oldfelt, V.: Incontinentia pigmenti. J. Pediatr. 54:446, 1959. 12. Lenz, W.: Zur Genetik der Incontinentia Pigmenti. Ann. Paediatr. 196:146, 1961. 13. Asboe-Hansen, G.: Bullous keratogenous and pigmentary dermatitis with blood eosinophilia in newborn girls: Report of four cases. Arch. Dermatol. Syphilol. 67:152, 1953. 14. Epstein, S., Vedder, J. S., and Pinkus, H.: Bullous variety of incontinentia pigmenti. (Bloch-Sulzberger). Arch. Dermatol. Syphilol. 65:557, 1952. 15. Schamburg-Lever, G., and Lever, W. F.: Electron microscopy of incontinenti pigmenti. Inv. Dermatol. 61:151, 1973. 16. Caputo, R., Gianotti, F., and Innocenti, M.: Ultrastructural findings in incontinentia pigmenti. Int. J. Dermatol. 14:46, 1975. 17. Kelly, T. E., Rary, J. M., and Young, L.: Incontinentia pigmenti: A chromosomal breakage syndrome. Heredit. 67:171, 1976. 18. McKusick, V. A.: Mendelian inheritance in man. Catalogs of autosomal dominant, recessive and X-linked phenotypes. Baltimore, Johns Hopkins University Press, 1976, p. 635. 19. Jelinek, J. E., Bart, R. S., and Schiff, G. W.: Hypomelanosis of Ito (Incontinentia pigmenti achromians) Arch. Dermatol. 107:596, 1973. 20. Haber, H.: The Bloch-Sulzberger syndrome (incontinentia pigmenti). Br. J. Dermatol. 64: 129, 1952. 21.
Palmgren, B.: The relationship of dermatitis herpetiformis to incontinentia pigmenti in in newborn infants. Pediatrics 29:295, 1962. 22. Werner, A.: Kongenitale dermatitis herpetiformis Duhring. Am. Paediatr. 182:176, 1964. 23. Findlay, G. H.: On the pathogenesis of incontinentia pigmenti with observations on an associated eye disturbance resembling retrolental fibroplasia. Br. J. Dermatol. 4:141, 1952.
