Arch. Derm. Forsch. 251, 277--280 (1975) © by Springer-Verlag 1975
Delayed Hypersensitivity in Xeroderma pigmentosum T. Salam0n, M. Stojakovi6, a n d B. Bogdanovi6 Department of Dermatology, Medical Faculty University of Sarajevo (Yugoslavia) l~eceived July 24, 1974
Summary. Two cases of typical Xeroderma pigmentosum are described in which the delayed hypersensitivity reaction was examined. In neither of them sensitization to DNCB in the standard way could be achieved. The possible significance of this observation is discussed. Zusammen/assung. :Bei zwei Patienten mit typischem Xeroderma pigmentosum wurde das Verhalten der allergischen Sp~treaktion nach DNCB-Sensibilisierung untersucht. Bei keinem der Patienten konnte durch Routinesensibilisierung eine Kontaktallergie gegenfiber D:NCB ausgel5st werden. Die Bedeutung dieser Beobachtung wird diskutiert. X e r o d e r m a p i g m e n t o s u m (X. p.) is a r a r e a u t o s o m a l recessive g e n o d e r m a t o s i s . T h e incidence of t h e disease has been e s t i m a t e d a t b e t w e e n 1:65 000 a n d 1:100 000 of t h e p o p u l a t i o n (Dorn). T h e m e a n f e a t u r e s of t h e disease are s e n s i t i v i t y of t h e skin to s u n l i g h t w i t h d e v e l o p m e n t of p i g m e n t a r y changes, a t r o p h y , k e r a t o s e s a n d v a r i o u s n e o p l a s m s of t h e skin (carcinoma, k e r a t o a c a n t h o m a , m e l a n o m a , sarcoma) a t a n e a r l y age of life. T h e onset w i t h freckle-like lesions in light e x p o s e d a r e a s of skin occurs in t h e first y e a r s of life. T h e c o n s a n g u i n i t y of p a r e n t s is frequent. A c c o r d i n g to P a t h a k a n d J. E p s t e i n a g e n e t i c a l l y i n h e r i t e d e n z y m e defect has been r e p o r t e d which m a y be responsible, a t l e a s t in p a r t , for t h e cancer forming p o t e n t i a l in p a t i e n t s w i t h X . p . R e c e n t l y we h a d in our d e p a r t m e n t t w o children, of consanguineous p a r e n t s , a b o y a n d his sister, w i t h X . p . (s. t h e p e d i g r e e Fig. i). A b o u t t h e s e cases we would like r e p o r t briefly. R e p o r t of Cases The parents as well as the youngest sister were without skin diseases. In the boy, Ne . . . . 7 years old, there were freckle-like lesions symmetricaly on the front, face, nose, chin, ears, neck and dorsa of the hands. Later, papillomatous keratotic growth on the nose, the cheek and chin developed, while on the underlip and the left underlid the growth were histologically found to be squamons carcinomas (s. Fig.2). In the girl, En..., 4 years old, freckle-like lesions with atrophy on the same parts of the skin as in her brother were seen. Later on keratoses but no tumors developed on the skin of the girl (s. Fig. 3). X-ray diagrams of the chest were normal in both children. :No neurological symptoms were present. EEG normal in both; they were mentally retarded (I. Q. 46 and 52 respectively). Ophthalmologically Degeneratio tapetoretinalis oc. utq. typus Best, Atrophia papillae f. optici oc. utq. incipiens, :Nystagmus horisontalis, Blepharo-conjunctivitis catarrh, oe. utq., were found in the boy as well as in his sister.
Laboratory investiffation8 in the patient8 The hemogram, ESR, urine, SGOT, SGPT, serum iron and copper, ketosteroids, lipidogram, chromatogram of urine (on 2 occasions) yielded normal results in the boy and the girl.
T. Salamon et al.
278
/ Fig. 1
Fig. 2
Fig. 3
Alpha-2 globulin and IgG were increased; I g E was present in the serum of the boy, b u t not present in t h a t of the girl. I n the stool of b o t h children ova of Ascaris lumbricoides were found. The karyograms of the patients were normal (lymphocytes). The results of examinations of the state of delayed hypersensitivity in these patients are shown in the Table 1. I t follows inter alia t h a t in these children sensitization to I)NCB, performed in the standard way, could not be elicited. The concentration of DNCB for sensitization was subsequently increased to 30/0. Toxic reaction developed on the skin after 48 hrs. Histologically, blister formation, epidermal necrosis and heavy cellular infiltration in the dermis were found. There-
279
Delayed Hypersensitivity in Xeroderma pigmentosum Table 1. Investigations of Cellular Immunity Name Sex Years DNCB
1 and Try- Strepto- Staphy3 units chococcus loeoccus Iapp. IIapp. IIIapp. IVapp. Vapp. PPD phytin vaccine vaccine
En... F
5
Z
Z
Z
~
~
~
~
+
Z
after the challenge with 0.1 and 0.750/0 DNCB provoked an crythematous lesion only in the less affected girl. Course The children were during the summer 1972 and 1973 isolated in a dark chamber. 5°/o 5-fiuorouracyl ointment was applied twice a day on the lesions of the face. The keratoses vanished, but the squamons carcinomas in the boy had to be removed surgically.
Discussion Obviously our cases are cases of X.p. The most interesting problem is the question of etio-pathogenesis of the neoplasms in this genetically determined disorder. Painter and Cleaver have demonstrated the existence of genetically determined biochemical mechanisms which specifically repair nucleoprotein damage. This mechanism appears to be defective in skin fibroblasts of patients with X.p. in contrast to the fibroblasts of normal subjects. The fibroblasts of patients with X.p. are unable to repair damage caused by sunlight (Cleaver). According to a hypothesis alterations in the structure of DNA b y sunlight or other natural hazards t h a t remain unrepaired, might render surviving cells malignant. But this hypothesis is not obvious because although in patients with the Ataxia-teleangiectasia syndrome cells are able to repair DNA damage, tumors still develop. On the other hand some malignant cells, as e.g. H e L a cells, are able to repair DNA damage. Since the majority of reactions of hypersensitivity of delayed type in our patients were negative, it is possible t h a t the tumors of the skin in one of them were at least partly conditioned by a genetically determined defect of the mechanism of delayed hypersensitivity. I f this hypothesis corresponds to reality, then the investigation of delayed hypersensitivity reactions to DNCB and other antigens in further patients with X . p . will substantiate it.
References 1. Cleaver, J. E. : Defective repair replication of DNA in Xeroderma pigmentosmn. :Nature (Lond.) 218, 652--656 (1968) 2. Dorn, H. : Quoted in A. Rook, D. Wilkinson and F. J. G. Ebling: Textbook of dermatology II. Ed. I. t. Oxford-Edinburgh: Blackwell 1969 3. Painter, R. B., Cleaver, J. E. : Repair replication in HeLa cells after large doses of Xirradiation. Nature (Lond.) 216, 369--370 (1967)
280
T. ~alamon et al.
4. Pathak, M.A., Epstein, J. It. : Normal and abnormal reactions of man to light. In: Th. B. Fitzpatrick: Dermatology in general medicine. :New York: McGraw Hill Inc. 1971 5. Reed, W. B., Landig, B., Sugarman, G., Cleaver, J. E., Melnyk, J. : Xerodcrma pigmentosum. Clinical and laboratory investigation of its basic defect. J. Amcr. reed. Ass. 207, 2073--2079 (1969) Prof. Dr. T. ~alamon Dept. of Dermatology Medical Faculty Univ. of Sarajevo Sarajevo Yugoslavia Note Added in Proo]. The number of blast cells in the TTL was in both patients significantly decreased, in the boy more than in the girl.
Delayed Hypersensitivity in Xeroderma pigmentosum T. Salam0n, M. Stojakovi6, a n d B. Bogdanovi6 Department of Dermatology, Medical Faculty University of Sarajevo (Yugoslavia) l~eceived July 24, 1974
Summary. Two cases of typical Xeroderma pigmentosum are described in which the delayed hypersensitivity reaction was examined. In neither of them sensitization to DNCB in the standard way could be achieved. The possible significance of this observation is discussed. Zusammen/assung. :Bei zwei Patienten mit typischem Xeroderma pigmentosum wurde das Verhalten der allergischen Sp~treaktion nach DNCB-Sensibilisierung untersucht. Bei keinem der Patienten konnte durch Routinesensibilisierung eine Kontaktallergie gegenfiber D:NCB ausgel5st werden. Die Bedeutung dieser Beobachtung wird diskutiert. X e r o d e r m a p i g m e n t o s u m (X. p.) is a r a r e a u t o s o m a l recessive g e n o d e r m a t o s i s . T h e incidence of t h e disease has been e s t i m a t e d a t b e t w e e n 1:65 000 a n d 1:100 000 of t h e p o p u l a t i o n (Dorn). T h e m e a n f e a t u r e s of t h e disease are s e n s i t i v i t y of t h e skin to s u n l i g h t w i t h d e v e l o p m e n t of p i g m e n t a r y changes, a t r o p h y , k e r a t o s e s a n d v a r i o u s n e o p l a s m s of t h e skin (carcinoma, k e r a t o a c a n t h o m a , m e l a n o m a , sarcoma) a t a n e a r l y age of life. T h e onset w i t h freckle-like lesions in light e x p o s e d a r e a s of skin occurs in t h e first y e a r s of life. T h e c o n s a n g u i n i t y of p a r e n t s is frequent. A c c o r d i n g to P a t h a k a n d J. E p s t e i n a g e n e t i c a l l y i n h e r i t e d e n z y m e defect has been r e p o r t e d which m a y be responsible, a t l e a s t in p a r t , for t h e cancer forming p o t e n t i a l in p a t i e n t s w i t h X . p . R e c e n t l y we h a d in our d e p a r t m e n t t w o children, of consanguineous p a r e n t s , a b o y a n d his sister, w i t h X . p . (s. t h e p e d i g r e e Fig. i). A b o u t t h e s e cases we would like r e p o r t briefly. R e p o r t of Cases The parents as well as the youngest sister were without skin diseases. In the boy, Ne . . . . 7 years old, there were freckle-like lesions symmetricaly on the front, face, nose, chin, ears, neck and dorsa of the hands. Later, papillomatous keratotic growth on the nose, the cheek and chin developed, while on the underlip and the left underlid the growth were histologically found to be squamons carcinomas (s. Fig.2). In the girl, En..., 4 years old, freckle-like lesions with atrophy on the same parts of the skin as in her brother were seen. Later on keratoses but no tumors developed on the skin of the girl (s. Fig. 3). X-ray diagrams of the chest were normal in both children. :No neurological symptoms were present. EEG normal in both; they were mentally retarded (I. Q. 46 and 52 respectively). Ophthalmologically Degeneratio tapetoretinalis oc. utq. typus Best, Atrophia papillae f. optici oc. utq. incipiens, :Nystagmus horisontalis, Blepharo-conjunctivitis catarrh, oe. utq., were found in the boy as well as in his sister.
Laboratory investiffation8 in the patient8 The hemogram, ESR, urine, SGOT, SGPT, serum iron and copper, ketosteroids, lipidogram, chromatogram of urine (on 2 occasions) yielded normal results in the boy and the girl.
T. Salamon et al.
278
/ Fig. 1
Fig. 2
Fig. 3
Alpha-2 globulin and IgG were increased; I g E was present in the serum of the boy, b u t not present in t h a t of the girl. I n the stool of b o t h children ova of Ascaris lumbricoides were found. The karyograms of the patients were normal (lymphocytes). The results of examinations of the state of delayed hypersensitivity in these patients are shown in the Table 1. I t follows inter alia t h a t in these children sensitization to I)NCB, performed in the standard way, could not be elicited. The concentration of DNCB for sensitization was subsequently increased to 30/0. Toxic reaction developed on the skin after 48 hrs. Histologically, blister formation, epidermal necrosis and heavy cellular infiltration in the dermis were found. There-
279
Delayed Hypersensitivity in Xeroderma pigmentosum Table 1. Investigations of Cellular Immunity Name Sex Years DNCB
1 and Try- Strepto- Staphy3 units chococcus loeoccus Iapp. IIapp. IIIapp. IVapp. Vapp. PPD phytin vaccine vaccine
En... F
5
Z
Z
Z
~
~
~
~
+
Z
after the challenge with 0.1 and 0.750/0 DNCB provoked an crythematous lesion only in the less affected girl. Course The children were during the summer 1972 and 1973 isolated in a dark chamber. 5°/o 5-fiuorouracyl ointment was applied twice a day on the lesions of the face. The keratoses vanished, but the squamons carcinomas in the boy had to be removed surgically.
Discussion Obviously our cases are cases of X.p. The most interesting problem is the question of etio-pathogenesis of the neoplasms in this genetically determined disorder. Painter and Cleaver have demonstrated the existence of genetically determined biochemical mechanisms which specifically repair nucleoprotein damage. This mechanism appears to be defective in skin fibroblasts of patients with X.p. in contrast to the fibroblasts of normal subjects. The fibroblasts of patients with X.p. are unable to repair damage caused by sunlight (Cleaver). According to a hypothesis alterations in the structure of DNA b y sunlight or other natural hazards t h a t remain unrepaired, might render surviving cells malignant. But this hypothesis is not obvious because although in patients with the Ataxia-teleangiectasia syndrome cells are able to repair DNA damage, tumors still develop. On the other hand some malignant cells, as e.g. H e L a cells, are able to repair DNA damage. Since the majority of reactions of hypersensitivity of delayed type in our patients were negative, it is possible t h a t the tumors of the skin in one of them were at least partly conditioned by a genetically determined defect of the mechanism of delayed hypersensitivity. I f this hypothesis corresponds to reality, then the investigation of delayed hypersensitivity reactions to DNCB and other antigens in further patients with X . p . will substantiate it.
References 1. Cleaver, J. E. : Defective repair replication of DNA in Xeroderma pigmentosmn. :Nature (Lond.) 218, 652--656 (1968) 2. Dorn, H. : Quoted in A. Rook, D. Wilkinson and F. J. G. Ebling: Textbook of dermatology II. Ed. I. t. Oxford-Edinburgh: Blackwell 1969 3. Painter, R. B., Cleaver, J. E. : Repair replication in HeLa cells after large doses of Xirradiation. Nature (Lond.) 216, 369--370 (1967)
280
T. ~alamon et al.
4. Pathak, M.A., Epstein, J. It. : Normal and abnormal reactions of man to light. In: Th. B. Fitzpatrick: Dermatology in general medicine. :New York: McGraw Hill Inc. 1971 5. Reed, W. B., Landig, B., Sugarman, G., Cleaver, J. E., Melnyk, J. : Xerodcrma pigmentosum. Clinical and laboratory investigation of its basic defect. J. Amcr. reed. Ass. 207, 2073--2079 (1969) Prof. Dr. T. ~alamon Dept. of Dermatology Medical Faculty Univ. of Sarajevo Sarajevo Yugoslavia Note Added in Proo]. The number of blast cells in the TTL was in both patients significantly decreased, in the boy more than in the girl.
