Pediatric Dennatology Vol. 7 No. 2 132-135
Combined Immunodeficiency Associated with Xeroderma Pigmentosum Brahm Goldstein, M.D.,* Praveen KhUnani, M.D.,* Allen Lapey, M.D.,t James E. Cleaver, Ph.D.,t and Arthur R. Rhodes, M.D.§ *Pediatric Intensive Care Unit, fPediatric Pulmonary Unit, and §Dermatology Service, Massachusetts General Hospital, Departments of Pediatrics and Dermatology, Harvard Medical School, Boston, Massachusetts; and tLaboratory of Radiobiology and Environmental Health, University of California, San Erancisco. California
A b s t r a c t : we report a 15-month-old boy with xeroderma pigmentosum, a history of repeated Infections, and immune deficiency who developed a fatal pneumonia with parainftuenza type 1. immunoiogic evaluation revealed a severe combined immunodeficiency with hypogiobulinemia, C3 deficiency, anergic response to sitin testing, and an abnormai iymphocytic response to mitogens. We suggest that patients with xeroderma pigmentosum be evaluated carefully for immune deficiencies, shouid repeated infections occur.
The immunologic status of patients with xeroderma pigmentosum (XP) is usually normal; however, a number of reports have described immune abnormalities in patients with XP (1-8). We report a boy with XP and immune deficiency who developed fatal viral pneumonia. His immunologic abnormalities, previously undescribed in the medical literature, included severe combined immunodeficiency with hypogiobulinemia, C3 deficiency, anergic response to skin testing, and an abnormal lymphocytic response to mitogens. Patients with XP should be evaluated carefully for immune deficiencies if they are afflicted with repeated infections.
This work was supported in part by the Office of Health and Environmental Research, U.S. Department of Energy, contract no. DE-AC03-76-SF0I012 Address correspondence to Brahm Goldstein, M.D.. Associate Director. Strong Children's Critical Care Center, Box 667, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642.
132
CASE REPORT
A 15-month-old white boy was admitted to our pediatric intensive care unit because of pneumonia and respiratory distress. He was a full-term infant, weighing 2.3 kg, who was born to a healthy, 19year-old, gravida 1, para 1. white female and a 21year-old white male. There was no family history of skin disorders or recurrent infections. At 4 months of age the patient developed a rotavirus gastroenteritis. At 6 months, after brief exposure to sunlight, he developed a sunburn reaction lasting three weeks. At 7 months, a similar sunburn reaction.
Goldstein et al: Xeroderma Pigmentosum and Immunodeficiency
with blisters lasting one week, recurred after a second sunlight exposure of 5 minutes' duration. Antinuclear antibody was negative. Results of urine porphyrin and amino acid studies were normal. Skin biopsies of sun-protected normal skin were obtained at age 10 months. Fibroblast cultures were developed and analyzed according to methods previously described for their sensitivity to ultraviolet (UV) light and their capacity for DNA repair (9,10) (Table 1). The patient's fibroblasts were clearly sensitive to UV light and were extremely repair deficient, consistent with the diagnosis of xeroderma pigmentosum. The patient had a history of repeated episodes of gastroenteritis between 8 and 15 months of age, with positive rotavirus test results on two separate occasions. At 10 months he was hospitalized for pneumonia secondary to parainfluenza virus (type unknown), which resolved with conservative treatment. Hypogammaglobulinemia and decreased serum C3 levels were noted at that time. At 12 months, an immunologic evaluation revealed decreased serum IgG and IgA ievels. Peripheral T cell studies revealed a normal helper:suppressor ratio, but depressed T cell function in response to concanavalin A (ConA), pokeweed mitogen (PWM), and phytohemagglutinin (PHA). Immanologic testing of both parents was normal, and there was no family history of recurrent bacterial or viral infections. The patient's behavior and development up to 15 months were normal. Neurologic examination one month prior to admission also was normal. On admission to the pediatric intensive care unit, the boy's temperature was 102.4T, pulse 145/ minute, and respirations 56/minute. Mild subcostal retractions were present, and diffuse rhonchi were heard throughout both lung fields. No rash or skin lesions were present. Chest radiograph revealed diffuse interstitial pneumonitis, most pronounced in
133
the lower lobes. Arterial partial pressure of oxygen was 62 mm Hg. The patient was given oxygen, 5 L/minute by face mask, with a resultant increase in oxygen saturation to 99%. Blood, urine, and nasopharyngeal cultures were obtained, and intravenous cefuroxime and erythromycin were begun empirically. Laboratory examination revealed a white blood cell count of 4800/mm^ (68% neutrophils, 22% lymphocytes, 10% monocytes). Hemoglobin and hematocrit were iO.l g/dl and 30.6%, respectively. Platelets were 300,000/mm^ Serum levels of IgG and IgA were below normal. Purified protein derivative and Candida skin testing were both nonreactive. Human immunodeficiency virus (HIV) antibody test by enzyme-linked immunosorbent assay was negative. Antitetanus antibody was present. Table 2 summarizes the child's immunologic and laboratory evaluations. By day 2 his condition worsened, and he required endotracheal intubation and mechanical ventilation. An open lung biopsy was performed on day 3. Frozen sections of the lung parenchyma were consistent with viral pneumonia and subsequently grew parainfiuenza type 1. Despite maximum ventilatory support (forced inspiration of oxygen 1.0, positive end-expiratory pressure 30 cm HjO), the patient died on day 9. Permission for autopsy was not granted. DISCUSSION
Xeroderma pigmentosum is a rare, autosomal recessive, progressive, and degenerative disease characterized by abnormal skin sensitivity to tiltraviolet irradiation (UVC or UVB) and the development of cutaneous malignancy early in life. These abnormalities are believed to be due to defective DNA repair after exposure to UV radiation (II).
TABLE 1. Toxicity and DNA Repair After Ultraviolet Radiation 37% Survival Dose (joules/m^) Ultraviolet light toxicity* Normal cells Patient Typical XP (groups A, C, D) DNA excision repairt Normal Patient
No. Repair Events per 2 X 10* Dalton
Relative to Normal (%)
9.0 0.0
100
20.2 0.8 0.8-5.0 0
Data from the Laboratory of Radiobiology and Environmental Health. University of California. San Francisco. * Amount of energy at 254 nm required to reduce cultured fibroblasts to 37% of their original number. 1" Number of repair events occurring in cultured fibroblasts during 6 hours immediately after 13 J/m^ UV light exposure (wavelength = 254 nm).
134
Pediatric Dennatology Vol. 7 No. 2 June 1990
TABLE 2. Immunologic History and Laboratory Results Age (mo)
Test
3 10
IgG (mg/dl) IgG C3 (mg/dl) IgG IgA IgM Lymphocyte subsets CD8
12
Result (normal value)*
315 218 62 202 13 46
CD4
15
CD3 CDla NK Bcell PHA (cpm) ConA (cpm) PWM (cpm) IgG IgA IgM Antitetanus antibody (U/ml) HIV antibody (ELISA) PPD and Candida skin test
(280-750) (300-1500) (70-160) (300-1500) (25-115) (16-100)
26% 52% 76% 4% 4% 17%
98,427 (239,710) 1166 (51,552) 4740 (51,552) 151 (40&-1300) 19 (32-120) 27 (20-130) 0.52 (>0.50) Negative Negative
* Normal values obtained from Immunology Laboratory. Children's Hospital, Boston, Massachusetts. HA = phytohemagglutimn;cpm = counts per minute; PPD = purified protein derivative; ConA = concanavafin A; PWM = pokeweed mitogen.
Extracutaneous manifestations of XP have been reported and include ectropion, comeal opacities, eye and tongue neoplasms, mental retardation, and abnormal motor activity (8). Exposure to UV radiation is strongly suspected to be the cause of the ocular and oral lesions. The neurologic abnormalities are associated with absence or decreased numbers of neurons, particularly in the cerebral cortex and cerebellum, but the specific pathophysiologic mechanisms are largely unexplained. Although immunologic function is usually normal in XP, a distinct proportion of patients have been reported with some form of immune alteration. Kraemer et al (8) described 35 (4%) of 830 patients as having immune abnormahties, but only 10(1.2%) of the 35 had frequent infections. Reported immunologic abnormalities include C8 deficiency, delayed rejection of skin grafts, abnormal immune response to contact sensitizers applied to sunexposed skin, and circulating lymphocyte inhibitory factors (1-^,8). We are aware of only one report ofa child who had agammaglobulinemia and abnormal T cell response to PHA (7). Although the etiology of the immunologie alterations in XP is unknown, it is hypothesized there is a relationship between UV irradiation and immunologic changes, and that these changes may also play a role in the development of UV-induced skin tumors (5). Our patient demonstrated severe combined immunodeficiency with hypogiobulinemia, decreased
C3 levels, anergic response to skin testing, and abnormal lymphoproliferative responses to PHA, ConA. and PWM. He had numerous viral infections of both the respiratory and gastrointestinal tracts. Parinfluenza type 1, an extremely uncommon cause of lower respiratory infection in the immunocompetent host (12), was identified as the causative agent in his pneumonitis, which resulted in respiratory failure and death. Immune deficiency seen in XP has been thought to be caused by genes linked to the XP gene. This was unlikely in our patient, as genes for immune deficiencies such as X-linked agammaglobuhnemia and X-linked severe combined immunodeficiency are located on the X chromosome, whereas the location of XP group A gene is on human chromosome 9 (13). It is interesting to speculate that other genes near the XP gene may help regulate immune function. Although chromosomal studies were not done in this patient, examination of other patients with XP with immune deficiencies for interstitial deletions near the XP locus may be useful. The diagnosis of XP should be considered in the differential diagnosis of patients who have immune abnormalities, particularly if they have a history of persistent sunburn to minimal exposure of sunhght or UV radiation. Patients with documented XP should be monitored closely for signs of infection and evaluated for both cellular and humoral immune deficiencies, should repeated viral or bacte-
Goldstein et al: Xerodenna Pigmentosum and Immunodeficiency
rial infections be evident. Early recognition of immune dysfunction might lead to reconstitution where possible.
6.
ACKNOWLEDGMENTS
7.
The authors acknowledge Debra Wood, Peggy Hamblin, Anthony A. Gaspari, M.D., Ph.D., and Gilbert Forbes, M.D., for their assistance in the preparation of this manuscript.
8.
REFERENCES
9.
1. Lafforet D, Dupuy JM. Inhibitory factors of lymphocyte proliferation in serum from patients with xeroderma pigmentosum. Clin Immunol Immunopathol 1977:8:377-384. 2. Dupuy JM, Lafforet D. A defect of cellular immunity in xeroderma pigmentosum. Clin Immunol Immunopathol 1974 ;3:52-58. 3. Berkel AI, Kiran O. Immunological studies in children with xeroderma pigmentosum. Turk J Pediatrics 1974;16:43-52. 4. Giraldo G, Degos L, Beth E. C8 deficiency in a family with xeroderma pigmentosum: lack of linkage to the HLA region. Clin Immunol Immunopathol 1977; 8:377-384. 5. Wysenbeek AJ, Weiss H. Immunologic alterations in
10.
11. 12.
13.
135
xerodenna pigmentosum patients. Cancer 1986;5: 219-221. Salamon T, Stojakovic M, Bogdanovic B. Delayed hypersensitivity in xerodenna pigmentosum. Arch Dermatol Forsch 1975;251:277-280. Wysenbeek AJ, Pick AL, Weiss H, Vana D, Atsmon A. Tumores rad et inusitati: impaired humoral and cellular immunity in xeroderma pigmentosum. Clin Oncol 1980;65:361-365. Kraemer H, Lee M, Scotto J. Xerodenna pigmentosum: cutaneous ocular, and neurologic abnormalities in 830 published cases. Arch Dermato! 1987;123:241250. Cleaver JE, Thomas GH. Rapid diagnosis of sensitivity to ultraviolet light in fibroblasts from dermatoiogical disorders, with particular reference to xeroderma pigmentosa. J Invest Dermatol 1988;90:467-471. Cleaver JE, Charles WC, Kong SH. Efficiency of repair of pyrimidine dimers and psoralen monoadducts in nonnal and xerodenna pigmentosum human cells. Photochem Photobiol 1984;40:621-629. Cleaver JE. Defective repair replication of DNA in xerodenna pigmentosum. Nature 1968;218:652-656. Glezen WP, Loda FA, Denny FW. Parainfluenza viruses. In: Evans AS, ed. Viral infections of humans, epidemiology and control. New York: Plenum, 1984: 448. Kauer GP, Athwal RF. Correction of repair defect in xeroderma pigmentosa group A cells by transfer of human chromosome 9. Am J Hum Genet i989;45: A200.
Combined Immunodeficiency Associated with Xeroderma Pigmentosum Brahm Goldstein, M.D.,* Praveen KhUnani, M.D.,* Allen Lapey, M.D.,t James E. Cleaver, Ph.D.,t and Arthur R. Rhodes, M.D.§ *Pediatric Intensive Care Unit, fPediatric Pulmonary Unit, and §Dermatology Service, Massachusetts General Hospital, Departments of Pediatrics and Dermatology, Harvard Medical School, Boston, Massachusetts; and tLaboratory of Radiobiology and Environmental Health, University of California, San Erancisco. California
A b s t r a c t : we report a 15-month-old boy with xeroderma pigmentosum, a history of repeated Infections, and immune deficiency who developed a fatal pneumonia with parainftuenza type 1. immunoiogic evaluation revealed a severe combined immunodeficiency with hypogiobulinemia, C3 deficiency, anergic response to sitin testing, and an abnormai iymphocytic response to mitogens. We suggest that patients with xeroderma pigmentosum be evaluated carefully for immune deficiencies, shouid repeated infections occur.
The immunologic status of patients with xeroderma pigmentosum (XP) is usually normal; however, a number of reports have described immune abnormalities in patients with XP (1-8). We report a boy with XP and immune deficiency who developed fatal viral pneumonia. His immunologic abnormalities, previously undescribed in the medical literature, included severe combined immunodeficiency with hypogiobulinemia, C3 deficiency, anergic response to skin testing, and an abnormal lymphocytic response to mitogens. Patients with XP should be evaluated carefully for immune deficiencies if they are afflicted with repeated infections.
This work was supported in part by the Office of Health and Environmental Research, U.S. Department of Energy, contract no. DE-AC03-76-SF0I012 Address correspondence to Brahm Goldstein, M.D.. Associate Director. Strong Children's Critical Care Center, Box 667, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642.
132
CASE REPORT
A 15-month-old white boy was admitted to our pediatric intensive care unit because of pneumonia and respiratory distress. He was a full-term infant, weighing 2.3 kg, who was born to a healthy, 19year-old, gravida 1, para 1. white female and a 21year-old white male. There was no family history of skin disorders or recurrent infections. At 4 months of age the patient developed a rotavirus gastroenteritis. At 6 months, after brief exposure to sunlight, he developed a sunburn reaction lasting three weeks. At 7 months, a similar sunburn reaction.
Goldstein et al: Xeroderma Pigmentosum and Immunodeficiency
with blisters lasting one week, recurred after a second sunlight exposure of 5 minutes' duration. Antinuclear antibody was negative. Results of urine porphyrin and amino acid studies were normal. Skin biopsies of sun-protected normal skin were obtained at age 10 months. Fibroblast cultures were developed and analyzed according to methods previously described for their sensitivity to ultraviolet (UV) light and their capacity for DNA repair (9,10) (Table 1). The patient's fibroblasts were clearly sensitive to UV light and were extremely repair deficient, consistent with the diagnosis of xeroderma pigmentosum. The patient had a history of repeated episodes of gastroenteritis between 8 and 15 months of age, with positive rotavirus test results on two separate occasions. At 10 months he was hospitalized for pneumonia secondary to parainfluenza virus (type unknown), which resolved with conservative treatment. Hypogammaglobulinemia and decreased serum C3 levels were noted at that time. At 12 months, an immunologic evaluation revealed decreased serum IgG and IgA ievels. Peripheral T cell studies revealed a normal helper:suppressor ratio, but depressed T cell function in response to concanavalin A (ConA), pokeweed mitogen (PWM), and phytohemagglutinin (PHA). Immanologic testing of both parents was normal, and there was no family history of recurrent bacterial or viral infections. The patient's behavior and development up to 15 months were normal. Neurologic examination one month prior to admission also was normal. On admission to the pediatric intensive care unit, the boy's temperature was 102.4T, pulse 145/ minute, and respirations 56/minute. Mild subcostal retractions were present, and diffuse rhonchi were heard throughout both lung fields. No rash or skin lesions were present. Chest radiograph revealed diffuse interstitial pneumonitis, most pronounced in
133
the lower lobes. Arterial partial pressure of oxygen was 62 mm Hg. The patient was given oxygen, 5 L/minute by face mask, with a resultant increase in oxygen saturation to 99%. Blood, urine, and nasopharyngeal cultures were obtained, and intravenous cefuroxime and erythromycin were begun empirically. Laboratory examination revealed a white blood cell count of 4800/mm^ (68% neutrophils, 22% lymphocytes, 10% monocytes). Hemoglobin and hematocrit were iO.l g/dl and 30.6%, respectively. Platelets were 300,000/mm^ Serum levels of IgG and IgA were below normal. Purified protein derivative and Candida skin testing were both nonreactive. Human immunodeficiency virus (HIV) antibody test by enzyme-linked immunosorbent assay was negative. Antitetanus antibody was present. Table 2 summarizes the child's immunologic and laboratory evaluations. By day 2 his condition worsened, and he required endotracheal intubation and mechanical ventilation. An open lung biopsy was performed on day 3. Frozen sections of the lung parenchyma were consistent with viral pneumonia and subsequently grew parainfiuenza type 1. Despite maximum ventilatory support (forced inspiration of oxygen 1.0, positive end-expiratory pressure 30 cm HjO), the patient died on day 9. Permission for autopsy was not granted. DISCUSSION
Xeroderma pigmentosum is a rare, autosomal recessive, progressive, and degenerative disease characterized by abnormal skin sensitivity to tiltraviolet irradiation (UVC or UVB) and the development of cutaneous malignancy early in life. These abnormalities are believed to be due to defective DNA repair after exposure to UV radiation (II).
TABLE 1. Toxicity and DNA Repair After Ultraviolet Radiation 37% Survival Dose (joules/m^) Ultraviolet light toxicity* Normal cells Patient Typical XP (groups A, C, D) DNA excision repairt Normal Patient
No. Repair Events per 2 X 10* Dalton
Relative to Normal (%)
9.0 0.0
100
20.2 0.8 0.8-5.0 0
Data from the Laboratory of Radiobiology and Environmental Health. University of California. San Francisco. * Amount of energy at 254 nm required to reduce cultured fibroblasts to 37% of their original number. 1" Number of repair events occurring in cultured fibroblasts during 6 hours immediately after 13 J/m^ UV light exposure (wavelength = 254 nm).
134
Pediatric Dennatology Vol. 7 No. 2 June 1990
TABLE 2. Immunologic History and Laboratory Results Age (mo)
Test
3 10
IgG (mg/dl) IgG C3 (mg/dl) IgG IgA IgM Lymphocyte subsets CD8
12
Result (normal value)*
315 218 62 202 13 46
CD4
15
CD3 CDla NK Bcell PHA (cpm) ConA (cpm) PWM (cpm) IgG IgA IgM Antitetanus antibody (U/ml) HIV antibody (ELISA) PPD and Candida skin test
(280-750) (300-1500) (70-160) (300-1500) (25-115) (16-100)
26% 52% 76% 4% 4% 17%
98,427 (239,710) 1166 (51,552) 4740 (51,552) 151 (40&-1300) 19 (32-120) 27 (20-130) 0.52 (>0.50) Negative Negative
* Normal values obtained from Immunology Laboratory. Children's Hospital, Boston, Massachusetts. HA = phytohemagglutimn;cpm = counts per minute; PPD = purified protein derivative; ConA = concanavafin A; PWM = pokeweed mitogen.
Extracutaneous manifestations of XP have been reported and include ectropion, comeal opacities, eye and tongue neoplasms, mental retardation, and abnormal motor activity (8). Exposure to UV radiation is strongly suspected to be the cause of the ocular and oral lesions. The neurologic abnormalities are associated with absence or decreased numbers of neurons, particularly in the cerebral cortex and cerebellum, but the specific pathophysiologic mechanisms are largely unexplained. Although immunologic function is usually normal in XP, a distinct proportion of patients have been reported with some form of immune alteration. Kraemer et al (8) described 35 (4%) of 830 patients as having immune abnormahties, but only 10(1.2%) of the 35 had frequent infections. Reported immunologic abnormalities include C8 deficiency, delayed rejection of skin grafts, abnormal immune response to contact sensitizers applied to sunexposed skin, and circulating lymphocyte inhibitory factors (1-^,8). We are aware of only one report ofa child who had agammaglobulinemia and abnormal T cell response to PHA (7). Although the etiology of the immunologie alterations in XP is unknown, it is hypothesized there is a relationship between UV irradiation and immunologic changes, and that these changes may also play a role in the development of UV-induced skin tumors (5). Our patient demonstrated severe combined immunodeficiency with hypogiobulinemia, decreased
C3 levels, anergic response to skin testing, and abnormal lymphoproliferative responses to PHA, ConA. and PWM. He had numerous viral infections of both the respiratory and gastrointestinal tracts. Parinfluenza type 1, an extremely uncommon cause of lower respiratory infection in the immunocompetent host (12), was identified as the causative agent in his pneumonitis, which resulted in respiratory failure and death. Immune deficiency seen in XP has been thought to be caused by genes linked to the XP gene. This was unlikely in our patient, as genes for immune deficiencies such as X-linked agammaglobuhnemia and X-linked severe combined immunodeficiency are located on the X chromosome, whereas the location of XP group A gene is on human chromosome 9 (13). It is interesting to speculate that other genes near the XP gene may help regulate immune function. Although chromosomal studies were not done in this patient, examination of other patients with XP with immune deficiencies for interstitial deletions near the XP locus may be useful. The diagnosis of XP should be considered in the differential diagnosis of patients who have immune abnormalities, particularly if they have a history of persistent sunburn to minimal exposure of sunhght or UV radiation. Patients with documented XP should be monitored closely for signs of infection and evaluated for both cellular and humoral immune deficiencies, should repeated viral or bacte-
Goldstein et al: Xerodenna Pigmentosum and Immunodeficiency
rial infections be evident. Early recognition of immune dysfunction might lead to reconstitution where possible.
6.
ACKNOWLEDGMENTS
7.
The authors acknowledge Debra Wood, Peggy Hamblin, Anthony A. Gaspari, M.D., Ph.D., and Gilbert Forbes, M.D., for their assistance in the preparation of this manuscript.
8.
REFERENCES
9.
1. Lafforet D, Dupuy JM. Inhibitory factors of lymphocyte proliferation in serum from patients with xeroderma pigmentosum. Clin Immunol Immunopathol 1977:8:377-384. 2. Dupuy JM, Lafforet D. A defect of cellular immunity in xeroderma pigmentosum. Clin Immunol Immunopathol 1974 ;3:52-58. 3. Berkel AI, Kiran O. Immunological studies in children with xeroderma pigmentosum. Turk J Pediatrics 1974;16:43-52. 4. Giraldo G, Degos L, Beth E. C8 deficiency in a family with xeroderma pigmentosum: lack of linkage to the HLA region. Clin Immunol Immunopathol 1977; 8:377-384. 5. Wysenbeek AJ, Weiss H. Immunologic alterations in
10.
11. 12.
13.
135
xerodenna pigmentosum patients. Cancer 1986;5: 219-221. Salamon T, Stojakovic M, Bogdanovic B. Delayed hypersensitivity in xerodenna pigmentosum. Arch Dermatol Forsch 1975;251:277-280. Wysenbeek AJ, Pick AL, Weiss H, Vana D, Atsmon A. Tumores rad et inusitati: impaired humoral and cellular immunity in xeroderma pigmentosum. Clin Oncol 1980;65:361-365. Kraemer H, Lee M, Scotto J. Xerodenna pigmentosum: cutaneous ocular, and neurologic abnormalities in 830 published cases. Arch Dermato! 1987;123:241250. Cleaver JE, Thomas GH. Rapid diagnosis of sensitivity to ultraviolet light in fibroblasts from dermatoiogical disorders, with particular reference to xeroderma pigmentosa. J Invest Dermatol 1988;90:467-471. Cleaver JE, Charles WC, Kong SH. Efficiency of repair of pyrimidine dimers and psoralen monoadducts in nonnal and xerodenna pigmentosum human cells. Photochem Photobiol 1984;40:621-629. Cleaver JE. Defective repair replication of DNA in xerodenna pigmentosum. Nature 1968;218:652-656. Glezen WP, Loda FA, Denny FW. Parainfluenza viruses. In: Evans AS, ed. Viral infections of humans, epidemiology and control. New York: Plenum, 1984: 448. Kauer GP, Athwal RF. Correction of repair defect in xeroderma pigmentosa group A cells by transfer of human chromosome 9. Am J Hum Genet i989;45: A200.
