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Aniridia, Cataracts, and wilms' Tumor in Monozygous Twins
ANIRIDIA, CATARACTS, AND W I L M S ' T U M O R IN MONOZYGOUS TWINS E D W A R D C O T L I E R , M.D., M A R C R O S E , A N D S T E V E N A. M O E L
Chicago, Illinois The association of Wilms' tumor and aniridia in h u m a n s demonstrates a link between the inherited and mutagenic ef fects of genes and their expression 1 - 5 and represents a joint manifestation of cancer and a congenital structural tissue defect. According to Knudson, 6 the expression of the Wilms' tumor gene may result from two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells, and the other, in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. 6 Knudson 7 has developed a similar theory to explain inherited and nonherited forms of retinoblastoma. T h e genetic basis for the development of Wilms' tumor is firm ly supported by its familial nature, 8 " 1 4 and by its occurrence in monozygous t w i n s . 1 5 - 1 8 The explanation for the genet ic mutation in the Wilms' tumor-aniridia syndrome appears more complex. In one patient with the syndrome, a chromosmal translocation was found, 1 9 but such an occurence has not been reported in fami lies. We describe a heretofore unreported genetic curiosity in identical twins, both of whom have bilateral aniridia and cata racts, but only one of whom has Wilms' tumor.
several episodes of vaginal bleeding. Calcium and iron medications were prescribed during the last months of the pregnancy. Labor was difficult and lasted four hours, and delivery occurred under gen eral anesthesia. The twins had three brothers: two, aged 15 and 14 years, respectively, without phenotypic abnormali ties; and one who had had multiple congenital malformations including cleft palate, syndactyly, and psychomotor retardation, and who had died of pneumonia at the age of 4 years. Neither side of the family had a history of consanguineous marriage, mental retardation, or neurologic disease. A mater nal uncle had had congenital cataracts in both eyes, and each side of the family had a history of diabetes mellitus. The family pedigree appears in Figure 1. Case 1—At birth, the younger twin (Fig. 2, left) weighed 2,353 g. Shortly thereafter, aniridia and cataracts were detected in her. When she was 5 months old, an examination under anesthesia re vealed bilateral increased intraocular pressure, which was treated with pilocarpine 4% drops to both eyes three times a day. When the child was 3 years old, the mother noted a lump on the left side of the child's abdomen. An intravenous pyelogram revealed a large mass in the left kidney and delayed excretion of dye with distorted calyces. An explora tory laparotomy revealed on the left side a Wilm's tumor, which was removed. Thirteen months later, a contralateral Wilms' tumor was found, and a right heminephrectomy was performed. After each resec tion, radiotherapy was given, supplemented with actinomycin D therapy (15 mg/kg of body weight) to the retroperitoneal area. The second course of radia-
ti
I
CASE REPORT
Twin girls were born after a full-term pregnancy to a 32-year-old mother and a 39-year-old father, both of whom were phenotypically normal. Fetal movements were felt at 4x/2 months of pregnancy. The mother gained 42 pounds during gestation. She had no fever, viral infection, or exposure to teratogenic chemicals during pregnancy, but she did have
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III
From the University of Illinois Eye and Ear Infirmary, Chicago, Illinois. Reprint requests to Edward Cotlier, M.D., Depart ment of Ophthalmology and Visual Science, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510.
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Wilms' Tumor Dead, Multiple Congenital Anomalies
Fig. 1 (Cotlier, Rose, and Moel). Pedigree of family with aniridia and Wilms' tumor in identical twins.
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Fig. 2 (Cotlier, Rose, and Moel). Left, Case 1. The younger twin with aniridia and Wilms' tumor. Right, Case 2. The older twin with aniridia but clinically free of Wilms' tumor.
tion was interrupted when the child developed right lower lobe pneumonitis, urinary tract infection, and persistent fever, all of which responded well to antibiotic therapy. Radiotherapy was then resumed and the course completed. At age 6 months, the child could turn in her bed, and by 1 year, she was able to crawl, albeit awk wardly. At 15 months, when she showed no initia tive in pulling herself up to walk, a diagnosis of developmental retardation was made. At age 2 years, she was able to sit unsupported and could eat table food with her hands. However, she would not play, socialize, or react at peer level. By age 3, she was able to pull herself up, stand, and take one or two steps with support. She did not speak, but made some sounds and apparently understood a few ver bal commands. She often ground her teeth. The parents noted that the child's eyes moved about in a random, searching way with rotary, jerking move ments. At age 7 years, severe psychomotor retarda tion was diagnosed. Complete blood cell count, urinalysis, urinary mucopolysaccharide test, amino acids in urine, and Giemsa-banded karyotype (46 XX) were normal. Electroencephalograms revealed an abnormal delta rhythm with diffuse abnormal spikes suggesting cortical and subcortical structural brain damage. Zygosity was determined by blood-group analysis (ABO, P, Rh, Kelly, Lewis, MNS, Lutheran, Duff) and three serum factors (haptoglobin, transferrin, Gm), and the twins were found to be monozygotic. Several eye examinations under anesthesia when the child was between 4 and 7 years of age revealed bilateral aniridia, bilateral anterior and posterior polar cataracts, bilateral myopia of - 6 . 0 0 , alternat ing exotropia of 30 prism diopters, searching ny stagmus, and glaucoma (Fig. 3). Electroretinograms were normal bilaterally, and gonioscopy re vealed small rudimentary iris nubs in both anterior chamber angles. An examination in April 1973 re vealed intraocular pressure of 29 and 51 mm Hg in the right and left eyes, respectively, with C-values of 0.10 on the right and 0.01 on the left. The cup:disk ratio was 0.5 on the right eye, and 0.7 on the left. Administration of pilocarpine 4% drops four times a day and epinephrine 2% drops twice a day decreased the intraocular pressure to 16 mm Hg in the right eye and 22 mm Hg in the left eye. Case 2—In the older twin (Fig. 2, right), a diagno sis of congenital aniridia, cortical cataracts, and glaucoma was made shortly after birth. At age 3 years, the child had marked psychomotor retarda
tion with wandering eye movements and body rock ing. The anteroposterior diameter of the head was shortened. The child was hyperactive and able to walk stiffly for two to three steps. She had uniformly depressed deep tendon reflexes and no superficial abdominal reflexes. Laboratory tests including complete blood cell count and urinalysis were negative. Giemsabanding karyotype was normal (46 XX). No evidence of Wilms' tumor was found, although depression and rotation of the left kidney was noted on the intravenous pyelogram. Repeated intravenous pyelograms during a four-year period failed to reveal any tumoral kidney growth. Several eye examinations when the child was between 3 and 7 years of age revealed aniridia, bilateral polar cataracts, and 20 degrees exotropia in the primary gaze (Fig. 2, right). Examination under anesthesia in 1973 revealed intraocular pressure of 30 mm Hg in the right eye and 50 mm Hg in the left. Tonography gave a C-value of 0.07 for the right eye and 0.03 for the left eye. Retinoscopy revealed —5.00 diopter of bilateral myopia. The electroretinogram was within normal limits. The retina showed slight bilateral peripheral pigment mottling. Gonioscopy
Fig. 3 (Cotlier, Rose, and Moel). Case 1. Aniridia and cortical cataracts.
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revealed small rudimentary iris nubs bilaterally. The patient received pilocarpine 4% drops, four times a day and epinephrine 1% drops twice a day, with subsequent reduction of intraocular pressure to 18 mm Hg in the right eye and 22 mm Hg in the left eye. DISCUSSION
Wilms' tumor (nephroblastoma) is the second most common neoplasm among children. Thirty-eight percent of the cases are inherited, 6 and the remaining 62% occur at random. The inherited form oc curs earlier and is much more frequently bilateral. 6 The median age at diagnosis for the noninherited Wilms' tumor is 3 to 4 years, whereas the hereditary form man ifests itself at approximately 2 years of age. 6 Bilateral tumors are found in 5 to 10% of the total cases, but in 2 1 % of the hereditary form. 6 Knudson 6 has therefore suggested a single-event prezygotic, zygotic, or immediately postzygotic muta tion for the hereditary form of Wilms' tumor and a double mutation (zygotic and somatic cells) for the nonhereditary forms of the tumor. Knudson 7 previously pro posed a similar concept regarding the inherited and noninherited forms of retinoblastoma. Maslow 8 was the first to re port Wilms' tumor in three of four sib lings. Other instances of Wilms' tumor in siblings were documented by Mackay, 9 Chapian, 1 0 and Collins. 1 1 In 1955, Fitz gerald reported Wilms' tumor in a father and in two of his three daughters, 1 2 and, subsequently, Brown, Puranik, Altman, and Hardin 1 3 found a Wilms' tumor in a 6-month-old child of the surviving daughter. Other cases of Wilms' tumor reported in families and in successive generations have been tabulated by Juberg, Martin, and Hundley. 1 4 Six in stances of this neoplasm in twins have been reported, 1 , 1 4 - 1 8 but except for one case of identical twins, the status of zygosity in the others remains uncertain. Although the occurrence of this tumor in siblings and in twins represents over whelming evidence for genetic muta tions, the case of Juberg, Martin, and
131
Hundley 1 4 in which the tumor was clini cally present in only one of identical twins provides support for an environ mental mutation. The association of aniridia and Wilms' tumor was first uncovered by the review of 440 cases of the tumor by Miller, Fraumeni, and Manning. 1 They found an incidence of six aniridics among their pa tients with Wilms' tumor, or 1:73, which is markedly greater than the 1:50,000 incidence of aniridia among the gen eral population. 2 0 Patients with Wilms' tumor alone, and with Wilms' tumor and aniridia have a higher incidence of men tal retardation, hypospadias and undescended testes, and hemihypertrophy than the population of the same general a g e 1,4,21 T } l u S j i n 1964, Miller, Fraumeni, and Manning 1 questioned whether the aniridia and Wilms' tumor syndrome is genetically determined, whether the tumor results from a concurrent mutation of a different gene, or whether the aniridia gene enhances the expression of the Wilms' tumor gene. Reviewing previous studies in 1975, Piling 5 revealed 35 cases of Wilms' tumor with aniridia, but only one of them in families and none in twins. Fraumeni and Glass 2 found Wilms' tumor with associated congenital aniridia in seven of 28 children under age 4 years. Of these cases, the Wilms' tumor was present in one child on admission to the hospital, and it developed later in the six other children. When combined with the series of Miller, Fraumeni, and Manning, 1 a total of 35 infants, the Wilms' tumor de veloped in one third of the infants with congenital sporadic aniridia. 5 Only one case of Wilms' tumor in a child with familial aniridia has ever been reported. Expression of a dominant gene in two siblings, but with unaffected parents, oc curs in gonadal mosaicism. In gonadal mosaicism, the frequency of gene expres sion depends on the degree of gonadal involvement. However, the twins in our study were identical, and a " p u r e " gonad-
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al mutation would not apply to the ex pression of the Wilms' tumor gene. Juberg, Martin, and Hundley 1 4 found Wilms' tumor in one of the monozygous twins and in one other sibling. Aniridia was absent in all of these cases. Juberg, Martin, and Hundley 1 4 believed this pattern of gene expression supported the environmental theory of Wilms' tumor. In our patients, we must consider the likelihood of a combined gonadal-somatic cell mutation in the younger twin and a gonadal mutation in the older twin. A gonadal somatic mutation probably oc curred in a Wilms' tumor allele and a pure gonadal mosaicism affected the aniridia allele. A two-allele gonadal and a somatic mutation could explain the manifestation of Wilms' tumor in only one twin. A more remote possibility would in volve a single-locus, three-allele muta tion, which for the manifestation of Wilms' tumor requires an additional so matic mutation. Lada, Atkins, and Littlefield 19 found a chromosomal translocation t (8 pt; llq—) in a patient with both aniridia and Wilms' tumor. Computer analysis of the chromosomes was re quired because they appeared balanced by standard techniques including band ing. Our patients' karyotypes were normal by Giemsa banding, but may have ap peared abnormal by computer analysis of the chromosomes. SUMMARY
We studied the first instance of aniridia-Wilms' tumor syndrome in twins who were mentally retarded. Both of them had congenital aniridia, cataracts, and glaucoma; only one subsequently de veloped a Wilms' tumor. A two-allele, two-step mutation is the most likely ex planation of this genetically abnormal syndrome in twins. The aniridia-Wilms' tumor syndrome in twins further docu ments the relationship of teratogenic mal formations and neoplasias.
JULY, 1978
REFERENCES 1. Miller, R. W., Fraumeni, J. F., and Manning, M. D,: Association of Wilms' tumor with aniridia, hemihypertrophy and other congenital malforma tions. N. Engl. J. Med. 170:922, 1964. 2. Fraumeni, J. F., Jr., and Glass, A. G.: Wilms' tumor and congenital aniridia. J.A.M.A., 206:825, 1968. 3. Flanagan, J. C , and DiGeorge, A. M.: Sporadic aniridia and Wilms' tumor. Am. J. Ophthalmol. 67:558, 1969. 4. Haicken, B. N., and Miller, D. R.: Simultane ous occurrence of congenital aniridia, hamartoma and Wilms' tumor. J. Pediatr. 78:497, 1971. 5. Piling, G. P., IV: Wilms' tumor in seven chil dren with congenital aniridia. J. Pediatr. Surg. 10: 87, 1975. 6. Knudson, A. G., Jr., and Strong, L. C : Muta tion and Wilms' tumor. J. Natl. Cancer Inst. 48:313, 1972. 7. Knudson, A. G., Jr.: Mutation and cancer. Sta tistical study of retinoblastoma. Proc. Natl. Acad. Sci. U.S.A. 68:820, 1971. 8. Maslow, L. A.: Wilms' tumor. Report of three cases and a possible fourth one in the same family. J. Urol. 43:75, 1940. 9. Mackay, H.: Congenital bilateral megaloureters with hydronephrosis. A remarkable family history. Proc. R. Soc. Med. 38:567, 1945. 10. Chapian, M. A.: Wilms' tumor. Report of two cases in the same family. R.I. Med. J. 31:105, 1948. 11. Collins, V. P.: Wilms' tumor. Its behavior and prognosis. J. La. State Med. Soc. 107:474, 1955. 12. Fitzgerald, W. L., and Hardin, H. C , Jr.: Bilateral Wilms' tumor in a Wilms' tumor family. Case report. J. Urol. 73:468, 1955. 13. Brown, W. R., Puranik, S. R., Altman, D. H., and Hardin, H. C , Jr.: Wilms' tumor in three succes sive generations. Surgery 72:756, 1972. 14. Juberg, R. C , Martin, E. C , and Hundley, J. L.: Familial occurrence of Wilms' tumor. Nephroblastoma in one of monozygous twins and in another sibling. Am. J. Hum. Genet. 27:155, 1975. 15. Gaulin, E.: Simultaneous Wilms' tumor in identical twins. J. Urol. 66:547, 1951. 16. Hewitt, D., Lashof, J. C , and Stewart, A. M.: Childhood cancer in twins. Cancer 19:157, 1966. 17. Murphy, M. L.: Curability of cancer in chil dren. Cancer 22:779, 1968. 18. Ledlie, E. M., Mynors, L. S., Draper, G. J., and Gorbach, P. D.: Natural history and treatment of Wilms's tumor. An analysis of 335 cases occurring in England and Wales, 1962-1966. Br. Med. J. 4:195, 1970. 19. Lada, R., Atkins, L., and Littlefield, J.: Computer-assisted analysis of chromosomal abnor malities. Detection of a deletion in aniridia/Wilms' tumor syndrome. Science 185:785, 1974. 20. Shaw, M. W., Falls, H. F., and Neel, J. V.: Congenital aniridia. Am. J. Hum. Genet. 12:389, 1960. 21. Pendergrass, T. W.: Congenital anomalies in children with Wilms' tumor. Cancer 37:403, 1976.
Chicago, Illinois The association of Wilms' tumor and aniridia in h u m a n s demonstrates a link between the inherited and mutagenic ef fects of genes and their expression 1 - 5 and represents a joint manifestation of cancer and a congenital structural tissue defect. According to Knudson, 6 the expression of the Wilms' tumor gene may result from two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells, and the other, in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. 6 Knudson 7 has developed a similar theory to explain inherited and nonherited forms of retinoblastoma. T h e genetic basis for the development of Wilms' tumor is firm ly supported by its familial nature, 8 " 1 4 and by its occurrence in monozygous t w i n s . 1 5 - 1 8 The explanation for the genet ic mutation in the Wilms' tumor-aniridia syndrome appears more complex. In one patient with the syndrome, a chromosmal translocation was found, 1 9 but such an occurence has not been reported in fami lies. We describe a heretofore unreported genetic curiosity in identical twins, both of whom have bilateral aniridia and cata racts, but only one of whom has Wilms' tumor.
several episodes of vaginal bleeding. Calcium and iron medications were prescribed during the last months of the pregnancy. Labor was difficult and lasted four hours, and delivery occurred under gen eral anesthesia. The twins had three brothers: two, aged 15 and 14 years, respectively, without phenotypic abnormali ties; and one who had had multiple congenital malformations including cleft palate, syndactyly, and psychomotor retardation, and who had died of pneumonia at the age of 4 years. Neither side of the family had a history of consanguineous marriage, mental retardation, or neurologic disease. A mater nal uncle had had congenital cataracts in both eyes, and each side of the family had a history of diabetes mellitus. The family pedigree appears in Figure 1. Case 1—At birth, the younger twin (Fig. 2, left) weighed 2,353 g. Shortly thereafter, aniridia and cataracts were detected in her. When she was 5 months old, an examination under anesthesia re vealed bilateral increased intraocular pressure, which was treated with pilocarpine 4% drops to both eyes three times a day. When the child was 3 years old, the mother noted a lump on the left side of the child's abdomen. An intravenous pyelogram revealed a large mass in the left kidney and delayed excretion of dye with distorted calyces. An explora tory laparotomy revealed on the left side a Wilm's tumor, which was removed. Thirteen months later, a contralateral Wilms' tumor was found, and a right heminephrectomy was performed. After each resec tion, radiotherapy was given, supplemented with actinomycin D therapy (15 mg/kg of body weight) to the retroperitoneal area. The second course of radia-
ti
I
CASE REPORT
Twin girls were born after a full-term pregnancy to a 32-year-old mother and a 39-year-old father, both of whom were phenotypically normal. Fetal movements were felt at 4x/2 months of pregnancy. The mother gained 42 pounds during gestation. She had no fever, viral infection, or exposure to teratogenic chemicals during pregnancy, but she did have
ll
III
From the University of Illinois Eye and Ear Infirmary, Chicago, Illinois. Reprint requests to Edward Cotlier, M.D., Depart ment of Ophthalmology and Visual Science, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510.
o
121
□ ^-b
□
*
•: Aniridia
/
Congenital
-o
X
■
Wilms' Tumor Dead, Multiple Congenital Anomalies
Fig. 1 (Cotlier, Rose, and Moel). Pedigree of family with aniridia and Wilms' tumor in identical twins.
AMERICAN JOURNAL OF OPHTHALMOLOGY 86:129-132, 1978
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Fig. 2 (Cotlier, Rose, and Moel). Left, Case 1. The younger twin with aniridia and Wilms' tumor. Right, Case 2. The older twin with aniridia but clinically free of Wilms' tumor.
tion was interrupted when the child developed right lower lobe pneumonitis, urinary tract infection, and persistent fever, all of which responded well to antibiotic therapy. Radiotherapy was then resumed and the course completed. At age 6 months, the child could turn in her bed, and by 1 year, she was able to crawl, albeit awk wardly. At 15 months, when she showed no initia tive in pulling herself up to walk, a diagnosis of developmental retardation was made. At age 2 years, she was able to sit unsupported and could eat table food with her hands. However, she would not play, socialize, or react at peer level. By age 3, she was able to pull herself up, stand, and take one or two steps with support. She did not speak, but made some sounds and apparently understood a few ver bal commands. She often ground her teeth. The parents noted that the child's eyes moved about in a random, searching way with rotary, jerking move ments. At age 7 years, severe psychomotor retarda tion was diagnosed. Complete blood cell count, urinalysis, urinary mucopolysaccharide test, amino acids in urine, and Giemsa-banded karyotype (46 XX) were normal. Electroencephalograms revealed an abnormal delta rhythm with diffuse abnormal spikes suggesting cortical and subcortical structural brain damage. Zygosity was determined by blood-group analysis (ABO, P, Rh, Kelly, Lewis, MNS, Lutheran, Duff) and three serum factors (haptoglobin, transferrin, Gm), and the twins were found to be monozygotic. Several eye examinations under anesthesia when the child was between 4 and 7 years of age revealed bilateral aniridia, bilateral anterior and posterior polar cataracts, bilateral myopia of - 6 . 0 0 , alternat ing exotropia of 30 prism diopters, searching ny stagmus, and glaucoma (Fig. 3). Electroretinograms were normal bilaterally, and gonioscopy re vealed small rudimentary iris nubs in both anterior chamber angles. An examination in April 1973 re vealed intraocular pressure of 29 and 51 mm Hg in the right and left eyes, respectively, with C-values of 0.10 on the right and 0.01 on the left. The cup:disk ratio was 0.5 on the right eye, and 0.7 on the left. Administration of pilocarpine 4% drops four times a day and epinephrine 2% drops twice a day decreased the intraocular pressure to 16 mm Hg in the right eye and 22 mm Hg in the left eye. Case 2—In the older twin (Fig. 2, right), a diagno sis of congenital aniridia, cortical cataracts, and glaucoma was made shortly after birth. At age 3 years, the child had marked psychomotor retarda
tion with wandering eye movements and body rock ing. The anteroposterior diameter of the head was shortened. The child was hyperactive and able to walk stiffly for two to three steps. She had uniformly depressed deep tendon reflexes and no superficial abdominal reflexes. Laboratory tests including complete blood cell count and urinalysis were negative. Giemsabanding karyotype was normal (46 XX). No evidence of Wilms' tumor was found, although depression and rotation of the left kidney was noted on the intravenous pyelogram. Repeated intravenous pyelograms during a four-year period failed to reveal any tumoral kidney growth. Several eye examinations when the child was between 3 and 7 years of age revealed aniridia, bilateral polar cataracts, and 20 degrees exotropia in the primary gaze (Fig. 2, right). Examination under anesthesia in 1973 revealed intraocular pressure of 30 mm Hg in the right eye and 50 mm Hg in the left. Tonography gave a C-value of 0.07 for the right eye and 0.03 for the left eye. Retinoscopy revealed —5.00 diopter of bilateral myopia. The electroretinogram was within normal limits. The retina showed slight bilateral peripheral pigment mottling. Gonioscopy
Fig. 3 (Cotlier, Rose, and Moel). Case 1. Aniridia and cortical cataracts.
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ANIRIDIA, CATARACTS AND WILMS' TUMOR
revealed small rudimentary iris nubs bilaterally. The patient received pilocarpine 4% drops, four times a day and epinephrine 1% drops twice a day, with subsequent reduction of intraocular pressure to 18 mm Hg in the right eye and 22 mm Hg in the left eye. DISCUSSION
Wilms' tumor (nephroblastoma) is the second most common neoplasm among children. Thirty-eight percent of the cases are inherited, 6 and the remaining 62% occur at random. The inherited form oc curs earlier and is much more frequently bilateral. 6 The median age at diagnosis for the noninherited Wilms' tumor is 3 to 4 years, whereas the hereditary form man ifests itself at approximately 2 years of age. 6 Bilateral tumors are found in 5 to 10% of the total cases, but in 2 1 % of the hereditary form. 6 Knudson 6 has therefore suggested a single-event prezygotic, zygotic, or immediately postzygotic muta tion for the hereditary form of Wilms' tumor and a double mutation (zygotic and somatic cells) for the nonhereditary forms of the tumor. Knudson 7 previously pro posed a similar concept regarding the inherited and noninherited forms of retinoblastoma. Maslow 8 was the first to re port Wilms' tumor in three of four sib lings. Other instances of Wilms' tumor in siblings were documented by Mackay, 9 Chapian, 1 0 and Collins. 1 1 In 1955, Fitz gerald reported Wilms' tumor in a father and in two of his three daughters, 1 2 and, subsequently, Brown, Puranik, Altman, and Hardin 1 3 found a Wilms' tumor in a 6-month-old child of the surviving daughter. Other cases of Wilms' tumor reported in families and in successive generations have been tabulated by Juberg, Martin, and Hundley. 1 4 Six in stances of this neoplasm in twins have been reported, 1 , 1 4 - 1 8 but except for one case of identical twins, the status of zygosity in the others remains uncertain. Although the occurrence of this tumor in siblings and in twins represents over whelming evidence for genetic muta tions, the case of Juberg, Martin, and
131
Hundley 1 4 in which the tumor was clini cally present in only one of identical twins provides support for an environ mental mutation. The association of aniridia and Wilms' tumor was first uncovered by the review of 440 cases of the tumor by Miller, Fraumeni, and Manning. 1 They found an incidence of six aniridics among their pa tients with Wilms' tumor, or 1:73, which is markedly greater than the 1:50,000 incidence of aniridia among the gen eral population. 2 0 Patients with Wilms' tumor alone, and with Wilms' tumor and aniridia have a higher incidence of men tal retardation, hypospadias and undescended testes, and hemihypertrophy than the population of the same general a g e 1,4,21 T } l u S j i n 1964, Miller, Fraumeni, and Manning 1 questioned whether the aniridia and Wilms' tumor syndrome is genetically determined, whether the tumor results from a concurrent mutation of a different gene, or whether the aniridia gene enhances the expression of the Wilms' tumor gene. Reviewing previous studies in 1975, Piling 5 revealed 35 cases of Wilms' tumor with aniridia, but only one of them in families and none in twins. Fraumeni and Glass 2 found Wilms' tumor with associated congenital aniridia in seven of 28 children under age 4 years. Of these cases, the Wilms' tumor was present in one child on admission to the hospital, and it developed later in the six other children. When combined with the series of Miller, Fraumeni, and Manning, 1 a total of 35 infants, the Wilms' tumor de veloped in one third of the infants with congenital sporadic aniridia. 5 Only one case of Wilms' tumor in a child with familial aniridia has ever been reported. Expression of a dominant gene in two siblings, but with unaffected parents, oc curs in gonadal mosaicism. In gonadal mosaicism, the frequency of gene expres sion depends on the degree of gonadal involvement. However, the twins in our study were identical, and a " p u r e " gonad-
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al mutation would not apply to the ex pression of the Wilms' tumor gene. Juberg, Martin, and Hundley 1 4 found Wilms' tumor in one of the monozygous twins and in one other sibling. Aniridia was absent in all of these cases. Juberg, Martin, and Hundley 1 4 believed this pattern of gene expression supported the environmental theory of Wilms' tumor. In our patients, we must consider the likelihood of a combined gonadal-somatic cell mutation in the younger twin and a gonadal mutation in the older twin. A gonadal somatic mutation probably oc curred in a Wilms' tumor allele and a pure gonadal mosaicism affected the aniridia allele. A two-allele gonadal and a somatic mutation could explain the manifestation of Wilms' tumor in only one twin. A more remote possibility would in volve a single-locus, three-allele muta tion, which for the manifestation of Wilms' tumor requires an additional so matic mutation. Lada, Atkins, and Littlefield 19 found a chromosomal translocation t (8 pt; llq—) in a patient with both aniridia and Wilms' tumor. Computer analysis of the chromosomes was re quired because they appeared balanced by standard techniques including band ing. Our patients' karyotypes were normal by Giemsa banding, but may have ap peared abnormal by computer analysis of the chromosomes. SUMMARY
We studied the first instance of aniridia-Wilms' tumor syndrome in twins who were mentally retarded. Both of them had congenital aniridia, cataracts, and glaucoma; only one subsequently de veloped a Wilms' tumor. A two-allele, two-step mutation is the most likely ex planation of this genetically abnormal syndrome in twins. The aniridia-Wilms' tumor syndrome in twins further docu ments the relationship of teratogenic mal formations and neoplasias.
JULY, 1978
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