Pediat. Res. 3: 389-397 (1969) Cancer human genetics congenital defects leukemia

Childhood Cancer and Congenital Defects A Study of U. S. Death Certificates During the Period 1960-1966

R.W. MILLER^^']

Epidemiology Branch, National Cancer Institute, Bethesda, Maryland, USA

Extract

Study was made of the death certificates for all 29,457 children under 15 years of age who died of cancer in the United States during 1960-1966. Congenital defects were greatly underreported, but from the anomalies that were recorded, some new understanding of the relation between oncogenesis and teratogenesis may be derived. On 146 death certificates, Down's syndrome was listed with leukemia, an 1l-fold excess over normal expectation. The peak mortality occurred at two years of age. In the general population, the peak occurs two years later and is due to an increase in the rates for acute lymphocytic leukemia. This study and others indicate that, contrary to popular opinion, myelogenous leukemia is not significantly more common than usual in Down's syndrome.. The association of Wilms' tumor with aniridia'or renal anomalies, unknown when the death certi- ficates were made out, was nevertheless apparent. There were previously unreported cases of leukemia with osteogenesis imperfects, Marfan's syndrome, Treacher-Collins syndrome, and Ollier's syndrome. These cases, and others described in the literature, raise the possibility that certain genetically in- duced disorders of bone or connective tissue may predispose to leukemia. There were also four new cases of leukemia-lymphoma with immunological abnormality (two with myasthenia gravis; one each with ataxia-telangiectasia and agamrnaglobulinernia), and two with leukemia and congenital granu- locytic abnormalities (one each with agranulocytosis and familial granulomatosis). Other concur- rences of possible etiologic significance included two of pheliylketonuria and leukemia-lymphoma, three of tetralogy of Fallot and glioma and one of cleidocranial and medulloblastoma. Clari- fication of these relations may come from studies of susceptibility to viral transformation in vitro of skin fibroblasts from children with the anomalies noted above. This study indicates that greater accuracy and completeness in filling out death certificates would greatly aid research and the clinical benefits derived from it.

Speculation

Although imperfect, diagnoses recorded on death certificates may provide clues to as yet unknown relations between cancer and congenital defects. MILLER Childhood cancer and congenital defects.

Introduction Contrary to popular opinion, myelogenous leukemia is not the predominant form of the in Down's New understanding of the origins of certain childhood syndrome. Studies of case series have revealed that cancers has come from recognition of their association the distribution by cell type differs little from normal with specific congenital defects. A ready source of new [28,29]. Leukemia with Down's syndrome was speci- clues to such concurrences is the recently established fied as myelogenous in 13.7% of the cases in our study, national registry of death certificates concerning child- as compared with 10.5 % in the general population. hood cancer. This report concerns the congenital de- Among 44 children who died of leukemia under 28 fects found on death certificates for a 7-year interval. days of age, eight were reported to have Down's syn- drome [21]. This frequency, 1 : 5.5, is much higher than that, 1 :36, reported for leukemia with Down's syn- drome later in childhood [51]. The syndrome did not Methods occur excessively with other (table I, Cases 38-41). The National Vital Statistics Division, U.S. Public Health Service, provided copies of death certificates Aniridia and Wilms' Tumor (Cases 1-3) for all persons under 15 years of age who died of cancer At the time the death certificates for 1960-64 were in the United States during 1960-66, except for those made out, the excessive occurrence of aniridia and in Louisiana and Missouri during 1965-66. Deaths Wilms' tumor was unknown. Yet three physicians re- from histiocytosis were excluded. The 29,457 certifi- corded the anomaly on death certificates of children cates bore the International List Numbers 140-205 with the tumor (table I). The frequency of aniridia 1301. Abstracted from each death certificate were de- in the general population is at most 1 :50,000 1491. mographic data, cell type of the cancer diagnosed, and Finding three children with the eye defect among 1,585 all congenital anomalies listed. with Wilms' tumor is most unlikely to be due to chance. The numbers of specific malformations expected by If the relation between the two were not now chance in our sample were estimated, insofar as pos- known [37], it would have been suggested by the death sible, from published reports of the frequencies in the certificate study, even though aniridia was markedly general population. When such data were unavailable, underreported. Other studies [37, 481 have shown the a disproportion was sought in the distribution of cancer rate of the defect in children with Wilms' tumor to be deaths by type for a given class of anomalies, the normal about 1 :80. Hence, there should have been about 20 distribution (number and relative frequency) under such cases in our series. 15 years of age being: leukemia 14,240 (48 %), central nervous system tumors 4,680 (16 %), lymphoma 2,231 Brain Defects (Cases I, 4-37 and 4245) (8 %), neuroblastoma2,093 (7 %), Wilrns' tumor 1,585 Cerebral palsy was recorded as often with leukemia (5 %), and all other cancers 4,628 (16 %) [34]. as with other cancer. Neither the array of neoplasms To avoid overlooking single concurrences of po- nor individual cases suggested an etiologic relation in tential etiological significance, evidence has been cited the concurrences observed. from the literature concerning possible links among the Death certificates that specified mental retardation diseases in question. The diagnoses have not been were somewhat less common for leukemia (7 cases) standardized or refined, but are as given on the death than for other cancers (13 cases). Of the neoplasms certificates. involved, only the Wilms' tumor-aniridia syndrome (Case 1) is known to occur with mental retardation [37]. It is noteworthy that phenylketonuria was ob- Results served twice, though with dissimilar cancers-acute Down's Syndrome myelogenous leukemia and lymphosarcoma. Such con- There were 146 children recorded as having Down's currences have not been described previously, and no syndrome with leukemia, an 11-fold excess over normal judgment can be made at present as to the oncogenic expectation, but less than the 15- to 20-fold excess re- influence of this congenitaldefect or the treatment for it. ported in studies with more complete ascertainment Hydrocephalus was recorded for one child with of cases [27, 5 11. As in a British study [29], the peak in leukemia and for three with brain tumors, two of whom leukemia mortality occurred two years earlier than had multiple anomalies of the central nervous system usual. In the general population, the peak at four years (Cases 44 and 45). There is a possibility that hydroce- of age is due to an increase in acute lymphocytic leu- phalus in the third child (Case 42), though specified as kemia, there being little variation in the rates for mye- congenital at a university hospital, was secondary to logenous leukemia with age during childhood [7]. the brain tumor. A study of U.S. death certificates during the period 1960-1966 39 1

Table I. Congenital defects recorded on death certificates of U.S. children who died of cancer, 1960-1966*sZ

Case Congenital defects and cancer Case Congenital defects and cancer No. I No: Aniridia Down's syndrome With Wilms' tumor : With neoplasia other than leukemia : 1 M.R. (M, 5) 38-41 4 cases; 1 each with lymphoblastic 2 Aplastic kidney; congenital dislocated lymphoma and AL (M, 4) ;Ewing's tumor [251 (F, 1) and L, NOS (F, 7) ; neuroblastoma 3 Aplastic kidney (M, 1) (M, 5m) ; retinoblastoma (M, 1)

Cerebral palsy Hydrocephalus; neural-tube defects With leukemia : With leukemia : 4-11 8 cases (7M:lF, 5-14); 2 with quadriple- 42 Hydrocephalus (M, 1) gia and M.R. With other neoplasia : With other neoplasia: 43 Congenital hydrocephalus with malignant 12- 19 8 cases; 2 with neuroblastoma (M, 4; M, 7), brain tumor (M, 6) and 1 each with Hodgkin's (M, 11) ; 44 Hydrocephalus, congenital porencephaly, medulloblastoma (F, 8) ; , agenesis of corpus callbsum, infantile posterior fossa (F, 9) ; congenitally dis- spasm, M.R. with malignant tumor of located with retinoblastoma (F, 3) ; cervical lymph gland (F, 2) spastic quadriplegia and M.R. with 45 Arnold-Chiari deformity with malignant sclerosing metastic hemangioma of gums brain tumor (F, 5) (M, 6) ;and carcinoma ofjaw, NOS (M, 9). 46 Meningocele with cancer of the , NOS (I?, 4) Mental retardation Cranial and/orfacial dysostosis (see also Case 20) With leukemia (see also Cases 4 and 5) : 20-26 7 cases (4M: 3F, 2-14) ; 1 with congenital With leukemia : microcephaly and ALL (F, 12) and 1 with 47 with AL (F, 10m) phenylketonuria and AML (F, 14) 48 Treacher-Collins syndrome with AMoL With other neoplasia (see also Cases, 1, 18 (M, 2) and 44) : With other neoplasia : 27-37 11 cases; 1 each with phenylketonuria and 49 Cleft liplpalate, , , lymphosarcoma (F, 14); absence of corpus platybasia with reticulum cell callosum and malignant lymphoma (M, 2) (F, 11); malignant lymphoma and LL 50 Cleft lip with neuroblastoma (F, 6) (M, 14); lymphosarcoma (M, 10) ;cerebral 5 1 with medullo- defect due to maldevelopment with pos- blastoma (F, 7) sible lymphoma (F, 3) ; astrocytoma 52 Pierre-Robin syndrome with retino- (M,3) ; blind, deaf, epilepsy, I.Q. = 17, blastoma (F, 2) with astrocytoma (M, 9) ;retinoblastoma (F, 3) ; neuroblastoma (M, 1) ;papillary Other skeletal defects carcinoma of kidney (M, 9) ; carcinoma of With leukemia (see also Cases 6 1 and 143) : lung, NOS (F, 2). 53 Marfan's syndrome with AL (F, 9)

Excludes 146 with Down's syndrome and leukemia. a Abbreviations: m = months; d = days; NOS = not otherwise specified; M.R. = mental retardation; types of leukemia (L) :AL = acute; LL = lymphocytic; ML = myelogenous; MoL = monocytic; SCL = stem cell. 8 Sex and age in years. 3 92 MILLER Childhood cancer and congenital defects.

Table I. (Continued)

Case Congenital defects and cancer Case Congenital defects and cancer No. I No.

Marfan's syndrome with SCL [14] (M, 11) With other neoplasms : with L, NOS 75 Muscular with cerebellar tumor (F, 2) (M, 13) Ollier's syndrome with AML (F, 7) 76 Muscular dystrophy with embryonal With other neoplasia (see also Cases 2 and rhabdomyosarcoma (M, 13) 17) : with neuroblastoma Heart defects (M, 4) With leukemia: Chondrodystrophy with Wilms' tumor 77-78 2 with I-A septal defects (2M, 2, 3) (F, 4) 79 Ostium primum (F, 1) of hips with teratoma (F,

Table I. (Continued)

Case Congenital defects and cancer Case Congenital defects and cancer No. I No.

Genitourinary-tract ddects domyosarcoma of the heart (M,

Cranial andlor Facial Dysostoses (Cases 20 and 47-52) revealed that two children with Marfan's syndrome Of special interest was the occurrence of brain tumor had leukemia; one of them had been reported by REIS- with cleidocranial dysostosis, a syndrome in which MAN et al. [46]. Our case with osteogenesis imperfecta cerebral maldevelopment occurs [14], and of retino- was the third described with leukemia, the other two blastoma with Pierre-Robin syndrome, a disorder with having been siblings [23]. The occurrence of' leukemia a high frequency of brain and ocular abnormalities with Ollier's syndrome (osteochondromatosis) in our 1501- study is the first known to us. Perhaps in the same cate- gory are previously reported cases of myelogenous leu- Other Skeletal Defects (Cases 534,142 and 143) kemia in a newborn with Klippel-Feil syndrome [2] The frequency of general skeletal abnormalities in and in another with a possible variant of the Ellis-van our series was too small to show any definitive associa- Creveld syndrome 1331, as well as cases of acute lym- tion with neoplasia, but in conjunction with case re- phocytic leukemia in one child with ports in the literature, there is reason to suspect that [I81 and in another with the xerodermic idiocy of de certain genetically induced disorders of bone may carry SAMCTISand CACCHIONE[45]. an increased risk of leukemia. The death certificates In our study the child with Fanconi's aplastic ane- 394 MILLERChildhood canlcer and congenital defects. mia and leukemia (Case 61) had been reported by Immunological Defects (Cases 70-73) BLOOMet al. [3]. Their description indicates that in There is mounting evidence that genetic immuno- this child, as in the other three known to date [3, 12, logical disorders predispose to lymphoma and, less so, 241, the leukemia was of the acute monocytic type. to leukemia [19]. The death certificate survey revealed The influence of chance on these concurrences may be previously unreported cases of agammaglobulinemia clarified by determining if children with the above- with leukemia of unspecified type and ataxia-telangiec- mentioned anomalies exhibit increased susceptibility tasia with lymphosarcoma of the pharynx. Perhaps in of their skin fibroblasts in culture to transformation by a related category is myasthenia gravis, which occurred the oncogenic virus, SV40. Increased susceptibility has in one child with chronic lyrnphocytic leukemia and been demonstrated in the homozygote and in the hete- in another with lymphosarcoma. Only one case of the rozygote for Fanconi's anemia and, to a lesser extent, former has been reported previously [6]. The excessive for Down's syndrome, anomalies with dissimilar chro- occurrence of myasthenia gravis with thymoma has mosomal aberrations and a predisposition to leukemia been well established by other investigators [44]. POI. Musnrlar Disorders (Cases 74-76) Hematologic Abnormalities (Cases 61-69) Muscular dystrophy was noted in three adolescent In addition to Fanconi's anemia, two other congeni- boys with neoplasms, the dissimilarity of which sug- tal blood dyscrasias-agranulocytosis and familial gra- gests chance occurrence. nulomatosis-were recorded on death certificates of children with leukemia. To our knowledge, neither Congenital Heart Disease (Cases 77-109 and 122) anomaly has been reported previously in persons with The distribution of neoplasms in 34 children with neoplasia, but myelogenous leukemia has been describ- cardiac anomalies did not differ from normal expecta- ed twice in siblings of persons with hereditary neutro- tion. Certain classes of heart defects, however, tended penia [lo, 561. Lymphosarcoma has been reported in to occur with specific neoplasms. Among ten children three persons with cyclical neutropenia [41]. These in- with septa1 defects and cancer, five would be expected born blood dyscrasias may mimic leukemia [8], or leu- to have leukemia, but all ten did. There was a deficien- kemia may induce a hematologic disorder that mimics cy of leukemia in children with other forms of congeni- them. Neither error seems to have been made in the tal heart disease. Among 24 children with cancer, only cases cited above from the literature nor in our series six had leukemia. The difference in the two distri- on the death certificate for a 14-year-old boy who died butions is highly significant statistically (pt0.0004; of congenital agranulocytosis at a leading university Fisher's exact test), but the groupine may be regarded hospital. He had acute monocytic leukemia, the same as contrived since various forms of congenital heart type seen in Fanconi's anemia. In this connection, one disease, from the very complex to isolated septaldefects, wonders if, as in all leukemia-prone conditions known may have origins in common. Thus, autopsies of 272 to date [35], congenital neutropenia also exhibits chro- children with Down's syndrome, which predisposes to mosomal abnormalities. Data are limited to several leukemia, revealed 20 types of cardiac malformation cytogenetic aberrations described in a single case of 1521- hereditary infantile agranulocytosis (Kostmann's dis- Tetralogy of Fallot was another anomaly with an ease) [31]. unusual array of neoplasms : three gliomas, one hepa- Malignant lymphoma with ChediAk-Higashi syn- toma and one leukemia. There is no direct evidence in drome, a disorder characterized by granulocyte ab- the literature concerning high risk of cancer in tetra- normalities [4], was recorded on the death certificate logy of Fallot. There is, however, a constellation of of a child previously described by PAGEet al. [43]. diseases through which the two diseases may be linked. Other case reports attest to the malignant nature of It includes multiple neurofibromatosis, glioma, pheo- the neoplasia [9] and indicate that its occurrence in chromocytoma and congenital heart disease [36]. Fur- children with the syndrome is unlikely to be due to thermore, neurofibromatosis has been observed in two chance [19]. The syndrome has not been reported with children with coarctation of the aorta [13], and at least leukemia. one other case has been reported in the voluminous Hemophilia was noted on three death certificates as literature on von Recklinghausen's disease [54]. A compared with the two expected if there had been no possibleforme fmste of neurofibromatosisin which there underreporting. The frequency of hemophilia has been are multiple cafk-au-lait spots, dull intelligence and estimated to be 1.44/10,000 males under 19 years of familial pulmonic stenosis has been described [54]. age [26]. The dissimilarity in the neoplasms observed, These observations indicate that as series of children however, suggests that the presence of these growths with cardiac anomalies are followed over a period of was fortuitous. time at large medical centers, and as their survival A study of U.S. death certificates during the period 1960-1966 395 rates increase, it would be of interest to evaluate the trary to that in Fanconi's anemia, has not been mono- frequency of disorders related to neurofibromatosis cytic [47]. [36]. . One girl with a death certificate diagnosis of 'pseudo- There were seven deaths from neuroblastoma in Turner's syndrome', made at a university hospital, children with congenital heart disease as compared had acute lymphocytic leukemia. There is no reason with 2.4 expected (7 % of 34 children with cardiac at present, however, to suspect an increased risk of defects). Study of 502 hospital records of children with leukemia in this syndrome. neuroblastoma [38] revealed six with congenital heart Preexistent discase of the liver apparently predis- disease. This frequency was not significantly greater poses to neoplasia of that organ in childhood [20]. Our than expectation (5.5/1,000 grammar school children case with von Gierke's disease and hepatoma, not [42]). At present it appears that congenital heart previously reported, is the third known to us. disease is associated with little, if any, increased risk of neuroblastoma. Discussion Cystic Fibrosis of the Pancreas (Cases 110-114) Cystic fibrosis of the pancreas (CF) was reported in The death certificates indicated that cancer in child- three children with leukemia and in two with Wilms' hood is largely diagnosed at major medical centers. tumor. Since about 2,000 children are born each year The percentage will vary from one area to another. with CF [ll] and about half survive until 10 years of Our data revealed, for example, that more than 75 % age [53], 70,000-100,000 child-years-at-risk are in- of children who died of cancer in Los Angeles County volved in children under 15 years of age during a 7-year were seen at a university hospital. In two recent British interval. Thus, five to seven children with CF would studies [l, 251, the diagnosis of childhood cancer on be expected to die of neoplasia by chance. In future death certificates showed only an 11 % discrepancy studies of mortality pertaining to CF, the possible leu- from that on hospital charts. kemogenic influence of chloramphenicol treatment Listing congenital defects on death certificates of should be considered [5, 161. children who die of cancer will depend in part on the physician's knowledge that the two diseases are related Genitourinary Anomalies (Cases 2 and 115-122) and on the lethality of the congenital abnormality. Of the eight children with kidney anomalies, six had Thus, as the physician makes out the death certificate Wilms' tumor, an excess in agreement with the esta- for a child with leukemia and Down's syndrome, he is blished association between the neoplasm and renal likely to recall that the two diseases are linked, or, when malformations [37]. a child has died of cancer and hemophilia or CF, he may record the congenital defects because these can Hamartomas (Cases 18,56,73 and 12%14l) be lethal alone. In contrast, cleft liplpalate, which is in The well-known predisposition to cancer in hamar- neither of these categories, was recorded on only two tomatous syndromes [32, 551 was reflected in death death certificates of children with cancer, as compared certificates for five children with tuberous sclerosis, with about 50 expected. In this instance, the possibility ten with multiple neurofibromatosis and two with that the anomaly may be associated with resistance to intestinal polyposis. One other child had had sclerosing cancer cannot be excluded. Certain cancers may, of metastatic hemangioma of the gum (Case 18). Two course, be related to congenital defects even though children had hemangiomas and leukemia (Cases 123 no such concurrences were recorded on the death cer- and 124), and one, already discussed, had osteochon- tificates, as, for example, Wiskott-Aldrich syndrome dromatosis and leukemia (Case 56). Previous observa- with lymphoreticular neoplasia or Wilms' tumor with tions indicate a relation between hamartomas and hemihypertrophy [19, 391. Wilms' tumor [39] and between hamartomas and It is unfortunate that physicians do not regularly adrenocortical neoplasia [22]. follow the simple practice of listing on death certificates significant diseases other than the underlying cause of Miscellaneous Defects (Cases 142-156) death. If they did so, relations that involve diseases too Bloom's syndrome in one child who died of leulre- rare to be studied on anything less than a national mia (case 142) together with two other such cases, scale might be recognized. Screening of death certifi- have been reported previously by SAWITSKYet a!. [47]. cates is simple and can be carried out anywhere in The syndrome, in common with Fanconi's anemia, the world, since no special equipment is needed. displays excessive chromosomal fragility in culture, a Several of the death certificates recorded relations feature of possible importance in oncogenesis [47]. between congenital defects and cancer of considerable The cell type of leukemia in Bloom's syndrome, con- clinical and research interest. Failure of the attending 396 MILLERChildhood cancer and congenital defects. physicians to publish brief descriptions and interpre- the skull surfaces in infancy and childhood. J. tations of these remarkable cases may delay progress Pediat. 70: 636 (1967). in understanding the diseases involved. 15. FONTANA,V. J.; FERRARA,A. and PERCIACCANTE, R. :Wilms' tumor and associated anomalies. Amer. J. Dis. Child. 109: 459 (1965). 16. FRAUMENI,J. F., Jr. : Bone marrow depression in- Referaces and Notes duced by chloramphenicol or phenylbutazone. J. arner. med. Ass. 201: 828 (1967). 1. ALDERSON,M.R. and MEADE,T.W.: Accuracy of 17. FRAUMENI,J. F., Jr. and GLASS,A.G. : Wilms' tumor diagnosis on death certificates compared with that and congenital aniridia. J. amer. med. Ass. 206: 825 in hospital records. Brit. J. prev. soc. Med. 21: 22 (1968). (1967). 18. FRAUMENI,J. F., Jr. and MANNING,M. D. : Achon- 2. BERNHARD,W. G.; GORE,I. and KILBY,R. A. : droplasia and leukemia. Brit. med.J. ii: 680 (1967). Congenital leukemia. Blood 6: 990 (1951). 19. FRAUMENI,J. F., Jr, and MILLER,R. W. : Epidemi- 3. BLOOM,G. E.; WARNER,S.; PARK,S. G. and DIA- ology of human leukemia: Recent observations. MOND, L. D. : Chromosome abnormalities in con- J.nat. Cancer Inst. 38: 593 (1967). stitutional aplastic anemia. New Engl.J. Med. 274: 20. FRAUMENI,J.F., Jr.; MILLER,R.W. and HILL, 8 (1966). J. A. : Primary carcinoma of the liver in childhood : 4. BLUME,R. S. ; BENNETT,J. M. ; YANKEE,R. A. and An epidemiologic study. J.nat.Cancer Inst. 40: WOLFF,S. M. : Defective granulocyte regulation in 1087 (1968). the Chediak-Higashi syndrome. New Engl. J. Med. 2 1. FRAUMENI,J. F., Jr. and MILLER,R.W. : Cancer 279: 1009 (1968). deaths in the newborn. Amer. J. Dis. Child. 117: 186 5. BRAUER,M. J. and DAMESHEK,W. : Hypoplastic (1969). anemia and myeloblastic leukemia following chlor- 22. FRAUMENI,J. F., Jr. and MILLER,R.W.: Adreno- amphenicol therapy..Report of three cases. New cortical neoplasms with hemihypertrophy, brain Engl.J. Med. 277: 1003 (1967). tumors,andotherdisorders. J.Pediat. 70: 129 (1967). 6. COHEN,S. M. and WAXMAN,S. : Myasthenia gravis, 23. GILCHRIST,G. S. and SHORE,N. A. : Familial leu- chronic lymphocytic leukemia, and autoimmune kemia and osteogenesis imperfecta. J.Pediat. 71: hemolytic anemia. 'A spectrum of thymic abnor- 115 (1967). malities?' Arch. intern. Med. 120: 71 7 (1967). 24. GMYREK,D. ; WITKOWSKI,R. ; SYLLM-RAPOPORT, 7. COURTBROWN, W. M. and DOLL,R. : Leukaemia I. and JACOBASCH, G. : Chromosomal aberrations in childhood and young adult life: Trends in mor- and abnormalities of red-cell metabolism in a case tality in relation to aetiology. Brit.med.J. i: 981 of Fanconi's anaemia before and after development (1961). of leukemia. German med. Mthl. (English-lan- 8. CUTTING,H. 0.and LAND,J. E. : Familial benign guage edition) 13: 105 (1968). chronic neutropenia. Ann. intern. Med. 61: 876 25. HEASMAN,M. A. and LIPWORTH,L. : Accuracy of (1964). certification of cause of death. Great Britain, Gen- 9. DENT,P.B.; FISH,L. A,; WHITE,J. G. and GOOD, eral Register Office, Studies on Medical and Popu- R. A. : Chediak-Higashi syndrome. Observations lation Subjects No.20. (Her Majesty's Stationary on the nature of the associated malignancy. Lab. Office, London 1966.) Invest. 15: 1634 (1966). 26. HEWITT,D. and MILNER,J. : Prevalence of haem- 10. DE VRIES,A.; F'EKETH,L. ~~~JOSHUA,H. : Leukae- ophilia in Ontario, 1966. (To be published.) mia and agranulocytosis in a member of a family 27. HOLLAND,W.W.; DOLL,R. and CARTER,(3.0.: with hereditary leukopenia. Acta med.orient. 27: The mortality from leukaemia and other cancers 26 (1958). among patients with Down's syndrome (mongols) 11. DI SANT'AGNESE,P. A. : Pathogenesis and physio- and among their parents. Brit. J. Cancer 16: 177 pathology of cystic fibrosis of the pancreas. Fibro- (1962). cystic disease of the pancreas (mucoviscidosis). 28. JACKSON, E.W.; TURNER,J. H.; KLAUBER,M. R. New Engl. J. Med. 277: 1287 (1967). and NORRIS,F.D.: Down's syndrome: Variation 12. DOSIK,H.; HSU,L.Y.; TODARO,G.J.; LEE, S.L.; of leukemia occurrence in institutionalized popu- HIRSCHHORN,K. ; SELIRIO, E. S. and ALTER,A. A. : lations. J. chron. Dis. 21: 247 (1968). Malignant transformation in Fanconi's anemia. 29. LASHOF,J. C. and STEWART,A.: Oxford survey of Clin. Res. (Abstr.) 17: 324 (1969). childhood cancers. Progress report I11 : Leukaemia 13. ENGLE,M. A. : Personal communication. and Down's syndrome. Mthl. Bull. Minist. Hlth 14. EPSTEIN,J. A. and EPSTEIN,B. S. : Deformities of 24: 136 (1965). A study of U.S. death certificates during the period 1960-1966

30. Manual of the international statistical classification 45. REED, W.B.; LANDING,B.; SUGARMAN,G.; of diseases, injuries and causes of death; 7th revi- CLEAVER,J. E. and MELNYK,J. : Xeroderma pig- sion (WHO, Geneva 1967). mentosum. Clinical and laboratory investigation 3 1. MATSANIOTIS,N. ; KIOSSOGLOU,K. A. ; KARPOU- of its basic defect. J.amer.med.Ass. 207: 2073 ZAS,J. and ANASTASEA-VLACHOU,K.: Chromo- (1969). somes in Kostmann's disease. Lancet ii: 104 (1966). 46. REISMAN,L.E.; MITANI,M. and ZUELZER,W.: 32. MCKUSICK,V.A.: Genetic factors in intestinal Chromosome studies in leukemia. I. Evidence for polyposis. J. amer. med. Ass. 182: 271 (1962). the origin of leukemia stem lines from aneuploid 33. MILLER,D. R. ;NEWSTEAD, G.J. and YOUNG,L.W. : mutants. New Engl.J.Med. 270: 591 (1964). Perinatal leukemia with a possible variant of the 47. SAWITSKY,A.;BLOOM, D. and GERMAN,J. : Chromo- Ellis-van Creveldsyndrome.J.Pediat.74: 300 (1969). somal breakage and acute leukemia in congenital 34. MILLER,R.W. : 52 forms of childhood cancer: U.S. telangiectatic erythema and stunted growth. Ann. mortality experience, 1960-66. J. Pediat. (in press). intern. Med. 65: 487 (1966). 35. MILLER,R.W. : Penons at exceptionally high.risk 48. SCHWEISGUTH,0.; CAMPINCHI,R.; PIVOTEAU,B. of leukemia. Cancer Res. 27: 2420 (1967). et LEMERLE,J. : L'association aniridie-tumeur du 36. MILLER,R.W.: Wilms' tumor, congenital heart rein chez l'enfant. A propos de 4 cas. Bull.Soc. defects, pheochromocytomas and thyroid cancer. Ophtal. France. 67: 1099 (1967). Amer. J. Dis. Child. 116: 564 (1968). . 49. SHAW,M.W.; FALLS,H.F. and NEEL,J.V.: Con- 37. MILLER,R.W. ; FRAUMENI,J. F., Jr. and MANNING, genital aniridia. Amer. J. hum. Genet. 12: 389 M. D. : Association of Wilms' tumor with aniridia, (1960). hemihypertrophy and other congenital malfor- 50. SMITH,J. L. and STOWE,F. R. : The Pierre Robin mations. New Engl. J.Med. 270: 922 (1964). syndrome (glossoptosis, micrognathia, cleft pa- 38. MILLER,R.W.; FRAUMENI,J.F., Jr. and. HILL, late). A review of 39 cases with emphasis on asso- J.A. : Neuroblastoma: Epidemiologic approach to ciated ocular lesions. Pediatrics 27: 128 (196 1). its origin. Amer. J. Dis. Child 115: 253 (1968). 51. STEWART,A.; WEBB,J. and H~wrrr,D. : A survey 39. MILLER,R.W. : Relation between cancer and con- of childhood malignancies. Brit.med.J. i: 1495 genital defects: An epidemiologic evaluation. J. (1958). nat. Cancer Inst. 40: 1079 (1968). 52. WARKANY,J.; PASSARGE,E. and SMITH,L. B. : Con- 40. MILLER,R.W. and TODARO,G. J. : Viral trans- genital malformations in autosomal trisomy syn- formation of cells from persons at high risk of can- dromes. Amer. J. Dis. Child. 112: 502 (1966). cer. Lancet i: 81 (1969). 53. WARWICK,W. J. : Cystic fibrosis. Nature and prog- 41. MORLEY,A. A. ; CAREW,J. P. and BAIKIE,A. G. : nosis. Minnesota Med. 50: 1049 (1967). Familial cyclical neutropenia. Brit. J. Haemat. 13: 54. WATSON,G.H.: Pulmonary stenosis, caf6-au-lait 719 (1967). spots, and dull intelligence. Arch. Dis. Childh. 42: 42. MORTON,W. : Heart disease prevalence in school 303 (1967). children in two Colorado communities. Amer. J. 55. WILLIS,R. A. : The borderland of embryology and publ.Hlth 52: 991 (1962). pathology, p. 351 (Butterworth, London 1958). 43. PAGE,A. R.; BERENDES,H. ;WARNER; J. and GOOD, 56. WOLFF, E.: Agranulozytose und Myeloblasten- R.A. : The Chediik-Higashi syndrome. Blood 20: leukamie als Reaktionsformen auf denselben In- 330 (1962). fekt bei zwei Geschwistern. Folia haemat. 44: 38 44. PERLO,V. P.; SCHWAB,R. S. and CASTLEMAN,B. : (1931). Myasthenia gravis and thymoma; in W. BRAINand 57. Requests for reprints should be addressed to: Ro- F. H. NORRIS,Jr. The remote effects of cancer on BERT W. MILLER,M.D., National Institutes of the nervous system; vol. 1, p.55 (Grune and Strat- Health, NCI, Wiscon Building, Room 402 A, ton, New York 1965). Bethesda, Maryland 20014, USA.