Bloom's Syndrome. I. Genetical and Clinical Observations in the First Twenty-Seven Patients JAMES GERMAN'

Bloom's Syndrome. I. Genetical and Clinical Observations in the First Twenty-seven Patients JAMES GERMAN'

INTRODUCTION Bloom's syndrome, also termed congenital telangiectatic erythema and stunted growth, was first recognized and described as a clinical syndrome by Dr. David Bloom (1954a). In 1966, he reviewed his observations and experiences with the condition and named its "three cardinal features" (Bloom, 1966): (a) telangiectatic erythema appearing in infancy, affecting almost exclusively the butterfly regions of the face, cheeks, nose, margins of the eyelids, lips, forehead, and ears, but occasionally also affecting the dorsa of the hands and the forearms; (b) sun sensitivity, so that the telangiectatic skin lesions often first appear or become accentuated in summertime and usually ameliorate when protected from sunlight; and (c) stunted growth, the most conspicuous feature of the syndrome. This last feature is distinguished by smaller than average size both at birth and also during various periods of childhood and adulthood. The maximum height achieved has been 161.3 cm, in a boy who is now 17 years old; no other individual has exceeded 148 cm (Table 1, Col. X). The body proportions appear approximately normal, but the patients usually are delicate and slender. There is disproportionate microcephaly, which is accentuated by the delicacy and narrowness of the face. The affected individuals bear a striking general resemblance to one another because of the small, narrow face, the dolichocephalic head, the localized red lupus erythematosus-like facial skin lesion, and the conspicuous dwarfism. The skin lesion tends to become less severe as the individual grows older, but sometimes scarring, atrophy, depigmentation, and loss of eyelashes become prominent and disfiguring. The affected persons usually are of average intelligence, and they tend to be affable but may develop unusual personality features as psycho- logical consequences of their unusual appearance and size. Their health is generally good, although sometimes feeding difficulties occur in infancy, and many have had increased numbers of infections of the respiratory tract or ears requiring antibiotic therapy in infancy and early childhood. Satisfactory treatment for neither the telangiectasia nor the growth retardation has been found. Three additional recent observations have increased the scientific importance of this rare condition and have stimulated a series of reports from this laboratory (Ger-

Received September 3, 1968. This investigation was supported by Public Health Service research grant HD 04134 from the National Institute of Child Health and Human Development and by grant E-461 from the American Cancer Society. l The New York Blood Center, New York, New York 10021. 196 BLOOM'S SYNDROME 197 man, 1964; German et al., 1965; German and Crippa, 1966a, b; German, 1969; Sawitsky et al., 1965; Sawitsky et al., 1966), and others will follow (German and Bloom, in preparation; German and Crippa, in preparation; German and La Rock, in preparation; Passarge and German, in preparation). These observations are: (a) Familial clustering (Szalay, 1963; Wolf, 1963) and an increased frequency of parental consanguinity and Jewish ancestry have suggested a recessive pattern of inheritance (German et al., 1965), but the genetic analysis of the condition has awaited recognition of a larger number of affected families. (b) Cytogenetic studies in 22 affected individuals have demonstrated a consistent abnormality in cells cultured in vitro, a tendency to chromosomal breakage and rearrangement (German, 1964; German et al., 1965; German and Crippa, 1966a, b; Grouchy, 1966; Hooft et al., 1967; Keutel et al., 1967; Landau et al., 1966; Sawitsky et al., 1965; Sawitsky et al., 1966; Sizonenko et al., 1967a, b), and, as a consequence, a high incidence of aneuploidy (German and Crippa, 1966a). Breakage and rearrangements are also found in moderately increased numbers in cultured cells from some parents of individuals with this syndrome (Sawitsky et al., 1966; German, unpublished observations). (c) There is an increased expectancy for the development of malignant neoplasia for individuals affected with the syndrome (German et al., 1965; Sawitsky et al., 1965, 1966). The present report, which is the first in a series on Bloom's syndrome, consists of various observations which have been made on the first 27 individuals to have been recognized as affected with this rare disorder. The purposes of the report are to add to the understanding of the clinical features and course of the disorder and to compile the evidence required for definition of its genetics.

MATERLALS For clarity and conservation of space, a tabular style for presenting most of the observations has been chosen (Tables 1-7; Figs. 1, 4, and 5). The tables and figures contain cross-references, so that from them a fairly complete description of each individual can be reconstructed. In Column I of Table 1, each of the 27 affected persons has been assigned a case identification number in the approximate order in which they were recognized or reported in medical journals. Each person is further identified by the first letters in his first name and family name. (Names are not known for patients 8, 9, and 21, so the initials of the author reporting each case were employed.) The initials of the family name of the propositus and the identification number of the propositus are used to identify each pedigree in Figure 1. These identi- fying numbers and initials will be employed consistently in subsequent reports from this laboratory. Photographs of some of the individuals in the series are shown in Figures 2 and 3. Ascertainment of Affected Families Ascertainment in these families was through an affected individual, and these individuals have come to my attention during the past eight years in one of the following ways: (a) Through Dr. David Bloom. The first patient to enter into the series (2, Su. Bu.; Fig. 2i, j) was studied in 1960 at the request of Dr. Bloom, who felt that the etiology of the syndrome might be an imbalance of the chromosomal complement. TABLE 1 SUMMARY OF DATA CONCERNING THE FIRST 27 INDIVIDUALS A blank space indicates that the

= I II III IV V VI VII VIII Ix x XI XII XIII I_ -I

n .b 0 bo 40 4) s .0 . > Cd -e O -o -o .0 0 Z Bn H0 -c cd 0 0 P-4 .i .z I._ 0 E400 00 E 11 cd .) 0)0aw Po p0 Q0 + cd x 3.. 1.... Ce. So. '33 M 29/29 1,815 25/obese 25/145 + 2.. Su. Bu. '50 F 28/25 +++ 1,362 13/31 13/ 132 3/40 ++ 3.... Ho. Co. '49 M 1,760 17/55.5 17/161.3 28/21 3.5/43.8 + 4.... Ge. Ho. '33 M 33/25 ± 1,910 33/54 33/146 5.... Ja. Oa. '34 M 36/28 + 1,986 29/36 30/142.5 32/47 ±Z( 6.... De. Sou. '47 M 27/25 2,116 18/35 18/ 143 +7~ ± 18/148 += + 7.... IRFo. Ta. '46 M 2,215 18/40 +n~ + 8.... Ka.' '57 M 2,350 2. 7/8.3 45 2.7/78 +n ++ ± 9.... Ka.' '49 M + 2,000 10/17.3 10/118 +n ++ + 10.... Gr. St. '50 M 28/28 2,016 10/14.5 10/112 10/45.7 + 11.... Ia. Th. '49 M 28/26 ++ 2,100 11/18.9 11/119 11/50.3 12.... De. Th. '53 F 32/30 2,043 8/12.4 8/102 8/49.5 13.... De. Si. '54 F ++ 1,590 5/11 ++ 14.... le. Si. '55 M 1,818 5/11 15.... Ma. Ro. '61 M 30/25 1,760 4/9.4 39.4 4/86 + 16.... Et. Fi. '61 F 42/31 1,532 2.3/5.8 2.3/74 17.... Ch. Sm. '57 M 18/20 2,485 7/16 7/102 5/45.7 18.... La. Sm. '60 M 21/23 + 2,925 5/9.6 5/81 5/43.2 + 19.... Sy. Tik. '42 F 4-2/36 32 wk. 1,600 23/35 23/134 + 20.... Bo. Le. '65 M 30/25 + 1,980 1/5.2 41.5 1/61 1.1/39 21.... La.' '(0 M 25/27 2,000 5.7,/9.9 46 5.7/92 4.5/45.2 + M + 46.2 11/127 13/46.9 ++ 22.... El. Ha. '56 43/32 ++ 2,371 11/17 + 23.... Na. Ha. '59 44/33 2,279 8/23 46.2 8/126 12/47.4 + 24.... Ro. So. '32 F 27/27 ++ 1,362 32 wk. + 25.... St. Ti. '63 F 2,130 2.5/7.5 2.5/76 1.5/42 26.... Sa. Ti. '64 F + 2,229 1.3/6.3 1.30/1 1/40.8 27.... Ly. Se '64 F 25/26 + 1,960 2/6.8 2/74 0.09/32.7 M 2,100 4/91 28.... Cas.' '61 4/11.3 2. +- 29.... Cas.2 '62 F 2,300 2.5/8 2/745/77.4 30.... Ke.' '64 M 29/27 1,350 2/6.5 40 + 31.... Ca. D. '55 F 1,980 8.2/13.1 8.2/105 8.2/46.5 32.... Mi. Ko. '62 M 30/25 1,307 5/9.1 5/87.5 + 33.... Be. Be. '54 F 42/ 2,359

198 To BE RECOGNIZED (1-27) AND SIX MORE RECENTLY RECOGNIZED (28-33) information could not be obtained. = =

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10 + 25 yr./ leukemia '54 Bloom, 1954a, b, 1966; Sawitsky etal., 1965, 1966; Cellis et al., 1966*** 9 13 yr./leukemia Bloom, 1954a, 1965, 1966; Torre and Cramer, 1954; German, 1964; Sawitsky et al., 1965, *** + 1966; Gellis et al., 1966**, 3 Bloom, 1954a, 1966; Curth, 1964**, 3 '57 Brunsting, 1957** 7 +(1/32) 32I yr./carcinoma '5 Lewis, 1957; German and Crippa, 1966** 3 +d '5 Hillman et al., 1957; Fitzpatrick, 1962** 3 * +(1/32) '58 Stritzler, 1958; Stritzler and Stritzler, 1966**, *** 3 '60 Katzenellenbogen and Laron, 1960; J. Landau et al., 1966 Birth + Katzenellenbogen and Laron, +0 '60 1960; J. Landau + et 1966 + al., 6 +V +(1/16) + O*'63 V Szalay, 1963** 4 + + '63 Szalay, 1963**, *** 12 '63 Szalay, 1963**, *** + (+) 3 '63 L. C. + Wolf, 1963; Harber, unpublished*** 8 '63 Wolf, 1963; L. C. Harber, unpublished*** 1 + (+) '66 Bloom, 1966; Schoen and Shearn, 1967*** 18 + '66 *** (+) Bloom, 1966**, 9 + +(1/32) '66 *** (+) Bloom, 1966**, 12 +(1/32) '66 Bloom, 1966**, *** 8 +(1/32) 23 yr.1/leukemia '66 Sawitsky et al., 1966 6 '66 Grouchy, 1966; Sizonenko et al., 1967 a, b**, 6 +(1/64) '66 J. W. Landau et al., 1966 36 +(1/64) J. Opitz, unpublished** +(1/64) J. Opitz, unpublished** 3 mo./failure to thrive 6 E. C. Liss and C. R. Yoder, unpublished** *** 36 E. C. Liss and C. R. Yoder, unpublished**" , 9 + J. P. Rauh, I unpublished 5 + + - +(1/16) '66 Casado de Frias, 1966 7 - + - +(1/16) '66 Casado de Frias, 1966 20 + - - (+) '67 Keutel et al., 1967 70 + _ - '67 Hooft et al., 1967 12 + + + - + - * * * 6 + - + - - * P. E. Conen, unpublished"*

199 200 GERMAN The complement was found to be normal, but the unexpected finding of an increased incidence of chromosomal breakage in this individual's lymphocytes in short-term culture, at that time an undescribed phenomenon in human cytogenetics, stimulated my interest in the phenomenon of spontaneous chromosomal rearrangement and led to a search for other individuals affected with this syndrome. Patients 15-18, 25, and 26 came to the attention of Dr. Bloom through referral or personal reporting to him by other physicians, and he in turn told me of them; certain of these have been reported subsequently (15-18). (b) Through a personal search. I learned of patients 19, 20, 22, 23, and 27 from other geneticists or physicians who knew of this laboratory's interest in the syndrome. Patient 24 (Ro. So.), the dead sib of the first patient to have been described with Bloom's syndrome (1, Ge. So.), was discovered during my visit with the surviving mother of patient 1 in her home, where she had kept photographs and birth and infancy records concerning both her children. (c) Through published papers. Patients 1-14 had been reported in the medical journals before the survey began, and additional data have been obtained by personal correspondence or conversation with

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Affected male Small symbols: Clf Unaffected, dead male <9 Spontaneous abortion 6t Unaffected female, infantile death I Induced abortion < Sex unknown E Consanguineous union j \b Twin pregnancy, the male affected, the female stillborn ow FIG. 1.-Pedigrees extended to include all members of the generation before, of, and following the 27 patients with Bloom's syndrome. The 21 families are presented in alphabetical order, the identify- ing numbers and initials being those used in Table 1. After preparation of this figure and Table 6, it was learned that the unaffected sibs of patient 27 (Le. S*t) were a girl and a boy, and of patient 10 (Gr. St.) a boy and a girl (two sibs only, rather than the three diagrammed). b

a: *w-

c d FIG. 2a-d.-Photographs of individuals with Bloom's syndrome. The facial skin lesions appearing gray in these prints actually are bright red and telangiectatic. a, Patient 24 before age three months. Note resemblance to her affected sib, patient 1, shown in Fig. 2b. b-d, Patient 1 in early and mid- childhood and at age 25, shortly before developing acute leukemia.

201 e f

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g h FIG. 2e-h.-Patient 6 at ages six months, five years, 11 years, and 14 years. An extensive, bright red, disfiguring facial lesion persists now at age 20.

202 i J

k I FIG. 2i-l.-i-j, Patient 2 at age two and a half. She had only four toes on one foot and an anoma- lous thumb shown here. Minor anomalies of various types were often recorded in this group of patients. k, Patient 16 at age six.!, Patient 17 at age eight.

203 M 11

FIG. 2m-p.-m-n, Patient 26 at ages two and three. o-p, Patient 25 at age four

204 q r FIG. 2q-r.-Patient 5, at age 32 one of the oldest individuals known to have this syndrome. He weighed 21 kg (56 pounds) when photographed, partly because of dysphagia consequent to lingual carcinoma.

a b

FIG. 3-Affected individual 15. a, Photographed at the age of eight weeks. From the age of six weeks he had been able to stand supported by grasping his father's finger, apparently because of mature newborn development combined with his minute body mass. At birth he weighed only 1,760 g (3 lb., 14 oz.) after a full gestational period. b, At age six and a half years, weight 11 kg, height 97.5 cm. A bright red facial lesion was present. 205 206 GERMAN the reporting physicians and by my personal contact with the patients (2-7) and/or family (1). Other patients have been reported or recognized during the course of the survey (20 and 21), and additional data concerning them have been sought through personal contacts with the reporting physicians (21) and the family (20).* A patient was accepted for inclusion in this series only after Dr. Bloom and I had discussed the case and had agreed that, from the published report and photographs, from additional personally acquired photographs and information, or from our personal examinations, the patient indeed represents an example of this particular syndrome. I have examined 17 and Dr. Bloom 15 of these first 27 patients (Table 1, Col. XXII). General Categories of Study (a) Clinical: Case histories, serial physical findings including weights and lengths, and clinical laboratory studies have been accumulated and are summarized here. Hematological data, although scanty, have been compiled (Table 2). The presence of minor developmental defects in addition to the cardinal features of the syndrome has been tabulated (Table 3). A more detailed clinical description and growth record of a number of previously undescribed patients will be reported separately (Pas- sarge and German, in preparation). (b) Cytogenetics: Studies of blood cells, bone marrow cells, and fibroblasts in culture have been made in both homozygous and hetero- zygous individuals, and extensive reports of cytological and cytogenetic abnormalities have or will be made, as referred to above. (c) Pathological: Individuals 2 and 5 have been studied at autopsy, and detailed reports are in preparation. The findings in patient 2 have been briefly reported (Sawitsky et al., 1966). (Dr. Jean Priest's co- operation in assuring the complete autopsy examination for patient 5, who died in Denver, is gratefully acknowledged.) (d) Genetic: Pedigree data have been accumulated (Fig. 1), and segregation analysis has been made to determine whether the familial distribution supports the statistical expectation for autosomal recessive transmission. Investigation has been made into the ancestral geographic origins and migrations of the 27 affected individuals, all but three of whom were born in North America (Table 4; Fig. 5). In a search for genetic heterogeneity, correlations have been made between certain clinical features and ancestry.

OBSERVATIONS The findings are summarized as follows: Table 1 includes most of the data of a general nature. The 21 pedigrees are diagrammed in Figure 1. Special data are presented in Tables 2-3 and Figures 2-4 and 7-8. Genetic data appear in Tables 4-7 and Figures 1 and 5. * Excellent reports of four other affected European individuals have become known to me since the present compilation was completed. They are designated cases 28 (Cas.1) and 29 (Cas.2) (Casado de Frias, 1966); 30 (Kel) (Keutel et al., 1967); and 31 (Ca. D.) (Hooft et al., 1967). In case 30, Keutel et al. (1967) report a partial pituitary insufficiency, including decreased secretion of ACTH and STH. Another unreported individual, to be referred to as case 32 (Mi. Ko.), is a new patient in our clinic, and another, patient 33, has been recognized in Canada (P. E. Conen, unpublished). The findings in these six new cases are not included in Tables 2-8, nor are they commented on in the text of this paper; however, they have been appended to Table 1. BLOOM'S SYNDROME 207 General Description of the Group Each of the 27 individuals included had the clinical criteria described in the In- troduction, and these "cardinal features" will not be discussed extensively in this report. Twenty-one families (Fig. 1) comprising 27 affected individuals (Table 1) have been studied. Sibs were affected in six families. (In Table 1, Col. II, sibs can be recognized as those individuals having the same family-name initials [pairs 11 and 12, 13 and 14, 17 and 18, 22 and 23, 25 and 26, and 1 and 24], the same family name initials as used in Fig. 1.) No family with more than two affected members has yet been found. At the time of writing (mid-1967), the group is young (Table 1, Col. III), the average age of living males being 14 years and of living females 7 years (Table 6, II). Five TABLE 2 HEMATOLOGICAL DATA

tification Age Hemoglobin RBC Hemato- Comment No. (Years) g/100 ml X106/mm3 crit

1 ...25 ..9.5-11.0 ...... Leukemia present (Sawitsky el alt, 1966) . . 14.31 ...... 36 2 9.6-10.5 3.3 34 ......

3 11.2 3.6 ...... 4 11.3 3.7 9 13.0 10 10.8 12 10.2 13 4.0 ...... 12 Leukemia demonstrable in blood and marrow at age 13. Complete data published by Sawitsky et al. (1966). 3..... 14 13.7 4.5 ...... Bone marrow normal 17 16.9 ...... 48 Retic. 1.2%

4. . . 34 14.4 4.95 42 ......

5...... 27 13.1 ...... 40 ...... 27 11.8 37 28 13.4 ...... 42 ......

30 12.8 ...... 40 Bone marrow normal

8 ...... 10.82 3.5 ......

14 ...... 11.76 4.0 ...... 16 ...... 13.66 ...... 37.5 Fetal hemoglobin 1.3%; retic.3.2%

21 ...... 6 "Normal" ... J. W. Landau et al., 1966

25 ...... < 1 11.2-13.6 4.5 31-38

1 12.2 . 3 11.1 4.0 31

4 11.1 ...... 33 Retic. 1.0%

26 ...... 2 11.2 ......

3 9.6 .5 ...... 29.5 Retic. 1.0%0 208 GERMAN individuals in the series died between the ages of 13 and 32 (Table 1, Col. XX), and in each case (except for patient 24, Fig. 2a, who weighed only 1,362 g at birth, developed an abscess of the buttocks, failed to thrive, and died at home for unknown reasons at three months of age), the cause of death has been either acute leukemia or cancer (squamous cell carcinoma of the tongue) (Sawitsky et al., 1965, 1966). No deviation from the expected parental ages exists in these 21 families, mean paternal age being 31, maternal 27 (Table 1, Col. V).

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FIG. 4.-Birth weights of each male and female affected individual (black circles) shown in relation to the generally accepted normal ranges (stippled area= normal mean + 2 SD). The mean (horizontal line) of affected males is 2,094 g; of affected females 1,841 g. The mean of all affected individuals, exclusive of the single pre-term individual (19), is 1,988 g (p = pre-term; t = dead individual). Only one of the group weighed > 2,500 g; 15 weighed 2,000 g or less. The mean birth weight of the affected Jewish individuals was 1,825 g (male, 1,916 g; female, 1,740 g); of non-Jewish individuals it was 2,209 g (male, 2,219 g; female, 2,161 g). The lowest birth weights (1,362 g) occurred in two Jewish girls; one of these (24) failed to thrive and died of unknown causes at three months of age, whereas the other (2) remained healthy until she died of acute leukemia at 13 years of age. The two heaviest affected newborns in the series (sibs 17 and 18) had unaffected sibs who weighed 4,402 g and 5,027 g at birth; their mother weighs 126 kg, and their maternal grandfather weighed 198 kg (436 lb.). Specific Physical Abnormalities The strikingly low birth weight (Table 1, Col. VII; Fig. 4) is not a consequence of prematurity in the 25 patients from whom information is available (Table 1, Col. VI), because only one (19) was born before term and three (11, 17, and 18) were slightly post-term as calculated by the mother. Affected females are often very small and as a group have a mean birth weight lower than that of males (Fig. 4). The mean birth length (Table 1, Col. IX) was 44 cm in the six individuals tabulated (mean normal = 50 cm). Despite very small size, there were no signs of developmental prematurity, and, although continuing to show growth retardation, subjects reached BLOOM'S SYNDROME 209 the usual developmental milestones such as walking and talking at the expected times if not earlier (see Fig. 3). Increases in body weight and height are severely retarded at all ages after birth, as will be documented more extensively in a subsequent publication (Passarge and German, in preparation). The maximum body height achieved in an affected male has been 161.3 cm (patient 3; Table 1, Col. X), in a female, 134 cm (patient 19). The head circumference appeared inordinately small at birth (no actual measurements have been found) and remained so at subsequent ages (Table 1, Col. XI). Skin abnormalities (Table 1, Cols. XII and XIV) in the characteristic facial areas, usually appearing during the first year of life, were severe in all but five patients (12, 18, 23, 24, and 26). Exposure to sunlight often was followed by increased erythema, cracking and crusting of the skin and lips, and conjunctivitis and loss of eyelashes. In several older patients, the abnormality became less severe with advancing age; sometimes, however, although the lesion became quiescent and less sensitive to sunlight, there was serious permanent disfiguring from scarring, depigmentation, and atrophy (e.g., Fig. 2h). In a minority of patients, the initially severe skin lesions re- gressed considerably in early childhood without serious disfigurement but with continuing localized areas of telangiectatic erythema which did not interfere seriously with appearance. In at least eight patients, sun-sensitive skin lesions were present over the dorsa of the hands or forearms (Table 1, Col. XIII) or on the back of the neck and ears (patient 11), in addition to those on the facial areas. In an occasional patient, small localized telangiectatic lesions were noted elsewhere on the skin surface. Skin areas other than the face, hands, and forearms did not appear unduly sensitive to sunlight; for example, several affected children have played throughout the sum- mer, with the skin of almost the entire body exposed, without detrimental effects except over the facial areas. In three patients, phototests have been performed during which normal-appearing skin of both lumbar and facial areas was irradiated with both ultraviolet and visible light (L. C. Harber, unpublished). No abnormalities in the erythema threshold, magnitude of response, or persistence of erythema were noted. In addition to the telangiectatic erythema, several other skin abnormalities occurred in these patients (Table 1, Col. XV; Table 3), most notably cafe au lait spots in more than half the patients for whom information as to their presence or absence was obtainable. Additional Physical Abnormalities In addition to Bloom's "three cardinal features," minor defects were frequently detected in these individuals (Table 1, Col. XVI; Table 3; Fig. 2j). Information, although not always complete, was available concerning the presence or absence of such defects in most individuals, and in 22 of these at least one developmental defect was recorded. Mental retardation has occurred but is uncommon, and congenital heart disease has not yet been described. Abnormalities of bony development of various types were found in 12 patients. "Colloid-body-like spots" in Bruch's membrane of the eye have recently been reported in two patients (J. Landau et al., 1966). A disturbance of testicular function may exist, because testicular atrophy was found at autopsy in patient 5 (German, unpublished), and the testes are unusually small in patient 3 (Bloom, 1965); they are both unusually small and also soft in patients 4, 10, 210 GERMAN and 22. In addition, the testes were undescended in four patients. However, in patient 11 the testes are proportionately small for total body size and have normal consist- ency. The existence of an abnormality of immunoglobulin levels has recently been recognized (J. W. Landau et al., 1966; Schoen and Shearn, 1967). A mild and unexplained anemia has occasionally been recorded (Table 2). Geography, Ancestry, and Consanguinity Eight of the individuals affected with Bloom's syndrome in this series are clustered in the New York City area (Table 4, I; Fig. 5), and the families of at least four others

TABLE 3 DEVELOPMENTAL OR OTHER DEFECTS,* OMITTING FROM THE TABULATION THE CARDINAL FEATURES OF THE SYNDROME

|No. of Case Identification No. Abnormality Individuals of Those Affected Affected Skin, teeth, and eyes: Cafe au lait spots...... 16 1,2,4,5,6, 7,9, 10, 11, 12, 15, 17, 19, 22, 23, 27 Absence of lateral incisors...... 3 10, 11, 12 Hypertrichosis .. 2 13, 14 Colloid-body-like spots in Bruch's membrane...... 2 8, 9 Telangiectasia of bulbar conjunctivae ...... 1 11 Ichthyosis hystrix...... 1 1 Acanthosis nigricans...... 1 3 "Two rows of teeth"...... 1 17 Unusual dermatoglyphics...... 2* 4, 5 Bone and digits: Clinodactyly...... 5 13, 14, 17-, 18, 2t Syndactyly, mild...... 3 4, 17, 18 Double (fused) left thumb, with four left toes. 1 2 Short, stubby fingers...... 1 4 Dislocation of hips...... 1 20 Asymmetry of femoral necks...... 1 15 Genu recurvatum ...... 1 25 Equinovarus deformity, mild...... 1 21 Genitalia: Undescended testes...... 4 3, 8, 14, 17 Urethral stricture or meatal narrowing...... 3 4, 5, 11 Hypospadias ...... 1 8 Testicular atrophy or hypoplasia...... 4 4, 5, 10, 22 Other: High-pitched voice...... 7 1, 2, 4, 8, 9, 15, 16 Pilonidal cyst or sacral dimple ...... 6 1, 14, 16, 24, 25, 26 Protruding ears...... 4 10, 12, 17, 24 Mental retardation, mild...... 2 10, 22 Diminished immunoglobulins...... 6 11, 12, 15, 21, 22, 23 "Walks on tiptoes"...... 1 21 Diabetes mellitus...... 1 3 Anemia, mild, unexplained...... 1 5

* In five, and possibly more, of the 27 individuals, the records were considered inadequate for tabulating of such additional defects. These figures, therefore, indicate the minimum number of additional minor defects. However, it seems im- probable that other prominent malformations existed and went unnoticed. ** Dermatoglyphics were not examined in the other patients. 0 * '4 e Cd

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° t .SO TABLE 4 GEOGRAPHIC LOCATION AND ANCESTRAL ORIGINS OF PATIENTS

I. Present Location of Patient Case Identification Nos. (New York City...... 1*, 2*, 3*, 7, 13*, 14*, 16*, 24* California ...... 15*, 21 Indiana ...... 25*, 26* U.S.A. |Pennsylvania .... 17, 18 * Wisconsin ...... 22, 23 Colorado ...... 5 Maine ...... 6 Ohio ...... 27* Canada ...... 4*, 10, 11, 12 France (Brittany)...... 20 Israel...... 8*, 9* Mexico (D.F.)...... 19*

II. Ancestral Origins, Jewish Patients Case Identification Nos. Bialostok ...... 8, 19 Glogow ...... 2 Krakow ...... 2, 8 Poland Mezherichi . 9 Warsaw ...... 2 Unknown town...... 3 Zemberer** ...... 15 (p)t Berestechko ...... 16 Borzna ...... 1, 24 Kasperovtse ...... 4 (m)t Ukraine Kiev ...... 15 (m) Oleyevo Korolvka... 4 (m) Lvov ...... 15 (p) Rivna ...... 4 (p) Vladimir Volynskv ..... 16 Austria ...... 3 Moldavia ...... 1, 24 Hungary ...... 16, 25-26 (p) Lithuania (Retavas)...... 2 Russia (Odessa)...... 15 (m) White Russia (Volozhin) ...... 2

III. Ancestral Origins, Non-Jewish Patients Case Identification Nos. England ...... 6 (p), 10, 11, 12, 21, 25-26 (m) "Anglo-Saxon"...... 22, 23 France...... 5 (m), 6 (m and p), 25-26 (m) Brittany ...... 20 (m and p) "for nine generations," same village Germany ...... 5 (m and p), 17-18 (p) "Pennsylvania Dutch' ...... 5 (p) Holland ...... 17-18 (m and p) Ireland ...... 5 (m), 17-18 (m and p), 22, 23 .Italy ...... 7 (m and p) Mexico ...... 17-18 (m) Scotland 5 (m), 6 (mand p)

* Jewish ancestry. ** Phonetic spelling. t Ancestral origins of patient's father (p) or mother (m). BLOOM'S SYNDROME 213 (15, 25-27) are emigrants from that area. Affected individuals have so far been recognized in eight states of the United States and in four other countries (Table 4, I; Fig. 5). In general, they have been diagnosed by American dermatologists, partly because the syndrome has been given much attention in American dermatological journals and partly because the disfiguring facial lesion resembles lupus erythematosus and is most often the major problem in clinical management. Jewish ancestry is recognized in 12 of the 21 affected families, or in 15 of the 27 affected individuals (Table 1, Col. XVII; Tables 4-5). The Jewish families are of eastern European origin in each instance in which information was available (Table 4, II; Fig. 5), and the patients may be considered members of the Ashkenazim. One family (Ti.) represents the union of a Jewish father and a non-Jewish mother. Family So. left eastern Europe, lived in England for many years, and then settled in Brook- lyn, where patients 1 and 24 were born. Families Bu., Co., and Fi. went directly from eastern Europe to the New York City area; Family Ho. directly to Canada; Family TABLE 5 ANCESTRY AND PARENTAL CONSANGUINITY OF AFFECTED SIBSHIPS

PARENTAL CONSANGUINITY ANCESTRY TOTAL No Infor- Yes No mation Jewish ...... 1 9 2* 12 Non-Jewish ...... 6 3 0 9 Total ...... 7 12 2 21

* Patients 8 and 9. Tik. directly to Mexico; and families Ka'. and Ka2. directly to Israel. Families Ro., Se., and Ti. left eastern Europe, lived in New York City a few years, and then moved, respectively, to San Francisco, Cincinnati, and Elkhart, Indiana. History about family origins could not be obtained in the case of the Jewish family Si. In the families listed as non-Jewish in Table 4, III, the history was usually vague and uncertain as to the land of origin of ancestors, as is characteristic of many families who have lived in America for several generations. Parental consanguinity (Table 1, Col. XVIII; Table 5; Fig. 1) was documented in seven of the 19 affected families from whom information could be obtained. As is shown in Table 5, however, the incidence of consanguinity among the Jewish families is low (one of 10) but very high in the non-Jewish (six of nine). There was first-cousin consanguinity in only one mating (10), with first cousins once removed in two (5, 17-18), half first cousins in two (7 and 19), and second cousins in two (21 and 22-23). Pedigree Data and Analysis for Proportion of Affected Individuals The family data (Fig. 1) exclude simple dominant and X-linked recessive inheritance, whereas the high consanguinity rate and the affected sibs in six of 21 214 GERMAN families suggest that the disorder is transmitted as an autosomal recessive. The de- gree of completeness of ascertainment of this condition is unknown, in part because it is as yet unknown whether there are variations in clinical manifestations. Criteria for inclusion in the present series were, as described above, quite rigid in order to assure purity of the sample. Assuming incomplete ascertainment, and by subtracting one affected individual from each of the 21 families (Li, 1961), the corrected estimate of the proportion of homozygous affected individuals (b) is: b = (27 - 21)/(62 - 21) = 0.146, with SE = 0.0551. If, on the other hand, complete ascertainment was assumed, the maximum- likelihood method (Li, 1961, Tables 5-2A and 5-2B) yields b = 0.250, with SE = 0.00636. By the new method of Li and Mantel (1968), the "method of discarding the singles," b = (R - J)/(T - J) = (27 - 15)/(62 - 15) = 0.255, with SE = 0.00406 TABLE 6 NUMBER OF LIVEBORN AFFECTED AND UNAFFECTED SIBS, SEXES, AND AGES IN THE JEWISH AND NON-JEWISH

Sex Sex Individuals Male Female knownUn- Total Ratio M/F I: Affected, Jewish + non-Jewish (number) ...... 17 10 0 27 1 70 Jewish ...... 7 8 0 15 0.88 Non-Jewish ...... 10 2 0 12 5.00 Unaffected, Jewish + non-Jewish ...... 14 13 8 35 1.08* Jewish ...... 5 5 5 15 1.00 Non-Jewish ...... 9 8 3 20 1.12 Total, affected + unaffected, all families ..... 31 23 8 62 1. 35*

Age, mean (years) of all living affected ...... 14.7 7.3 ...... 12.3 ...... Age, mean (years) of all living Jewish affected .... 16.2 5.8 ...... 11.4 ...... Age, mean (years) of all living non-Jewish affected 13.7 11.0 ...... 13.2 ......

* Of individuals of known sex.

(where T = total number of all children, R= total number of affected, and J = number of sibships with only one affected). The true situation is somewhere between very incomplete (single) and complete ascertainment, and a correct estimate of the recessive proportion is impossible to obtain but lies between 0.146 and 0.255. Interesting results are obtained if the data are analyzed by the "first-appearance method" (Li, 1966), whereby it is possible to detect differences in the probability of an affected homozygous individual being the first-born in a sibship rather than a later-born sib. The analysis of the Bloom's sibships indicates that there is an increased number of first-born affected (Po = 0.188; pi = 0.529), but the small number of families and the incomplete ascertainment make the significance of this uncertain for the present. (The author is indebted to Professor C. C. Li for pointing out this interesting characteristic of the present data.) The sex ratio of affected individuals in the 21 sibships is distorted (1.70), whereas it is 1.08 among their unaffected sibs (Table 6). If the entire group of sibs (affected plus unaffected) is examined, there are eight too few females (31 males, 23 females), and BLOOM'S SYNDROME 215 they are missing from the non-Jewish families; in each of the eight non-Jewish families, the first affected was male. There are seven too few females in the affected group as a whole (17 males, 10 females), according to a recessive hypothesis, and again the non-Jewish families display a striking distortion (10:2).

DISCUSSION Mode of Inheritance of Bloom's Syndrome The data are best explained on the basis of a single autosomal gene with recessive effects. Sibs may be affected, and the estimated ratio of affected to unaffected among children of two heterozygotes lies somewhere between 0.146 (method of discarding the propositus) and 0.255 (method of discarding the "singles"). The explanation for the observed value of 0.146 is not certain, but could result from loss during embryonic life of some of the homozygotes, as discussed in Figure 6. The very low birth weight of those surviving intrauterine life suggests that such weights are near a threshold below which survival is unlikely. The disorder has been recognized predominantly in individuals of Jewish ancestry. However, this high incidence of Jews in the series (Table 1, Col. XVIt; Tables 4 6) must be considered in relation to two factors: (a) Dr. Bloom, who originally described the condition and who has maintained an active search for additional patients, practices private and consultative dermatology in New York City. In addition, the patients my laboratory is most likely to learn of live in the greater New York City area. (b) There is a great concentration of the world's Jewish population in the United States (42%V) and in the greater New York City area particularly (186 c) (Table 7). Of all Jews in the United States, 426,/ live in the greater New York City area, where they constitute 21%'o of the entire population. Of individuals in the New York City area affected with Bloom's syndrome, seven of the eight are Jewish (Table 4, 1). If the gene frequencies were the same in Jewish and in non-Jewish populations, the expected number of Jewish patients would have been only 1.1 (Table 7), assuming the non-Jewish individuals had an equal chance of being detected clinically. Of all 19 affected individuals in the United States, 11 were Jewish, whereas only 0.6 would have been expected, because only 2.9%o of the total population of the United States is Jewish. It seems, therefore, that, regardless of the two considerations mentioned above, the gene is much commoner in the Jewish population of the United States. The conclusion apparently can be extended to other areas of the western world, because of the eight affected who do not live in the United States, half are Jewish (Table 4, I). Other evidence for a higher frequency among Jews of the gene for Bloom's syndrome exists: Among 10 affected Jewish matings, parental consanguinity is known in only one (Table 1, Col. XVIII; Table 5), whereas among the nine non-Jewish, six record parental consanguinity. This very high parental consanguinity rate for the non-Jewish affected individuals indicates that the gene is very uncommon in non- Jewish American and western European populations, in striking contrast to its relatively higher frequency among the Ashkenazim. It seems of little practical value here to attempt estimates of gene frequency more precise than "very uncommon," not only because of the usual limitations of methods based on consanguinity rate (Stein- 216 GERMAN berg, 1959) but also because of the small number of families in the present series and the preponderance of relationships more distant than first cousins. A survey of geographic ancestral origins of the first 27 recognized patients affected with Bloom's syndrome gives rise to certain interesting conjectures concerning the origin of this gene. It has been difficult to obtain accurate or meaningful data concerning the historical and geographic origins of parents of most non-Jewish families, and the general impression is that they are of western European Christian ancestry. In contrast, the Jewish parents in nine of 11 families were able to provide the precise town or region from which they or their ancestors had emigrated (Table 4, II).

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FIG. 6.hihypothetical diagram, providinge arpossiblcaesteexpllmanatoo distrtio winhotheexece are i te dagam, amot lwas eig aoredeary n reganythediorer oud e dtete prprin(.5onlfhomoxygoussordicll,afcelthug individualsi woldocasinalybewheepesnuvewtnamlil,afetherendifthegeerais autosormoalereraefrecssv hertransamissieson,wul b an inrae aetlcnanunt ae ne uc icmtnetegeeitooymgtb bytheovrokdopropoexas.ifclenoetbis.Etnigteienicesnl rae nrutrnuteirnoaamgtb otltmosbeeesteftlbdodtc mAssimbercomesmoepa gee wichhenhomxygosdimiutive Thenverallosnumicbleriofheaffectedsipeltrsonsmactuallitraternuvvl avilabler forilinical detec-y teepce1in4pootionn n would bhesomevfactio homoyguafetdzygotesof the whic hadbe phresolducdmastrshow by Karnh andiblPnrose (1951) decresbusoeinbithweighabeomlowy abots 1agsthassctiaitedgwurithl90no grasether mortality regarles ofl there bingfaefultermlguviestation. eetdciicly(h < 2 arain theisga)hpteialmsdagram, thelagearrowtdeaindiae thegnanctua mhea bisrthr weight ofdthect27 hoozlyguinordividuyalshuginth presenocsurvely,wit fanilaffectedraiofther removaferomar ther famile of the indrexse patientaofonlya0.146.the range.ofnobervebuhirthweghstincs Blom' syndromeeisg inicatbed therexpeced 1rdinfiu4portionesabls.Etndinwich thesriveal ofurther ho moigotbe impsatrshold maentodterbt cas thnewhmc youh fetusonlyg nvery infrequentlyteinsurvivest aedeetdcincly(te«.2 BLOOM'S SYNDROME 217 These data were used to draw a map of migrations of Jewish patients' ancestors (Fig. 5), which shows that the gene was concentrated in the Ashkenazim of the Ukraine and neighboring eastern European regions, whence it was dispersed to the New World. The towns of ancestral origin cluster neatly in a small area several hundred miles across centering in the Lvov-Krakow-Berestechko region. This is the case not only for New York families but also for those now residing in Indiana, Ohio, and California (three of these families had, incidentally, also lived in New York City until less than 10 years ago), Canada, Mexico, and Israel. Comparing this map for the Bloom's syndrome gene with that for the Tay-Sachs disease gene (Myrianthopoulos and Aronson, 1967, their Fig. 1) demonstrates a clear difference; the Tay-Sachs disease gene in the present-day Ashkenazic Jews of the

TABLE 7 JEWISH POPULATIONS, ESTIMATES FOR 1964-1967 *

Category 'Number Jews in world ...... 13,302,700 Jews in U.S.A...... 5 ,600,000 Jews in New York City areat...... 2,381000 Total population in U.S.A ...... ca. 18,000,000 Total population in New York City areat...... 11260,000

Expec ted + Detected

All Bloom's syndrome patients, total number in U.S.A.§ . . 19 All Bloom's syndrome patients, total number in New York City area§. 1.1 8 Jews (only), Bloom's syndrome patients, total in U.S.A ...... 0.6 11 Jesw s (on1y), Bloom's syndrome patients, total in New York City area... 0 27

* Based on population figures printed in the 1967 World Almanac (New York: Newspaper Enterprise, Inc.), pp. 321-384. t Includes the five boroughs of New York City plus the counties of Nassau, Rockland, Suffolk, and Westchester. I If there were an equal gene frequency in Jewish and in non-Jewish populations, or approximately one affected indli- vidual with Bloom's syndrome detected per 10 million population in the U.S.A. § Jewish + non-Jewsish.

United States came from farther north, "from the provinces neighboring upon the Baltic sea, namely the regions of south Lithuania (Kovno) and the adjacent provinces of Suwalki and Grodno." The concentration in New York of recognized affected individuals during the 13 years since the syndrome was first defined reflects the heavy Jewish emigration from eastern Europe beginning in 1860 and continuing until 1924, when approximately 2,500,000 persons came from Russia, the Ukraine, Poland, and Rumania to live in the United States. These immigrants concentrated and remained mainly in the New York City area, in contrast to Jews emigrating from Germany between 1830 and 1881 (some 265,000), who tended to disseminate throughout the various states. From 1936 to 1946, an additional 250,000 Jews fled to the United States from Nazi-overrun countries, and these were predominantly Ashkenazic, including many from eastern European regions. (There was no major entry of the Sephardim into the United 218 GERMAN States after 1800, when the number of Jews was only something over 2,500 [Fischel, 1967].) A single mutation in an Ashkenazi is a possible explanation for the observations, gene frequency increasing by random drift or conceivably because of a presently unrecognized selective advantage during the bleak centuries of repeated massacres, crowding, and varied persecutions and restrictions. (The heterozygote will be the subject of a subsequent report [German and Crippa, in preparation], and at present not much can be said with certainty except that no striking growth retardation or increased familial incidence of neoplasms is yet apparent.) Even less can be said about the source of the gene in the non-Jewish families, but distant Jewish ancestry cannot be eliminated as a possibility in any one of them. In the United States, perhaps 5% of Jews marrying outside areas of mass settlement have chosen non-Jewish mates, and not uncommonly discriminatory employment practices probably have prompted sup- pression of accurate ancestral data. However, mutation in the non-Jewish remains an equally good possibility. Is the condition heterogeneous? Clinical evidence, including the personal view of Dr. Bloom, suggests that there is no difference in the general manifestations in the different families. The cardinal features as well as an increased incidence of various minor developmental defects and the consistent finding of chromosomal breakage and rearrangements are present in both Jews and non-Jews. The family Ti. (sib patients 25-26) is interesting in this respect and provides suggestive evidence favoring genetic homogeneity. During the interview with the father in this currently Christian family, it was disclosed that his paternal grandmother was a Hungarian Jewess, whereas the mother's ancestors reportedly are non-Jewish western European. This family may rep- resent a union of the gene of the Jewish and that of the non-Jewish populations, and the clinical features of the affected ("homozygous") children are indistinguishable from those of other patients. (Alternatively, each affected child could be a double heterozygote for different rare alleles at the Bloom's gene locus, each rare allele coding for a protein with similar functional properties so that the phenotype remains the typ- ical Bloom's syndrome.) Somewhat suggestive of heterogeneity, however, are (a) the distorted sex ratio among the non-Jews (Table 6) and (b) the different mean birth weights in the two groups (see caption of Fig. 4). More cases should be observed before the question of heterogeneity can be examined more carefully. The curious distortion in the sex ratio (M: F = 5.0) among affected non-Jewish individuals remains unexplained. It might be due to loss from the series of affected non-Jewish females, for presently unknown reasons. The over-all distortion of the sex ratio of all sibs in these 21 families (31:23) would become more meaningful if larger numbers of individuals were being considered, but for the present it raises the possibility that affected females are not being detected because of death in ulero or in early infancy (such a possibility as considered in Fig. 6). The mean birth weight of all affected females is lower than that of males (Fig. 4); several females have been very small at birth, and one (24) failed to thrive and died at three months of age. However, non-Jewish affected newborns actually tend to weigh somewhat more than the Jewish (see caption of Fig. 4), and girls weigh about the same as boys. The two non-Jewish stillborns (Fig. 1) were female, but one of these (family Sm.) is known to have BLOOM'S SYNDROME 219 weighed 3,124 g and so probably was not affected with Bloom's syndrome. The spontaneous abortion rate in these 21 families does not appear to be elevated (seven of 73 recognized pregnancies; Fig. 1). There is an unexplained age difference of the sexes (Table 1, Cols. III and IV; Table 6, II; Fig. 9), living males averaging 14 and living females only 7 years of age, so that an alternative explanation is that affected females are for some reason going unrecognized clinically, perhaps because of phenotypic manifestations of the syndrome which might be milder than in the male. Patients 12, 23, 24, and 26 possibly would not have been diagnosed had not a sib of each clearly presented the classic features of the syndrome, because in these four female individuals the skin lesions were minimal or absent early in life. In attempting to fit the ratios obtained in this collection of families to a simple Mendelian recessive, therefore, either a reduced viability of the female or the failure to recognize her because of a less striking phenotype might be considered a satisfactory explanation for the somewhat deficient number of affected individuals and for the distortion of the sex ratio. However, the persistence of the deficiency of those affected in these carefully scrutinized families, even after removal of the first recognized affected individual and the absence of a reversed sex ratio among the presumed unaffected (i.e., too many females), makes the possibility of diagnostic error less likely. Other explanations also exist, but more data are required before the true one can be recognized. One is sampling error; if, for example, the births following the first affected in each family are considered, there is no distortion of the sex ratio either among affected (4:3) or among unaffected (10:9) (Fig. 1). Also, as can be seen in Table 1, Columns IV and XXI, had this analysis been made before 1966, the sex ratio would have appeared even more abnormal (11:3). Bloom's Syndrome and Malignant Neoplasia The association in Bloom's syndrome of a simple genetics and a high incidence of neoplasia obviously is of more than passing interest, as discussed previously (Sawit- sky et al., 1966). The gene product is unknown, as are the steps between the gene and the final event constituting malignant transformation of a cell. However, this disorder assumes eminence as one in which genetic factors of importance in malignancy might be elucidated. At this point, it is worth noting that this syndrome has certain features in common with Fanconi's anemia, such as mode of inheritance, intrauterine growth retardation, and the occurrence of various developmental anomalies. An occasional patient with Bloom's syndrome may have a mild anemia of a type as yet unspecified (Table 2). In Fanconi's anemia, a severe anemia usually causes early death, but sometimes leukemia occurs. In both conditions there is an increase in chromosomal rearrangements in lymphocytes (for Fanconi's anemia, see Schroeder et al., 1964; Bloom et al., 1965; Schmid et al., 1965; Bloom et al., 1966; Schroeder, 1966) and in skin fibroblasts in culture (German and Crippa, 1966a, b; Swift and Hirschhorn, 1966; German and Bloom, in preparation), and possibly this occurs in vivo as well (Schroeder et al., 1964; J. W. Landau et al., 1966; Swift and Hirschhorn, 1966), although the latter possibility has been difficult to examine. More progress has been made to date in the search for the biochemical error in Fanconi's anemia than in Bloom's syndrome, a disturbance of hexokinase metabolism in the former having been detected by German 220 GERMAN investigators (Schroeder et al., 1964; Lihr et al., 1965a, b; Schroeder, 1966). A third disorder, the Louis-Bar syndrome or ataxia telangiectasia, may be considered here also, because it appears to be recessively transmitted and is reported to show chromosomal breakage (Hecht et al., 1966; Gropp and Flatz, 1967) and to have an increased expectancy for malignancy. Bloom's syndrome, Fanconi's anemia, and the Louis-Bar syndrome differ in multiple ways and are due to different genes, but that chromosomal changes and malignancy are common to all three suggests that the chromosomal phenomenon, regardless of its cause, could be of fundamental importance in the pathogenesis of neoplasia. Growth Retardation The mechanism by which the individual homozygous for the Bloom's syndrome gene is retarded in growth in utero, in infancy, and in later life is also subject to study. If the affected fetus after 266 days (the normal human gestation) weighs only 1,988 g, whereas the normal fetus has developed much greater mass (3,450 g at The New York Hospital) over the same period, the former has either fewer or smaller cells. Methods are available for measuring the cell size, and this might be done, but visually neither blood cells nor fibroblasts in culture derived from these patients appear unusually small, thus favoring the explanation that there are just fewer cells per individual. For there to be fewer cells after the same period of growth, either fewer cells must be produced, perhaps through prolongation of the cell generation time, or the cells produced through mitosis must have a high mortality rate. It has been shown in long-term cell cultures derived from biopsies of skin from individuals with Bloom's syndrome that, in contrast to cultures derived from nonaffected individuals, a high proportion of cells in anaphase and telophase show bridges, lag, or loss through nondisjunction of chromosomes or chromosomal fragments (Fig. 7) (German and Crippa, 1966a, b). Cor- respondingly, many cells in interphase have aneuploid nuclei, with distortion of nuclear contour, binucleus, or one or more micronuclei (Fig. 8). Many such cells are able to survive in vitro but would be incapable of many successful subsequent divi- sions. Chromosomal breakage and rearrangement cause this phenomenon (German and Crippa, 1966a, b). It seems reasonable to postulate that such events occur in vivo, and the high mortality, or inability to divide, of genetically unbalanced daughters of cells in which chromosomal aberrations have occurred may therefore be the best explanation presently available for the presumed abnormally small number of cells in the term fetus. This phenomenon could play a further role in growth retardation after birth. The minuteness of individuals with Bloom's syndrome in combination with an absence of serious body disproportion is perhaps the most conspicuous feature of this disorder, and it is striking indeed (Figs. 2 and 3). In contrast to newborns who are small because of premature birth, the newborns with Bloom's syndrome seem quite normally mature and, except for minor gastrointestinal difficulties or respiratory tract infections, generally do well during infancy and childhood. Development of intelligence, personality, and physical agility has, in general, been comparable with that in persons of normal body size, but a noteworthy problem of those affected appears to BLOOM'S SYNDROME 221 have been that of adjusting psychologically to a society composed almost entirely of much larger individuals. They eat less, which often is a concern to their parents. They often suffer during childhood because other children tease them or discriminate against them because of their smallness. The girls (2 and 23) who have passed puberty for whom I have records menstruated regularly and showed no evidence that they could not have carried a fetus had it been as small as are those fetuses homozygous for the Bloom's syndrome gene. There has been no recorded mating of two homozygotes, who would of course themselves conceive only homozygotes. This mutation might have been a reasonably good one to have increased in frequency, had there ever been a selective premium on small body size. Against this possibility, however, would have been the infertility of at least some affected males, discussed

.. .-

FIG. 7. Abnormal mitotic figures are found in cultures of skin fibroblasts derived from normal individuals (B, E, G, and H) but much more frequently in those derived from individuals with Bloom's syndrome (A. C. D. and F). These mitotic cells growing on coverglasses were fixed without colcemide or hyposmotic pretreatment and were stained with the Feulgen reaction followed by 1% light green (except in G which had only Feulgen to demonstrate the black and white reproduction of the Feulgen- positive material in these cells). A, Metaphase with two displaced chromatin masses. B-G, Anaphases and telophases with chromatin bridges or lagging chromosomes or chromosomal fragments. In C, a faint bridge exists between the two separating chromosomal masses, and there is also a chromatin mass displaced to the periphery of the cell (3 o'clock). In D, two large and two minute pieces are lagging midway between the separating chromosomes. H, Daughter cell with its chromatin still tightly condensed; two small chromatin masses are displaced from the major nucleus and presumably would have given rise to an interphase cell with micronuclei like those in Fig. 8g-i, one of which would be attached by a filament to the major nucleus as in Figs. 8f and 81. These cell lines were derived from biopsies of the skin of patients 3 and 5 (from German and Crippa 1966a). FIG. 8.-Cells in late telophase (A), interphase (B-I and K-M), and early prophase (J) growing on coverglasses, fixed without colcemide or hyposmotic pretreatment, and stained with the Feulgen reaction followed by 1% light green (except M, which had no light green counterstaining to demonstrate the black and white photographic reproduction of Feulgen-positive material; the green cellular portions reproduce as a faint gray). Phase contrast microscopy in C and G only. Sources of cells: skin fibroblast cell lines from Bloom's syndrome patients 3 and 5 (A-F, H, J-L); normal human skin fibroblast cell lines (G, I, and M). A-B, Chromatin filaments, possibly broken, remain stretched between these daughter nuclei. C, A Feulgen-positive filament continues to connect these two sister cells, whose nuclei are distorted at the points of the filament's connections. A piece of condensed chromatin in the otherwise greatly extended filament is seen near the cell on the right. D, Cell with an approximately double amount of nuclear material. This quasi-binucleated cell has the two major nuclear masses con- nected by a curved filament. A further remarkable symmetry is imparted by two larger micronuclei (longer arrows) and two smaller micronuclei (shorter arrows). Such cells presumably contain chromosomal rearrangements and may be interphase counterparts of tetraploid metaphases, in which it is not uncommon to detect rearrangements. E-F, Feulgen-positive nuclear appendages. G, In this cell, in a culture derived from a normal female, there is nuclear deformity and a micronucleus. Note the sex chromatin mass of Barr (short arrow) in the major nucleus and condensed chromatin (long arrow) in the micronucleus. Such abnormal cells exist in increased frequency in Bloom's syndrome lines. H-I, Feulgen-positive micronuclei. In H, two masses of condensed chromatin are visible. J, A cell in early prophase in which the chromosomes are beginning to condense in both the major nuclei and the micronuclei. K, Cell with three micronuclei, one of which contains a fleck of condensed chromatin (arrow). L, Multiple micronuclei, one very large with its own appendage and nucleoli. M, The cell extending across the field has had its nucleus replaced by multiple (at least 20) micronuclei. A normal nucleus lies just below this cell. (From German and Crippa, 1966a.) BLOOM'S SYNDROME 223 above, and the tendency of those affected to develop infections of the respiratory and gastrointestinal tracts. The clinical implications of these considerations are that affected individuals, who constitute a young group, require careful surveillance and study in order that better understanding of the course of the disease may be obtained. The ages of the 22 living affected individuals fall into an interesting distribution (Fig. 9). Through the age of 14, there are about the same number of boys and girls living, but no female is known to be alive beyond that age. Through the age of 21, there are 21 individuals alive at various ages, but after that age there is the isolated example of patient 4 (Ge. Ho.), who at age 34 represents the oldest known affected individual. Of the six who have passed their twenty-first birthdays, three have died of leukemia or cancer (Fig. 9). Possible explanations for the age distribution among those living include the following: (a) Perhaps the most reasonable is a greatly increased chance of survival for these NUMBER OF DEAD

.0 = MALE 4_3 =FEMALE

LIVING 2-

, Io : , I,I AIII 2 4 6 8 40 42 14 46 18 20 22 24 26 28 30 32 34 36 38 Z3S AGE (4967) FIG. 9.-Age distribution and sex of the 27 persons with Bloom's syndrome, as of 1967. Seven males but no female is living beyond age 15. Only one patient is known to be alive beyond age 21. Half of those who have survived to age 21 have subsequently died of malignant neoplasia. very small infants as a result of the widespread use of antibiotics since the mid-1940's along with improved facilities for caring for the newborn of low birth weight. This appears reasonable in view of the observation that many infants and children with Bloom's syndrome clearly have an increased susceptibility to infections. Furthermore, it would account for our failure to have recognized this striking syndrome before 1954 (Bloom, 1954a), about the same time Bruton (1952) recognized X-linked congenital agammaglobulinemia. (b) Individuals beyond age 21 could also be lost from our series because of death from malignancy. (c) There conceivably could be a failure by physicians treating the adolescent and adult populations to diagnose the condition. The true explanation for this unusual age distribution will come with long-term observation of the presently recognized affected individuals. Hopefully, other affected individuals will also come under study, and measures for management of the three major aspects-growth delay, the disfiguring skin condition, and the possibility of malignancy-will be forthcoming. In addition, medical surveillance of this group may shed new light on the pathogenesis of malignant neoplasia. 224 GERMAN

SUMMARY Bloom's syndrome, or congenital telangiectatic erythema and stunted growth, is a recently recognized, infrequently encountered disorder. Its predominating clinical features are small body size and a sun-sensitive telangiectatic skin lesion which in its facial distribution resembles lupus erythematosus. Growth retardation, both intrauterine and extrauterine, is severe, the average full-term birth weight being 1,988 g, and the average height of the individuals who have passed the age of 20 years being 142 cm. The well-proportioned minuteness of the affected individual is the most striking clinical feature of the syndrome. In addition to these three cardinal clinical features, various minor congenital anomalies commonly occur. In tissue cultures of blood and skin cells derived from affected individuals, a high incidence of chromosomal rearrangement of a characteristic type is regularly demonstrable, with a con- comitant increase in incidence in long-term cultures of living but aneuploid cells. The group is young, the living males (as of mid-1967) averaging 14 years, the females 7. More affected males than females have been recognized, the sex ratio being 1.70. Five individuals have died: one failed to thrive and died in early infancy, three died of acute leukemia, and one died of a carcinoma. Three of the six who have passed the age of 21 have died of malignancy. Recognition of more affected persons and careful, prolonged surveillance of the group are required for the accumulation of adequate understanding of the natural course of the disorder. Therapeutic needs include a treatment for the growth disorder, improved management of the skin lesion, and early recognition and control of neoplasia should it appear in other individuals with the syndrome. The genetic data are best explained on the basis of a single autosomal gene with recessive effects. The discovery during the past 13 years of only 27 affected individuals is a reflection of the infrequency of the gene in the general population. Twelve of the 21 affected families are of the Ashkenazim, and in these only one parental union was consanguineous. In contrast, in the non-Jewish families, six of nine were consanguineous, indicating that there is relatively a much lower frequency in the non-Jewish than in the Jewish European-American population. The Jewish gene in the American population had its immediate origin in a localized area of eastern Europe, and the ancestral towns or regions have been tabulated for most families. No clinical evidence exists for different forms of the condition. However, the distorted sex ratio in the non- Jewish families (5.0) but not in the Jewish (1.08) and the higher birth weight in the former (2,209 g versus 1,825 g) may possibly be indications of genetic heterogeneity. This paper, the first in a series on Bloom's syndrome, summarizes clinical and genetical observations which are available from the first 27 affected individuals to have been recognized. Subsequent papers will report the cytogenetics of the homo- zygote and heterozygote and further details of the clinical syndrome in a group of previously undescribed patients. ACKNOWLEDGMENTS Dr. David Bloom, who first called my attention to this syndrome in 1960 when he re- quested cytogenetic evaluation of patient Su. Bu. (Table 1), has repeatedly provided advice BLOOM'S SYNDROME 225 and assistance during this study, and in addition we have made several field trips. I wish to thank him for this most valuable and enjoyable co-operation. To Professor Reginald Archibald of Rockefeller University I am indebted for stimulating discussions and for helpful opinions in the clinical evaluation of several patients. Professor C. C. Li gave me helpful advice concerning application to the present data of his new method of estimating the segregation ratio prior to its publication (Li and Mantel, 1968). The author gratefully acknowledges the assistance of the following physicians, whose help made a co-operative study of this magnitude possible. Through their kind co-operation and sincere interest both in the patients and in this newly recognized syndrome, it has been possible to arrange clinic and home visits, to conduct autopsies, to collect the required data from old medical records, and to obtain specimens, photographs, and pedigree details: Dr. Lewis Brunsting, Mayo Clinic, Rochester, Minnesota; Dr. A. Chute, Hospital for Sick Children, Toronto; Dr. Patrick E. Conen, Hospital for Sick Children, Toronto; Dr. Jean de Grouchy, Hopital des Enfants Malades, Paris; Dr. Cutting B. Favour, St. Mary's Hospital, San Francisco; Professor Thomas B. Fitzpatrick, Harvard Medical School, Boston; Dr. W. S. Gibson, Pittsburgh; Dr. L. C. Harber, New York University Medical Center, New York City; Dr. V. N. Kyle, Port Arthur, Ontario; Dr. J. W. Landau, University of California School of Medicine, Los Angeles; Dr. E. C. Liss, South Bend, Indiana; Dr. Barton Lewis, Colorado Springs, Colorado; Dr. John Opitz, University of Wisconsin School of Medicine, Madison; Dr. Eberhard Passarge, Cornell University Medical College, New York City; Dr. Jean Priest, University of Colorado Medical Center, Denver; Dr. Joseph L. Rauh, Cincinnati; Dr. Jacob S. Rosen, Brooklyn, New York; Professor A. Rossier, Hopital St. Vincent-de-Paul, Paris; Dr. Arthur Sawitsky, Long Island Jewish Hospital, New Hyde Park, New York; Dr. S. N. Schiewe, Port Arthur, Ontario; Dr. E. J. Schoen, Oakland, California; Dr. Irwin H. Schwab, Colorado Springs, Colorado; Dr. P. Sizonenko, Hopital St. Vincent-de-Paul, Paris; Dr. Edward A. Tibbets, Portland, Maine; Dr. Irene Uchida, Winnipeg, Manitoba; and Dr. C. R. Yoder, Elkhart, Indiana. REFERENCES BLOOM, D. 1954a. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs. Amer. J. Dis. Child. 88:754-758. BLOOM, D. 1954b. Congenital telangiectatic erythema in a Levi-Lorain dwarf. Arch. Derm. 69:526. BLOOM, D. 1965. Genodermatoses. Med. Clin. N. Amer. 49:695-708. BLOOM, D. 1966. The syndrome of congenital telangiectatic erythema and stunted growth: observations and studies. J. Pediat. 68:103-113. BLOOM, G. E., GERALD, P. S., WARNER, S., and DIAMOND, L. K. 1965. Chromosome aberrations in constitutional aplastic anemia and their possible relation to other hematopoietic disorders. J. Pediat. 67:924-925. BLOOM, G. E., WARNER, S., GERALD, P. S., and DIAMOND, L. 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Corrigendum In the article "Inheritance of Multiple Epiphyseal Dysplasia, Tarda," by Rich- ard C. Juberg and John F. Holt, which appeared in the November, 1968, issue (Vol. 20, pp. 549-563), Figure 8 was inadvertently printed upside down.