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Bloom's Syndrome. I. Genetical and Clinical Observationsin the First Twenty-seven Patients
JAMES GERMAN'
INTRODUCTION
Bloom's syndrome, also termed congenital telangiectatic erythema and stuntedgrowth, 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 andnamed its "three cardinal features" (Bloom, 1966): (a) telangiectatic erythema ap-pearing in infancy, affecting almost exclusively the butterfly regions of the face,cheeks, nose, margins of the eyelids, lips, forehead, and ears, but occasionally alsoaffecting the dorsa of the hands and the forearms; (b) sun sensitivity, so that thetelangiectatic skin lesions often first appear or become accentuated in summertimeand usually ameliorate when protected from sunlight; and (c) stunted growth, themost conspicuous feature of the syndrome. This last feature is distinguished bysmaller than average size both at birth and also during various periods of childhoodand adulthood. The maximum height achieved has been 161.3 cm, in a boy who isnow 17 years old; no other individual has exceeded 148 cm (Table 1, Col. X). Thebody proportions appear approximately normal, but the patients usually are delicateand slender. There is disproportionate microcephaly, which is accentuated by thedelicacy and narrowness of the face. The affected individuals bear a striking generalresemblance to one another because of the small, narrow face, the dolichocephalichead, the localized red lupus erythematosus-like facial skin lesion, and the conspicu-ous dwarfism. The skin lesion tends to become less severe as the individual growsolder, but sometimes scarring, atrophy, depigmentation, and loss of eyelashes becomeprominent 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 generallygood, although sometimes feeding difficulties occur in infancy, and many have hadincreased numbers of infections of the respiratory tract or ears requiring antibiotictherapy in infancy and early childhood. Satisfactory treatment for neither the telan-giectasia nor the growth retardation has been found.
Three additional recent observations have increased the scientific importance ofthis 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 theNational Institute of Child Health and Human Development and by grant E-461 from the AmericanCancer Society.
l The New York Blood Center, New York, New York 10021.
196
BLOOM'S SYNDROME
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 andBloom, 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 parentalconsanguinity and Jewish ancestry have suggested a recessive pattern of inheritance(German et al., 1965), but the genetic analysis of the condition has awaited recognitionof a larger number of affected families. (b) Cytogenetic studies in 22 affected indi-viduals have demonstrated a consistent abnormality in cells cultured in vitro, atendency 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 numbersin cultured cells from some parents of individuals with this syndrome (Sawitsky et al.,1966; German, unpublished observations). (c) There is an increased expectancy forthe 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 beenrecognized as affected with this rare disorder. The purposes of the report are to addto the understanding of the clinical features and course of the disorder and to compilethe evidence required for definition of its genetics.
MATERLALS
For clarity and conservation of space, a tabular style for presenting most of theobservations has been chosen (Tables 1-7; Figs. 1, 4, and 5). The tables and figurescontain cross-references, so that from them a fairly complete description of eachindividual can be reconstructed. In Column I of Table 1, each of the 27 affectedpersons has been assigned a case identification number in the approximate order inwhich they were recognized or reported in medical journals. Each person is furtheridentified by the first letters in his first name and family name. (Names are notknown for patients 8, 9, and 21, so the initials of the author reporting each case wereemployed.) The initials of the family name of the propositus and the identificationnumber 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 fromthis laboratory. Photographs of some of the individuals in the series are shown inFigures 2 and 3.
Ascertainment of Affected Families
Ascertainment in these families was through an affected individual, and theseindividuals have come to my attention during the past eight years in one of the follow-ing 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 thatthe etiology of the syndrome might be an imbalance of the chromosomal complement.
197
TABLE 1 SUMMARY OF DATA CONCERNING THE FIRST 27 INDIVIDUALSA blank space indicates that the
I II IIII_ -I
-o
3..
.z
1....
2..
3....4....5....6....7....8....
9....
10....11....12....13....14....15....16....17....18....19....20....21....22....23....24....
25....26....27....
28....29....30....31....32....33....
-e
-c
Ce. So.
Su. Bu.
Ho. Co.Ge. Ho.Ja. Oa.De. Sou.IRFo. Ta.Ka.'
Ka.'
Gr. St.Ia. Th.De. Th.De. Si.le. Si.Ma. Ro.Et. Fi.Ch. Sm.La. Sm.Sy. Tik.Bo. Le.La.'El. Ha.Na. Ha.Ro. So.
St. Ti.Sa. Ti.Ly. Se
Cas.'Cas.2Ke.'Ca. D.Mi. Ko.Be. Be.
I._Po
cd
'33
'50
'49'33'34'47'46'57
'49
'50'49'53'54'55'61'61'57'60'42'65'(0'56'59'32
'63'64'64'61'62'64'55'62'54
IV
x
M
F
MMMMMM
M
MMFFMMFMMFMMM
F
FFF
MFMFMF
V VI VII
4)
cdP-4
.0
0
p0
29/29
28/25
28/2133/2536/2827/25
28/2828/2632/30
30/2542/3118/2021/234-2/3630/2525/2743/3244/3327/27
25/26
29/27
30/2542/
0
. s
O >
0 0Z Bn
E 11
+
+++
±+±
+++
++++
32 wk.
++
+
++++++
32 wk.
++
Cd
.0
cd
1,815
1,362
1,7601,9101,9862,1162,2152,350
2,000
2,0162,1002,0431,5901,8181,7601,5322,4852,9251,6001,9802,0002,3712,2791,362
2,1302,2291,960
2,1002,3001,3501,9801,3072,359
VIII
n
00.)
25/obese
13/31
17/55.533/5429/3618/3518/402. 7/8.3
10/17.3
10/14.511/18.98/12.45/115/114/9.42.3/5.87/165/9.623/351/5.25.7,/9.911/178/23
2.5/7.51.3/6.32/6.8
4/11.32.5/82/6.58.2/13.15/9.1
Ix
45
39.4
41.54646.246.2
40
x
-o0
25/14513/ 132
17/161.333/14630/142.518/ 14318/1482.7/78
10/118
10/11211/1198/102
4/862.3/747/1025/8123/1341/615.7/9211/1278/126
2.5/761.30/12/74
4/912.5/77.42/748.2/1055/87.5
XI
_s
bo
3/40
3.5/43.832/47
10/45.711/50.38/49.5
5/45.75/43.2
1.1/394.5/45.213/46.912/47.4
1.5/421/40.80.09/32.7
8.2/46.5
XII
40.b
H0.i0)0aw
E400Q0
+
++
+++++++++++
±Z(+7~+=+n~+n±+n
XIII
+
++
++
+
+
+-++
198
=
To BE RECOGNIZED (1-27) AND SIX MORE RECENTLY RECOGNIZED (28-33)information could not be obtained.
xx
Q~~~~
0
Cd
25 yr./ leukemia
13 yr./leukemia
32 yr./carcinoma
23 yr.1/leukemia
3 mo./failure to
thrive
xxI
0
Ou 0
P4 -0 0'-0
I..
-'54
'54
'57'5'5'58'60
'60
'63'63'63'63'63'66'66'66'66'66'66'66
*
O* V
XXII
_
,: -4
.0
.0 c,H cu-44
uw *g mE- 'd -
0 3
; * 0r.
0
Bloom, 1954a, b, 1966; Sawitsky etal., 1965, 1966;Cellis et al., 1966***
Bloom, 1954a, 1965, 1966; Torre and Cramer,1954; German, 1964; Sawitsky et al., 1965,1966; Gellis et al., 1966**, ***
Bloom, 1954a, 1966; Curth, 1964**,Brunsting, 1957**Lewis, 1957; German and Crippa, 1966**Hillman et al., 1957; Fitzpatrick, 1962**Stritzler, 1958; Stritzler and Stritzler, 1966**, ***
Katzenellenbogen and Laron, 1960; J. Landauet al., 1966
Katzenellenbogen and Laron, 1960; J. Landauet al., 1966
Szalay, 1963**Szalay, 1963**, ***
Szalay, 1963**, ***
Wolf, 1963; L. C. Harber, unpublished***Wolf, 1963; L. C. Harber, unpublished***Bloom, 1966; Schoen and Shearn, 1967***Bloom, 1966**, ***
Bloom, 1966**, ***
Bloom, 1966**, ***
Sawitsky et al., 1966Grouchy, 1966; Sizonenko et al., 1967 a, b**,J. W. Landau et al., 1966J. Opitz, unpublished**J. Opitz, unpublished**
E. C. Liss and C. R. Yoder, unpublished** ***
E. C. Liss and C. R. Yoder, unpublished**" ,
J. P. Rauh, unpublished
199
XVI XVI .IXIV
-!r.0
*0v)
._0
.4
-4'
cn
be
10
9
3
3
7
3
3
3
Birth
6
4
12
3
8
118
912
8
6
6
36
XVIII
.61
U
b.D
r.0
p14 1
o ZcdEn
_
+(1/32)
+(1/32)
+(1/16)
+(1/32)+(1/32)+(1/32)
+(1/64)+(1/64)+(1/64)
XV
En
0
a
C)
~4cd
+
+
+
+
+d
0
p4
Q
+_
ed
._
:t
+
+
+0
+V
XI)
I0
4'1cd
0
4) B
v o~
0_.0
cd cd
00E F-en 0
U
+
+
+
+
(+)
(+)(+)(+)
+
'n
+
+
+
6369
5 + + - +(1/16) '66 Casado de Frias, 19667 - + - +(1/16) '66 Casado de Frias, 1966
20 + - - (+) '67 Keutel et al., 196770 + _ - '67 Hooft et al., 196712 + + + - + - * * *6 + - + - - * P. E. Conen, unpublished"*
1-..l
=
I
::K.
I
=
The complement was found to be normal, but the unexpected finding of an increasedincidence of chromosomal breakage in this individual's lymphocytes in short-term cul-ture, at that time an undescribed phenomenon in human cytogenetics, stimulated myinterest in the phenomenon of spontaneous chromosomal rearrangement and led to asearch for other individuals affected with this syndrome. Patients 15-18, 25, and 26came to the attention of Dr. Bloom through referral or personal reporting to him byother physicians, and he in turn told me of them; certain of these have been reportedsubsequently (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 interestin the syndrome. Patient 24 (Ro. So.), the dead sib of the first patient to have beendescribed with Bloom's syndrome (1, Ge. So.), was discovered during my visit withthe surviving mother of patient 1 in her home, where she had kept photographs andbirth 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, andadditional data have been obtained by personal correspondence or conversation with
Bu Co. fS. Ha. Ho. KatO TO 0 s a OTO OT
2 3 ~~ ~~~~16 22 23 4 8
Ka.2 La' Le. Oa. Ro.
9 a 21 2051
Se. Si. Sm. So. Sou.
OTr° 0 OTO or6~~~~~~_8;8 IL;1bS i 1 bA
27 13 14 17 18 24 f1 61
St. Ta Th. Ti. Tik.
10 7 11 12 25 26 9
LEGEND
Affected male Small symbols:
Clf Unaffected, dead male <9 Spontaneous abortion
6t Unaffected female, infantile death I Induced abortion
< Sex unknownE Consanguineous unionj \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 the27 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 patient27 (Le. S*t) were a girl and a boy, and of patient 10 (Gr. St.) a boy and a girl (two sibs only, ratherthan the three diagrammed).
200 GERMAN
b
a:*w-
c d
FIG. 2a-d.-Photographs of individuals with Bloom's syndrome. The facial skin lesions appearinggray 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
4
P.
g hFIG. 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
f
Al-
NI iwt;.
.-0 IW
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 pa-tients. k, Patient 16 at age six. !, Patient 17 at age eight.
203
M
FIG. 2m-p.-m-n, Patient 26 at ages two and three. o-p, Patient 25 at age four
204
11
q r
FIG. 2q-r.-Patient 5, at age 32 one of the oldest individuals known to have this syndrome. Heweighed 21 kg (56 pounds) when photographed, partly because of dysphagia consequent to lingualcarcinoma.
a b
FIG. 3-Affected individual 15. a, Photographed at the age of eight weeks. From the age of sixweeks he had been able to stand supported by grasping his father's finger, apparently because ofmature 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 97.5cm. A bright red facial lesion was present.
205
the reporting physicians and by my personal contact with the patients (2-7) and/orfamily (1). Other patients have been reported or recognized during the course of thesurvey (20 and 21), and additional data concerning them have been sought throughpersonal 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 per-sonal examinations, the patient indeed represents an example of this particularsyndrome. 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 andlengths, and clinical laboratory studies have been accumulated and are summarizedhere. Hematological data, although scanty, have been compiled (Table 2). The pres-ence of minor developmental defects in addition to the cardinal features of the syn-drome has been tabulated (Table 3). A more detailed clinical description and growthrecord of a number of previously undescribed patients will be reported separately (Pas-sarge and German, in preparation). (b) Cytogenetics: Studies of blood cells, bone mar-row cells, and fibroblasts in culture have been made in both homozygous and hetero-zygous individuals, and extensive reports of cytological and cytogenetic abnormalitieshave or will be made, as referred to above. (c) Pathological: Individuals 2 and 5 havebeen studied at autopsy, and detailed reports are in preparation. The findings inpatient 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 inDenver, is gratefully acknowledged.) (d) Genetic: Pedigree data have been accumu-lated (Fig. 1), and segregation analysis has been made to determine whether thefamilial distribution supports the statistical expectation for autosomal recessivetransmission. Investigation has been made into the ancestral geographic origins andmigrations of the 27 affected individuals, all but three of whom were born in NorthAmerica (Table 4; Fig. 5). In a search for genetic heterogeneity, correlations havebeen made between certain clinical features and ancestry.
OBSERVATIONS
The findings are summarized as follows: Table 1 includes most of the data of ageneral nature. The 21 pedigrees are diagrammed in Figure 1. Special data are pre-sented in Tables 2-3 and Figures 2-4 and 7-8. Genetic data appear in Tables 4-7and Figures 1 and 5.
* Excellent reports of four other affected European individuals have become known to me sincethe present compilation was completed. They are designated cases 28 (Cas.1) and 29 (Cas.2) (Casadode Frias, 1966); 30 (Kel) (Keutel et al., 1967); and 31 (Ca. D.) (Hooft et al., 1967). In case 30, Keutelet 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 inthese six new cases are not included in Tables 2-8, nor are they commented on in the text of thispaper; however, they have been appended to Table 1.
206 GERMAN
BLOOM'S SYNDROME 207
General Description of the GroupEach of the 27 individuals included had the clinical criteria described in the In-
troduction, and these "cardinal features" will not be discussed extensively in thisreport. 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 berecognized 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 nameinitials as used in Fig. 1.) No family with more than two affected members has yetbeen found.
At the time of writing (mid-1967), the group is young (Table 1, Col. III), the aver-age 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- CommentNo. (Years) g/100 ml X106/mm3 crit
1 ... ..25 9.5-11.0 .......... ......... Leukemia present (Sawitsky el alt,1966)
. . . . 114.3 ...... 362 9.6-10.5 3.3 34 .................................
3 11 .2 3.6 ......... ......................
4 11.3 3.79 13.010 10.812 10.213 4.0 .......... 12 Leukemia demonstrable in blood and
marrow at age 13. Complete datapublished by Sawitsky et al. (1966).
3..... 14 13.7 4.5 ......... Bone marrow normal17 16.9 .......... 48 Retic. 1.2%
4. . . 34 14.4 4.95 42 ..............................
5. . . ..... 27 13.1 ........ 40 .............................
27 11 .8 3728 13.4 .......... 42 ................................30 12.8 .......... 40 Bone marrow normal
8 .. . ...210.8 3.5 ......... ................................
14 .. . ...611.7 4.0 ......... .................................
16 .. . ...613.6 .......... 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 31-381 12 .2 .
3 11.1 4.0 314 11.1 .......... 33 Retic. 1.0%
26 . ..... 2 11.2 ..........
3 9.6 .5 .......... 29.5 Retic. 1.0%0
individuals in the series died between the ages of 13 and 32 (Table 1, Col. XX), andin each case (except for patient 24, Fig. 2a, who weighed only 1,362 g at birth, de-veloped an abscess of the buttocks, failed to thrive, and died at home for unknownreasons at three months of age), the cause of death has been either acute leukemia orcancer (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).
Male Female5
+2o' . +2o'4
+ Cr~
Kg 3
2 o
pi~e**
FIG. 4.-Birth weights of each male and female affected individual (black circles) shown in rela-tion 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 in-dividuals, exclusive of the single pre-term individual (19), is 1,988 g (p = pre-term; t = dead in-dividual).
Only one of the group weighed > 2,500 g; 15 weighed 2,000 g or less. The mean birth weight ofthe affected Jewish individuals was 1,825 g (male, 1,916 g; female, 1,740 g); of non-Jewish individ-uals 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 thriveand died of unknown causes at three months of age, whereas the other (2) remained healthy until shedied of acute leukemia at 13 years of age. The two heaviest affected newborns in the series (sibs 17and 18) had unaffected sibs who weighed 4,402 g and 5,027 g at birth; their mother weighs 126 kg, andtheir maternal grandfather weighed 198 kg (436 lb.).
Specific Physical AbnormalitiesThe 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 smalland as a group have a mean birth weight lower than that of males (Fig. 4). The meanbirth length (Table 1, Col. IX) was 44 cm in the six individuals tabulated (meannormal = 50 cm). Despite very small size, there were no signs of developmentalprematurity, and, although continuing to show growth retardation, subjects reached
208 GERMAN
BLOOM'S SYNDROME
the usual developmental milestones such as walking and talking at the expectedtimes if not earlier (see Fig. 3). Increases in body weight and height are severely re-tarded at all ages after birth, as will be documented more extensively in a subsequentpublication (Passarge and German, in preparation). The maximum body heightachieved in an affected male has been 161.3 cm (patient 3; Table 1, Col. X), in a fe-male, 134 cm (patient 19). The head circumference appeared inordinately small atbirth (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 sun-light, there was serious permanent disfiguring from scarring, depigmentation, andatrophy (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 con-tinuing localized areas of telangiectatic erythema which did not interfere seriouslywith appearance. In at least eight patients, sun-sensitive skin lesions were presentover the dorsa of the hands or forearms (Table 1, Col. XIII) or on the back of theneck and ears (patient 11), in addition to those on the facial areas. In an occasionalpatient, small localized telangiectatic lesions were noted elsewhere on the skin surface.Skin areas other than the face, hands, and forearms did not appear unduly sensitiveto sunlight; for example, several affected children have played throughout the sum-mer, with the skin of almost the entire body exposed, without detrimental effects ex-cept over the facial areas. In three patients, phototests have been performed duringwhich normal-appearing skin of both lumbar and facial areas was irradiated with bothultraviolet and visible light (L. C. Harber, unpublished). No abnormalities in theerythema threshold, magnitude of response, or persistence of erythema were noted.
In addition to the telangiectatic erythema, several other skin abnormalities oc-curred in these patients (Table 1, Col. XV; Table 3), most notably cafe au lait spotsin more than half the patients for whom information as to their presence or absencewas obtainable.
Additional Physical AbnormalitiesIn addition to Bloom's "three cardinal features," minor defects were frequently de-
tected in these individuals (Table 1, Col. XVI; Table 3; Fig. 2j). Information, al-though not always complete, was available concerning the presence or absence ofsuch defects in most individuals, and in 22 of these at least one developmental defectwas recorded. Mental retardation has occurred but is uncommon, and congenitalheart disease has not yet been described. Abnormalities of bony development ofvarious types were found in 12 patients. "Colloid-body-like spots" in Bruch's mem-brane 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 foundat autopsy in patient 5 (German, unpublished), and the testes are unusually small inpatient 3 (Bloom, 1965); they are both unusually small and also soft in patients 4, 10,
209
210 GERMAN
and 22. In addition, the testes were undescended in four patients. However, in patient11 the testes are proportionately small for total body size and have normal consist-ency. The existence of an abnormality of immunoglobulin levels has recentlybeen recognized (J. W. Landau et al., 1966; Schoen and Shearn, 1967). A mild andunexplained anemia has occasionally been recorded (Table 2).
Geography, Ancestry, and ConsanguinityEight 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 THETABULATION THE CARDINAL FEATURES OF THE SYNDROME
|No. of Case Identification No.Abnormality Individuals of Those AffectedAffected
Skin, teeth, and eyes:Cafe au lait spots...............................
Absence of lateral incisors.......................Hypertrichosis ..Colloid-body-like spots in Bruch's membrane......Telangiectasia of bulbar conjunctivae .............Ichthyosis hystrix..............................Acanthosis nigricans..........................."Two rows of teeth"............................Unusual dermatoglyphics......................
Bone and digits:Clinodactyly.................................Syndactyly, mild...............................Double (fused) left thumb, with four left toes.Short, stubby fingers............................Dislocation of hips.............................Asymmetry of femoral necks.....................Genu recurvatum ............................Equinovarus deformity, mild.....................
Genitalia:Undescended testes............................Urethral stricture or meatal narrowing............Hypospadias ................................Testicular atrophy or hypoplasia.................
Other:High-pitched voice.............................Pilonidal cyst or sacral dimple ...................Protruding ears.................................Mental retardation, mild........................Diminished immunoglobulins..................."Walks on tiptoes".............................Diabetes mellitus..............................Anemia, mild, unexplained......................
16
32211112*
53111111
4314
76426111
1,2,4,5,6, 7,9, 10, 11, 12,15, 17, 19, 22, 23, 27
10, 11, 1213, 148, 91113174, 5
13, 14, 17-, 18, 2t4, 17, 182420152521
3, 8, 14, 174, 5, 1184, 5, 10, 22
1, 2, 4, 8, 9, 15, 161, 14, 16, 24, 25, 2610, 12, 17, 2410, 2211, 12, 15, 21, 22, 232135
* In five, and possibly more, of the 27 individuals, the records were considered inadequate for tabulating of such addi-tional 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.
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TABLE 4
GEOGRAPHIC LOCATION AND ANCESTRAL ORIGINS OF PATIENTS
I. Present Location of Patient
(New York City................California .....................Indiana .......................
U.S.A. |Pennsylvania ....* Wisconsin .....................Colorado ......................Maine ........................Ohio ..........................
Canada ..............................France (Brittany)......................Israel..................................Mexico (D.F.). ........................
II. Ancestral Origins, Jewish Patients
Bialostok .............Glogow ..............Krakow ..............
Poland Mezherichi .Warsaw ..............Unknown town........Zemberer** ..........
Berestechko ...........Borzna ...............Kasperovtse ..........
Ukraine Kiev .........Oleyevo Korolvka...Lvov .................Rivna ................Vladimir Volynskv .....
Austria .......................Moldavia .....................Hungary .....................Lithuania (Retavas)............Russia (Odessa)................White Russia (Volozhin) .... ....
Case Identification Nos.
1*, 2*, 3*, 7, 13*, 14*, 16*, 24*15*, 2125*, 26*17, 1822, 235627*4*, 10, 11, 12208*, 9*19*
Case Identification Nos.
8, 1922, 892315 (p)t161, 244 (m)t15 (m)4 (m)15 (p)4 (p)1631, 2416, 25-26 (p)215 (m)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 genera-
tions," same villageGermany . ................. 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, 23Italy. ................................. 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
(15, 25-27) are emigrants from that area. Affected individuals have so far beenrecognized 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 be-cause the syndrome has been given much attention in American dermatologicaljournals and partly because the disfiguring facial lesion resembles lupus erythem-atosus 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 27affected individuals (Table 1, Col. XVII; Tables 4-5). The Jewish families are ofeastern European origin in each instance in which information was available (Table4, II; Fig. 5), and the patients may be considered members of the Ashkenazim. Onefamily (Ti.) represents the union of a Jewish father and a non-Jewish mother. FamilySo. 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 fromeastern Europe to the New York City area; Family Ho. directly to Canada; Family
TABLE 5
ANCESTRY AND PARENTAL CONSANGUINITYOF AFFECTED SIBSHIPS
PARENTAL CONSANGUINITY
ANCESTRY TOTAL
Yes No No Infor-mation
Jewish ........... 1 9 2* 12Non-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 aboutfamily origins could not be obtained in the case of the Jewish family Si. In the familieslisted as non-Jewish in Table 4, III, the history was usually vague and uncertain asto the land of origin of ancestors, as is characteristic of many families who have livedin America for several generations.
Parental consanguinity (Table 1, Col. XVIII; Table 5; Fig. 1) was documented inseven of the 19 affected families from whom information could be obtained. As isshown in Table 5, however, the incidence of consanguinity among the Jewish familiesis low (one of 10) but very high in the non-Jewish (six of nine). There was first-cousinconsanguinity 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 in-heritance, whereas the high consanguinity rate and the affected sibs in six of 21
213
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 becauseit is as yet unknown whether there are variations in clinical manifestations. Criteriafor inclusion in the present series were, as described above, quite rigid in order toassure purity of the sample.
Assuming incomplete ascertainment, and by subtracting one affected individualfrom each of the 21 families (Li, 1961), the corrected estimate of the proportion ofhomozygous 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 thesingles," 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
Individuals Male Female Sex Un- Total Sexknown Ratio M/F
I:Affected, Jewish + non-Jewish (number) ...... 17 10 0 27 1 70
Jewish ..................................... 7 8 0 15 0.88Non-Jewish ................................ 10 2 0 12 5.00
Unaffected, Jewish + non-Jewish ............... 14 13 8 35 1.08*Jewish ..................................... 5 5 5 15 1.00Non-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 betweenvery incomplete (single) and complete ascertainment, and a correct estimate of therecessive 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-appearancemethod" (Li, 1966), whereby it is possible to detect differences in the probability ofan affected homozygous individual being the first-born in a sibship rather than alater-born sib. The analysis of the Bloom's sibships indicates that there is an in-creased number of first-born affected (Po = 0.188; pi = 0.529), but the small num-ber of families and the incomplete ascertainment make the significance of this uncer-tain for the present. (The author is indebted to Professor C. C. Li for pointing out thisinteresting characteristic of the present data.)
The sex ratio of affected individuals in the 21 sibships is distorted (1.70), whereas itis 1.08 among their unaffected sibs (Table 6). If the entire group of sibs (affected plusunaffected) is examined, there are eight too few females (31 males, 23 females), and
214 GERMAN
BLOOM'S SYNDROME
they are missing from the non-Jewish families; in each of the eight non-Jewish fami-lies, the first affected was male. There are seven too few females in the affected groupas a whole (17 males, 10 females), according to a recessive hypothesis, and again thenon-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 recessiveeffects. Sibs may be affected, and the estimated ratio of affected to unaffected amongchildren of two heterozygotes lies somewhere between 0.146 (method of discardingthe propositus) and 0.255 (method of discarding the "singles"). The explanation forthe observed value of 0.146 is not certain, but could result from loss during embryoniclife of some of the homozygotes, as discussed in Figure 6. The very low birth weight ofthose surviving intrauterine life suggests that such weights are near a threshold belowwhich 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 describedthe condition and who has maintained an active search for additional patients, prac-tices private and consultative dermatology in New York City. In addition, the pa-tients 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 UnitedStates (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, wherethey constitute 21%'o of the entire population. Of individuals in the New York Cityarea affected with Bloom's syndrome, seven of the eight are Jewish (Table 4, 1). Ifthe gene frequencies were the same in Jewish and in non-Jewish populations, the ex-pected number of Jewish patients would have been only 1.1 (Table 7), assuming thenon-Jewish individuals had an equal chance of being detected clinically. Of all 19affected individuals in the United States, 11 were Jewish, whereas only 0.6 would havebeen expected, because only 2.9%o of the total population of the United States isJewish. It seems, therefore, that, regardless of the two considerations mentionedabove, 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, be-cause 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 syn-drome exists: Among 10 affected Jewish matings, parental consanguinity is knownin only one (Table 1, Col. XVIII; Table 5), whereas among the nine non-Jewish, sixrecord parental consanguinity. This very high parental consanguinity rate for thenon-Jewish affected individuals indicates that the gene is very uncommon in non-Jewish American and western European populations, in striking contrast to its rela-tively higher frequency among the Ashkenazim. It seems of little practical value hereto attempt estimates of gene frequency more precise than "very uncommon," notonly because of the usual limitations of methods based on consanguinity rate (Stein-
215
berg, 1959) but also because of the small number of families in the present series andthe 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 theorigin of this gene. It has been difficult to obtain accurate or meaningful data con-cerning 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 precisetown or region from which they or their ancestors had emigrated (Table 4, II).
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216 GERMAN
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 andneighboring eastern European regions, whence it was dispersed to the New World.The towns of ancestral origin cluster neatly in a small area several hundred milesacross centering in the Lvov-Krakow-Berestechko region. This is the case not onlyfor 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 than10 years ago), Canada, Mexico, and Israel.
Comparing this map for the Bloom's syndrome gene with that for the Tay-Sachsdisease gene (Myrianthopoulos and Aronson, 1967, their Fig. 1) demonstrates a cleardifference; 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 ................................................... 13,302,700Jews in U.S.A.................................................... 5 ,600,000Jews in New York City areat...................................... 2,381000Total population in U.S.A ......................................... ca. 18,000,000Total population in New York City areat.......................... 11260,000
Expec ted + Detected
All Bloom's syndrome patients, total number in U.S.A.§ . . 19All Bloom's syndrome patients, total number in New York City area§. 1.1 8Jews (only), Bloom's syndrome patients, total in U.S.A ................ 0.6 11Jesw 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 theBaltic sea, namely the regions of south Lithuania (Kovno) and the adjacent provincesof 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 fromeastern Europe beginning in 1860 and continuing until 1924, when approximately2,500,000 persons came from Russia, the Ukraine, Poland, and Rumania to live in theUnited States. These immigrants concentrated and remained mainly in the NewYork 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 1936to 1946, an additional 250,000 Jews fled to the United States from Nazi-overruncountries, and these were predominantly Ashkenazic, including many from easternEuropean regions. (There was no major entry of the Sephardim into the United
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 un-recognized selective advantage during the bleak centuries of repeated massacres,crowding, and varied persecutions and restrictions. (The heterozygote will be the sub-ject of a subsequent report [German and Crippa, in preparation], and at present notmuch can be said with certainty except that no striking growth retardation or in-creased familial incidence of neoplasms is yet apparent.) Even less can be said aboutthe source of the gene in the non-Jewish families, but distant Jewish ancestry cannotbe eliminated as a possibility in any one of them. In the United States, perhaps 5% ofJews marrying outside areas of mass settlement have chosen non-Jewish mates, andnot uncommonly discriminatory employment practices probably have prompted sup-pression of accurate ancestral data. However, mutation in the non-Jewish remains anequally good possibility.
Is the condition heterogeneous? Clinical evidence, including the personal view ofDr. Bloom, suggests that there is no difference in the general manifestations in thedifferent families. The cardinal features as well as an increased incidence of variousminor developmental defects and the consistent finding of chromosomal breakage andrearrangements are present in both Jews and non-Jews. The family Ti. (sib patients25-26) is interesting in this respect and provides suggestive evidence favoring genetichomogeneity. During the interview with the father in this currently Christian family,it was disclosed that his paternal grandmother was a Hungarian Jewess, whereas themother'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, andthe clinical features of the affected ("homozygous") children are indistinguishablefrom those of other patients. (Alternatively, each affected child could be a doubleheterozygote for different rare alleles at the Bloom's gene locus, each rare allele codingfor a protein with similar functional properties so that the phenotype remains the typ-ical Bloom's syndrome.) Somewhat suggestive of heterogeneity, however, are (a) thedistorted sex ratio among the non-Jews (Table 6) and (b) the different mean birthweights in the two groups (see caption of Fig. 4). More cases should be observed be-fore the question of heterogeneity can be examined more carefully.
The curious distortion in the sex ratio (M: F = 5.0) among affected non-Jewishindividuals remains unexplained. It might be due to loss from the series of affectednon-Jewish females, for presently unknown reasons. The over-all distortion of the sexratio of all sibs in these 21 families (31:23) would become more meaningful if largernumbers of individuals were being considered, but for the present it raises the possibil-ity that affected females are not being detected because of death in ulero or in earlyinfancy (such a possibility as considered in Fig. 6). The mean birth weight of allaffected females is lower than that of males (Fig. 4); several females have been verysmall 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-Jewishstillborns (Fig. 1) were female, but one of these (family Sm.) is known to have
218 GERMAN
BLOOM'S SYNDROME
weighed 3,124 g and so probably was not affected with Bloom's syndrome. The spon-taneous abortion rate in these 21 families does not appear to be elevated (seven of 73recognized 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 livingfemales only 7 years of age, so that an alternative explanation is that affected femalesare for some reason going unrecognized clinically, perhaps because of phenotypicmanifestations 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 clearlypresented the classic features of the syndrome, because in these four female individ-uals the skin lesions were minimal or absent early in life.
In attempting to fit the ratios obtained in this collection of families to a simpleMendelian recessive, therefore, either a reduced viability of the female or the failureto recognize her because of a less striking phenotype might be considered a satisfac-tory explanation for the somewhat deficient number of affected individuals and forthe distortion of the sex ratio. However, the persistence of the deficiency of those af-fected in these carefully scrutinized families, even after removal of the first recognizedaffected individual and the absence of a reversed sex ratio among the presumed un-affected (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 berecognized. One is sampling error; if, for example, the births following the first af-fected in each family are considered, there is no distortion of the sex ratio eitheramong affected (4:3) or among unaffected (10:9) (Fig. 1). Also, as can be seen inTable 1, Columns IV and XXI, had this analysis been made before 1966, the sexratio 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 ofneoplasia 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 andthe final event constituting malignant transformation of a cell. However, this disorderassumes eminence as one in which genetic factors of importance in malignancy mightbe elucidated. At this point, it is worth noting that this syndrome has certain featuresin common with Fanconi's anemia, such as mode of inheritance, intrauterine growthretardation, and the occurrence of various developmental anomalies. An occasionalpatient 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 some-times leukemia occurs. In both conditions there is an increase in chromosomal rear-rangements in lymphocytes (for Fanconi's anemia, see Schroeder et al., 1964; Bloom etal., 1965; Schmid et al., 1965; Bloom et al., 1966; Schroeder, 1966) and in skin fibro-blasts in culture (German and Crippa, 1966a, b; Swift and Hirschhorn, 1966; Germanand 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 latterpossibility has been difficult to examine. More progress has been made to date in thesearch for the biochemical error in Fanconi's anemia than in Bloom's syndrome, adisturbance of hexokinase metabolism in the former having been detected by German
219
investigators (Schroeder et al., 1964; Lihr et al., 1965a, b; Schroeder, 1966). A thirddisorder, the Louis-Bar syndrome or ataxia telangiectasia, may be considered herealso, because it appears to be recessively transmitted and is reported to show chro-mosomal breakage (Hecht et al., 1966; Gropp and Flatz, 1967) and to have an in-creased expectancy for malignancy. Bloom's syndrome, Fanconi's anemia, and theLouis-Bar syndrome differ in multiple ways and are due to different genes, but thatchromosomal changes and malignancy are common to all three suggests that the chro-mosomal phenomenon, regardless of its cause, could be of fundamental importance inthe pathogenesis of neoplasia.
Growth Retardation
The mechanism by which the individual homozygous for the Bloom's syndromegene 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 YorkHospital) over the same period, the former has either fewer or smaller cells. Methodsare available for measuring the cell size, and this might be done, but visually neitherblood cells nor fibroblasts in culture derived from these patients appear unusuallysmall, thus favoring the explanation that there are just fewer cells per individual. Forthere to be fewer cells after the same period of growth, either fewer cells must be pro-duced, perhaps through prolongation of the cell generation time, or the cells producedthrough mitosis must have a high mortality rate. It has been shown in long-term cellcultures derived from biopsies of skin from individuals with Bloom's syndrome that,in contrast to cultures derived from nonaffected individuals, a high proportion of cellsin anaphase and telophase show bridges, lag, or loss through nondisjunction ofchromosomes or chromosomal fragments (Fig. 7) (German and Crippa, 1966a, b). Cor-respondingly, many cells in interphase have aneuploid nuclei, with distortion ofnuclear contour, binucleus, or one or more micronuclei (Fig. 8). Many such cells areable to survive in vitro but would be incapable of many successful subsequent divi-sions. Chromosomal breakage and rearrangement cause this phenomenon (Germanand 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 ofcells in which chromosomal aberrations have occurred may therefore be the bestexplanation presently available for the presumed abnormally small number of cellsin the term fetus. This phenomenon could play a further role in growth retardationafter 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 thisdisorder, and it is striking indeed (Figs. 2 and 3). In contrast to newborns who aresmall because of premature birth, the newborns with Bloom's syndrome seem quitenormally mature and, except for minor gastrointestinal difficulties or respiratory tractinfections, generally do well during infancy and childhood. Development of intelli-gence, personality, and physical agility has, in general, been comparable with that inpersons of normal body size, but a noteworthy problem of those affected appears to
220 GERMAN
BLOOM'S SYNDROME
have been that of adjusting psychologically to a society composed almost entirely ofmuch larger individuals. They eat less, which often is a concern to their parents. Theyoften suffer during childhood because other children tease them or discriminateagainst them because of their smallness. The girls (2 and 23) who have passedpuberty for whom I have records menstruated regularly and showed no evidence thatthey could not have carried a fetus had it been as small as are those fetuses homo-zygous for the Bloom's syndrome gene. There has been no recorded mating of twohomozygotes, who would of course themselves conceive only homozygotes. This mu-tation might have been a reasonably good one to have increased in frequency, hadthere 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 normalindividuals (B, E, G, and H) but much more frequently in those derived from individuals with Bloom'ssyndrome (A. C. D. and F). These mitotic cells growing on coverglasses were fixed without colcemideor 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, Anaphasesand telophases with chromatin bridges or lagging chromosomes or chromosomal fragments. In C, afaint bridge exists between the two separating chromosomal masses, and there is also a chromatinmass displaced to the periphery of the cell (3 o'clock). In D, two large and two minute pieces arelagging midway between the separating chromosomes. H, Daughter cell with its chromatin stilltightly condensed; two small chromatin masses are displaced from the major nucleus and presumablywould have given rise to an interphase cell with micronuclei like those in Fig. 8g-i, one of whichwould 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 Crippa1966a).
221
FIG. 8.-Cells in late telophase (A), interphase (B-I and K-M), and early prophase (J) growingon coverglasses, fixed without colcemide or hyposmotic pretreatment, and stained with the Feulgenreaction followed by 1% light green (except M, which had no light green counterstaining to demon-strate the black and white photographic reproduction of Feulgen-positive material; the green cellularportions reproduce as a faint gray). Phase contrast microscopy in C and G only. Sources of cells: skinfibroblast cell lines from Bloom's syndrome patients 3 and 5 (A-F, H, J-L); normal human skin fibro-blast cell lines (G, I, and M). A-B, Chromatin filaments, possibly broken, remain stretched betweenthese daughter nuclei. C, A Feulgen-positive filament continues to connect these two sister cells, whosenuclei are distorted at the points of the filament's connections. A piece of condensed chromatin in theotherwise greatly extended filament is seen near the cell on the right. D, Cell with an approximatelydouble 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 chromo-somal rearrangements and may be interphase counterparts of tetraploid metaphases, in which it isnot uncommon to detect rearrangements. E-F, Feulgen-positive nuclear appendages. G, In this cell, ina culture derived from a normal female, there is nuclear deformity and a micronucleus. Note the sexchromatin mass of Barr (short arrow) in the major nucleus and condensed chromatin (long arrow) inthe 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 earlyprophase in which the chromosomes are beginning to condense in both the major nuclei and themicronuclei. 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 cellextending across the field has had its nucleus replaced by multiple (at least 20) micronuclei. A normalnucleus lies just below this cell. (From German and Crippa, 1966a.)
BLOOM'S SYNDROME
above, and the tendency of those affected to develop infections of the respiratoryand 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 betterunderstanding of the course of the disease may be obtained. The ages of the 22 livingaffected individuals fall into an interesting distribution (Fig. 9). Through the age of14, there are about the same number of boys and girls living, but no female is knownto be alive beyond that age. Through the age of 21, there are 21 individuals alive atvarious 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 havepassed their twenty-first birthdays, three have died of leukemia or cancer (Fig. 9).Possible explanations for the age distribution among those living include the follow-ing: (a) Perhaps the most reasonable is a greatly increased chance of survival for these
NUMBEROFDEAD
.0= MALE
4_3 =FEMALE
LIVING 2-
, Io : , I,I AIII2 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 ofthose 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'salong with improved facilities for caring for the newborn of low birth weight. Thisappears reasonable in view of the observation that many infants and children withBloom'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 congenitalagammaglobulinemia. (b) Individuals beyond age 21 could also be lost from our seriesbecause of death from malignancy. (c) There conceivably could be a failure by physi-cians treating the adolescent and adult populations to diagnose the condition. Thetrue explanation for this unusual age distribution will come with long-term observa-tion of the presently recognized affected individuals.
Hopefully, other affected individuals will also come under study, and measures formanagement of the three major aspects-growth delay, the disfiguring skin condition,and the possibility of malignancy-will be forthcoming. In addition, medical sur-veillance of this group may shed new light on the pathogenesis of malignant neoplasia.
223
GERMAN
SUMMARY
Bloom's syndrome, or congenital telangiectatic erythema and stunted growth,is a recently recognized, infrequently encountered disorder. Its predominating clinicalfeatures are small body size and a sun-sensitive telangiectatic skin lesion which in itsfacial distribution resembles lupus erythematosus. Growth retardation, both intra-uterine 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 being142 cm. The well-proportioned minuteness of the affected individual is the moststriking clinical feature of the syndrome. In addition to these three cardinal clinicalfeatures, various minor congenital anomalies commonly occur. In tissue cultures ofblood and skin cells derived from affected individuals, a high incidence of chromo-somal 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, thefemales 7. More affected males than females have been recognized, the sex ratio being1.70. Five individuals have died: one failed to thrive and died in early infancy, threedied of acute leukemia, and one died of a carcinoma. Three of the six who have passedthe age of 21 have died of malignancy. Recognition of more affected persons andcareful, prolonged surveillance of the group are required for the accumulation ofadequate understanding of the natural course of the disorder. Therapeutic needs in-clude a treatment for the growth disorder, improved management of the skin lesion,and early recognition and control of neoplasia should it appear in other individualswith the syndrome.
The genetic data are best explained on the basis of a single autosomal gene withrecessive effects. The discovery during the past 13 years of only 27 affected individualsis a reflection of the infrequency of the gene in the general population. Twelve of the21 affected families are of the Ashkenazim, and in these only one parental union wasconsanguineous. In contrast, in the non-Jewish families, six of nine were consanguine-ous, indicating that there is relatively a much lower frequency in the non-Jewish thanin the Jewish European-American population. The Jewish gene in the Americanpopulation had its immediate origin in a localized area of eastern Europe, and theancestral towns or regions have been tabulated for most families. No clinical evidenceexists 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 theformer (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 andgenetical observations which are available from the first 27 affected individuals tohave been recognized. Subsequent papers will report the cytogenetics of the homo-zygote and heterozygote and further details of the clinical syndrome in a group ofpreviously 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
224
BLOOM'S SYNDROME
and assistance during this study, and in addition we have made several field trips. I wishto thank him for this most valuable and enjoyable co-operation. To Professor ReginaldArchibald of Rockefeller University I am indebted for stimulating discussions and forhelpful opinions in the clinical evaluation of several patients. Professor C. C. Li gave mehelpful advice concerning application to the present data of his new method of estimating thesegregation ratio prior to its publication (Li and Mantel, 1968).
The author gratefully acknowledges the assistance of the following physicians, whosehelp made a co-operative study of this magnitude possible. Through their kind co-operationand sincere interest both in the patients and in this newly recognized syndrome, it has beenpossible to arrange clinic and home visits, to conduct autopsies, to collect the required datafrom old medical records, and to obtain specimens, photographs, and pedigree details:Dr. Lewis Brunsting, Mayo Clinic, Rochester, Minnesota; Dr. A. Chute, Hospital for SickChildren, Toronto; Dr. Patrick E. Conen, Hospital for Sick Children, Toronto; Dr. Jean deGrouchy, 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 YorkCity; Dr. V. N. Kyle, Port Arthur, Ontario; Dr. J. W. Landau, University of CaliforniaSchool 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 HydePark, 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, HopitalSt. Vincent-de-Paul, Paris; Dr. Edward A. Tibbets, Portland, Maine; Dr. Irene Uchida,Winnipeg, Manitoba; and Dr. C. R. Yoder, Elkhart, Indiana.
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CorrigendumIn 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.
