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The occurrence of rheumatoid factor and other abnormalities in families of patients with agammaglobulinemia.

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The Occurrence of Rheumatoid Factor and Other
Abnormalities in Families of Patients
with Agammaglobulinemia
By HUGHFUDENBERG,
JAMESL. GERMAN
111 AND HENRYG. KUNKEL
The incidence of rheumatoid agglutinating activity (RAA) in parents and
siblings of patients with acquired agammsglobulinemia was found to be considerably higher than the incidence of
RAA in the normal population. Elevated
y-globulin levels were also occasionally
present, as well as alterations in the &,
and &N proteins in such relatives. Laboratory findings suggestive of lupus
erythematosus were observed in two
instances. The high incidence of serum
y-globulin abnormalities in relatives of
patients with idiopathic “acquired
agammaglobulinemia suggests that this
is a genetically determined disorder.
Le incidentia de rheumatoide activitate
agglutinante in parentes e fraternos de
patientes con acquirite agammaglobulinemia se revelava como considerabilemente plus aIte que in le population
normal. Elevate nivellos de globulina
gamma esseva etiam presente in certe
casos, si ben como alterationes in le
proteinas PaA e BaM. Constatationes
laboratorial que poteva suggerer lupus
erythematose esseva facite in duo casos.
Le alte incidentia de anormalitates de
globulina gamma in consanguineos de
patientes con idiopathic “acquirite”
agammaglobulinemia permitte le supposition que iste disordine es genticamente determinate.
R
ECENT STUDIES in several laboratories have demonstrated positive scrological reactions for rheumatoid factor in asymptomatic relatives of patients with rheumatoid arthritis.’r2 During the course of similar family studies
in patients with various abnormalities in y-globulin, a family was encountered
in which several members had positive serological tests although the proband
had “acquired agammaglobulinemia”. This finding stimulated an investigation
of relatives of patients with both acquired and congenital agammaglobulinemia
with tests for rheumatoid factors, certain of the serum factors associated with
lupus erythematosus, and other abnormalities of the immunoglobulins. The
reports of hypergammaglobulinemia in parents of patients with acquired agammaglobulinemia3 and the findings of hypergammaglobulinemia in some parents
of children with Still’s d i ~ e a s eas
, ~ well as the observations of an increased incidence of arthritis and other forms of connective tissue disease in agammag l ~ b u l i n e r n i aadded
~ ~ ~ further impetus to this study.
It has been clearly shown that patients with agammaglobulinemia and
manifestations of arthritis lack rheumatoid factors in their
This represents one of a number of arguments against a primary role of these factors in
producing the joint lesions. However, with the evidence that rheumatoid factors
represent useful markers in family studies in rheumatoid arthritis, it seemed
particularly important to test the families of patients showing the combination
of agammaglobulinemia and arthritis or other connective tissue disorder. The
From The Rockefeller Institute, New York, N . Y.
565
ARTHRITIS
AND
RHEUMATISM,VOL. 5, No. 6 (DECEMBER),
1962
566
FUDENBERG, GERMAN AND KUNKEL
results obtained suggest the possibility that these disorders may be intimately
related and perhaps can be associated on a genetic basis. A preliminary report of these findings has been published.x
MATERIALS
AND METHODS
Clinical Material
Twenty-two families were studied. In Group I (table I ) probands 1-7 had idiopathic’
“acquired agammaglobulineinia”; in Group I1 (table 2 ) probands 8-22 had typical “congenital agammaglobulinemia” with onset of symptoms prior to age three. Exact classification
of individual cases within one or another of the two groups was occasionally very difficult.
For example, proband 5 had the onset of clinical symptoiiis of recurrent infections at age
one and one-half, but is classed as acquired because y-globulin levels at that time were
greater than 200 mg. per cent. Levels, subsequently, slowly diminished, reaching values
below 100 mg. per cent for the first time a t age eight. Proband 13, a girl, was included in
the “congenital” category, although this may not be justified, both because the occurrence
of unequivocal congenital agammaglobulinemia in females has not been fully documented,
and because she suffered no verified bacterial infections prior to age five.
Patients and family members of families 1-5, 17 and 20 were examined or treated a t
the Hospital of the Rockefeller Institute. Families 7-11 were seen at the National Institutes
of Health by one of the authors.! All family members personally examined were questioned
as to the presence of symptoms of joint pain or morning stiffness, of repeated infection, of
chronic respiratory distress, and of alcoholism or liver disease.9 Relatives with positive
serologic tests for “rheumatoid factor” had X-rays of the hands and chest.
The sera of probands and relatives of the other families included in this study were forwarded by cooperative physicians in New York City and elsewhere in the United States
and Canada.’ Clinical and laboratory features of these patients were typical of aganimaglobulinemia. Several of the probands thus included have been the subject of previous
case reports,3*43-48and the others were studied at various university hospitals throughout
the country.
With one exception (proband 5, vide supra), the patients with acquired agammaglobulinemia ranged in age from 36 to 65 at the time of study; their siblings were from 26 to 49
years old with the exception of family 5 (sibling age 8 ) , and family 7 (sibs 49 and 57 years),
The patients with congenital agammaglobulineinia were 2 to 18 years old at the time of
study, and their parents age 2445. In control families, parents were 24 to 45 years in age,
and children 2 to 16 years.
Gamma Globulin Measurements
Gamma globulin levels were measured by a variety of methods. Electrophoretic assays
were carried out on the sera of all the agammaglobulineniic patients and certain of the
relatives. These were done primarily by a modification of the zone electrophoretic method
in starch-supporting medium.10 The lack of absorption of 7-globulin in the starch-supporting medium allowed more accurate results than were obtainable by paper electrophoresis,
particularly in the low range of y-globulin levels. Certain of the determinations were carried out by paper electrophoresis.
“No symptoms of leukeumia, lymphoma, or other underlying disease for at least 5 years
after the onset of symptoms of agammaglobulinemia.
+We are indebted to Dr. John Utz of the NLH for making m m y of these families available for study.
‘We are indebted to the following physicians for making the sera of these patients and
their relatives available to us: Drs. I. Zelman (family 6 ) , J. Gould (family 9 ) , J. Nasou
(family lo), D. Palmer and W. Hammack (family 12), J. Hardy (family 13), M. Ziff (family 14),T. Tomasi (family 15), W. Henle (family 16), H. Porter (family 17), M. Erlandson (families 19 and 20),J. Bruce and G. Carter (family 21), and C. Brubaker (family 2 2 ) .
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
567
For purposes of screening, a modified zinc turbidity method of 7-globulin measurement
was also employed. This proved uniquely useful for the large-scale testing carried out in
this study and therefore is described in some detail. The present modification, herein
designated zinc turbidity No. 2 test, was designed to increase the turbidity range encompassing normal and hypogammaglobulinemia levels. Quantitative differences within
this range were difficult to evaluate by the older method11 because of the low turbidity
obtained, although gross abnormalities were detectable. Various other disadvantagey of
the earlier method were also eliminated. A stronger buffer was employed which gave a
more stable reagent; higher zinc concentiations were used which were not as sensitive to
zinc-binding agents that might be present; also, the distinctly greater precipitation of
7-globulin from normal serum obtained with the newer method reduced the yensitivity to
variation in technique. Serum, 0.1 ml., was diluted with 3 ml. of R reagent containing 3.1
Gm. barbital, 2.1 Gm. Na barbital, and 0.8 Gm. (Zn SO,, . 7 H 2 0 ) per one liter distilled
water. The standardization and technique of measurement is the same as in the earlier
procedure.11 The mean value in 36 normal white adults was 42.2 t 4.2 turbidity units.*
All the probands of the present study showed values markedly below the normal range.
In Group I (table 1 ) the range was 5 to 20 units,t in Group I1 (table 2) 2 to 18.5 units.+
Values above 55 turbidity units were considered as indicative of a significant elevation of
serum 7-globulin. Table 3 illustrates the results of simultaneous turbidity and electrophoretic measurements on the same sera from certain of the individuals of the present
study. A plot of these and of additional results indicated a relatively straight line relationship
over the range from 1040 units. Below I 0 units, the values appeared less quantitative
and simply indicated very low 7-globulin levels. Above 40 units, the correlation became
less linear and larger increase in 7-globulin produced relatively smaller increments
in turbidity. Occasional discrepancies were encountered in the modcrate hypogammaglobuhernia range such as serum No. 7 in table 3, Also, the sera of some patients with myeloma
and macroglobulinemia gave low turbidity values despite high electrophoretic 7-globulin
components. Despite these limitations, the procedure proved of considerable value for
screening purposes, particularly because of good reproducibility on several specimens obtained at varying time intervals from the same patient.
Quantitative determinations of the & and p,, proteins3611 were performed by a modification of the agar diffusion method of Oudin,Zlb using adsorbed antisera specific for
these proteins. Gross abnormalities were confirmed by immunoelectrophoresiq.
Serologic! Methods
All sera of probands and relatives were tested for “rheumatoid agglutinating activity”
(RAA) by sensitized human Rho red cell and latex fixation12 methods. Positive sera were
further tested by F I1 tanned cell13 and sensitized sheep cell14 methods. Complement fixation reactions with DNA, nucleoprotein, and other antigens were kindly performed by Dr.
H. R. Holman. The Rho test was used as the primary screening method in this study since
intensive investigations of its mechanism were being carried out during the same period
and was performed by the same investigator for both the experimental and control studies.
A detailed description follows:
A two-tube modification of the test system described independently by Grubblj and
by Waller and Vaughanle was employed. This system utilizes human Rho positive red cells
as inert carriers and an anti-Rho “incomplete” antibody as the 7-globulin “coating” the
indicator cells. The modification employed resulted in a sensitive test which permitted
screening of two dozen sera within a two-hour period.
*Measured by per cent transmission on a Coleman Jr., spectrophotometer-1 unit = 1%
change in transmission.
+Inonly two instances ( proband 12, zinc turbidity 10 units and proband 20, zinc turbidity
2 units) was serum obtainable prior to institution of parenteral therapy with y-globulin.
Therapeutic doses in the treated patients was widely variable, total monthly dosages ranging from 20 mg. per Kg. to 1400 mg. per Kg.
S68
FUDENBERG, GERMAN AND KUNKEL
Whole blood was obtained from the same 0 Rh, donor a t periodic intervals, mixed with
an equal volume of Alsever’s solution, and stored at 4 C. for not longer than two weeks.
For use, 0.5 ml. aliquots were taken, the red cells washed three times with a 50-fold volume
of normal saline, and reconstituted to a 2 per cent suspension with saline. An equal volume
of an optimal dilution of the standard anti-Rh, “coating” reagent* was then added, the
cells mixed by inversion and shaking, and the mixture incubated at 37 C. for one hour.
Following incubation, the coated red cells were washed three times with 50-fold volumes
of normal saline, and again reconstituted as a 2 per cent suspension in saline. The reactions
of the coated cells and of non-coated control cells with 1:5 and 1:40 dilutions of test
serum, after incubation for one hour a t 37 C., were read with the aid of a hand lens after
spinning for 30 seconds in a serological centrifuge.1
In general, titers obtained with the Rh, test were one fourth as great as those obtained
in the latex fixation tests. Identical serologic conclusions (“RAA positive” or “RAA negative”) were obtained with these two methods in 96 per cent of 150 sera in which double
blind clinical and serological testings were employed. These sera, supplied by Dr. John
Ward, Massachusetts General Hospital, represented 100 patients with rheumatoid arthritis
or variants and 50 patients with gout, degenerative arthritis and miscellaneous disorders.
RESULTS
Serological Parameters
Group I : acquired aga~nmaglohri1iiacmia.-Table 1 indicates the high incidence of positive reactions for RAA in relatives of patients with idiopathic acquired agammaglobulinemia. Positive reactions of moderate to high titer
were present in two or more test systems in at least one close relative (parent,
or sibling) of all of the 7 probands in this group. Although the sensitized human
cell (Rhorheumatoid reaction) was the primary test method, positive titers of
comparable magnitude were obtained with the latex fixation reaction in all but
two instances, and in these the F I1 tanned cell reactions were positive in moderate titer. Positive reactions in the sensitized sheep cell (SSC) tests were obtained in six of the eight sera positive in the other test systems. Of all relatives
tested three of eight parents and five of eleven siblings were “seropositive” for
RAA; clinical evidence of rheumatoid arthritis was present in one or more parents or siblings in three of the seven families.
The relative incidence of positive families in the acquired agammaglobulinemia group was seven out of seven (table 6 ) , despite the fact that relatively
few relatives were available per family.
Family 1 (fig. 1) is of particular interest and was studied in considerable
detail. The presence of RAA and hypergammaglobulinemia in both the mother
( 115) and the sister (111,) of the proband ( 1118) is evident from figure 1. M.
Mey, mother of the proband had a zinc turbidity value of 58 units and a y-globd i n level of 1500mg. per cent by starch block electrophoresis quantitation. Her
“The same standard diIution of the same anti-Rho serum (MTJ) was used throughout.
This reagent (and its optimal dilution) was selected from 36 high-titer anti-Rho sera
(titer > 1600) on the basis of results obtained in “checkerboard titrations” with strong
and with weak RAA sera. Cells coated with the 1:8 dilution of the MU serum reacted with
1:5 dilutions of weakly positive M A sera (titer 1:20 or 1:40 by latex fixation) and did not
give negative (prozone) reactions at dilutions greater than 1:40 with strongly positive
rheumatoid sera (titer 1:640,0W by latex fixation).
t“Serofuge,” Clay-Adams, New York.
569
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
Table I.-G?oup I . Acquired Agammaglobulinemia. Some Qualitative and
Quantitatiue Parameters of y-Globulin in Acquired
Agammaglobulinemia _Families
_
_
_
~
Family members
____
1. Sca.
GSc ( f., age 37)
MMey
AMey
HMey
3. Far.
AFar (m., age 56)
PFar
MSch
3. Ka.
LKa (ni., age 41)
FKa
SKa
RKa
LKa
4. Al.
NA1 (m., age 36)
SCa
JCa
DCa
5. Di.
CDi (m., age 10)
FDi
MDi
SDi
F I1
CF
(nuclei)
titer7
Relation
to proband
Zn
No. 2
test*
proband
mother
&ter**
brother
13 (156)
58 (1690)
56(1500)
50
0
320
20
0
0
160
640
0
0
0
996
448
0
proband
father
sister""
11 (190)
41
45
0
0
320
0
0
2560
0
1024
0
16000
proband
father
brother
brother
sister
5 (30)
0
0
0
0
0
0
0
0
448
proband
mother
half-brother
hnlf-brother
45
43
43
41
Itho
titer?
Latex
titerf
0
0
0
0
0
0
6 (70)
43
53
36
0
0
640
0
0
0
0
0
proband
12 (184)
0
0
father
mother
sister
42.5
39.5
41
40
0
0
16
0
0
proband
father
mother
17 (345)
0
60 (1950) 40
50 (1450) 0
0
proband
,ister* "
20 (283)
50
brother
52
80
SCC
titers
0
32
It;
tanned
cell test11
0
0
0
0
0
0
0
0
0
0
0
0
0
0
996
16
0
0
0
anticomplementary
448
0
0
0
6. So.
JSo (m., age 52)
ESo
MSo
7 . Hu.
RHu (f., age 65)
HHu
VHu
0
80
128
0
0
0
320
0
0
2560
32
0
0
448
0
0
0
996
0
0
(pos. LE
Test)
0
0
"Figure in parenthesis indicates y-globulin, nig. %, determined by starch block electrophoresis.
to = neg. at 1:5.
40 = neg. at 1:20.
50 = neg. at 1:8.
110 = neg. at 1:28.
70 = neg. at 1:4.
*"Clinical rheumatoid arthritis.
titers in the Rho, latex fixation, F I1 tanned cell, and sensitized sheep cell tests
were 320,160,996, and 32 respectively. It is evident from figure 1 and from table
4 that RAA and hypergammaglobulinemia were widely distributed throughout
570
FUDENBERG, GERMAN AND KUNKEL
Table B.-Group I I . Congenital Agammaglobulinemia. S0m.e Qualitative and
Quantitative Parameters of y-Globulin in Congenital
Agammaglobulinemia Families
Family members
8. Bo.
PBo (m., age 17)
PBo, sr.
FBo
JBo
PaBo
CBo
9. He.
DHe (m., age 18)
WHe
EHe
LHe
VHe
10. St.
RiSt (m., age 11)
RaSt
Rust
RoSt
HKo
11. Re.
RRe (m., age 18)
JRe
HRe
EHe
CRe
12. We.
DWe (m., age 4 )
JWe
CWe
GWe
RWe
13. Ha.
DHs (f., age 12)
FHa
MHa
RHa
RHa
PHa
14. Co.
ACo (m., age 8)
ECo
Relation
to proband
Zn
No. 2
teat*
proband""
father
mother
sister
sister
r;isler
12 (170) 0
59.5 (1980) 0
58 (1670) 80
0
58
0
58
58.5
5
proband
father
mother
sister
sister
4.5
58
66
56
52
0
0
0
0
0
proband
father
mother
brother
sister
7
43
56
46
47.5
0
0
0
0
0
proband
father
mother
sister
hrother
5
45
59
42
66
0
0
0
0
80
0
0
0
0
320
proband
f:ither
mother
brother
frat. twin bro
10
34
49
24
23
0
0
0
0
0
0
0
0
0
0
proband
father
mother
sister
sister
yister
7 (40)
38.5
0
31
37
160
20
0
0
0
0
1280
40
0
0
0
proband"*
father
6 (50)
59.5
0
0
49
49
Rho
titerf
Latex
titerj
0
0
80
0
0
20
SCC
titer!
0
0
0
8
F I1
CF
tanned
(nurlei)
cell test]]
titer11
8
16
0
0
112
0
0
112
64
224
0
0
996
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
16
8
0
0
0
0
0
0
0
0
0
"Figure in parenthesis indicates 7-globulin, nig. 70,determined by starch block elect rophoresis .
10 = neg. at 1:5.
40 = neg. at 1:20.
50 = neg. at 1:8.
110 = neg. at 1:28.
70 = neg. at 1:4.
"9Clinical rheumatoid arthritis.
571
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
Table 2.--Continued
Zn
Family members
ACo
PCo (age 21 mos)
15. Da.
KDa (in., age 12)
KDa
VDa
EDa
GDa
16. An.
RbAn (m., age 3 )
RlAn (m., age 3)
FAn
MAn
17. Ma.
RMa (in.,age 8 )
RMa
OMa
18. Fo.
RFo (m., age 9)
FFo
JFo
19. Me.
LMe (m., age 2)
FMe
MMe
EMe
20. Po.
PPo (m., age 4 )
JPO
JaPo
MPO
21. Vi.
CVi (m., age 14)
W i
MVi
22. Mo.
VMo. (m., age I )
JMo
MMo
Relation
to proband
No. 2
testC
mother
sister
titert
Lattx
titer$
36
21
0
0
0
0
proband
father
mother
sister
sister
1 4 (289)
38.5
42 (677)
32.5
49
0
0
0
0
0
0
0
0
0
proband
proband (twin)
father
mother
8
8 (140)
36
43
0
0
0
0
0
0
0
0
proband
father
mother
11 (230)
55
42
0
0
0
0
0
proband
father
mother
18.5
41
42
0
0
0
0
0
0
proband
father
mother
brother
6.5
49
50
30
0
proband'*
father
mother
sister
2
45
43
40
0
proband
father
mother
11
36
0
0
37
0
proband
father
mother
5.5
42
45
0
0
Rho
0
80
0
0
0
0
0
0
0
0
0
F I1
tanned
cell test11
CF
(nuclei)
titer7
0
0
0
0
0
0
80
0
0
0
SCC
titer5
0
112
0
0
0
0
0
0
this kindred. Although the patient's father is not alive, the finding of RAA in
one and hypergammaglobulinemiain two of his three living sibs" suggests that
similar abnormalities were perhaps present in his serum as well. RAA was
present in both paternal and maternal relatives of JFai ( V1 in fig. l), another
'The manner of sudden death in two siblings possibly suggests agammaglobulinemia,
though death occurred prior to the introduction of antibiotics. 1. Girl, born deaf, died at
age 19, after 3 days of questionable meningitis. 2. Boy, died at age 20, after one day of
pulmonary infection.
572
FUDENBERG, GERMAN AND KUNKEL
Table 3.-Comparison of Serum y-Globulin Levels of Various Patients of this Series
b y Starch Block Electrophoresis and by Zinc No. 2 Turbidity Test
Serum
1. L. Ka.
2. A. Co.
3. N. Al.
4. G. Sc.
5. C. Di.
6. A. Far.
7. R. Ma.
8. K. Da.
9. J. Fai.
10. N. Co.
11. G. Ge.
12. Fr. (norm.)
13. A. Mey.
14. F. Bo.
___-_______
~
~
~
Gammaalobulin
(electrophoresis)
mgm%*
Zn SO,
Turbidity
units
30
50
70
156
184
190
230
289
469
580
617
880
1500
1670
5
6
6
13
12
11
11
_
_
_
1t
_
_
~
-
~
-
21
27
33
42
36
58
-
_
_
-. -
“As measured by Fohn reaction in comparison with standard normal 3erum. 0. D. of
standard normal serum was converted into mgm of 7-globulin, using a standard curve
obtained with micro-Kjeldahl analyses of a preparation of normal fraction I1 human
7-globulin (Lederle No. C-439).
Table 4.-Family 1. Aberrations in y-Globulin in Family 1 (Proband
G1. Sc., Acquired Agammaglobulinemin)
Name
Relation
G. Sc.
Rl. Mey.
Ar. Mey.
Her. Mey.
R. sc.
Paternal
L. Ku.
proband
mother
sister
brother
daughter
Symbol
Fig. 1
Zinc2
Rh*
Latext
SSCS
0
32
16
F I1
tanned
eel&
0
996
448
0
111,
11,
111,
111,
I”,
13
58
56
50
36
0
320
20
0
0
0
160
80
0
0
0
0
117
69
20
20
0
0
III,,
1111
142
0
0
10
0
160
40
0
0
0
0
160
160
0
0
0
0
0
0
0
11119
1112,
56
59
56
56
52
49
32
56
64
v*
20
0
0
0
0
0
111,
IV2
56
62
0
40
0
40
0
0
256
224
0
0
0
0
TdQi%VeS
N. Ku.
J. Mey.
Ed. Mey.
1). Fr.
S. Fr.
E. Fai.
J. Fai.
aunt
cousin (son
of L. Ku.)
uncle
cousin
cousin
cousin
cousin
grands. of
E. Fai.
1%
0
Maternal relatives
Ch. Te.
Fr. Hen.
“0
Comp.
fix./(
cousin
cousin’s son
= neg. a t 1:5.
to = neg.
at 1:20.
40 = neg. at 1:8.
$0 = neg. at 1:28.
110 = neg. at 1:4.
573
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
Table 5.--Incidence of Rheumatoid Agglutinating Activity in Parents
Sibs of Patients with Agammaglobulinemia
Sibs
Parents
and
Total
positive
No.
tested
No.
positive
No.
tested
No.
positive
NO.
NO.
tested
Controls
Malc
Female
23
23
2
1.
21
25
0
1
92
4
Congenitals
Male
Female
13
13
2
2
4
14
1
1
44
6*
Acquired
Male
Female
4
4
1
2
'p
tp
~
> 0.05.
< 0.001.
hypogammaglobulinemic subject in this kindred. t EFai ( IIIzO),grandmother
of JFai and a cousin of the proband ( IILS) displayed chronic discoid lupus,
false positive serology,+ positive complement fixation reactions with nucleoprotein, positive serologic tests for RAA, and joint symptoms suggestive of
rheumatoid arthritis. Patient AFar, proband 2, also had clinical features suggestive of disseminated lupus, e.g., acquired hemolytic anemia of moderate severity, severe thrombocytopenia, and splenomegaly ( this combination, often
termed Evans' syndrome,l7 is known often to eventuate into clinically recognizable disseminated lupus erythematosus ) . Repeated LE preparations were negative, however, as were complement fixation tests with his serum. Despite the extremely low 7-globulin level, a positive direct antiglobulin ( Coombs' ) reaction
was demonstrable. This autoantibody could be recovered by elution and displayed no specificity when tested at 37 c. against a panel of red cells of varying
antigenic composition; the eluate failed to react at 20 C. or at 4 C.I*
The sister (H.Hu) of one other proband ( 7 , R.Hu) had frank arthritis with
Table 6.--Incidence
of
Rheumatoid Agglutinating Activity in Families
of Patients with Aeammuelobulinemia
Group
Control
Congenital agammaglobulinemia
Acquired agammaglobulinemia
Seropositive
families'
Familiea with
one or both
parents seropos.
No positive
sibs.
Families with
one or more
seropos. sibs.
No positive
yarents
4/23
3/23
1/23
0/23
4/15"
2115
2/10
1/10
2/6
4/7
7/7t
Familiw with
sempositive
parents and
seropositive
sibs.
_
_
1At least one seropositive parent or sibling.
*p > 0.05 relative to control group.
t p < 0.01 relative to control group.
t JFai developed recurrent cutaneous, gastro-intestinal and upper respiratory infections
without pneumonia at age 10 months; these persisted until age 16 months a t which time
a 7-globulin level of 410 mg. per cent was found. Gammaglobulin therapy was then begun
and he has subsequently been free of symptoms.
+Positive Mazzini and Wasserman. Negative Treponema Pallidum immobilization test.
~
574
FUDENBERG, GERMAN AND KUNKEL
FAMILIES O F PATIENTS WITH AGAMMAGLOBULINEMIA
575
0 Negative serological tests
Rheumatoid factor
Positive L.E.preparation
Increased v-glob.
Decreased )-’-glob.
t o r N.T Serum not tested
R A-Clinical rheumatoid arthritis
If
Proband
Fig. 2.-Aberrations in y-globulin in family 7 (proband RHu acquired agammaglobulinemia)
.
rheumatoid factor and a positive LE cell test but negative complement fixation
reactions against nuclei (fig. 2). The proband ( K.Hu) manifested thrombocytopenic purpura as well as repeated bacterial infection^.^^
Proband 5. ( C.Di ) eventually developed clinical symptoms somewhat suggestive of periarteritis nodosa; tissue biopsy material obtained at exploratory
laparotomy was compatible with this diagnosis. The presence of anticomplementary reactions in his serum, despite the marked diminution in y-globillin,
may represent an additional qualitative abnormality in y-globulin.
Group ZZ: congenital agal7imnglobulin~?~ia.-l’he incidence of RAA in parents and siblings of patients with “congenital” agammaglobulinemia was considerably lower than that observed in families with the “acquired form of the
disorder. As is evident from table 2, positive Rho and latex fixation rheumatoid
factor reactions were demonstrable in six subjects in 4 of the 15families studied,
SSC reactions were weakly positive, and tanned cell reactions moderately positive in almost all of the positive reactions. This 26.7 per cent incidence of
families with at least one “seropositive” member is not significantly different
from the incidence in the control family groups. The total number of seropositive parents and siblings ( 6 of 44) is also not significantly dihrent. These
data are summarized in tables 5 and 6. Three probands in this group had classi-
576
FUDENBERG, GERMAN AND KUNKEL
cal rheumatoid arthritis with joint effusions and typical radiologic changes;
positive serologic reactions were observed in family members of one of these
three probands (proband S ) , and in three additional families as well.
Control Studies
The incidence of positive Rh,, tests in 28 pairs of “normal control” parents,
selected to correspond closely in age and ethnic origin to the parents of the
congenital agammaglobulinemic probands and the siblings of the acquired
agammaglobulinemic probands, was 6 per cent. Weakly positive reactions were
obtained in the Rho test with 3 of these 56 control sera; in two of the three,
latex fixation reactions were also positive in low titer. These sera were also
used as the control in population for y-globulin measurement. Eleven additional sera were provided by the marital partners of the family members listed in
kindred one; none of these sera, tested simultaneously with the sera of family
members, gave positive reactions. The value of such marital partner controls
in the evaluation of family studies has been emphasized by Leonhart.19 An
additional 23 non-selected, presumably normal families in each instance comprising father, mother, and one to four children, were also tested. Only four
of these 92 sera gave positive results, an incidence of 4.4 per cent. No control
family had more than one seropositive member, so that the incidence of positive families (4/23) was 17.4 per cent.
Gamma Globulin Levels
Group Z: acquired agammagZobzilinemi~.-The serum 7-globulin concentration, as measured by the zinc turbidity No. 2 test and confirmed by starch block
electrophoresis, was elevated in 2 of 7 parents, and 1of 11 adult sibs of patients
with acquired agammaglobulinemia, as compared with the concentrations in
the 56 normal control sera. Zinc turbidity levels of 56 or more units, corresponding to electrophoretic values of approximately 1500 mg. per cent, were accepted as abnormal. However, there is evidence that 7-globulin concentrations
increase in the older-age groups,4Qso that levels even as high as 1500 mg. per
cent in the parents of the patients with acquired agammaglobulinemia may
perhaps be within normal limits in these elderly individuals. Nonetheless, the
values obtained in the siblings of the probands of the acquired group are strictly
comparable to those of the control group, as none of these siblings were more
than 45 years old.” Tables 7a and 7b demonstrate that hypergammaglobulinemia was present in 2 of the 7 families in this group. In view of the reservations
above, statistical analysis of the significance of this finding in this limited
number of families was not carried out.
Group ZZ: congenital agammaglobu1inemia.-Table 7b also demonstrates
that 7-globulin levels were significantly elevated (zinc turbidity of 56 or more
units) in 5 of the 15 families of the congenital group. Especially noteworthy
*Indeed, the control group was selected to correspond, insofar as possible, to the age
range and ethnic distribution of the siblings of the acquired agammaglobulinemia patients
and the parents of the congenital agammaglobulinemics. It was not possible to obtain blood
samples from the children of the normal donors in the control group.
577
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
Control
population
Agammaglobuline m i c patients
Ac- Congenuired ital
Zinc No.:
turbidity
units
Relatives of
congenitals
R e l a t i v e s of
Sib5 Pa~ents
Sibs Parents
I
I
I
I
*
I
I
I
I
aJ
I
I
; 50
I
ON;
C
6
.
.
1
I
I
I
+%+,:a
I
I
I
I
c---
I
I
30
I
I
I
.
. , .*..
I
I
20
* ;
I
2
.
0
:
*
I
I
**
8
I
I
I
I
I
I
.
I
I
I
I
'
.
I
I
.
.
I
f.
I
. I .
0.
w.:
I..*.
I
I
. I
10
I
I.
I.
I
I
I
.
I
. . I...
*
I
6 bj
I
I
I
I
I
I
4
I
I
I
I.
I
I...
..I
I
r--:
I
I
I
5
I
I
I
60
acquireds
0.
.
I.
I..
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
Fig. 3.-Gamma globulin levels by zinc turbidity test in agammaglobulinemic
probands and their relatives.
T
Negative serological tests
Rheumatoid factor
5 Positive L E preparation
Increased Y -glob
~
R
A
Decreased f -glob
t o r NT-Serum not tested
R A-Clinical rheumatoid arthritis
f
Proband
Fig. 4.-Aberrations in y-globulin in family 8 (proband PBo congenital agammaglobulinemia)
.
578
FUDENBERG, GERMAN AND KUNKEL
Rheumatoid factor
@
Malar butterfly rash, arthralgia
negative serologic tests for D.L.E.
R.A= Clinical rheumatoid arthritis
Fig. 5.-Aberrations
maglobulinemia)
.
in y-globulin in family 13 (proband DHa congenital agam-
were the elevated levels in the paternal (3/15) and maternal (4/15) sera.
(Elevations occurred in both parents in two families.) The levels in these parents, as a group, were significantly different from that of the control population
( p < 0.01). Values of 56 or more zinc turbidity units were also encountered
in 5 of the 19 siblings of the patients with congenital agammaglobulinemia, but
such elevations were confined to those families in which elevations also occurred in paternal or maternal sera (table 7 ) . No matched control sera were
available comparable to the age range encompassed by the sibs of the congenital agammaglobulinemias.
It is noteworthy that positive reactions for RAA were obtained with 4 of
the 12 hypergammaglobulinemic sera in the 5 “congenital” families and also
in sera with normal 7-globulin levels. Of special interest are the uniformly
elevated r-globulin levels in the parents and the three sibs of proband 8, P.Bo.
Table 7a.-Zncidence of Elevated y-Globulin Levels” tn Parents and
Siblings of Patients with Agammaglobulinemia
_
_
Sibs
Parents
Grouo
No. pw./
No. tested
Controls
Congenital
Acquired
0/56
7/30
2/7
D.
value:
No. pos./
No. tested
-
-
<0.01
6/17
1/11
t
D. valuei
t
>0.05
_
~
579
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
Table 7b.-Families with Zinc Turbidity Values 1 56.0
Group
Parents or sibs
No. PW.
P. value
-
Control
Congenital
Acquired
5/15
2/7
Parents
No. pos.
p. value
Sibs
No. pos.
-
0/28
+
<0.01
5.'15
2/6
p. value
<0.01
3! 10
115
t
>0.05
"Mean for control group 42.2 & 4.2 zinc turbidity #2 units. Elevated y-globulin defined
56.0 units.
t t - test comparison with control group.
+No adequate control group of comparable age (see text). Hence statistical evaluation
not valid.
as
Table 8.-Group
Family members
1. sc.
GSc.
MMey
AMey
HMey
2. Far.
AFar
PFar
MSch
3. Ka.
LKa
FKa
SKa
RKa
LKa
RiKa
JKa
PKa
4. Ale.
NA1
SCa
JCa
5. Di.
CDi
FDi
MDi
SDi
8. So.
JSo
ESo
MSo
7. Hu.
RHu
HHu
VHu
I . Acquired Agammaglobulinemia. PBAand
Acquired Agammaglobulinemia Families
PBarLevels
Relation to
proband
P2.4
P2M
proband
inother
sister
brother
0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
proband
father
sister
0.2
2.0
1.0
proband
father
brother
brother
sister
son
daughter
daughter
0
1.0
0.87
1.0
0.67
1.0
0
1.0
1.0
1.0
1.0
3.0
proband
mother
half-brother
0.125
1.0
1.0
proband
father
mother
sister
0
1.0
1.0
1.0
3.0
1.0
1.0
1.0
proband
father
mother
0
1.5
1.0
0.06
1.0
1.0
proband
sister
brother
0
1.0
1.0
in
Table 9.-Group
ZZ. Congenital Agammaglobulinemia. ,Baal and /IsJu
Levels
in Congenital Agammaglobulinemia Families
~
Family members
8. Bo.
PBo
PBo
FBo
JBo
PaBo
CBo
9. He.
DHe
WHe
EHe
LHe
VHe
10. St.
RiSt
RaSt
Rust
RoSt
HKo
11. Re.
RRe
JRe
HRe
EHe
CRe
12. We.
DWe
JWe
CWe
GWe
RWe
13. Ha.
14. Co.
15. Da.
KDa
KDa, Sr.
VDa
EDa
GDa
16. An.
RbAn
RlAn
FAn
MAn
17. Ma.
RMa
RMa
OMa
18. Fo.
19. Me.
LMe
FMe
MMe
EMe
20. Po.
PPo
JPo
JaPo
21. vi.
22. Mo.
Relation to
proband
P2*
rB2M
proband
father
mother
sister
sister
sister
0
0
1.o
1.0
1.0
1.0
1.0
proband
father
mother
sister
sister
0
1.o
0
1.o
1.0
1.0
1.0
proband
father
mother
brother
sister
1.0
1.0
1.0
1.0
-
proband
father
mother
sister
brotlier
0
-
proband
father
mother
brother
frat. twin brother
Not done
Not done
0
1.o
proband
father
mother
sister
sister
0
1.0
1.0
-
-
0
1.0
1.o
0.67
1.0
proband
proband (Twin)
father
mother
0
0
1.0
1.0
0
0
1.o
1.0
proband
father
mother
Not done
0
proband
father
mother
brother
0.25
1.0
3.0
-
proband
father
mother
Not done
Not done
0
1.0
1.o
0
1.o
1.0
1.o
1.0
0.67
1.o
1.5
0.5
0.67
0.5
0.5
580
0
1.0
0.67
-
1.o
-
-
3.0
1.o
1.0
1.0
1.0
0
1.0
0.33
0.5
1.5
1.o
2.0
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
581
It is apparent from figure 4 that quantitative and qualitative abnormalities occurred on both the paternal and maternal side of the family. Qualitative abnormalities without elevation in y-globulin concentration, involving both maternal and paternal relatives was evident in the family of D.Ha, the one proband with questionable congenital agammaglobulinemia included in this series
(fig. 5j.
The concentrations of the PZAand PZM“immunoglobulins”36*were measured
immunochemically in 50 normal sera and the mean value for each of these
proteins arbitrarily designated as 1.0 unit.’ Results were then expressed relative to these means. In the normal sera, values ranged from 0.75 to 1.3 units.’
and/or PaM immunoglobulins were ocTables 8 and 9 demonstrate that
casionally normal (proband 1) or even elevated ( prohand 5 ) in the acquired
agammaglobulinemic patients, but were uniformly absent in the patients with
congenital agammaglobulinemia. Similar observations have been made by
Bridges and Good.6h Of additional interest are the abnormally high and abnormally low values often encountered in the family members of both groups
of probands, with values ranging from three times the normal (e.g., J.Ka, family 3) to complete absence ( CWe mother, family 12).
DISCUSSION
The serologic evidence obtained in these studies suggests that the incidence
of rheumatoid agglutinating activity (RAA) in parents and sibs of patients
with idiopathic acquired agammaglobulinemia is significantly higher ( p <
0.001) than that found in normal families. The slight increase in incidence of
RAA in parents and sibs of the congenital group is statistically insignificant
and in addition may be due to the possible inclusion of acquired cases.
The dividing line between the congenital and the acquired groups was frequently difficult to determine and probably a number of subgroups are present.
One of the positive families in !he congenital group (Ha, 13) has a female
propositus and it is not certain that this family should be classified in this
way. Perhaps family investigations will aid in providing better means of classification in the future..
Increased serum 7-globulin levels also were occasionally found in family
members of both groups. Such findings, previously cited in acquired agammag l o b ~ l i n e m i awere
~ ~ ~ ~present with even greater frequency in parents of
children with congenital agammaglobulinemia. The sibs of children with the
congenital form showed an interesting distribution of 7-globulin levels, wme
strikingly low, some normal, and some definitely elevated. There was no direct
correlation between the presence of RAA and of hypergammaglobulinemia in
a given serum; many of the sera with grossly elevated r-globulin values showed
no serologic abnormalities.
It should be emphasized that the presence of positive serologic tests for RAA
in these relatives certainly is not indicative of rheumatoid arthritis. Positive
*The normal &A globulin level, as measured by the Oudin tube single diffusion method,
appears to be of the order of 1.12 mg/ml. for white adults. A mean value of 0.75 mg/ml.
globulin.
was found for the
582
FUDENBERG, GERMAN AND KUNKEL
results in the latex fixation, tanned cell, and Rho tests have been obtained with
considerable frequency in sarcoidosis,21 liver disease,g syphilis,22 and other
disease states not associated with joint abnormalities.” Positive serologic tests
in these conditions occur primarily with those systems utilizing human 7-globulin as the “reactant”;21the sensitized sheep cell reaction (SSC), employing
rabbit y-globulin as the reactant, has been more uniformly negative with such
pathologic
Positive reactors in the family studies cited herein were
positive in the SSC in almost all incidences in which moderate to strong titers
were obtained with the other serologic test system. Positive SSC reactions
have also been observed in clinically normal subjects, most notably in 5.7 per
cent of the 1165 individuals over the age of 25 tested included in the survey
by Lawrence and Ball2in a small village in Lancashire, England. This incidence
is similar to that observed in normals with the Rh,) method employed in this
study. The incidence in “normals” varies greatly in different racial groups inhabiting the same geographic area23but whether or not “normals” with positive results represent familial aberrations cannot be answered from the data
presented in this or previous investigators.
Ziff’ using the sheep cell inhibition reaction has noted an increased incidence
of “rheumatoid factor” in parents and siblings of patients with rheumatoid
arthritis. A high familial incidence (20 per cent) of positive reactions was also
noted in the Lancashire study in parents and siblings of patients with “seropositive” rheumatoid arthritis”; in “seronegative rheumatoid arthritis” the incidence of positive reactors in relatives did not exceed that of the control
population.2 Experience in this laboratory with the syndrome of rheumatoid
arthritis accompanied by hepatosplenomegaly, lymphadenopathy, and delayed
maturation (Still’s disease) has also indicated a high familial incidence of
positive reactor^.^ Also of interest, but of questionable significance, is the
appearance of rheumatoid factor and other abnormalities in the 7-globulins in
the descendants of the two consanguineous marriages in kindred 1 (see Fig. 1,
IIlo and IIIS1).
It is noteworthy that y-globulin subgroups under genetic control have been
established in both
and man,27,28,29
the latter demonstrable by
serologic techniques comparable to those employed in the Rho test for RAA.
The variations in racial and familial incidence suggest that the protein( s ) responsible for RAA are particularly amenable to genetical control. Assumption
of this hypothesis, however, raises fundamental questions as to the interrelationship between “rheumatoid factor” and the disease responsible for its nosologic
importance. A possible analogy may be invoked between this laboratory parameter and its corresponding “disease”, and the relationship between erythrocyte-reduced glutathione instability and drug-induced hemolytic anemia. As
demonstrated by Beutler30 and others, the glutathione stability test provides a
useful laboratory parameter for mensuration of a genetically-determined de“Although some association with the degree of hypergamm;iglobulinemia is present in
these latter conditions, the relationship is not a direct one.
*“Seropositive” defined as rheumatoid arthritis with positive SSC and “seronegative” defined as rheumatoid arthritis with negative SSC.
FAMILIES OF PATIENTS WITH AGAMMAGLOBULINEMIA
583
ficiency in erythrocyte glucose-6-phosphate dehydrogenase. Subjects homozygous for the abnormal gene responsible for the enzymatic defect suffer no
clinical symptoms unless exposed to primaquine or other chemical agents,31
but upon such exposure usually develop severe hemolytic anemia. Similwly,
the presence of rheumatoid factor perhaps delineates that segment of the
population genetically susceptible to development of rheumatoid arthritis following exposure to bacterial, viral, chemical, or other environmental agents.
A high prevalence of clinical and/or radiologic signs of mild rheumatoid arthritis was indeed noted among the seropositive relatives of the propositi both in
the Lawrence and Ball study,2 and in our own (eg., M.Mey and A.Mey family
1 ) . Thus the rheumatoid factor, like the positive-reduced glutathione stability
test, may represent a laboratory index of an inherited biochemical characteristic
which predisposes the individual concerned to a certain type of disease. The
frequent occurrence of rheumatoid arthritis in multiple family members and
especially a frequent simultaneous occurrence in identical twins3z*33lends
further credence to this concept.
The relationship between the positive serologic reactions and the possible
later development of clinical rheumatoid arthritis in these family members is
as yet unexplored. However, a number of investigators5*6have noted that
rheumatoid arthritis-like syndromes occur not infrequently in patients with
agammaglobulinemia of the congenital variety. Good has described the development of manifestations of rheumatoid arthritis or other collagen disease in
patients with acquired agammaglobulinemia as
Three patients with congenital agammaglobulinemia in our series had typical rheumatoid arthritis.
Positive serologic results were obtained in the families of two of these patients.
Proband 2, A.Fa. in the acquired group, had clinical findings suggestive of disseminated lupus, and proband 5, C.Di., eventually developed clinical symptoms
and tissue biopsy evidence of polyarteritis. Further, the presence of laboratory
findings suggestive of lupus erythematosus in relatives of two probands with
adult acquired agammaglobulinemia raises the possibility that the diseases
rheumatoid arthritis, lupus erythematosus, and agammaglobulinemia are directly interreIated in a manner similar to the familial interrelationships between
hypergammaglobulinemia and LE delineated by Leonhardtl9 and by Holman
et ales4
Too little data is available to draw any conclusions regarding the mode of
inheritance of idiopathic acquired agammaglobulinemia. However, it is apparent that quantitative and qualitative abnormalities in 7-globulin occur at an
unusually high rate in family members and probably are present in both the
maternal and the paternal relatives of each propositus. The observations reported by Zelman and Lewin3 of elevated 7-globulin levels in parents have been
confirmed in this series. In addition, the further abnormality of positive lests
for RAA has been found as have occasionally positive tests for lupus. These
findings suggest that certain basic immunologic alterations occur in families
of acquired agammaglobulinemia patients, resulting in elevation or depression
of the 7-globulin levels, as well as in qualitative changes in 7-globulin detectable by various serologic parameters. Although environmental factors may play
a role, the great variability of the 7-globulin alterations encountered suggests
584
1
FUDENBERG, GERMAN AND KUNKEL
“T”
h-0
I1
Rheumatoid factor
Increased Y-glob
Decraeed J- glob
@ mot tested
Fig. 6.-Aberrations in y-globulin in the family of a proband with infantile hypogammaglobulinemia (see text). Identical titers for rheumatoid factor in three serologic test systems were present in the sera of the two identical twins, one the
mother of the proband.
that these are differingphenotypic expressions controlled by more than a single
genetic determinant. The multiple abnormalities present in the relatives in
family 1 provide further evidence for this concept. The presence of identical
titers for RAA in three separate test systems in a set of identical twins, vide
infra, is illustrated in figure 6 and is also compatible with an important role of
genetic mechanisms in elaboration of the 7-globulin abnormalities cited. These
various observations suggest that acquired agammaglobulinemia too is genetically determined, a possibility previously raised by Gitlin et al.35In addition,
an absence of the &A and
“immunoglobulins”despite normal 7s 7-globulin
levels in several relatives of patients with acquired agammaglobulinemia has
been observed. These observations lend further support for postulating a
hereditary basis for these disorders. The delay in onset of clinical symptoms
may reflect a genetic basis for an abiotrophic decline in 7-globulin with aging,
differing from the presumed sex-linked recessive mechanism involved in congenital agammaglobulinemia. Further, some subjects with persistent absence
of 7-globulin on electrophoresis have shown no increased liability to infecti0n,”7,3~so that the adult form may represent delayed clinical manifestations
of a congenital disorder.
Observations to be reported elsewhere3gon a group of infants” with moder*These infants did not develop pneumonia, but had unusually frequent cutaneous, gastrointestinal and upper respiratory infections, which no longer recurred following institution
of 7-globulin therapy. Hypergammaglobulinemia and RAA have been occasionally noted
in their parents and sibling.; and in one instance identical titers of RAA were present in Rho,
latex fixation and F I1 tanned cell tests in both the mother of the proband and in her sister,
an identical twin (see Fig. 6 ) .
FAMILIES O F PATIENTS WITH AGAMMAGLOBULINEMIA
585
ately decreased y-globulin levels (300-450 mg. per cent) at 2-3 years of age,
raise the possibility that such infants represent a population reservoir from
which clinical cases of adult idiopathic agammaglobulinemia are derived. The
presence in kindred 1, figure 1, both of a patient with adult acquired agammaglobulinemia and of an infant with moderate hypogammaglobulinemia and
clinical symptoms typical of this group of infants, lend further support to this
hypothesis.
It is of interest that other known genetically determined disorders, usually
congenital, may not become apparent until adulthood. For example, Dent and
Harris40 have studied three families originating from a single proband with the
De Toni-Fanconi syndrome ( aminoaciduria and renal glycosuria ) ; in one
family the disease developed in childhood, but in the other two families it
became apparent only in adult life. In particular in one family member aminoaciduria and glycosuria were found at age 42; no glycosuria was noted on
three separate urinalyses at age 24 during hospitalization for other reasons.
Other familial disorders, presumably genetic, do not express themselves until
adult life, e.g., Huntington’s chorea4l and pseudoxanthoma e l a s t i c ~ m . ~ ~
The possible genetic interrelationship between “acquired agammaglobulinemia” and the rheumatoid and lupus factors perhaps raises important therapeutic implications because of the clinical effectiveness of the hydroxy-corticoids in the diseases responsible for the nosologic significance of the above
factors. Small doses of prednisone (10 mg. daily) have consequently been
administered to the first five of the probands in the “acquired agammaglcbulinemia” group; moderate clinical improvement has subsequently been noted
in several respects. Although these patients no longer suffered bacterial pneumonias after introduction of y-globulin therapy, upper respiratory infections
characterized by purulent sputum and fever without demonstrable pulmonary
changes by physical examination or by X-ray still recurred at regular intervals,
ranging from every 23 weeks to every 2-3 months in the individual subjects.
A subjective feeling of chronic fatigue was also uniformly present. The addition
of hydroxy-corticoids to the therapeutic regimen was followed by the disappearance of both the recurrent upper respiratory infections and the fatigue.
The longest period of such therapy is three years (two patients); the other
three individuals have been on such medication for one to two years. No adverse effects, particularly as concerns infection, have been noted. Although the
mechanism responsible for the actions of the hydroxy-corticoids in such individuals remains uncertain, 7-globulin levels have risen in two of the subjects
so treated. A striking increase in 7-globulin levels following institution of corticoid therapy also occurred in JFai family 1 ( Vz in fig. 1 ), the hypogammaglobulinemic infant previously cited (vide supra). Clinical improvement also accompanied his rise in y-globulin. In addition, proband 13 had been treated
with steroids for several years by Dr. Janet Hardy at Johns Hopkins Hospital
and in her opinion improved on such therapy. These clinical observations,
subjective to be sure, suggest that cautious use of hydroxy-corticoids
may be of value in selected patients with agammaglobulinemia, when administered in conjunction with parenteral 7-globulin and antibiotics when indicated.
586
FUDENBERG, GERMAN AND KUNKEL
CONCLUSIONS
The incidence of rheumatoid agglutinating activity (RAA) in parents and
siblings of patients with acquired agamrnaglobulinemia has been found to be
considerably higher than the incidence of RAA in the normal population. In
similar relatives of probands with congenital agamrnaglobulinemia only a few
positive families were encountered and these may reflect difficulties in classification. Elevated 7-globulin levels were occasionally found in relatives of both the
acquired and congenital patients along with alterations in the
and &M
proteins. Laboratory findings suggestive of lupus erythematosus were aIso observed in relatives of two of the acquired agammaglobulinemia cases. The high
incidence of qualitative and quantitative abnormalities in the serum 7-globulin
in relatives of patients with idiopathic “acquired adult agammaglobulinemia
suggests that this may also be a genetically determined disorder. The possible
relationship of acquired agamrnaglobulinemia to the connective tissue disorders
is discussed.
ACKNOWLEDGMENTS
We are very grateful to Drs. I. Zelman, Janet Hardy, and Morris Ziff for their efforts in
collecting sera from the widely scattered family members of families 6, 13, and 14. We
are indebted to Dr. A. G. Bearn for helpful discussion and aid with the manuscript, and
to Miss Dolores Czerwinski for skilled technical assistance.
ADDENDUM
Another family has been studied recently with Dr. C . K. Osterland where the mother
of a patient with acquired agammaglobulinemia has clinical evidence of systemic lupus
erythematosus with positive L.E. cells and nuclear complement fixation reactions.
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