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Mixed connective tissue disease in siblings.

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709
MIXED CONNECTIVE TISSUE DISEASE
IN SIBLINGS
JOHN R. HORN, JANET J. KAPUR, and SARA E. WALKER
Mixed connective tissue disease (MCTD) was
diagnosed in a brother and sister, and 18 additional family
members spanning three generations were studied to detect evidence of autoimmune disease. Symptoms or signs
of MCTD without complete expression of the disease were
found in 8 relatives of the original cases. Antibodies to
ribonucleoprotein and high-titer antinuclear antibodies
were found only in the affected siblings. Tests for rheumatoid factor were positive in 9 of 17 relatives of the patients; the titers ranged from l :160 to l :2560. The brother
and sister with MCTD had an identical HLA genotype11,12/2,12. The same genotype was inherited by 3 of their
siblings, who had impressive rheumatic complaints. This
report emphasizes the association between inflammatory
From the Department of Internal Medicine, College of Human Medicine, Michigan State University, The Veterans Administration Hospital, Ann Arbor, Michigan, and The Rackham Arthritis
Research Unit and the Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Michigan.
Supported by the Medical Research Service of the Veterans
Administration; Grant C A 13297 from the National Cancer Institute,
National Institute of Health, United States Public Health Service; and
a Research Grant from the Michigan Chapter of the Arthritis Foundation.
John R. Horn, M.D.: Associate Clinical Professor in the
Department of Medicine, College of Human Medicine; Janet J. Kapur, B.A., M.T. (A.S.C.P.): The Veterans Administration Hospital,
Ann Arbor, Michigan; Sara E. Walker, M.D.: Assistant Professor of
Internal Medicine, The University of Michigan Medical Center, Ann
Arbor, Michigan.
Address reprint requests to Sara E. Walker, M.D., R4633
Kresge I, 1405 East Ann Street, Ann Arbor, Michigan 48109.
Submitted for publication October 17, 1977; accepted in revised form April 10, 1978.
Arthritis and Rheumatism, Vol. 21, No. 6 (July-August 1978)
connective tissue disease and a specific HLA type within a
single kindred.
Mixed connective tissue disease (MCTD) is an
inflammatory disease of unknown etiology which may
have overlapping characteristics of systemic lupus erythematosus, scleroderma, and polymyositis. Commonly, patients with MCTD have arthritis, swollen
hands and fingers, abnormal esophageal motility, Raynaud’s phenomenon, and active myositis. They may also
experience lymphadenopathy, fever, hepatomegaly,
serositis, and splenomegaly. Renal disease is rare in
mixed connective tissue disease (1). Sera from these
patients give positive indirect immunofluorescent tests
for antinuclear antibodies (ANA) with a characteristic
coarse speckled pattern. The diagnosis is confirmed by
finding serum antibodies directed against ribonucleoprotein (RNP), a ribonuclease-sensitive component of
extractable nuclear antigen (ENA) (2).
This report presents the first description of
MCTD in 2 members of the same family. In 1975,
MCTD was diagnosed in a 20-year-old woman and her
25-year-old brother. Eighteen additional family members were subsequently evaluated for clinical and serologic evidence of autoimmune disease, and serologic
HLA typing was performed to determine if occurrence
of MCTD was associated with a specific haplotype.
Eight relatives of the propositi had histories of arthritis,
arthralgia, swollen hands and fingers, Raynaud’s phenomenon, and/or pleurisy. The mother and a maternal
HORN ET AL
7 10
aunt had dilated periungual capillaries. The siblings
with MCTD and 9 family members, including one 3year-old girl, had positive tests for rheumatoid factor.
Anti-RNP and high titer ANA were found only in the
patients with MCTD, who had an identical genotype,
11,12/2,12.
METHODS
The siblings with MCTD were evaluated for connective tissue disease as described in Case Reports. These
patients and their I8 relatives gave medical histories and had
physical examinations performed by a rheumatologist (JRH or
SEW). The integument and musculoskeletal system were examined carefully for signs of connective tissue disease. Periungual capillaries were evaluated by direct visualization using
the naked eye.
Sera from each subject were tested for antibodies to
ENA by means of a hemagglutination technique (2). The 2
positive serum samples from the propositi were tested further
by Ouchterlony immunodiffusion to determine whether the
anti-ENA antibodies were directed against RNP, Sm, or both
(3). Although ENA is active in the hemagglutination test, it
precipitates poorly with anti-ENA antibodies in agarose gel
diffusion (4). Therefore, saline-soluble calf thymus nuclear
extract (CTE) (5) was used as antigen in the immunodiffusion
studies. The patients’ sera were placed in wells on diffusion
plates and tested for ability to react with CTE. Standard
reference sera previously characterized as containing only antiR N P or anti-Sm antibodies were placed in adjacent wells.
Additional immunodiffusion testing employed ribonucleasedigested CTE.
The following tests were performed on each patient in
this study: hemoglobin, hematocrit, white blood cell count;
erythrocyte sedimentation rate (Westergren); indirect immunofluorescent ANA test (6) utilizing sera diluted l:lO, 1:40;
1:160, 1:640, and 1:2560; modified Farr test for anti-doublestranded D N A (7); modified Singer-Plotz agglutination test
for rheumatoid factor (8). Peripheral blood lymphocytes were
tested for HLA antigens using a standard microcytotoxicity
assay (9). There was no clinical evidence of myositis or esophageal dysfunction in members of this family when they were
examined. Therefore, muscle enzyme tests, electromyograms,
muscle biopsies, and esophageal motility studies were not done
routinely.
CASE REPORTS
Patient I1 5. A 26-year-old man employed as a stock
mover in a foundry became ill in January 1975. He developed
an urticaria-like skin eruption with raised, pruritic, serpiginous lesions which persisted for 2 days. His joints and muscles were painful, and his oral temperature was 105°F. The
fever, arthralgia, and myalgia resolved after 2 weeks. Three
months later, fever and urticaria recurred. The elbows, wrists,
metacarpophalangeal and proximal interphalangeal finger
joints, knees, ankles, and metatarsophalangeal joints became
swollen and painful. Morning stiffness appeared lasting 1 to 3
hours. There was no history of skin edema or tightening,
dysphagia, or muscle weakness.
Initial physical examination was performed in June
1975. Blood pressure was 1l6/76, the pulse 88, and the respirations 16. The patient was afebrile. Oropharyngeal mucous
membranes were erythematous. The skin was normal. Periungual capillaries were not dilated. There were no enlarged
lymph nodes. N o abnormalities were found in examining the
lungs, heart, and abdomen. The spleen was not palpable. Both.
elbows had 15” flexion contractures, and the metacarpophalangeal and proximal interphalangeal finger joints were swollen.
Muscle bulk and strength were normal.
The ANA test was positive in serum diluted 1 :640, and
a coarse speckled pattern was observed. Anti-ENA were detected by hemagglutination in a serum titer greater than
1 : 100,000. Ouchterlony immunodiffusion of this patient’s
serum and CTE gave a single line which was continuous with a
line formed by reacting CTE with anti-RNP in an adjacent
well. The serum did not react with anti-Sm. Additional testing
showed that ribonuclease-treated CTE did not react with the
patient’s serum or with anti-RNP. The erythrocyte sedimentation rate (Westergren) was 28 mm/hr, and the test for rheumatoid factor was present in serum diluted 1:2560. The following
laboratory studies were normal or nonreactive: hematocrit,
leukocyte count, differential leukocyte count, urinalysis, serum
creatinine, creatine phosphokinase, aldolase, serum protein
electrophoresis, VDRL, C3, and hemagglutination test for
anti-DN A. Electromyogram and muscle biopsy were not performed because there was no clinical evidence of myopathy.
Esophageal motility was not tested.
His symptoms improved initially with salicylate therapy. In September 1975 he developed Raynaud’s phenomenon
with cold-induced finger pain and color change from white to
blue. The leukocyte count was 4,300, and LE cell preparations
and a Farr anti-DNA test were negative. Two months later, his
spleen was palpable 3 cm below the left costal margin and he
developed transient alopecia. In February 1976 ulcers were
present on the oral mucous membranes for 2 weeks. In March
1976 he described bilateral chest pains that occurred with deep
breathing. The pains resolved after 2 days. In May 1976 fever
recurred and he complained of pleuritic chest pain on the left.
A chest roentgenogram showed blunting of the left costophrenic angle, and pleural fluid was seen layered above the
left chest wall in a left lateral decubitus film. Prednisone, 30
mg/day, was added to the therapeutic regime. He improved
and returned to work. His dose of prednisone was decreased to
20 mg every other day, and his only complaints at present are
arthralgia and Raynaud’s phenomenon. in January I978 physical examination showed normal skin over the face and extremities, with no evidence of scleroderma.
Patient I1 9. An 18-year-old machine operator in a
shoe factory, a sister of patient I1 5, developed fatigue and
enlarged lymph nodes in 1973. The following year, her hands
and fingers swelled and her elbows and knees became enlarged
and painful. Three months later her hair began to fall out.
Anxiety or exposure to cold induced Raynaud’s phenomenon
in her hands and feet, with characteristic color changes from
white to blue to red.
Initial physical examination was performed in July
1975. Blood pressure was 122/82, the pulse 82, and the respirations 16. She was afebrile. Her fingers and hands were diffusely
MCTD IN SIBLINGS
71 1
Table I . Clinical Abnormalities and Auroanribodies in 2 Siblings with Mixed Connective Tissue Disease and 18 Family Members
~~
Family
Member
11
5t
II 9t
I I
2
3
4
5
6
Sib, MCTD
Sib, MCTD
Aunt
Mother
Aunt
Father
Aunt
Uncle
Age
21
21
56
58
55
62
58
53
Symptoms and Signs of MCTD*
Fever, Arthritis, PI, Ray
Large Spleen, Alopecia, Ulc
Large Lymph Nodes, SwH
Arthritis, Alopecia, Ray
Arthritis, SwH, Dil Cap
PI, SwH, Dil Cap
ANA
~~~
Anti-ENA (CTE)
Rheumatoid Factor
1:640, Coarse
> 1: 100,Ooo
speckled
1:640,Coarse
speckled
(RNP+, Sm-)
0
0
0
0
0
0
0
0
0
0
1:320
0
0
1:320
1:2560
1:640
0
0
0
1:lO. Nucleolar
1:40, Coarse
I :2560
1 :100.oO0
1:640
( R N P + , Sm-)
speckled
11 1
Cousin
2
3
4
6
Sib
Sib
Sib
Sib
1
Sib
Sib
8
111 I
2
3
4
5
Nephew
Nephew
Nephew
Daughter
Niece
26
34
32
30
26
24
23
8
12
2
3
8
0
0
0
0
0
0
0
Arthralgia, SwH
0
0
0
0
1:160
ND
1:320
0
1:320
0
I :640
0
0
0
0
Arthralgia
0
0
0
0
0
Arthritis
Arthralgia, PI, Ray
Arthritis
PI
* PI = pleurisy, Ray = Raynaud’s phenomenon, Ulc
capillaries.
t Propositi with MCTD.
$ Nonspecific agglutination.
=
oral ulcers, SwH
swollen, but there was no hidebound skin. Periungual capillaries were not dilated. Enlarged anterior and posterior cervical
lymph nodes were palpated. The lungs, heart, and abdomen
were normal. The spleen was not enlarged. The typical color
changes of Raynaud’s phenomenon were observed in the fingers. The muscles and joints were normal.
The A N A test was positive in a serum dilution of
1:640, with a coarse speckled pattern. Anti-ENA were detected
by hemagglutination testing in a serum titer of 1:100,000. After
ribonuclease digestion of ENA-coated sheep erythrocytes, the
positive titer fell t o 1:IOO. In the Ouchterlony immunodiffusion test, the patient’s serum was tested with CTE, antiRNP, and anti-Sm. A single precipitin line formed between
wells containing the patient’s serum and CTE; this line formed
a line of identity with the precipitin line between anti-RNP and
CTE. Ribnuclease-digested CTE did not react with the patient’s serum or with anti-RNP.
The Westergren erythrocyte sedimentation rate was 29
mm/hr. These laboratory tests were within normal limits or
negative: hematocrit, leukocyte count, differential leukocyte
count, urinalysis, serum creatinine, serum IgG, IgM, IgA,
rheumatoid factor test, VDRL, infectious mononucleosis spot
test, cryoproteins, C3, LE cell preparations, and hemagglutination test for anti-DNA. Tests for creatine phosphokinase
=
0
0
0
1:640
0
NSAS
diffusely swollen hands and fingers, Dil Cap
=
dilated periungual
and aldolase were not performed. A chest roentgenogram was
normal. Electromyogram and muscle biopsy were not performed. Esophageal motility was not tested.
Treatment with aspirin and phenoxybenzamine was
instituted, and the patient received a 3-month course of prednisone therapy, 7.5 mg/day. In September 1976 the rheumatoid factor test reverted from negative to positive in serum
titered 1:640, and a modified Farr test for anti-DNA was
negative. The patient quit work because activity caused pains
in the elbows, wrists, and metacarpophalangeal joints. In 1976,
she became pregnant and discontinued all medications. She
had a spontaneous delivery in August 1977 without exacerbation of her disease. Six weeks postpartum, she was
found to have carcinoma in situ of the cervix. Physical examination in January 1978 showed no scleroderma changes in the
skin and no evidence of active disease.
FAMILY STUDIES
All family members were questioned about exposure
to a possible common source of disease. The adults in this
study lived in different households, and there was no history of
keeping sick pets. In patient I 1 9, M C T D began 2 years before
HORN ET A L
patient I1 5 became ill. Although the siblings with M C T D lived
in the same small town, they did not live in the same house or
work in the same factory when their disease began. They
denied exposure to vibrating tools, vinyl chloride reactors, and
toxic substances.
Clinical abnormalities and tests for autoantibodies in
20 family members are listed in Table I. Swollen hands and
fingers, dilated periungual capillaries, arthritis, arthralgia,
pleurisy, and Raynaud's phenomenon were found in 8 of 18
first- and second-degree relatives of the siblings with MCTD.
Nine of these relatives had histories of disabling allergies to
dust and pollens. Family member 1 3 had a leukocyte count of
3500/mma. A paternal aunt of the affected siblings (I 5 ) had
persistent, unexplained elevations of the sedimentation rate
(79-85 mm/hr). Otherwise, blood counts and sedimentation
rates were normal. Two asymptomatic relatives in generation I
had positive ANA tests, but high-titer ANA and anti-ENA
were restricted to the 2 siblings with clearcut MCTD. Farr
tests for anti-DNA were negative in all 20 family members.
Sera from 9 of 17 relatives of the affected siblings were positive
for rheumatoid factor, with titers ranging from 1:160 to
1 :2560.
Figure 1 illustrates the family tree and inheritance of
HLA types within this kindred. I 2, the mother of the brother
and sister with MCTD, had a history of pleurisy and diffusely
swollen hands. Physical examination showed prominent dilated periungual capillaries. Her sister, I 1, stated that her
metacarpophalangeal and proximal interphalangeal finger
joints had been painful and swollen. She also gave a history of
intermittent, diffuse swelling of her hands. H e r only abnormal
physical finding was striking dilation of the periungual capillaries. I 2 married 1 4 , a man with no evidence of rheumatic
disease who has a positive latex agglutination test for rheumatoid factor. Two of their offspring, who inherited the identical
genotype 1 I,l2/2,12, developed typical MCTD. This genotype
was shared by 2 brothers ( I 1 3 and I1 4 ) and a sister (11 8).
Although these H LA identical siblings of the affected individuals were not severely ill, they had abnormalities that are
common in patients with MCTD. I1 3, a 32-year-old male
factory worker, had pleurisy, painful joints, and Raynaud's
phenomenon. I1 4, his brother, had a history of pain and
swelling involving the shoulders, elbows, metacarpophalangeal and proximal interphalangeal finger joints, and knees.
Their sister, I1 8, complained of arthralgia and recurring swelling of the hands and fingers.
Clinical and serologic abnormalities were common in
relatives who inherited haplotype 2, I2 without 11,12. Three of
6 individuals with 2,12 had rheumatic complaints. Positive
tests for rheumatoid factor were associated with the 2,12 haplotype in 3 family members. 111 4, the 3-year-old daughter of
the male propositus with MCTD, inherited 2,12 from her
father. Although she had no rheumatic complaints, she had a
positive latex test i n serum diluted 1:640.
DISCUSSION
This r e p o r t is t h e first description of MCTD occurring in t w o members of t h e same family. Other investigators h a v e mentioned t h e association of MCTD with
o t h e r connective tissue diseases i n close relatives. In one
kindred, a p a t i e n t with MCTD had a sister who died
with severe systemic lupus erythematosus (10). Two additional families in which MCTD coexisted with systemic lupus erythematosus and/or rhematoid arthritis
h a v e been discussed briefly ( 1 1). T h e s e familial clusters
of connective tissue diseases may be interpreted as showing t h a t MCTD is a variant of a n o t h e r disorder such as
systemic lupus erythematosus. However, in t h e family
described in this report, MCTD a p p e a r e d as a distinct
II
24,7/2,40
24,7/-,40
11,12/2,12
11,12/2,12
@
ll,l2/-,-
2,7/-,12
2,12/1,8
2,12/3,7
11,12/24,-
Y a MIXED CONNECTIVE TISSUE DISEASE
Figure 1. This family tree illustrates three generations of a family in which two siblings (I15 and I1 9)had MCTD. HLA types in 19
family members are listed.
MCTD IN SIBLINGS
clinical entity. The affected brother and sister had typical symptoms, physical signs, and serologic findings of
MCTD. ~~~~~~~~~~~i~and the hidebound skin ofscleroderma did not develop during a followup period Of
Years. Furthermore, negative tests for anti-DNA, norma1 serum complement levels, and absence of clinical
renal disease provided strong evidence that these patients had MCTD and not systemic lupus erythematosus. Although both patients had positive tests for
rheumatoid factor, they had no typical deformities of
rheumatoid disease. Positive latex agglutination tests are
compatible with MCTD; rheumatoid factor is present in
sera from 55% of MCTD patients (5).
Limitation of overt disease to only 2 members of
this family is not explained easily. Eight of 18 relatives
of these patients had complaints which may be associated with MCTD-arthritis, arthralgia, diffusely swollen hands, Raynaud’s phenomenon, and pleurisy. Dilated periungual capillaries were present in an aunt and
the mother of the propositi. These vascular lesions are
an important physical finding in MCTD. In a preliminary study, 13 of 26 patients with MCTD had abnormal
nailfold capillaries (12). It may be postulated that the
high frequency of rheumatic complaints and positive
latex agglutination tests in this kindred represented incomplete forms of disease. Characteristic MCTD with
antibodies to R N P in a brother and sister may have been
caused by unknown environmental o r genetic factors in
susceptible hosts.
Histocompatibility typing has been performed in
many patients with inflammatory disorders of connective tissue to search for associations between specific
HLA types and disease. An early report showed an
increased frequency of HLA-BS and B15 in systemic
lupus erythematosus, a disease which closely resembles
MCTD (13). However, a more recent study showed that
systemic lupus erythematosus was associated only with
HLA-B5 in black Americans (14). In families with multiple cases of systemic lupus erythematosus, disease inheritance is often associated with the same HLA types
within a well-defined kindred ( I 5). The family with
MCTD described in this report may represent inheritance of MCTD or “MCTD diathesis” associated with
certain histocompatability antigens. Surveys of additional patients will be needed to determine if HLA-A2,
All, or B12 are associated consistently with MCTD.
ACKNOWLEDGMENTS
Mrs. Noel Horn and Eric Hodeen, M.D., assisted the
authors by obtaining valuable clinical information from
713
M C T D patients and family members. Sera were tested for
E N A in the laboratory of Gordon C . Sharp, M.D., at the
University of Missouri Medical Center. H L A typing was performed in the Veterans Administration laboratory of Jane S.
Schultz, Ph.D., Assistant Professor of Human Genetics, University of Michigan Medical School. Barbara Boddy contributed expert technical assistance.
REFERENCES
I . Sharp G C , lrvin WS, Tan EM, Gould RG, Holman HR:
Mixed connective tissue disease-an apparently distinct
rheumatic disease syndrome associated with a specific
antibody to a n extractable nuclear antigen (ENA). Am J
Med 52:148-159, 1972
2. Sharp G C , Irvin WS, LaRoque, RL, Velez C, Daly V,
Kaiser AD, Holman HR: Association of autoantibodies
t o different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J Clin Invest
50350-359, 1971
3. Tan EM, Kunkel H G : Characteristics of a soluble nuclear
antigen precipitating with sera of patients with systemic
lupus erythematosus. J Immunol 96:464-47 1, 1966
4. Northway J D , Tan EM: Differentiation of antinuclear
antibodies giving speckled staining patterns in immunofluorescence. Clin lmmunol lmmunopathol 1 : 140-1 54,
I972
5 . Sharp G C , lrvin WS, May C M , Holman H R , McDuffie
FC, Hess EV, Schmid FR: Association of antibodies to
ribonucleoprotein and Sm antigens with mixed connective-tissue disease, systemic lupus erythematosus and
other rheumatic diseases. N Engl J Med 295:1149-1154,
1976
6. Kay D R , Bole GG Jr, Ledger WJ: Antinuclear antibodies,
rheumatoid factor and C-reactive protein in serum of
normal women using oral contraceptives. Arthritis
Rheum 14:239-248, 1971
7. Walker SE, Bole GG Jr: Selective suppression of autoantibody responses in NZB/NZW mice treated with longterm cyclophosphamide. Arthritis Rheum I8:265-272,
I975
8. Singer JM: Standardization of the latex test for rheumatoid arthritis serology. Bull Rheum Dis 24:762-769, 19734
9. Amos DB: Cytotoxicity testing, N I A I D Manual of Tissue
Typing Techniques (DHEW Publication N o ( N I H ) 76545). Edited by J G Ray Jr, D B Hare, PD Pedersen, DI
Mullally. Bethesda, Research Resources Branch
(NIAID), 1976, pp 25-28
10. Sharp GC: Autoantibodies and complement in SLE: a
reexamination. Hospital Practice 6:109-120, 1971
I I . Sharp GC: Mixed connective tissue disease. Current concepts (Audience discussion). Arthritis Rheum (supplement) 2O:S181-S186, 1977
12. Sharp GC: Personal communication
HORN ET AL
7 14
13. Grument FC, Coukell A, Bodmer JG, Bodmer WF,
McDevitt H O Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. A possible genetic predisposition to disease. N Engl J Med 285:193196, 1971
14. Nies K M , Brown JC, Dubois EL, Quismorio FP, Friou
G J , Terasaki PI: Histocompatibility (HL-A) antigens and
lymphocytotoxic antibodies in systemic lupus erythematosus (SLE). Arthritis Rheum I7:397-402, 1974
15. Cleland LG, Bell DA: HLA-SD haplotypes and immunological findings in SLE families. XIV International Congress of Rheumatology Abstracts, p 236, 1977
Errata
The title of the article by Bruce C. Gilliland er al. (April 1978, pages 330-336) should have been: “Synthesis of Rheumatoid
Factor by an Established Cell Line from a Rheumatoid Synovium.”
The second paragraph on page 529 (June 1978) of the article by Muhammad A. Khan er al.. “A Subgroup of Ankylosing Spondylitis Associated with HLA-B7 in American Blacks,” should have read:
Although our earlier study (7) showed no significant difference in age at onset of AS between B27-negative and B27positive patients, selection of the B7-positive subgroup from the larger group of B27-negative patients revealed later
onset of disease in these B7-positive American black patients. In a population of European and North-African patients,
Feldman el al. (20) noted onset of AS after the age of 40 years in 2 of 42 B27-positive and 3 of 8 B27-negative patients.
It is of interest that in psoriasis vulgaris, frequency of Bw17 has been reported to be significantly higher in patients with
onset before 35 years of age than in those with later onset (21,22).
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