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Report of the familial occurrence of systemic lupus erythematosus in male siblings.

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Report of the Familial Occurrence of Systemic Lupus
Erythematosus in Male Siblings
David A. Spector, Lee M. Jampol and John P. Hayslett
The occurrence of systemic lupus erythematosus (SLE) i s reported in 2
pairs of male siblings. Since the occurrence of idopathic SLE is uncommon
in the male, these cases provide additional support to the hypothesis that
genetic factors play an important role in pathogenesis. Of additional interest in these patients was the varied clinical manifestations of disease between brothers, suggesting that additional factors govern the clinical expression of this disorder.
T h e increasing evidence that systemic lupus
erythematosis (SLE) is, at least in part, genetically determined, is supported by familial
occurrence of the disease. Dubois gathered 66
cases from among 30 families in 1966 (1). Subsequently, 8 cases in 4 additional families have
been reported (2-S), making a total of 74 cases
in 34 families.
Because of the potential error in studies of
this kind, as shown by O’Brien (6), in denoting
a true increased familial incidence, reports of
concordance for SLE in twins are of special importance (2-3,7-11). In a similar way the occurrence of SLE among male siblings provides
From the Departments of Medicine, Pediatrics and Ophthalmology, Yale University School of Medicine, New
Haven, Conn.
Supported by US Public Health Service Grant TIAM
501 5 and The American Heart Association.
DAVID A. SPECTOR, MD: Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn; LEE M. JAMPOL, MD: Department of
Opthalmology, Yale University School of Medicine, New
Haven, Conn; JOHN P. HAYSLETT, MD: Department of Internal Medicine, Yale University School of Medicine, New
Haven, Conn, (Dr. Hayslett is an Established Investigator
of The American Heart Association).
Reprint requests should be addressed to: Dr. John P.
Hayslett, Department of Internal Medicine, Room 2074
LMP, Yale University School of Medicine, 333 Cedar
Street, New Haven, Conn 06510.
Submitted for publication Sept 25, 1972; accepted Nov
13. 1972.
additional evidence for the importance of genetic factors since.the sex incidence in SLE is
predominantly female, accounting for approximately 90% of cases (12). In the present report
2 sets of male siblings with S L E are described.
Family A
Case 1. Patient RA was admitted to the Yale-New
Haven Hospital in 1959, at age 14, because of a 2-month
history of arthritis. Evaluation revealed fusiform swelling of
wrists and interphalangeal joints, generalized lymphadenopathy, enlargement of liver and spleen and dependent
edema. Laboratory studies demonstrated a positive LE cell
preparation and antinuclear antibody test, a hematocrit of
23%, white blood cell count of 5350/cu mm, serum albumin
of 1.9 g% and serum globulin of 6.6 g%. Renal involvement
was indicated by elevated levels of nonprotein nitrogen, 43
to 67 mg% (normal: <45), 3+ proteinuria and microscopic
hematuria. Subsequent to treatment with cortisone and
chloroquine his symptoms resolved although photosensitivity and mild hypertension were noted.
Five years later, 1965, a renal biopsy was performed because of persistent proteinuria and demonstrated a mild diffuse proliferative glomerulonephritis. After the institution
of prednisone, 40 mg/day, he experienced a generalized
seizure associated with elevated blood pressure,
180/120 mmHg. T h e dose of prednisone was reduced and
discontinued in 1968 when aseptic necrosis of the right hip
was discovered. Hydroxychloroquine, begun in 1967,
400 mg/day, has been continued until the present time.
During the past 7 years he has remained free of symptoms and has been employed full time. Laboratory studies
Arthritis and Rheumatism, Vol. 16, No. 2 (March-April1973)
have demonstrated a serum creatinine of 1.1 mg%, consistently negative determinations of L E cell preparations
and antinuclear antibody tests, mild proteinuria of 0.8 g/
day and a normal urine sediment. Serial ophthalmologic examinations have shown no evidence of retinal disease.
Case 2.
Patient AA, brother of RA, developed symptoms of pain in his wrists and right shoulder in 1968, at age
28. Evaluation elsewhere demonstrated a positive latex fixation test and negative LE cell preparation. Symptomatic
treatment with salicylates, Butazolidine@, and indomethacin was prescribed and caused a resolution of pain.
Two years later he experienced symptoms of pain in the
interphalangeal joints of both hands, malaise, mild intermittent fever and transient episodes of diplopia. T h e diagnosis of SLE was made on the basis of the clinical manifestations and positive antinuclear antibody and LE cell tests.
In June 1970 he was admitted to the Yale-New Haven
Hospital because of a generalized seizure and cerebral vascular occlusion involving the left middle cerebral artery, associated with aphasia and profound paresis of the right upper and lower extremities. Since the electroencephalogram
was diffusely abnormal and no other cause was apparent, it
seemed likely that his cerebral vascular disease was related
to cerebral vasculitis. Further evaluation at that time revealed a positive L E cell preparation, false-positive VDRL,
hematocrit of 38%, white blood cell count of 7400/cu mm,
serum creatinine of 1.3 mg% and a normal urinanalysis. Serum albumin was 4.0 g% and globulin 3.6 g%. Treatment
with prednisone, 60 mg/day, was begun and gradually tapered over a 4-month period to 10 mg/day.
Subsequently there was a significant improvement in
both the aphasia and right-sided hemiparesis. Over the next
2 years there has been no recurrence of central nervous system manifestations or renal involvement. T h e L E cell preparation became negative, although the antinuclear antibody
titer remained positive at low titer, 1 :2.
Family C
Case 1. Patient P C was admitted to the Yale-New
Haven Hospital in 1966, at age 47, because of hemoptysis.
The past medical history was unremarkable and physical
examination was normal, except for a vocal cord polyp
which was excised. Laboratory studies included normal
hematocrit, white blood cell count, urinanalysis, chest
x-rays, bronchogram and bronchoscopic examination.
Subsequently he developed symptoms of arthritis involving hands and knees, a low-grade fever and weight loss.
During hospitalization in August 1967 the L E cell preparation and antinuclear antibody determination were positive.
Further studies revealed a hematocrit of 38%, white blood
cell count of 3200/cu mm, serum creatinine of 1.0 mg% and
normal urine analysis. His hospital course was complicated
by a lung abscess.
During the subsequent 7 years he has experienced episodes of joint pain, a facial rash and pleuritic chest pain,
which have responded to treatment with prednisone. There
is no evidence of renal involvement.
Case 2. Patient EC, brother of PC, was admitted to the
West Haven Veterans Administration Hospital in 1969, at
age 46, because of a 3-month history of arthralgias, proximal muscle pain, and weakness in the upper extremities.
Evaluation revealed an erythematous, maculopapular rash
on the shoulders and legs, cardiac failure, symmetrical
wasting of the shoulder girdle and fusiform swelling of the
proximal interphalangeal joints. T h e L E cell preparation
was positive and muscle enzymes, including lactic dehydrogenase, creatine phosphatokinase and serum glutamic
oxaloacetic transaminase, were elevated. Serum albumin
was 2.0 g% and globulin 3.7 g%. T h e serum creatinine and
urine analysis were normal. Muscle biopsy demonstrated
focal degeneration and an interstitial infiltration with
plasma cells and lymphocytes. Treatment with prednisone,
60 mg/day, was begun.
T h e hospital course was complicated by persistent fever,
leukopenia, anemia, a circulating anticoagulant to factor
IX, mental confusion and generalized seizures. He died 1 1
weeks after admission because of septicemia. No postmortem examination was performed.
Numerous studies have provided strong support for the hypothesis that SLE nephropathy,
and probably other manifestations of this disorder as well, are provoked by the deposition of
circulating antigen-antibody complexes (13, 14).
In addition to the immunologic factors involved in the immediate pathogenic mechanisms, it is apparent that host factors such
as age, race and sex are also important (12).
T h e possible contribution of genetic factors
to the pathogenesis of SLE has caused considerable interest in recent years. In 1961
Brunjes (1 5) reviewed the reported cases of
familial occurrence and recorded 10 new cases
of proven SLE occurring in 4 families, including 1 sibship with 4 sisters involved. He
collected a total of 44 cases in 20 families.
Dubois summarized reports of an additional 22
cases in 10 families (l), and 8 additional cases
in 4 families have subsequently been reported (2-5). In most instances sisters or
Arthritis and Rheumatism, Vol. 16, No. 2 (March-April 1973)
mother-daughter relationships were involved.
Systemic lupus erythematosus has been described previously in only 2 sets of brothers
(1, 15). Of special importance in support of
genetic factors is the occurrence of S L E in 5 sets
of identical twins (2, 3, 7-1 1).
In addition to evidence suggesting a familial
aggregation of SLE, there are reports of a
higher incidence of other collagen diseases and/
or serologic abnormalities in the families of
patients with SLE. Leonhardt (16) noted collagen diseases in 5.3% of 225 first-degree relatives
of 57 cases of SLE, comparcd to a 0.6% incidence in normal controls. T h e same author (17) found a higher incidence of hyperglobulinemia in family members of patients
with SLE than in controls. Holborow and
Johnson (18) and Pollak and associates (19)
have reported an increased frequency of positive
antinuclear factor tests in family members.
Additional evidence for the role of genetic
factors in the pathogenesis of SLE is provided
by 2 animal models. In the New Zealand
mouse, which develops a Coombs-positive hemolytic anemia, splenomegaly, immune complex nephritis and L E cell phenomena, predisposition seems to follow classical genetic
Recently (20) several colonies of dogs have
been established in which multiple serologic abnormalities, including positive L E cell tests, antinuclear antibodies, and rheumatoid factor
have been found. Analysis of the distribution
of these abnormalities does not reveal a simple
genetic mechanism of inheritance and suggests
that a transmissible infecting agent may be involved in genetically susceptible animals.
T h e cases described in this report are of interest in two ways. First, the occurrence of S L E
in 2 sets of male siblings give additional support
to the concept that genetic factors play an important role in this disorder. As O’Brien (6)
showed in a study of rheumatoid arthritis, there
are inherent problems in evaluating the familial
distribution of diseases because of limitations in
discerning the true distribution of the disorder
in question in a random population. Since the
occurrence of S L E in males is uncommon, accounting for only approximately 10% of all
cases, it is unlikely that SLE developed in a random fashion in these patients.
T h e second point of interest is the varied expression of clinical disease among the sibling
pairs. In the first pair of brothers for example,
RA experienced symptoms related to involvement of joints, skin, central nervous systems and kidney, while his brother, AA, exhibited joint and severe central nervous system
disease. In the other pair, PC developed symptoms due to involvement of joints, skin and
pleura, while E C demonstrated predominantly
skeletal muscle and central nervous system involvement.
Assuming that genetic factors were of importance in predisposing these patients to SLE,
these data suggest that other mechanisms govern the clinical expression of the disorder.
1 . Dubois E L : Lupus Erythematosus. First edition.
New York, McGraw-Hill, p p 140-144
2. Lieberman E, Heusser E, Hauson V, et al: Identical 3 year-old twins with disseminated lupus
erythematosus: One with nephrosis and one
with nephritis. Arthritis Rheum 11 :22-32, 1968
3. Jokinen EJ, Jankala ED: Antitissue antibodies
in monozygotic twins with systemic lupus erythematosus. Ann Rheum Dis 29:677-680,1970
4. Salazar FA, Robbins DN, Scaletter R: Familial
systemic lupus erythematosus. Med Ann D C
5. Randle APH, Bruckner F E : Familial lupus erythematosis. Ann Phys Med 8:229-302,1966
6. O’Brien W M , Burch TA, Bunin JJ: A genetic
analysis of the occurrence of rheumatoid factor
(RF) in 485 matings and 1633 sibling pairs in
Pima and Blackfeet Indians. Arthritis Rheum
7. Blumenfeld NB, Kaplan SB, Mills D M , et al:
Disseminated lupus erythematosus in identical
twins. JAMA 185:667-669,1963
8. Brunsting LA: Symposium on diseases of skin;
acute disseminated lupus erythematosus. Med
Clin North Am 35:399-400,1951
Arthritis and Rheumatism, Vol. 16, No. 2 (March-April 1973)
9. Davis M W , Gutridge GN: Disseminated lupus
erythematosus in identical twin sisters associated
with diabetes mellitus in one case. J Missouri
Med Assoc 48:446-450, 195 1
10. Joseph RR, Zarafonetis CJD: Fatal systemic
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249: 190-199,1965
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12. Dubois EL, Tuffanelli D L : Clinical manifestations of systemic lupus erythematosus. J A M A
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13. Koffler D, Schur D H , Kunkel H G : Immunological studies concerning the nephritis of systemic lupus erythematosis. J Exp Med 126:607624,1967
14. Andres GA, Accinni L, Beiser SM, et al: Localization of fluorescein-labeled antinucleoside antibodies in glomeruli of patients with active systemic lupus erythematosus nephritis. J CIin
Invest 49:2106-2118, 1970
15. Brunjes S, Zike K, Julian R: Familial systemic
lupus erythematosus. A review of the literature,
with a report of ten additional cases in four families. Am J Med 30:529-536, 1961
16. Leonhardt T: Family studies on systemic lupus
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17. Larsson 0, Leonhardt T: Hereditary hypergammaglobulinaemia and systemic lupus erythematosus. I. Clinical and electrophoretic studies. Acta Med Scand 165:371-393, 1959
18. Holborow J, Johnson G P : Antinuclear factor in
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Arthritis and Rheumatism, Vol. 16, No. 2 (March-April 1973)
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lupus, siblings, report, occurrence, systemic, malen, familiar, erythematosus
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