CORRESPONDENCE
THREE GENERATIONS OF
PATIENTS WITH LUPUS
ERYTHEMATOSUS AND
HEREDITARY
ANGIOEDEMA
To the Editor:
In 1974, Kohler et al (1) recognized
the association between hereditary
angioedema and lupus erythemato-
sus in a family with twin boys. Subse-
quent reports have confirmed this as-
sociation (2,3). The daughter of one
of the twins from Kohler’s report has
hereditary angioedema and systemic
lupus erythematosus (SLE). We re-
port her case and discuss the affected
family.
A 21-year-old woman has been fol-
lowed up for the management of he-
reditary angioedema and SLE (five
American College of Rheumatology
criteria). At the age of 13 years, she
began to experience recurrent epi-
sodes of nonpruritic, nonpitting
edema of the face and tongue, and
frequent episodes of abdominal pain
and diarrhea. She had no associated
urticaria. At the age of 14 years, she
developed a photosensitive skin erup-
tion on the face and upper extremi-
ties. She has occasional joint pain and
swelling, as well as persistent oral and
ocular dryness that improves after use
of eye drops.
Physical examination of her skin
revealed well-demarcated facial,
scalp, and forearm plaques with fol-
licular plugging in a photodistributed
pattern. Complement laboratory
studies performed during a quiescent
period showed CH50 of 0 U/mL
(normal range 171 to 423 U/mL), a
C1 esterase inhibitor function of 16%
(68% to 120%), C1 inhibitor esterase
level of 1 mg/mL (⬎20 mg/mL), C1q
of 7 mg/dL (7 to 24 mg/dL), C4 of 3
mg/dL (14 to 53 mg/dL), C5 of 70
U/mL (130 to 230 U/mL), and C4a of
5,600 ng/mL (0 to 2,830 ng/mL). The
antinuclear antibody titer was 1:80,
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with a speckled pattern. Anti-La/SSB
antibodies were detected.
Her family history is remarkable
for hereditary angioedema and SLE
(Figure). The patient’s father was di-
agnosed with discoid lupus at the age
of 5 years, and his twin brother was
diagnosed with the same condition at
age 8 years. Neither has developed sys-
temic manifestations of the disease.
The prevalence of SLE and other
lupuslike disorders in patients with
hereditary angioedema is 1% to 2%
per year (3,4), which is substantially
higher than the reported 2 to 8 cases
per 100,000 people per year in the
general population (5). A review of
reported cases of hereditary angio-
edema and lupus reveals that this as-
sociation occurs predominantly in
girls. Although not all patients have
systemic manifestations, skin abnor-
malities are very common. The form
of lupus seen in patients with heredi-
tary angioedema, and in our patient,
is phenotypically similar to the lupus
associated with inherited early com-
plement component deficiencies (C2
and C4) characterized by female pre-
dominance, low titers of antinuclear
Figure. Pedigree of the family with hereditary angioedema and lupus. The proband is
indicated by an arrow. Squares indicate men and circles indicate women. Family mem-
bers affected with hereditary angioedema are denoted by solid symbols. Family mem-
bers affected with lupus are denoted by striped symbols. A slash means that the person
is deceased.
antibodies, early age of onset, less se-
vere disease, and prominent discoid
skin lesions (6,7).
The clustering of lupus disease in
three generations of this family with
hereditary angioedema is unusual. It
is likely that the family members
share several lupus susceptibility
genes, and they may also have been
exposed to common environmental
triggers. In general, among families
that have several members with auto-
immune disorders, the affected mem-
bers do not all have the same disease
phenotype. In contrast, in this family,
members largely show the same phe-
notype, suggesting that specific geno-
types interact with specific environ-
mental agents.
Theresa R. Pacheco, MD
William L. Weston, MD
Departments of Dermatology, and
Pediatrics
University of Colorado Health
Sciences Center
Patricia C. Giclas, PhD
Department of Pediatrics
National Jewish Medical
and Research Center
0002-9343/00/$–see front matter
PII S0002-9343(00)00382-X

David H. Collier, MD
Lela A. Lee, MD
Department of Medicine
Denver Health Medical Center
Departments of Dermatology
and Medicine
University of Colorado Health
Sciences Center
Denver, Colorado
1. Kohler PF, Percy J, Campion WM, Smyth
CJ. Hereditary angioedema and “familial”
lupus erythematosus in identical twin boys.
Am J Med. 1974;56:406 – 411.
2. Agnello V. Lupus diseases associated with
hereditary and acquired deficiencies of
complement. Springer Semin Immunopath.
1986;9:161–178.
3. Brickman CM, Tsokos GC, Balow JE, et al.
Immunoregulatory disorders associated
with hereditary angioedema. I. Clinical
manifestations of autoimmune disease. J Al-
lergy Clin Immunol. 1986;77:749 –757.
4. Donaldson VH, Hess EV, McAdams AJ. Lu-
pus-erythematosus-like disease in three un-
related women with hereditary angioneu-
rotic edema. Ann Intern Med. 1977;86:312–
313.
5. Hochberg MC. The epidemiology of sys-
temic lupus erythematosus. In: Wallace DJ,
Hahn BH, eds. Dubois’ Lupus Erythemato-
sus. Baltimore, Md: Williams & Wilkins;
1997:49 – 65.
6. Agnello V. Association of systemic lupus er-
ythematosus and SLE-like syndromes with
hereditary and acquired complement defi-
ciency states. Arthritis Rheum. 1978;21:
5146 –5152.
7. Arnett FC, Reveille JD. Genetics of systemic
lupus erythematosus. Rheum Dis Clin North
Am. 1992;18:865– 891.
CHRONIC FATIGUE
SYNDROME
To the Editor:
Our clinical experience and re-
search in chronic fatigue syndrome
has led us to conclusions different
from those presented in the article by
De Meirleir et al (1) and the accom-
panying editorials (2,3).
In our Psychosomatic Rehabilita-
tion Center, located a few miles from
Dr. De Meirleir’s clinic in Brussels, we
have seen more than 1,500 patients
with chronic fatigue syndrome dur-
ing the past 5 years, and about 50 of
Letters to the Editor
them had already undergone a “diag-
nostic” RNase-L test. Throughout the
years, we have developed serious
doubts about the validity of this test
and its discriminative value. For ex-
ample, some patients with a “posi-
tive” test had a history of psychiatric
problems, including premorbid de-
pression, while others who attributed
their symptoms to a previous viral in-
fection had a “negative” test. The test
results failed to predict therapeutic
outcomes in patients who followed
our comprehensive rehabilitation
program. Moreover, we witnessed the
potentially detrimental psychological
and physical effects of the test: pa-
tients with typical symptoms of
chronic fatigue syndrome but a nega-
tive test often felt confused, fearing
the stigma of a psychiatric or— even
worse—imaginary illness, and some
of those with a positive test— con-
vinced that their illness was “prov-
en”— entered medicolegal disability
claims that clearly reinforced their
passive-regressive tendencies and
hampered attempts at rehabilitation.
Given our experience, we disagree
with Dr. Komaroff’s editorial (2) in
its support of the opposition between
“real” (ie, organic, testable) and
“imaginary” symptoms. In our view,
all symptoms, including psychologi-
cal or psychiatric distress, have a
“real” (neuro)-biological basis, al-
though often not yet clinically test-
able. Furthermore, we think that
mainstream medicine should pay
more attention to, and try to inte-
grate, the growing body of psycho-
neuroendocrinological/immunologi-
cal research, which suggests, for ex-
ample, that chronic stress may
influence susceptibility to infections
(4) and make it more likely that pain
becomes a chronic problem (5).
On the other hand, we believe that
a pure cognitive-behavioral model of
chronic fatigue syndrome, which—as
rightly stated by Dr. Manu (3)— has
proven its therapeutic value, is not
free from this duality either: the
model focuses on physical avoidance
behavior and the somatic attribution
August 15, 2000 THE AMERICAN JOURNAL OF MEDICINE威
of symptoms based on an unknown,
but most likely psychological or psy-
chiatric, illness.
We have recently found empirical
support for the pivotal effect of
chronic stress in chronic fatigue syn-
drome (6,7). Our results, which are in
accordance with the pathophysiolog-
ical hypothesis of hypothalamic-pitu-
itary-adrenal axis disturbances (8),
make a strong plea for abandoning
the fruitless debate about biological
versus psychological explanations of
chronic fatigue syndrome. A bio-
psychosocial approach, taking ac-
count of predisposing developmental
and personality factors, precipitating
physical and psychological stresses,
cognitive-behavioral and sociocul-
tural maintaining mechanisms, and
mediating psychoneuroendocrino-
logical/immunological interactions,
should direct our clinical work and
future research on chronic fatigue
syndrome. Such a multidimensional
approach seems to be most promis-
ing, not only for understanding these
patients’ suffering, but also for de-
signing multimodal rehabilitation
programs by which their helplessness
may be converted into adequate cop-
ing.
Boudewijn Van Houdenhove, MD
Stefaan Vanthuyne, MD
Eddy Neerinckx, PhD
Universitaire Ziekenhuizen K.U.
Leuven
Leuven, Belgium
1. De Meirleir K, Bisbal C, Campine I, et al. A
37 kDA 2–5A binding protein as a poten-
tial biochemical marker for chronic fatigue
syndrome. Am J Med. 2000;108:99 –105.
2. Komaroff AL. The biology of chronic fa-
tigue syndrome. Am J Med. 2000;108:169 –
171.
3. Manu P. Chronic fatigue syndrome: the
fundamentals still apply. Am J Med. 2000;
108:172–173.
4. Grant I. Caregiving may be hazardous to
your health. Psychosom Med. 1999 61:420 –
423.
5. Loeser JD, Melzack R. Pain: an overview.
Lancet. 1999;353:1607–1609.
6. Van Houdenhove B, Neerinckx E. Victim-
ization in fibromyalgia and chronic fatigue
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