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Identical 3-year-old Twins with Disseminated Lupus ErythematosusOne with Nephrosis and One with Nephritis.

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Identical 3-year-old Twins with Disseminated Lupus
Erythematosus: One with Nephrosis and
One with Nephritis
By ELLINLIEBERMAN,
EVAHEUSER,
VIRGILHANSON,
HELENKORNREICH,
GEORGEN. DONNELL,
AND BENJAMIN
H. LANDING
Sis
( SLE )
hn uncommon disorder in young children and is rarely considered as an explanation for renal disease in this age group.
Although there are many reports of disseminated lupus in identical twins, none of
these has concerned children.'"' The present report has a twofold purpose: the description of SLE in 3-year old identical
twins with differing renal and immunologic
involvement and, secondly, the description
of the response of a critically ill child with
lupus nephrosis to immunosuppressive
therapy.
YSTEMIC LUPUS ERYTHEMATOSUS
CASEDESCFUPTION
Patient No. 1.
A 3-year old Mexican-Filipino girl had always
been in good health and had not received drugs
for any prolonged period. Seven months prior to
admission to Childrens Hospital of Los Angeles
she developed a flat, red rash on the soles of the
feet and the palms of her hands. Arthritis, enlarged
lymph nodes and lethargy were noted during the
following months. Prednisone (15 mgm. daily)
From the Departments of Pedkrtrics and Pathology, University of Southern California School of
Medicine and the Childrens Hospital of Los
Angeles.
Supported in part b y the United States Public
Health Service (FR 86) and in part b y the Las
Madrinas Fund of the Childrens Hospital of Los
Angeles.
ELLINLIEBERMAN,
M.D.: Assistant Professor of
Pediatrics; Southern California School of Medicine
and Associate Attending Physician, Childrens Hospital of Los Angeles. EVA HEUSER,M.D.: Assistant
Professor of Pathology; C'outhern California School
Olf Medicine and Associate Pathologist, Childrens
22
was given for 3 months preceding admission. Dermatologic consultation was sought because of thinning hair. Generalized edema insidiously developed, with the feet, face and abdomen particularly
involved. On April 29, 1965 she was referred to
Childrens Hospital of Los Angeles for further
evaluation and management.
Family history revealed an identical twin with
evidence of disseminated lupus for the preceding
two months (Patient No. 2). Six siblings, the
parents and paternal grandparents had a negative
history for collagen disease and normal serum protein electrophoresis, uric acid and antinuclear factor
determinations ( ANF ) . A paternal great uncle
died with diabetes mellitus and renal disease and
another with chronic glomerulonephritis. The post
mortem findings of the latter were consistent with
chronic glomerulonephritis with marked foam cell
involvement.
Physical examination revealed a Cushingoid,
dark skinned 3-year-old girl with moon facies,
distended abdomen, anasarca, and an erythematous rash on the soles and palms. She was
photographed at the time of admission with her
twin (Fig. 1). A rash was also present on the
cheeks and the bridge of the nose. Additional
findings included moderately large, soft, movable
cervical nodes. The physical and laboratory findHospital of Los Angeles. Vmcn. HANSON,M.D.:
Associate Professor of Pediatrics; Southem California School of Medicine and Medical Director,
Childrens Hospital of Los Angeles Rehabibtion
Center. HELEN KOIINREICH, M.D.: Instructor qf
Pediatrics, Southern California Schod of Medicine
and Associate Attending Physician, ChiMrens Hospital of Los Angeles. GEORGEN . DONNELL,M.D.:
ProfesEor of Pediatrics; Southern California School
of Medicine and Assistant Physician-in-Chief,
Childrens Hospital of Los Angeles. BENJAMINH .
LANDING,M.D.: Professor of Pathology and Pediatrics; Southern California School of Medicine and
Director of Laboratories and Pathologist-in-Chief,
Childrens flozpital of Les Angeles.
ARTHRITIS AND RHEUhIATIShf, VOL. 11. NO. 1 (February 1968)
IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS
23
Fig. 1.-Patient
No. 1 on
the right and her twin, Patient No. 2 on the left a t the
time of admission, April 29,
1965.
ings of each twin at the time of admission are
summarized in Table 1. A 12-hour Addis count
was as follows:
Total volume
48 ml.
6.0
PH
Specific gravity
1.018
Protein
800 mg./100 ml.
Red blood cell-total
6,528,000
White blood cell-totnl
1,824,000
Casts-total
5,128
white blood cell
red blood cell
31,968
coarse granular
42,624
waxy
10,656
The results of erythrocyte blood grouping were
as follows:
A B C D E c e K Fy"
Twin No. 1: - Twin No. 2: - -
++++--+
++++--+
Dermatoglyphic patterns showed similarities in
the finger tip couplets and palmar ridge patterns.
Course in the hospital. Her clinical course is illustrated in Fig. 2, and was initially characterized by
persistent and gradually increasing edema and hypertension' and constant proteinuria despite prednisone (40 mg. daily), chloroquine (200 mg. daily),
diuretic and antihypertensive therapy. A renal biopsy, obtained surgically on the loth day of hospitalization, is described below. Generalized
seizures occurred on the 33rd and 34th hospital
days when she was still severely edematous and
her blood pressure was 165/120. Subsequently, increased antihypertensive therapy ( alpha methyldopa, guanethidine and hydralazine) was required.
Throughout the month she remained critically ill
and massively edematous with intermittent respiratory distress. Morphologic variation of erythrocytes was noted but the Coombs' test remained
24
LIEBERMAN ET AL.
Table 1.-Laboratory
Patient No. I
Findim
Hypercorticism
Anasarca
Rash
Facial
Peripheral
Lymphadenopathy
Hepatosplenomegaly
Arthritis
Alopecia
Blood pressure
Hemoglobin (gm/lOO ml)
Leukocyte count
Sedimentation rate (mm/hr)
Proteinuria
Hematuria
BUN (mg/100 ml)
q / G ratio (gm/lOO ml)
Cholesterol (mg/100 ml)
LE
Findings on Admission
++
++
++
-
+ (minimal)
-
++
+/-
2
140/100
12
12,Ooo
41
4+
Many RBC, with casts
Prep
Antinuclear factor
C-reactive protein
Protein electrophoresis (gmJl00 ml)
Total protein
Albumin
Alpha-I globulin
Alpha-2 globulin
Beta globulin
Gamma globulin
negative. Six weeks after admission ethacrynic
acid was started. Within six hours a gradual
diuresis began. One week later flaccid paralysis of
the legs was noted. Although her weight had
decreased moderately, she had not significantly improved despite substantial doses of prednisone for
six weeks; therefore, eight weeks after admission,
azathioprine (10 mg., 8 mg., and 6 mg./kg. for 2
days each, then 4 mg./kg. daily) was prescribed in
addition to prednisone (100 mg./day for 7 days,
then 60 mg./day for 21 days). Therapy with
ethacrynic acid was continued to keep her edemafree. Gradual improvement took place over the next
2 months.
After 3 months of immunosuppressive therapy a
second renal biopsy (percutaneous) was obtained
which is described below. Her muscle strength
gradually improved and she was discharged on
azathioprine, prednisone, antihypertensive therapy
and ethacrynic acid. The dosage of these medications was gradually reduced and azathioprine was
discontinued 6% months after discharge. Three
months after discharge routine urinalysis and serum
54
1.9/1.4
745
-
strongly
Patient No. 2
+
f
145/85
10.6
8,500
31
3+
5-8 RBC/hpf
22
3.8/2.6
240
++
+
3.1
1.3
0.2
6.3
3.8
0.2
0.7
06
0.5
0.6
0.4
1.1
chemistries became normal. She remained anemic.
At no time has she had a positive LE cell preparation, or positive nuclear fluorescence ( ANF).
Followup studies (12-18 months after admission)
are compared with those of her twin in Table 2.
Patient No. 2.
The less severely affected twin had been well
until 2 months prior to admission when the mother
noted swelling behind her ears, followed by a rash
on the soles and palms. Despite cortisone therapy
a flat, red rash appeared over the cheeks and bridge
of the nose, her knees became swollen, and her hair
became markedly thinner. She was admitted with
her twin sister on April 29, 1965 (Fig. 1).
Physical examination revealed a well developed,
well nourished dark skinned 3-year-old girl in no
acute distress. The signs of hypercorticism were
minimal. Her physical findings and laboratory data
are summarized in Tahle 1.
Course in the hospital. The patient initially was
treated with 15 mg. prednisone daily until an open
renal biopsy was obtained on May 7, 1965 (9th
25
IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS
PREDNISONE
DIURETICS
-:CHLOROTHIAZ
IDE
n
CHOLESTEROL
............,............,'................
BUN
MAY
Fig. 2.-Course
JUNE
JULY
AUGUST
SEPTENBER
OCTOBER
I
NWEMBER
of the nephrotic syndrome in Patient no. 1.
hospital day). Postoperatively, prednisone (60 mg.
daily) and chloroquine (200 mg. daily) were
given for one month. The chloroquine dose was
then reduced to 100 mg./day. The dose of corticosteroids was changed to alternate days and then
gradually tapered to 25 mg. every other day. She
was discharged after 20 hospital days and then
electively readmitted to the Clinical Research
Center 8 months later for repeat studies. Physical
examination showed signs of hypercorticism; no
signs of active lupus were present. Laboratory
data revealed a normal hemogram and urinalysis,
with the exception of many leucocytes per high
powered field and few erythrocytes per high
powered field. A 12-hour Addis count revealed a
total of 5,875,000 leucocytes and 2,750,000
erythrocytes. Serum chemical studies were within
normal limits.
A percutaneous renal biopsy was obtained without complications and is described below. She was
discharged on chloroquine, 100 mg. daily and
prednisone 20 mg. every other day. Four months
later she developed a recurrence of her facial rash
when exposed to sunlight but there were no associated signs or symptoms of reactivation of
lupus. Periodic ophthalmologic examinations have
not revealed any abnormality. Her laboratory
studies obtained 12-18 months after admission are
summarized in Table 2.
PATHOLOGY
Renal Biopsy 5/8/65 - Patient No. 1
(Fig. 3 )
The specimen contained 25 abnormal
glomeruli. Five glomeruli showed prominent cellular crescents. All glomeruli
showed centrilobular cellularity and three
resembled those of chronic hypertrophic
glomerulonephritis with hyalinized balls
replacing the lobules. Most of the glomeruli
26
LIEBERMAN ET AL.
Table 2.-Summary
of Laboratory Findings 12-18 Months After Admission
Patient No. 1
Findings
Hemogram:
Hemoglobin (Gm/100 nil.)
WBC
Sedimentation rate (mm./hr.)
Patient No. 2
12.8
7,400
12
Antinuclear factor:*
10.0
7,300
16
-
Routine urinalysis:
Specific gravity
Protein
WBC/hpf
RBC/hpf
1.023
0
0-3
rare
1.024
0
0-2
0
Serum chemistries:
BUN (mg./100 ml.)
Creatinine (mg./100 ml.)
Cholesterol (mg./100 ml.)
14
0.3
132
15
-
6.4
4.2
0.2
6.0
4.2
0.2
0.5
0.4
0.6
0.9
0.6
Protein electrophoresis:
Total protein
Albumin
Alpha-1 globulin
Alpha-2 globulin
Beta globulin
Gamma globulin
-
119
0.7
*13 months after admission.
showed evidence of inflammation, with
neutrophils and with karyorrhexis in the
glomerular tufts and with irregular but
prominent fibrinoid thickening of basement
membranes. The tubules were diffusely and
mildly atrophic; hyaline and urate casts
were present. The tubules were separated
by fibrotic interstitial tissue in which focal
accumulation of lymphocytes occurred.
The intralobular arteries were thickened
with hyaline medias but without obvious
vasculitis.
interstitial fibrosis and focal mononuclear
round cell accumulations were present. A
few very dilated tubules with hyaline casts
were present; other tubules contained calcified urates and occasional red blood cell
casts. A large intralobular artery was slightly dilated but cot otherwise remarkable.
The increase in fibrosis and parenchymal
atrophy with less evidence of active inflammation are the features which distinguish the second biopsy from the first.
Renal Biopsy 517165- Patient No. 2
(Fig. 5 )
The biopsy contained 6 glomeruli and
The second biopsy contained 20 glomer- consisted predominantly of medulla which
uli, 5 of which were completely hyalinized. was not obviously abnormal. The glomeruli
The remainder showed thickened hyaline all showed enlargement, centrilobular hyalobules with some centrilobular cellularity line thickening and cellularity with a few
but without exudation. There were adhe- neutrophils and basement membrane
sions but no proliferative crescents, and thickening without fibrinoid necrosis, exthick basement membranes which ap- cept for one glomerulus. There were no
peared hyaline rather than fibrinoid. Focal crescents. Bowman’s spaces contained
Renal Biopsy
(Fig. 4 )
1011165-Patient
No. 1
27
IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS
Fig. ?-Renal biopsy No. 1, 5/8/6%Patient No. 1: Initial biopsy of the renal
cortex illustrates the variable extent of glomerular involvement, with both glomeruli
showing largely centrilobular hypercellularity, with karyorrhexis and irregular thickening of the peripheral basement membranes. The glomerulus on the right also
shows an early cellular crescent (H & E X 300).
granular eosinophilic debris. There was
some medial thickening of intralobular and
afferent arterioles. The glomerular involvement was of similar extent and severity in
all the glomeruli, although it tended to be
somewhat segmental within any given glomerulus. The interstitial tissue surrounding
the most severely involved glomerulus
showed a minimal increase of fibrous tissue
and infiltration by a few mononuclear cells.
otherwise normal. The afferent arterioles
and tubules were within normal limits.
DIsCUssioN
In 1960 Cook et al.5 described 37 patients with systemic lupus erythematosus
who were all four years of age or older at
the time of onset. More recently, Duboise
mentioned three children between 0 and 4
years of age without giving any clinical deRenul Biopsy 11I66 -Patient No. 2 tails. Peterson et al.' included one child
who was four years of age at the time of
(Fig. 6 )
onset. These twins are the only patients
The second biopsy contain3d 18 glomer- seen at Childrens Hospital of Los Angeles
uli. All showed slight centrilobular cellu- whose illness began earlier than five years
larity and thickening, and slight basement of age.s Therefore, these 3-year old twins
membrane thickening. An occasional glo- represent the youngest reported patients
merulus showed pericapsular fibrosis and with SLE with the exception of one newa few synechiae. The interstitium was born with congenital SLE?
28
LIEBERMAN E T AL.
Fig. 4.-Renal biopsy No. 2, 10/1/65-Patient No. 1: Hyaline changes in capsule
and tufts of the glomerulus at the right and some centrilobular cellularity in both.
Some increase in interstitial fibrosis is also shown ( H & E X 300).
The probability that these children are ial discoid and systemic lupus and kinmonozygous twins is supported by their ap- ships with an increased incidence of autopearance, their sex, by identical major and immune disease, asymptomatic hypergamminor red blood cell groups and by their maglobulinemia, positive ANF or LE cell
dermatoglyphic patterns. No information preparations have been rep~rted.~':'~In
Concerning the placenta was available. the relatives of these twins ( 6 siblings, 2
Skin grafting was not done. The occurrence parents and 2 paternal grandparents) none
of SLE in these twins thus suggests the had a history suggestive of autoimmune
possibility of a genetic influence, even disease, laboratory evidence of hypergamthough environmental factors may have maglobulinemia, or positive ANF.
had a critical role. Several case reports atThe absence of antinuclear antibody in
test to the frequency of concordance of Patient No. 1 raises the question as to
SLE in twins and, thus, create a statistical whether she had SLE. Clinically she met
bias in favor of identical t w i n ~ . l A
- ~recent the criteria proposed by Bywaters15 and
report, however, emphasized the occur- Dubok6 All patients seen at Childrens
rence of SLE in one twin and multiple Hospital of Los Angeles with florid disease
sclerosis in another.1° Data concerning had positive ANF determinations regardlupus in discordant twins is not available. less of prior therapy. The hypogammaIt is less probable that these twins were globulinemia (0.4 Gm. per cent) might
dizygous and had a predisposition to SLE have resulted in antibody depletion and a
because of some familial tendency. Famil- negative test for nuclear fluorescence. In
29
IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS
Fig. 5.--Renal biopsy No. 1, 5/7/65-Patient No. 2: Initial biopsy of Patient No.
2 showed enlarged glomeruli with centrilobular hyaline thickening and cellularity,
including a few neutrophils and karyorrhectic nuclei (H & E X 350).
our experience antinuclear antibody titers
Although the course of SLE has been inhave decreased as the patients improved fluenced favorably by antibiotics, antimaand, therefore, it is not surprising that this larials and steroids, the presence of clinical
patient did not develop a positive ANF renal disease, especially the nephrotic syndetermination later. The course of disease drome, is generally regarded as of grave
in the less severely affected twin was simi- i m ~ 0 r t . l If
~ hypertension and azotemia
lar although less severe, without evidence were additional findings, most authors reof gamma globulin depletion. Both the LE garded the outlook as dismal prior to the
cell preparation and ANF determination use of high dose steroid therapy. The literwere positive at the time of admission and ature most often cited refers to adult pabecame negative with clinical recovery.
tients, but the few pediatric reports reflect
Table 3.-Antinuclear
Factor and Latex Fixation Tests
Antinuclear
Patient
F-
Date
Latex
Fixation
Patient No. 1
1%5 : 4/30,6/29, 7/15, 8/11
1966: 6/28
(All negative)
(All negative)
Patient No. 2
4/30/65
5/28/65
1/14/66
6/28/66
+ undiluted
+ undiluted
1 :32
negative
negative
negative
nemtive
negative
30
LIEBERMAN ET AL.
Fig. 6.- Renal biopsy No. 2, 1/18/6&Patient No. 2: Slight centrilobular prominence and cellularity and occasional synechiae in two glomeruli. The surrounding
parenchyma is normal (H & E X 350).
similar conclusion^.^^^ The effect of high
The patient described above (Patient
dose steroid therapy in advanced renal dis- No. 1) had remained desperately ill deease with and without the nephrotic syn- spite very large doses of prednisone and
drome is generally regarded as favorable therefore the decision was made to give
5,7~17 although notable exceptions exi~t.1~her a trial of immunosuppressive therapy,
Pollak et al. reported that 13 of 16 patients based on the optimistic results of Kellum,20
treated with low doses of steroids died Vernier,2l Michael,= and ad am^.^^ In
with renal failure, whereas only 13 of 31 this patient with “steroid resistance” (i.e.,
treated with high doses died with renal no response to steroid therapy in high dosfailure.ls These authors also described the age for six weeks) the achievements of imoutcome in terms of the initially observed munosuppressive therapy were dramatic.
renal histology. Of 47 patients with histo- She remains in clinical and chemical relogic lupus glomerulonephritis, 26 died mission with the exception of recently
with renal failure and 23 of these had the noted mild proteinuria (23 months after
nephrotic syndrome. In contrast, of 23 pa- admission). This experience is not unique;
tients with lupus glomerulitis only 2 died Vernier,21 G r ~ p e *and
~ KellumZ0have rewith renal failure.Is Changes in histology ported patients with extensive renal inin the first and second biopsies from both volvement, with or without the nephrotic
our patients are consistent with Pollak‘s syndrome, in whom immunosuppressive
findings and again illustrate the dissoci- therapy has induced a remission or marked
ation of severity and activity of renal le- clinical improvement.
sions.
31
IDENTICAL TWINS WITH LUPUS ERYTHEMATOSUS
ACKNOWLEDGMENTS
Ethacrynic acid - “Edecrin”@ was supplied by
Robert Dengler, M. D. of Merck Sharp and Dohme,
Inc.
Azathioprine - “1muran’”B was supplied by Donald S. Searle, Ph.D., M.D. of Burroughs Wellcome.
The authors are grateful to Dr. John R. Alniklov
for referral of these patients, to Dr. Robert Vernier
for his suggestions concerning immunosuppressive
therapy and to Dr. Harold H. Edelbrock for obtaining the renal biopsies.
SUMMARY
Twin 3-year old girls with SLE are described. They are the youngest reported patients
with SLE and the only twins with SLE in the pediatric age group. Patient No. 1 had
the nephrotic syndrome, hypertension and azotemia. She was treated with immunosuppressive therapy (azathioprine and prednisone) and gradually improved. Immunologic tests for SLE remained negative throughout her illness. Two renal biopsies
(with a five-month interval) are described and the dichotomy between the clinical
improvement which ultimately was dramatic and severe renal scarring is described.
The less severely affected twin had classical features of SLE with nephritis; her
LE cell preparation and ANF determination were positive initially. Two renal biopsies
(with an eight month interval) are described. Therapy consisted of chloroquine and
prednisone; she has been asymptomatic .except for recurrence of facial rash on one
occasion following exposure to sunlight.
SUMMARIOIN INTERLINGUA
Es describite un par de geninas identic de tres annos de etate con signos classic de
disseminate lupus erythematose sed con dif€erente affectiones renal e immunologic.
Gemina I esseva criticamente malade con nephrosis; remission clinic e chimic esseva
inducite per un therapia immunisuppressive. Gemina I1 habeva constatationes clinic e
histologic de nephritis. Es describite Ie tractamento, biopsias renal, e le responsa clinic.
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