efficacy of vinblastine and prednisone in multicentric
TRANSCRIPT
Efficacy of Vinblastine and Prednisone in Multicentric Reticulohistiocytosis With Onset in InfancyVijay Kumar Jha, MD, a Ravindra Kumar, MD, b Abhijeet Kunwar, MS, c Ankur Singh, MD, b Mahendra Kumar, MD, a Mohan Kumar, MD, a Rajniti Prasad, MDb
Departments of aPathology, bPediatrics, and cOrthopedics,
Institute of Medical Sciences, Banaras Hindu University,
Uttar Pradesh, India
Dr Jha made provisional pathological diagnosis
of multicentric reticulohistiocytosis, and
conceptualized and designed the study; Dr
Mahendra Kumar compiled data, drafted the initial
manuscript, and approved the fi nal manuscript
to be submitted; Dr Mohan Kumar fi nalized the
pathological diagnosis, and reviewed and approved
the manuscript submission; Dr Ravindra Kumar
obtained detailed clinical history of the patient
along with treatment history and response;
Dr Singh compiled clinical data and treatment
response; Mr Kunwar provided opinion regarding
joint deformities and helped to make the fi nal
diagnosis of multicentric reticulohistiocytosis;
and Dr Prasad fi nalized clinical and treatment
history, provided follow-up details and response
to treatment, and reviewed and approved the
manuscript for submission.
DOI: 10.1542/peds.2015-2118
Accepted for publication Feb 23, 2016
Address correspondence to Mahendra Kumar,
MD, Department of Pathology, Institute of
Medical Sciences, Banaras Hindu University,
Varanasi, Pin-231001, Uttar Pradesh, India. E-mail:
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2016 by the American Academy of
Pediatrics
FINANCIAL DISCLOSURE: The authors have
indicated they have no fi nancial relationships
relevant to this article to disclose.
Multicentric reticulohistiocytosis
(MRH) is an unusual systemic
inflammatory disorder of unknown
etiology, affecting skin, mucosa,
and joints; however, in some cases
visceral organs also may be involved.
Clinically, patients present with
cutaneous papulo-nodular lesions
and progressive symmetric and
erosive arthritis.1 Review of literature
showed ∼13 cases of childhood MRH,
including the present study, defining
its rarity in childhood.1, 2 To the best
of our knowledge, the present case
is the youngest in the literature with
onset of disease in infancy. MRH is
often misdiagnosed due to its rarity
and overlapping clinical and histologic
features. Characteristic histologic
findings include infiltration of
histiocytes and multinucleated giant
cells with a homogeneous eosinophilic
ground glass cytoplasm.1–4 Early
diagnosis and immediate treatment
are important to prevent irreversible
joint deformity. There is no definite
treatment protocol for MRH, and
various drugs have been attempted
with inconsistent results.1, 3 We tried
vinblastine and prednisone in this
case with good response, which has
not been attempted before.
CLINICAL HISTORY
A 3.5-year-old girl presented with
red-colored skin lesions with elevated
margins on the left lower neck along
with pain and swelling of multiple
fingers since 3 months of age. Skin
lesions started as a small swelling
measuring 1.5 × 1.5 cm at the left
lower side of neck at 3 months of age,
which gradually increased in size
abstractMulticentric reticulohistiocytosis (MRH) is a rare histiocytic proliferative
disorder of uncertain etiology, characterized by mucocutaneous
papulonodular lesions and progressive, symmetric erosive arthritis.
MRH can coexist with various autoimmune disorders, tuberculosis, and
malignancy. It usually occurs in the elderly and is very rare in children.
This is probably the first case in which disease manifestation appeared in
infancy in the form of skin lesions. The patient had recurrent ulceration of
cutaneous lesions, which is unusual in MRH. Early diagnosis and aggressive
treatment are essential to prevent progressive irreversible course and
development of arthritis mutilans. Various drugs, such as steroids,
nonsteroidal anti-inflammatory drugs, immunosuppressants, interleukin
inhibitors, and tumor necrosis factor-α antagonist, have been tried with
variable responses. The present case responded well to vinblastine and
steroid, which have not been reported previously. Here, we document a
case of MRH with early onset in infancy along with role of vinblastine and
prednisone in its treatment.
CASE REPORTPEDIATRICS Volume 137 , number 6 , June 2016 :e 20152118
To cite: Jha VK, Kumar R, Kunwar A, et al. Effi cacy
of Vinblastine and Prednisone in Multicentric
Reticulohistiocytosis With Onset in Infancy.
Pediatrics. 2016;137(6):e20152118
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JHA et al
and later developed a discharging
sinus that healed over the next 3
months, leaving behind a red-colored
scaly scab with nodular margin.
Skin lesions gradually increased
in size, involving the lower neck
and shoulder area with itching (Fig
1A). At 2 years of age, the child also
developed a similar lesion at the
lateral side of the left upper arm
and at the base of nose. In addition
to skin manifestations, the patient
also developed pain and swelling
of the right index finger at the age
of 7 months, which progressed to
involve the right middle finger and
left index finger during the course
of the next month. Fingers became
sausage shaped with multiple small
nodules (Fig 1 B and C), which
displayed recurrent ulceration and
healing leading to a small yellowish
scar during a period of 3 to 4 days.
Mainly metacarpophalangeal joints
and proximal interphalangeal (PIP)
joints were involved with joint laxity
and increased range of movement.
Later, at the age of 14 months, she
also developed painful swelling over
bilateral first metatarso-phalangeal
joints of feet. There was no
associated malignancy, autoimmune
disorder, hypercholesterolemia, or
significant family history.
Physical examination revealed
moderate pallor, generalized
lymphadenopathy, hepatomegaly of
size 5.5 cm, and mild splenomegaly
(1 cm below left costal margin).
Blood investigation revealed anemia
(hemoglobin 7.7g/dL), leukocytosis
(total leukocyte count 23 600/cmm)
with normal distribution of cells, and
raised erythrocyte sedimentation
rate (70 mm in first hour). Peripheral
blood smear demonstrated moderate
anisopoikilocytosis with presence
of microcytic hypochromic cells;
however, there were no blasts or
atypical cells. Her renal function, liver
function tests, and lipid profile were
within normal range. Mantoux test,
rheumatoid factor, C-reactive protein,
and collagen profile were negative.
Radiographs of both hands showed
lytic lesions with sclerotic margin in
the left second and fifth phalanges,
and right second and third phalanges
(Fig 1D). The patient was very ill
with progressive multiple skin
lesions, swelling of fingers and toes
with severe arthralgia, and bacterial
infection, for which the patient was
admitted to the hospital.
Fine needle aspiration cytology from
bony lesions revealed numerous
histiocytes with vesicular nuclei and
many multinucleated giant cells with
abundant homogeneous eosinophilic
cytoplasm. There was no associated
cytologic feature of Langerhans cell
histiocytosis (LCH); however, in view
of clinical and radiologic findings, the
possibility of LCH was suggested.
Histopathological Findings
Skin biopsy showed dense infiltrates
of mononuclear cells and many
multinucleated giant cells in the
dermis extending into subcutaneous
fat (Fig 2A). Mononuclear cells and
giant cells had round to oval vesicular
nuclei with moderate to abundant
fine granular eosinophilic “ground
glass” cytoplasm (Fig 2B). Overlying
epidermis was focally ulcerated.
Xanthogranulomatous changes,
Touton giant cells, necrosis, and
Langerhans cells were not seen. Ziehl
Neelsen stain and periodic acid-Schiff
stain did not reveal any organism.
Mononuclear cells and giant cells
were strongly positive for CD68 (Fig
2C) and negative for CD1a, S100,
CD20, CK (Pan CK), and CD34 (Fig 2
C and D).
In view of the possibility of LCH on
cytology, the patient was started on
vinblastine (6 mg/m2 once a week
for 6 weeks) and prednisolone
(40 mg/m2 daily for 6 weeks). This
combination of drugs is safe in
the pediatric population, and the
patient exhibited significant clinical
improvement, so we continued the
same drugs even after confirmation
of MRH on histopathology. Clinical
improvement was evident after 4
to 6 weeks of therapy. Skin lesions
showed relatively early response
as compared with bony lesions. The
patient developed systemic fungal
(Candida) infection after 2 months
and responded well to antifungal
therapy. After 6 weeks, we continued
e2
FIGURE 1A, Large scaly red skin lesion with elevated margins, along with, B, C, sausage-shaped swelling of fi ngers. D, Radiograph of hand shows lytic lesion with sclerotic margin of phalanges.
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PEDIATRICS Volume 137 , number 6 , June 2016
vinblastine (6 mg/m2 every 3 weeks)
and prednisone (40 mg/m2 daily
for 5 days at every 3 weeks) with
target of total duration of 6 months
of therapy. Recent follow-up of the
patient showed resolving skin lesions
with healing of ulcerated margin
(Fig 3A) and reduced joint swelling
(Fig 3B); however, radiology of the
hands revealed persistence of bony
lesions (Fig 3C). No fresh cutaneous
lesion appeared. Splenomegaly,
hepatomegaly, and lymphadenopathy
subsided. Erythrocyte sedimentation
rate became normal and hemoglobin
improved (9.6 g/dL). Liver function
tests, renal function test (RFT), and
other biochemical and hematologic
profiles became normal. The patient
did not develop hematologic or any
other toxicity.
DISCUSSION
MRH is a rare multisystem histiocytic
disorder, typically characterized
by chronic, destructive, disfiguring
polyarthritis and cutaneous nodules.
Exact pathogenesis is unknown;
however, a few theories suggest
inflammatory and others suggest
proliferative disorder.1–3 It usually
affects individuals in the fourth
decade of life and is very rare in
children.2–4 To the best of our
knowledge, ∼13 pediatric cases have
been reported (Table 1), our case
being the youngest of all with the
earliest presentation at the age of
3 months.1, 5, 6 MRH predominately
affects female individuals, both in the
adult and pediatric populations. In
adults, the male-to-female ratio is 1:2
to 3 and in the pediatric population,
12 of 13 reported cases are girls.1, 2, 6–17
Irrespective of age groups, this disease
is more prevalent in white ethnicity.2, 5
MRH manifests with 2 major clinical
features, the first being polyarthritis
and the second being skin lesions.
In adults, symmetric polyarthritis
is the initial symptom in two-thirds
of patients and skin manifestations
appear after an average period of 3
years of arthritis. Cutaneous lesions
as an initial manifestation are present
in 20% of patients and simultaneous
skin and joint lesions present in
the remainder. A similar pattern of
clinical presentation is also noticed in
pediatric MRH.2, 3
Skin lesions are usually in the form
of reddish brown papules and
nodules varying in size from a few
millimeters to several centimeters,
which are usually asymptomatic.
Skin ulceration is unusual in MRH18;
however, our patient had recurrent
ulceration and healing of skin
lesions. Both adult and pediatric
MRH have similar kinds of cutaneous
manifestations with respect to type
and distribution of lesions.
Cervical spondylitis may be a
manifestation in approximately
e3
FIGURE 2Panel of photomicrographs of skin biopsy shows mononuclear and multinucleated histiocytic giant cells extending throughout the dermis (A, hematoxylin-eosin stain, ×100) and their ground glass eosinophilic cytoplasm (B, hematoxylin-eosin stain, × 200). Immunohistochemistry highlights strong positivity for CD68 (C, ×200) and negativity for CD1a (D) in mononuclear and multinucleated giant cells.
FIGURE 3Panel of photographs demonstrating response to vinblastine and steroid. A, Skin lesions are resolving with healed ulcerated margins. B, Joint swelling is reduced. C, Radiology of hands revealed persistence of lytic bony lesions.
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JHA et al e4
TABL
E 1
Su
mm
ary
of 1
3 C
hild
hoo
d M
RH
Rep
orte
d in
Lit
erat
ure
SN
Ref
eren
ceAg
e/
Gen
der
Init
ial L
esio
ns
and
Pre
sen
tati
onC
uta
neo
us
Lesi
onB
ony
Lesi
ons
and
Joi
nt
Lesi
ons
Asso
ciat
ed
Dis
ease
s
Trea
tmen
t
1.M
elto
n a
nd
Irb
y
(197
2)7
16 y
/FAr
thri
tis
Per
iun
gual
red
dis
h b
row
n p
apu
les
Met
acar
pop
hal
ange
al jo
ints
,
wri
sts,
elb
ows,
sh
ould
ers,
knee
, an
d a
nkl
es
Non
eN
one;
Sel
f-lim
itin
g
2.S
togm
an e
t al
(197
5)8
10 y
/F—
Nod
ula
r le
sion
s m
ain
ly p
eriu
ngu
al in
volv
ing
seco
nd
to
fou
rth
fi n
gers
of
bot
h h
and
s
Eros
ive
arth
riti
s in
volv
ing
DIP
and
PIP
join
ts, b
ilate
ral k
nee
swel
ling
and
eff
usi
on
Non
e—
3.M
ign
one
et a
l
(197
9)9
7 y/
FAr
thri
tis,
fev
er, r
ash
Ras
h o
n e
xten
sor
asp
ect
of f
orea
rm a
nd
han
ds
Acu
te in
fl am
mat
ion
of
PIP
an
d
DIP
join
ts
Non
eAs
pir
in
4.S
cute
llari
et
al
(198
6)10
18 y
/FAr
thri
tis
Mu
ltip
le n
odu
les
on h
and
s, e
ar, f
oreh
ead
,
scal
p, a
nd
nas
al r
im
Eros
ive
arth
riti
s of
th
e P
IP a
nd
DIP
join
ts
Non
eN
one
5.O
md
al e
t al
(198
8)11
9 y/
FS
kin
lesi
on w
ith
itch
ing
at fi
nge
r ti
ps
Mu
ltip
le p
apu
les
and
nod
ule
s on
fi n
ger
tip
s
and
fro
nt
of t
hig
h
Arth
riti
s of
DIP
, PIP
, wri
st, k
nee
,
elb
ow, a
nd
an
kles
Non
eS
elf-
limit
ing
6.R
aph
ael e
t al
(198
9)12
14 y
/FAr
thri
tis
and
cu
tan
eou
s n
odu
les
Mu
ltip
le p
eriu
ngu
al v
erru
cou
s n
odu
les
and
dee
per
nod
ule
s al
ong
ten
don
sh
eath
Elb
ows,
wri
sts,
kn
ees,
an
d D
IP
wit
h jo
int
effu
sion
, no
eros
ion
seen
Non
eAs
pir
in
7.Ku
ram
oto
et a
l
(198
9)13
16 y
/MAg
e 6:
mu
ltip
le c
uta
neo
us
nod
ule
s
on f
ace
and
tru
nk
that
res
olve
d
spon
tan
eou
sly
Age
6: fl
esh
y p
apu
les
at a
ge 6
Non
eAt
age
16
dev
elop
ed
lym
ph
oma
Pre
dn
isol
one
and
cycl
osp
orin
e w
ith
no
resp
onse
; lat
er,
chem
oth
erap
y fo
r
lym
ph
oma
Kura
mot
o et
al
(199
1)14
Age
13: i
nd
ura
tion
an
d u
lcer
atio
n o
f
left
leg
Age
13: b
and
like
scle
rosi
s ex
ten
din
g fr
om
knee
to
ankl
e
8.Fr
ied
man
an
d
Kalis
her
(19
98)15
6 y/
FM
ult
iple
pal
mar
nod
ule
s an
d s
wel
ling
of
han
ds,
kn
ees,
an
d r
igh
t an
kle
Mu
ltip
le r
edd
ish
bro
wn
pap
ule
sS
ynov
itis
of
left
wri
sts,
bot
h
knee
s, a
nd
join
ts o
f h
and
s
Non
eN
ot m
enti
oned
9.C
and
ell C
hal
om e
t
al (
1998
)16
6 y/
FJo
int
swel
ling
and
fat
igu
eP
eriu
ngu
al p
apu
les
and
nod
ule
s an
d m
ult
iple
pal
mar
nod
ule
s
Syn
ovit
is o
f m
ult
iple
join
ts: l
eft
wri
st, b
ilate
ral k
nee
s an
d
han
d jo
ints
ANA
1:64
0;
Sp
eckl
ed
pat
tern
Par
tial
res
pon
se t
o
met
hot
rexa
te a
nd
pre
dn
ison
e
10.
Hav
ill e
t al
(19
99)17
12 y
/FAg
e 7.
5: p
ain
ful s
wel
ling
of t
he
bila
tera
l
knee
, an
kles
, wri
sts,
an
d fi
nge
rs
Age
8: m
ult
iple
pap
ula
r le
sion
s on
lip
, bu
ccal
mu
cosa
, an
d p
roxi
mal
nai
l fol
ds
Eros
ion
of
the
left
fou
rth
an
d
fi ft
h, r
igh
t se
con
d a
nd
th
ird
DIP
, eff
usi
on o
f b
oth
kn
ees
Non
eR
esp
ond
ed t
o n
apro
xen
11.
Mat
iz e
t al
(20
09)6
3 y/
FP
apu
lar
skin
lesi
ons
and
art
hra
lgia
Pin
k fl
at-t
opp
ed p
apu
lar
skin
lesi
ons
on t
he
fi n
ger
nai
l mar
gin
s of
han
ds,
sca
lp, a
nd
arou
nd
th
e n
ares
Arth
ralg
ias
of w
rist
s an
d
knee
s, o
steo
pen
ia, m
ult
iple
join
t ef
fusi
ons,
an
d s
ynov
ial
thic
ken
ing
Non
eN
apro
xen
, met
hot
rexa
te,
pre
dn
ison
e, e
tan
erce
pt,
infl
ixim
ab
12.
Ols
on e
t al
(20
15)1
2 y/
FAt
2 y
: cu
tan
eou
s p
apu
lar
lesi
ons
on t
he
thig
hs,
elb
ows,
an
d k
nee
sM
ult
iple
pin
k, p
apu
lar
lesi
ons
on e
lbow
an
d
knee
s, a
nd
late
r al
so d
evel
oped
on
nos
e,
fore
hea
d, e
ars,
dor
sal h
and
s, fi
nge
rs, a
nd
knu
ckle
s
Pol
yart
hri
tis
of t
he
cerv
ical
spin
e, b
ilate
ral w
rist
s, r
igh
t
ind
ex fi
nge
r, b
ilate
ral k
nee
s,
ankl
es a
nd
su
bta
lar
join
ts,
righ
t to
e b
ony
enla
rgem
ent
Non
eN
apro
xen
, met
hot
rexa
te,
tum
or n
ecro
sis
fact
or
inh
ibit
ors,
infl
ixim
ab t
o
wh
ich
goo
d r
esp
onse
was
seen
At 5
y: m
igra
tin
g jo
int
pai
n w
ith
sw
ellin
g
13.
Pre
sen
t ca
se3
mo/
FP
apu
lon
odu
lar
cuta
neo
us
lesi
ons
in
nec
k an
d s
hou
lder
reg
ion
Sp
read
ing
cuta
neo
us
lesi
on t
hat
ulc
erat
es,
hea
ls, a
nd
new
cro
p o
f fl
esh
y n
odu
les
app
ear
Pai
nfu
l sw
ellin
g of
mu
ltip
le
bila
tera
l han
d jo
ints
an
d
bila
tera
l met
atar
sop
hal
ange
al
join
ts
Non
eIn
itia
lly c
uta
neo
us
lesi
ons
resp
ond
ed
wel
l to
pre
dn
ison
e an
d
vin
bla
stin
e fo
r 2
mo;
aft
er
that
pat
ien
t d
evel
oped
recu
rren
ce o
f cu
tan
eou
s
lesi
ons
ANA,
an
tin
ucl
ear
anti
bod
y; D
IP, d
ista
l in
terp
hal
ange
al jo
int;
F, g
irl;
M, b
oy; S
N, s
eria
l nu
mb
er; —
, no
info
rmat
ion
ava
ilab
le in
res
pec
tive
stu
dy.
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PEDIATRICS Volume 137 , number 6 , June 2016
half of adult MRH cases; however,
in childhood MRH, only 1 case with
cervical joint involvement has been
reported.3 Only 2 pediatric cases
of MRH had involvement of foot
joints, including present case (Table
1). Many of the adult MRH cases
show association with autoimmune
disorders, 3–5, 7 tuberculosis, and
various malignancies (breast,
cervix, stomach, hematologic
malignancies, melanoma, lung and
colonic carcinoma).3, 4, 18 In contrast
to adult MRH, childhood MRH cases
usually do not show association
with autoimmune disorder and
malignancy; however, 1 case of
lymphoma and 1 case of autoimmune
disorder have been reported in
pediatric MRH.14, 16
Regarding involvement of other organs,
adult MRH may involve myocardium,
pericardium, and pleura. There are a
few case reports suggesting association
of MRH with trigeminal neuropathy,
central retinal vein thrombosis, and
fracture of femoral neck. Systemic
involvement has not been reported in
childhood MRH.2, 3
There is lack of a sufficient number
of MRH cases for clinical trial, so
there is no standardized treatment
protocol.1, 3 MRH has a variable
disease course. Some of the
patients have self-limiting disease,
and others have unpredictable
relapses and remissions or
progressive disease with joint
deformity. Nonsteroidal anti-
inflammatory drugs, corticosteroids,
cyclophosphamide, azathioprine,
methotrexate, chlorambucil, and
leflunomide have been used with
variable responses.3, 4, 19 Some recent
studies have demonstrated good
response with anti–tumor necrosis
factor-α (etanercept, infliximab),
anti–interleukin-1 (anakinra)
and interleukin-6 antagonists
(tocilizumab) both in adult and
pediatric cases.1, 20 Considering the
possibility of LCH on fine needle
aspiration cytology, we prescribed
vinblastine and prednisolone to our
patient and she responded well to
this regimen with significant clinical
improvement. In view of good
response and safety of these drugs
in childhood, we put the patient on
the same drugs. The organomegaly
resolved and most of the biochemical
and hematologic parameters became
near normal until recent follow-up. In
the present case, good response with
vinblastine and prednisone signifies
their role in treatment of childhood
MRH. This observation may help in
understanding of pathogenesis of
MRH; however, studies with large
sample sizes are required.
CONCLUSIONS
Childhood MRH is extremely rare,
although it should be considered
in patients presenting with erosive
arthritis and mucocutaneous
lesions. A high degree of clinical
suspicion, meticulous clinical
examination, radiologic correlation,
and histopathological examination
are essential to confirm the diagnosis
of MRH. Treatment with vinblastine
and steroid (prednisone) may be an
effective and safe alternative for the
treatment of childhood MRH.
e5
ABBREVIATIONS
LCH: Langerhans cell
histiocytosis
MRH: multicentric
reticulohistiocytosis
PIP: proximal interphalangeal
joints
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.
REFERENCES
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DOI: 10.1542/peds.2015-2118 originally published online May 19, 2016; 2016;137;Pediatrics
Kumar, Mohan Kumar and Rajniti PrasadVijay Kumar Jha, Ravindra Kumar, Abhijeet Kunwar, Ankur Singh, Mahendra
Onset in InfancyEfficacy of Vinblastine and Prednisone in Multicentric Reticulohistiocytosis With
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. ISSN:60007. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since . Pediatrics is owned, published, and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
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DOI: 10.1542/peds.2015-2118 originally published online May 19, 2016; 2016;137;Pediatrics
Kumar, Mohan Kumar and Rajniti PrasadVijay Kumar Jha, Ravindra Kumar, Abhijeet Kunwar, Ankur Singh, Mahendra
Onset in InfancyEfficacy of Vinblastine and Prednisone in Multicentric Reticulohistiocytosis With
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. ISSN:60007. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since . Pediatrics is owned, published, and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
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