This document discusses two medical cases presented in the Index of Suspicion column of Pediatrics in Review. Case 1 involves a 17-year-old girl with intermittent right arm swelling and pain over 2 years. After extensive testing, she was diagnosed with complex regional pain syndrome type 1 (CRPS). CRPS is caused by autonomic nervous system disruption and is characterized by severe pain, swelling, and skin changes. Case 2 presents a 7-year-old girl with a tender nodule behind her left ear. Imaging and biopsies confirmed the diagnosis.

1. DOI: 10.1542/pir.34-2-95
2013;34;95Pediatrics in Review
Rhina Castillo, Alfredo Torralbas, Josue Flores and Randolf Nunez
Index of Suspicion
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2. The reader is encouraged to write
possible diagnoses for each case before
turning to the discussion.
The editors and staff of Pediatrics in
Review find themselves in the
fortunate position of having too many
submissions for the Index of Suspicion
column. Our publication slots for Index
of Suspicion are filled through 2013.
Because we do not think it is fair to
delay publication longer than that, we
have decided not to accept new cases
for the present. We will make an
announcement in Pediatrics in Review
when we resume accepting new cases.
We apologize for having to take this
step, but we wish to be fair to all
authors. We are grateful for your
interest in the journal.
Author Disclosure
Drs Castillo, Flores, Nunez, and
Torralbas have disclosed no financial
relationships relevant to this article.
This commentary does not contain
discussion of unapproved/
investigative use of a commercial
product/device.
Case 1: Intermittent Swelling and Arm Pain for 2 Years
in an Adolescent Girl
Case 2: Tender Nodule in Left Mastoid Area of a
7-year-old Girl
Case 1 Presentation
A 17-year-old girl presents with inter-
mittent right upper extremity swell-
ing and pain over the past 2 years.
Her symptoms began after an episode
of Bell’s palsy. She describes swelling
and an “electrical shooting” pain in
the right shoulder that radiates to-
ward her hand, followed by a cool feel-
ing of the hand and decreased range
of motion of the arm. The episodes
occur during both summer and winter
and can last anywhere from 2 to 30
days. Initially, between these episodes,
she regained normal function, but re-
cently has noted residual weakness.
She denies any history of trauma, fe-
ver, rash, or muscle weakness.
On examination, there is swelling
of the entire right arm. The nails are
normal. The right arm is colder in
comparison with the left and has de-
creased hair growth. Peripheral pulses
and capillary refill were normal. Pin-
prick and temperature sensations are
intact, without hyperesthesia. Range
of motion of the right arm, forearm,
and hand is compromised because of
pain. Except for her right arm, she is
warm, well perfused, and free of joint
swelling. The muscle tone is normal,
and strength in the other muscle
groups is 5/5.
Laboratorystudiesrevealanerythro-
cyte sedimentation rate of 15 mm/h,
C-reactive protein <0.5 mg/dL, white
blood cell count of 6.3 to 103/mL, and
creatine phosphokinase level of 100
U/L. The results of additional labo-
ratory studies, including antinuclear
antibody, rheumatoid factor, anti-
body test for Borrelia burgdorferi,
rapid plasma regain test for syph-
ilis, urine-amplified DNA assay for
Chlamydia and gonorrhea, hemoglo-
bin electrophoresis, serum lactic acid
dehydrogenase level, and uric acid
level, are normal or negative.
Radiographs of cervical spine, chest,
right elbow, forearm, and hand as well
as magnetic resonance imaging (MRI)
of the brain, cervical spine, and entire
arm are normal. Right upper extrem-
ity vascular duplex ultrasonography
shows normal flow without evidence
of a deep venous thrombosis.
Case 2 Presentation
A previously healthy 7-year-old His-
panic girl presents with pain behind
the left ear. The mother reports that
3 days ago, while she was combing
her daughter’s hair, the patient com-
plained of pain, and the mother no-
ticed a red and irritated area behind
the left ear. There has been no fever,
loss of appetite or weight, sick con-
tacts, recent travel, trauma, or animal
contacts. Her family history is non-
contributory. Her immunizations are
up to date, and a recent tuberculin test
result was negative.
On physical examination, the girl
is not in acute distress. Her vital signs
are within normal limits. Her weight
and height are both at the 75th per-
centile for age. In the left mastoid
area there is a 2-cm yellowish-brown
nodule and numerous satellite pap-
ules around the primary lesion. The
nodule is tender to palpation. A num-
ber of firm and nontender posterior
cervical nodes are palpable bilaterally.
Findings on the rest of the examina-
tion are normal.
Laboratory tests, including com-
plete blood count, erythrocyte
index of suspicion
Pediatrics in Review Vol.34 No.2 February 2013 95
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3. sedimentation rate, and urinalysis, as
well as levels of serum electrolytes,
blood urea nitrogen, creatinine, liver
enzymes, and C-reactive protein are
normal. An imaging study explains
the lesion behind her left ear, and
the histologic findings of skin, bone,
and lymph node biopsies confirm the
diagnosis.
Case 1 Discussion
This patient was evaluated thoroughly
by consultants from anesthesiology,
neurology, and rheumatology. Her
pain was poorly controlled with mor-
phine. During her hospitalization,
the skin temperature along her right
arm became normal, but she devel-
oped hyperesthesia and allodynia
(perception of pain from a nonpainful
stimulus) of her right arm. She also
developed tenderness of the right tra-
pezius muscle. She was unable to
move her fingers because of weak-
ness. Temperature sensation was de-
creased over the entire surface of the
arm.
After ruling out other possible
causes, such as malignancy, postin-
fectious reaction, and rheumato-
logic diseases, it was felt that she
met criteria for complex regional
pain syndrome (CRPS). A trial of
gabapentin and amitriptyline was
begun and her symptoms improved.
Subsequently, she had a nerve block
placed, following which she regained
use of her arm. She has had some
residual weakness, for which she is
receiving physical and occupational
therapy.
The Condition
CRPS type 1, formerly known as re-
flex sympathetic dystrophy syndrome,
is a chronic progressive disease char-
acterized by severe pain, swelling,
and changes in the skin. Current un-
derstanding of this condition is that it
is caused by a disruption of the auto-
nomic nervous system. The Interna-
tional Association for the Study of
Pain (IASP) has divided CRPS into
two types based on the detection of
a nerve lesion. Type 1 is not associ-
ated with an identifiable nerve lesion,
whereas type 2, previously known as
causalgia, presents evidence of obvi-
ous nerve damage. It is unclear what
causes the abnormal pain sensations
that typify CRPS, but injury of the
affected body part and stress seem
to play a role.
Most cases of CRPS occur in the
fourth decade after birth. However,
the incidence of CRPS among chil-
dren is increasing.
Diagnosis
The most widely accepted criteria for
the diagnosis have been published by
IASP (1) and are as follows:
1. The presence of an initiating noxious
event or a cause for immobilization
2. Continuing pain, allodynia, or
hyperalgesia disproportionate to
the inciting event
3. Evidence at some time of edema,
changes in skin blood flow, or ab-
normal motor activity in the area
of pain
4. Exclusion of the diagnosis by the
existence of any condition that
would otherwise account for the
degree of pain and dysfunction.
Criteria 2 through 4 must be pres-
ent for the diagnosis.
According to the IASP, the diag-
nostic criteria for CRPS II (also
known as causalgia) are as follows:
1. The presence of continuing pain,
allodynia, or hyperalgesia after
a nerve injury, not necessarily lim-
ited to the distribution of the in-
jured nerve
2. Evidence at some time of edema,
changes in skin blood flow, or
abnormal motor activity in the re-
gion of pain
3. Exclusion of the diagnosis by
the existence of any condition that
would otherwise account for the
degree of pain and dysfunction.
All three criteria must be present
to make the diagnosis.
No specific laboratory or imaging
studies are available to establish the
diagnosis of CRPS, and most experts
agree that diagnostic studies are not
necessary to make the diagnosis.
However, the following tests have
been found useful in confirming the
diagnosis:
Three-phase bone scan and gado-
linium MRI have been used to diag-
nose and stage the disease. Although
radiographs can be normal in as
many as 30% of patients, osteoporo-
sis may be demonstrated as early as
3 to 5 weeks after the onset of the
symptoms. Laser Doppler flow stud-
ies have been used to monitor back-
ground vasomotor control. A cold
pressor test performed in conjunc-
tion with thermographic imaging
may demonstrate a vasoconstrictor
response.
Treatment
A number of different treatment mo-
dalities are available, including nerve
blockades; medications such as topi-
cal analgesics, gabapentin, tricyclic
antidepressants, and corticosteroids;
and psychotherapy. Physical therapy
is an essential and nonnegotiable part
of treatment. It is extremely impor-
tant to restore normal function of
the affected body part through vigor-
ous and intense physical therapy.
Additionally, tactile stimulation can
reduce the associated pain and swell-
ing significantly.
Prognosis
The prognosis is good if the condition
is treated early, ideally within the first 3
index of suspicion
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4. months of onset. Patients may develop
permanent muscle, nerve, and skin
damage if CRPS is not diagnosed
and treated in a timely fashion.
Lessons for the Clinician
• CRPS is a diagnosis that some-
times is overlooked but should
be considered if there is intense
and intractable pain, especially in
an isolated area
• For most patients, the diagnosis
and treatment are delayed by
months and even years
• Early diagnosis and treatment can
prevent long-term damage, such as
muscle atrophy, joint contractures,
and possible permanent loss of func-
tion of the affected extremity.
(Rhina Castillo, MD, Josue Flores,
MD, Randolf Nunez, MD, Depart-
ment of Pediatrics, Lincoln Medical
& Mental Health Center, New York,
NY)
Case 2 Discussion
CT scan of the temporal bones revealed
a destructive soft tissue lesion. The dif-
ferential diagnosis included a small
round cell tumor, such as neuroblas-
toma, rhabdomyosarcoma, and lym-
phoma or leukemia. Langerhans cell
histiocytosis was another consideration.
The patient was referred to the pedi-
atric hematologist/oncologist, who
obtained an MRI of the brain that con-
firmed the findings on CT scan. A skel-
etal survey showed an additional lytic
lesion of the right humeral epiphysis.
Her bone marrow examination yielded
normal results. Findings on biopsy con-
firmed the diagnosis of Langerhans cell
histiocytosis (LCH) of bone.
The Condition
LCH is a rare disorder that occurs at
any age but most frequently affects
young children. The incidence is
estimated to be 1/200,000 children
younger than 15 years of age. The
name of the disease is derived from
the type of cell involved, which is
the histiocyte. Normal histiocytes
originate from pluripotent stem cells,
which can be found in bone marrow.
Under the influence of various cyto-
kines, these precursor cells can be
committed to becoming specialized
cells, monocytes, which migrate from
the bloodstream to their various tis-
sue sites and differentiate into mac-
rophages and dendritic cells.
Macrophages are found in loose
connective tissues and some organs
(Kupffer cells of the liver), and
their main function is phagocytosis.
Dendritic cells, which are antigen-
presenting cells to T and B lympho-
cytes, are known as Langerhans cells
in the skin. Histiocytosis, with accu-
mulation and infiltration in the af-
fected tissues, is believed to be due
to dysfunction of lymphocytes and
cytokines. The Histiocytosis Society
classifies the histiocytic syndromes in-
to dendritic cell-related (Langerhans
cell histiocytosis and juvenile xanthog-
ranuloma) and macrophage-related
(hemophagocytic lymphohistiocytosis,
familial, or primary and acquired)
disorders.
One century has passed since his-
tiocytic disorders were recognized.
In 1987, the Histiocytosis Society
adopted the name LCH and defined
the criteria for diagnosis. Langer-
hans refers to Dr Paul Langerhans,
who first described these cells in
the skin. In the past, the condition
was called histiocytosis X, encom-
passing three clinical conditions: eo-
sinophilic granuloma (a disease that
affects a single part of the body,
eg, bones); Hand-Schuller-Christian
disease (involving bones, pituitary
gland causing diabetes insipidus,
and exophthalmos); and Letterer-
Siwe disease (which affects mainly
newborns and has systemic involvement,
including skin, liver, spleen, lung,
and bone marrow).
Clinical Presentation
The clinical manifestations depend
on the site of the lesions and on the
organs involved. LCH can affect a sin-
gle organ or multiple organs. Bone
involvement, which can be a single
lesion or multiple lesions, is observed
in 80% of patients. Skull bones are in-
volved in 50% of cases. Symptoms
due to bone involvement are swelling
or lumps on the skull, which can be
painful. Long-bone involvement can
cause fractures.
Cutaneous disease occurs in 50%
of patients, usually during the first
months after birth, presenting as
papulosquamous, erythematous, pete-
chial patches suggestive of eczema or
seborrheic dermatitis. Lymph node
enlargement is observed in 30% of pa-
tient, whereas pulmonary involvement
occurs in 20% to 40% of patients. Re-
spiratory symptoms include cough,
dyspnea, and chest pain due to pneu-
mothorax. Other organs also may
be involved, with hepatic manifesta-
tions that include hepatomegaly with
hypoalbuminemia, increased liver en-
zymes levels, and clotting factor
deficiency.
Patients also can present with diar-
rhea, gingival hypertrophy, ulcers of
the oral mucosa, and discharge from
the ear. Splenic involvement can lead
to hypersplenism. Both hypersplenism
and bone marrow involvement can
cause anemia and thrombocytopenia.
LCH can infiltrate various areas of
the brain, resulting in cerebellar dys-
function, seizures, and disruption of
hypothalamic and pituitary function
that can cause diabetes insipidus.
Diagnosis
Laboratory evaluation depends on
the extent of the disease suspected
on the basis of the history and phys-
ical findings. The diagnosis is always
index of suspicion
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5. made on cytologic examination. Re-
gardless of the clinical severity, the
histopathology of LCH generally is
uniform. An electron microscopic
finding of racquet-shaped bodies
(Birbeck granules) in the cells labeled
with anti-CD1a antibodies confirms
the pathologic diagnosis.
CT and MRI imaging are used to
determine the extent of organ system
involvement and can help in staging
the disease.
Treatment and Prognosis
Progress has been made in under-
standing the pathogenetic mecha-
nisms of LCH, which has helped to
design effective therapy. The goal of
therapy is to relieve clinical symptoms
and prevent complications. Multidisci-
plinary care is essential for all patients.
For single-system disease, observation
or local therapy only is recommended,
including topical corticosteroids for
skin lesions and curettage if there is lo-
calized bone involvement. This rec-
ommendation is based on the fact
that 15% to 20% of patients achieve
spontaneous regression when they
have localized disease.
Chemotherapy is recommended for
multisystemdisease.Anumberofcom-
binations of chemotherapeutic ag-
ents, including vinblastine, vincristine,
and 6-mercaptopurine as well as cor-
ticosteroids, are used for treating
multisystem disease. Radiation ther-
apy is effective for localized disease.
Myeloablative therapy followed by
bone marrow transplantation has been
tried in patients with refractory disease.
Long-term follow-up by a team of
individuals with experience in man-
aging patients with LCH is critical,
because there is a significant risk of
developing late complications of
the disease or adverse effects of treat-
ment. The extent of organ involvement
and the rapidity of the response to
chemotherapy correlate with the
prognosis.
This patient received a chemo-
therapeutic regimen which includ-
ed vinblastine and prednisone after
resection of her bony lesions. She
has responded well to therapy.
Lessons for the Clinician
• Because of its diverse clinical pre-
sentations, the differential diagno-
sis of LCH can be extensive.
• Timely intervention may decrease
morbidity and mortality and thus
improve prognosis.
(Alfredo Torralbas, MD, Doctors Medical
Center & Miami Children Hospital,
Miami, FL)
Reference
Merskey H, Bogduk N, eds. International
Association for the Study of Pain. Classi-
fication of Chronic Pain: Descriptions of
Chronic Pain Syndromes and Definitions
of Pain Terms. Seattle, WA: IASP Press;
1994
To view Suggested Reading lists
for these cases, visit http://pedsinreview.
aappublications.org and click on
the “Index of Suspicion” link.
Answer Key for February 2013 Issue:
Energy Drinks: 1. B; 2. A; 3. D; 4. B; 5. D
Childhood Brain Tumors: 1. D; 2. C; 3. E; 4. D; 5. D
Pediatric Pancreatitis: 1. C; 2. C; 3. C; 4. D; 5. C
index of suspicion
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6. DOI: 10.1542/pir.34-2-95
2013;34;95Pediatrics in Review
Rhina Castillo, Alfredo Torralbas, Josue Flores and Randolf Nunez
Index of Suspicion
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