Index of Suspicion

Karine Barseghyan, Kavita Parikh, Dhiren Patel, Eyal Ben-Isaac, Jessica Signoff,
Roberta L. DeBiasi, Anil Chhabra, H. Dele Davies, Shraddha Patel and Yakov Sigal
Pediatrics in Review 2014;35;42
DOI: 10.1542/pir.35-1-42

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/35/1/42

Data Supplement at:

http://pedsinreview.aappublications.org/content/suppl/2013/12/26/35.1.42.DCSupplementary_Data.htm
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publication, it has been published continuously since 1979. Pediatrics in Review is owned,
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index of suspicion
The reader is encouraged to write
possible diagnoses for each case before
turning to the discussion.
The reader is encouraged to write
possible diagnoses for each case
before turning to the discussion.
We invite readers to contribute case
presentations and discussions. Please
inquire first by contacting Dr. Deepak
Kamat at DKamat@med.wayne.edu.
Author Disclosure
Drs Barseghyan, Ben-Isaac, Parikh,
Signoff, DeBiasi, Patel, Chhabra,
Davies, and Sigal have disclosed no
financial relationships relevant to this
article. This commentary does not
contain discussion of unapproved/
investigative use of a commercial
product/device.
42 Pediatrics in Review Vol.35 No.1 January 2014
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Case 1: Anasarca in a 2-Year-Old Boy
Case 2: Daily Spiking Fevers in an 8-Year-Old Girl
Case 3: Poor Weight Gain and Excessive Sleepiness in
a 7-Week-Old Girl
Case 1 Presentation
A 2-year-old boy with a history of ec-
zema and food allergies to nuts and
soy presents to the emergency de-
partment with a 10-day history of
generalized edema. The swelling be-
gan in the periorbital area but soon
progressed to involve his entire body.
There have been no fevers or any re-
cent illnesses other than 1 day of cough
and a few watery stools. He has had no
new exposures to foods or other sub-
stances. His family history is remark-
able for multiple allergies and eczema.
Physical examination reveals a tem-
perature of 98.8°F (37.1oC), heart
rate of 98 beats per minute, respira-
tory rate of 36 breaths per minute,
blood pressure of 103/65 mm Hg,
and an oxygen saturation of 97% on
room air. His weight is 12.6 kg (34th
percentile). He is noted to have a mod-
erate amount of periorbital edema, de-
creased breath sounds at the lung bases
bilaterally, a protuberant abdomen,
and 2þ pitting edema on his lower
extremities. The rest of his physical
examination findings are within nor-
mal limits.
Laboratory evaluation reveals a
white blood cell count of 23,800/mL
(23.8  109/L), with 37% neutro-
phils, 49% lymphocytes, 4% bands,
7% monocytes, and 3% eosinophils;
hemoglobin level of 13.3 g/dL
(133 g/L); and platelet count of
427  103/mL (427  109/L). Se-
rum electrolyte, blood urea nitrogen,
and creatinine levels are normal.
Sodium level is 132 mEq/L (132
mmol/L). Serum albumin level is
1.7 g/dL (17 g/L) (reference range,
3.4-5.4 g/dL [34-54 g/L]). Total
protein level is 3.8 g/dL (38 g/L).
Aspartate aminotransferase, alanine
aminotransferase, and coagulation pro-
files are within normal limits. The uri-
nalysis result is negative for protein.
The patient is hospitalized for further
workup and management of his hy-
poalbuminemia and edema.
Case 2 Presentation
An 8-year-old girl is evaluated in the
emergency department for 6 days of
high fevers. Her family reports nightly
fever spikes to a temperature of
103.5°F (39.7°C) accompanied by
frontal headache, chills, and myalgias.
She reports decreased appetite, with
2 episodes of vomiting and 1 episode
of diarrhea. She has had no cough,
congestion, rhinorrhea, sore throat,
abdominal pain, rash, joint pain or
swelling, bruising, or bleeding. She
has a history of asthma with no recent
exacerbations. There is no history of
travel or exposure to wooded areas.
She has a pet kitten and turtle. One
month ago, she went on a class trip
to a petting zoo.
On physical examination, she is
not in acute distress. Her tempera-
ture is 103.5°F (39.7°C), heart rate
is 140 beats per minute, and respira-
tory rate is 20 breaths per minute.
Conjunctivae are clear, and fundu-
scopic examination results are normal.
Her lips are dry but not cracked or er-
ythematous, and her oropharynx is
benign. She has no neck stiffness.
There is no palpable lymphadenopa-
thy. There is no swelling of her joints
and no rash. The remainder of her phys-
ical examination findings are normal.
On laboratory evaluation her com-
plete blood cell count, electrolyte,
blood urea nitrogen, creatinine, and

liver enzyme values are normal. Her
erythrocyte sedimentation rate is
98 mm/h (reference range, 0-20
mm/h), and her C-reactive protein
level is 17.06 mg/L (162.5 nmol/L)
(reference range, 0.05-1.0 mg/L
[0.48-9.5 nmol/L).
She is hospitalized and continues
to have daily spiking fevers. Her chest
radiograph, abdominal ultrasono-
gram, head computed tomograph, and
transthoracic echocardiogram findings
are within normal limits. Chest, ab-
dominal, and pelvis computed tomog-
raphy reveals only a few enlarged right
axillary lymph nodes. Additional labo-
ratory evaluation reveals the cause of
her fever.
Case 3 Presentation
A 7-week-old girl is hospitalized for
poor weight gain (13 oz since birth)
and increased sleepiness for a few days
along with recent onset of decreased
formula intake. After hospitalization,
she develops loose, nonbloody, yel-
lowish brown stools and several
episodes of nonbilious, projectile vom-
iting. The mother is a known carrier
of hepatitis C and has a history of
smoking and drug abuse. Various milk
formulas had been tried in the past
without much improvement in weight.
History is also remarkable for one
acute life-threatening event that was
thought to be related to gastroesoph-
ageal reflux. The patient has no history
of fever, rash, or seizures. Antenatal
history is uncomplicated.
On physical examination, all vital
signs are normal for age. Her weight
is 3.36 kg (5th to 10th percentile),
head circumference is 36.4 cm (25th
to 50th percentile), and length is
58 cm (25th to 50th percentile). On
examination she is not interactive.
Cardiovascular examination reveals
a grade 2/6, soft, and nonradiating
systolic murmur, best heard at the left
sternal border. Neurologic examination
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reveals generalized hypotonia without
any focal deficits. Other physical ex-
amination findings are normal.
Laboratory values are as follows:
white blood cells, 11,800/mL (11.8 
109/L); hemoglobin, 10.5 g/dL
(105 g/L); platelets, 410  103/mL
(410  109/L); random blood glu-
cose, 59 mg/dL (3.3 mmol/L) (ref-
erence range, 70-100 mg/dL [3.9-5.6
mmol/L]); aspartate aminotransferase,
293 U/L (reference range, 0-120
U/L); alanine aminotransferase, 209
U/L (reference range, 2-45 U/L);
total bilirubin, 2.1 mg/dL (35.9
mmol/L) (reference range, 0.2-1.2
mg/dL [3.4-20.5 mmol/L]); activated
partial thromboplastin time, 54.6
seconds (reference range, 25-35 sec-
onds); g-glutamyltransferase, 334
U/L (reference range, 0-35 U/L);
ammonia, 104 mg/dL (74 mmol/L)
(reference range, 18-52 mg/dL [13-
37 mmol/L]); pyruvate, 0.22 mg/
dL (25 mmol/L) (reference range,
0.30-1.50 mg/dL [34-170 mmol/
L]); and lactate, 69.4 mg/dL (7.7
mmol/L) (reference range, 1.8-16.2
mg/dL [0.2-1.8 mmol/L]). Arterial
blood gas and electrolyte values are
normal. The patient is positive for hep-
atitis C antibody but negative for hep-
atitis C RNA quantitative viral load.
Abdominal ultrasonography reveals dif-
fuse increase in liver echogenicity. Ad-
ditional studies reveal the diagnosis.
Case 1 Discussion
The gastroenterology service was con-
sulted, and further workup for a
protein-losing enteropathy was initi-
ated. A chest radiograph revealed
bilateral pleural effusions, and an ab-
dominal ultrasonogram confirmed
ascites. An echocardiogram revealed
a mild pericardial effusion. Further
workup revealed an elevated fecal a1-
antitrypsin level of 20.5 mg/g (3.8
mmol/L) (reference range, 0-1 mg/g
index of suspicion
[0-0.2 mmol/L]). The patient under-
went esophagogastroduodenoscopy
with biopsies that revealed hypertro-
phic gastric rugae consistent with
Ménétrier disease. Cytomegalovirus
(CMV) quantitative polymerase chain
reaction (PCR) from the blood came
back at 21,555 copies/mL. The result
of the CMV PCR from the gastric tis-
sue was positive as well. He received
2 infusions of 1 g/kg of 25% albumin,
and his edema improved during the
next 4 days. His tachypnea resolved,
and he was discharged home; his albu-
min level at the time was 2.7 mg/dL
(27 g/L). He was followed up in the
gastroenterology clinic 3 weeks later
and was noted to be doing clinically
well without any further edema of
his face, abdomen, or extremities. His
serum albumin levels were within nor-
mal limits as well.
The Condition
Ménétrier disease, also known as
protein-losing hypertrophic gastro-
pathy, is a rare acquired condition
of the stomach. The pathogenesis of
the disease is not well understood
but is thought to involve increased
signaling of the epidermal growth fac-
tor receptor (EGFR), which results in
proliferation of mucosal epithelial cells
mainly in the body and fundus of the
stomach perhaps through an overex-
pression of transforming growth fac-
tor a. These cells replace the normal
chief and parietal cells, leading to ex-
cessive mucous production with little
acid secretion. Patients develop edema
secondary to hypoalbuminemia due
to protein leakage through the gastric
mucosa.
Patients with Ménétrier disease
often present with epigastric pain,
anorexia, vomiting, diarrhea, and
edema. They can develop additional
clinical features, such as ascites and
pleural and pericardial effusions.
Laboratory abnormalities typically
reveal hypoalbuminemia without
Pediatrics in Review Vol.35 No.1 January 2014 43
index of suspicion
proteinuria, malabsorption of fat
and fat-soluble vitamins, and re-
duced plasma concentrations of
g-globulins, cholesterol, a1-antitrypsin,
and fibrinogen.
One-third of cases that involved
children with Ménétrier disease are
thought to be due to or associated
with CMV infection; a few cases have
been associated with Helicobacter py-
lori infection. It has been postulated
that CMV infection leads to increased
signaling of the EGFR. As the CMV
virus is cleared from the system, the
stimulus to the EGFR decreases, re-
sulting in lessened cell proliferation
of gastric mucosal epithelial cells and
a return to normal anatomy. Thus,
CMV-associated Ménétrier disease
spontaneously resolves in 2 to 4 weeks
in immunocompetent children.
Differential Diagnosis
When the diagnosis of protein-losing
enteropathy is established, the clini-
cian should consider the following
differential diagnoses: milk protein
allergy, celiac disease, inflammatory
bowel disease, giardiasis, intestinal
lymphangiectasia, right-sided heart
dysfunction (after the Fontan pro-
cedure), and hypertrophic gastritis
(Ménétrier disease). The diagnosis
of Ménétrier disease is established
by the presence of enlarged gastric
rugae seen on barium radiologic
studies or endoscopy and by histo-
logic confirmation. Serologic testing
for CMV should also be considered,
but detection of CMV DNA in a gas-
tric biopsy sample by PCR is a more
sensitive assay for confirming a possi-
ble cause.
Management and Prognosis
In adults, Ménétrier disease is often
progressive. However, in children the
process is usually self-limiting and
resolves spontaneously within a few
weeks. Close follow-up is highly rec-
ommended to monitor these patients
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for reduction of symptoms and an in-
crease in serum protein levels. Severe
cases may require intravenous al-
bumin infusions. Oral proton pump
inhibitors or histamine2-receptor block-
ers can also be used to treat gastric
inflammation.
Immunocompetent children with
CMV-associated Ménétrier disease
also have a self-limiting course that
typically resolves in 2 to 4 weeks
without any therapy. Treatment with
ganciclovir should be considered
in immunocompromised hosts and
neonates who have an immature im-
mune system or healthy infants who
do not improve with supportive ther-
apy. Testing for H pylori should be
considered because coinfection with
CMV and H pylori has been reported
in the literature.
Other medical treatments being
studied in Ménétrier disease include
the use of octreotide (a somatostatin
analogue) and cetuximab (a mono-
clonal antibody to EFGR). Partial
gastrectomy is reserved for those pa-
tients with severe hemorrhage.
Lessons for the Clinician
• Protein-losing enteropathy evalua-
tion should be initiated in patients
presenting with hypoalbuminemia
and edema without proteinuria.
Cytomegalovirus (CMV)–associated
Ménétrier disease should be con-
sidered in the differential diagnosis.
• A gastroenterologist should be
consulted to perform esophago-
gastroduodenoscopy with biop-
sies to establish the diagnosis of
CMV-associated Ménétrier disease.
• CMV-associated Ménétrier disease
is usually a self-limiting process
that resolves in 2 to 4 weeks with-
out any treatment in immunocom-
petent children. Close follow-up is
highly recommended to monitor the
patients for reduction of symptoms
and an increase in serum protein
levels.
(Karine Barseghyan, MD, Eyal Ben-
Isaac, MD, Children’s Hospital Los
Angeles, Los Angeles, CA)
Case 2 Discussion
The initial differential diagnosis for
acute fever without focal findings is
extensive, including infectious, rheu-
matologic, and, less likely, oncologic
disorders. Infectious causes consid-
ered in our patients were Epstein-Barr
virus, CMV, and other viral infections,
as well as occult bacteremia. However,
when diagnostic test results for these
infections came back negative, the dif-
ferential diagnosis was expanded to
include Bartonella, Brucella, Myco-
plasma, Salmonella, and human her-
pesvirus 6 infections. Serologic tests
for Bartonella henselae (cat scratch dis-
ease [CSD]) revealed an IgM titer of
1:160 and an IgG titer greater than
1:1,024. The results of a thorough
evaluation for infectious and rheuma-
tologic disorders were negative.
The Condition
CSD is a common disease in children
mostly associated with self-limited re-
gional lymphadenopathy but known
to cause multiple clinical manifesta-
tions of varying severity. As reported
by Florin et al, the true incidence of
CSD is difficult to establish because
it is not a reportable disease, and it
is likely that many cases are not rec-
ognized because of self-resolution.
In 2000, national CSD hospitaliza-
tion rates ranged from 0.60 to 0.86
per 100,000 for children younger
than 18 years, with an increased inci-
dence in children younger than
5 years. Bartonella henselae, the caus-
ative organism, has broad distribution
in North America and worldwide.
The disease often follows a cat scratch
or bite, which results in inoculation of

the organism into the host. This aero-
bic gram-negative bacillus is transmit-
ted by the cat flea, Ctenocephalides
felis, between cats and transmitted to
humans via cat saliva or the scratch
of a cat. Cats, especially kittens youn-
ger than 1 year, are natural reservoirs
for B henselae because the organism
causes asymptomatic bacteremia that
persists for a year or longer.
Clinical Manifestations
The typical presentation of CSD (oc-
curring in 85%-90% of children with
Bartonella infection) is a cutaneous
lesion appearing 7 to 12 days after
a cat scratch or bite, followed days
to weeks later by localized lymphade-
nopathy or lymphadenitis. A total
of 10% to 30% of enlarged lymph no-
des become suppurative. Regional
lymphadenopathy is the hallmark of
CSD; commonly, cervical and axillary
lymph nodes are involved and can en-
large to several centimeters in diame-
ter. Lymphadenopathy may persist
for weeks to months, and patients
with localized disease generally have
a self-limited illness.
Fever occurs in 30% to 50% of pa-
tients with CSD and can reach max-
imal temperatures of up to 104°F
(40°C). However, in typical CSD,
less than 10% of patients have high fe-
ver (temperatures >102.2°F [>39°
C]), and one-third are actually afe-
brile. A total of 10% to 30% of
CSD patients have prolonged fever
as their only initial presenting symp-
tom. In fact, CSD is the third most
common infectious disease responsi-
ble for fever of unknown origin in
children after Epstein-Barr virus in-
fection and osteomyelitis. Fevers are
less commonly associated with ma-
laise, anorexia, rash, and other gener-
alized symptoms.
Manifestations of disseminated in-
fection include visceral organ, neuro-
logic, and ocular involvement. Visceral
organ involvement of CSD generally
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includes hepatic and/or splenic lesions,
one of the more common manifesta-
tions of CSD after isolated lymphade-
nopathy. However, many patients with
visceral involvement have no accompa-
nying peripheral adenopathy. CSD
may cause multifocal necrotizing
granulomas, leading to painful hepatos-
plenomegaly. Neurologic manifesta-
tions of CSD include encephalopathy
(most common) and other less com-
mon manifestations, including trans-
verse myelitis and cerebellar ataxia.
Most patients with CSD encephalop-
athy recover within several weeks,
but some patients have residual
neurologic defects. Ocular manifes-
tations of CSD include Parinaud
oculoglandular syndrome or neuro-
retinitis. Parinaud oculoglandular
syndrome has been reported in 2%
to 8% of patients with CSD and in-
cludes conjunctivitis, conjunctival
granuloma, and adjacent preauri-
cular lymphadenopathy. Approxi-
mately 1% to 2% of patients with
CSD develop neuroretinitis, pre-
senting with acute visual loss from
optic nerve edema, which generally
resolves.
Diagnosis
Diagnosis of CSD is often suspected
based on clinical findings; however,
laboratory confirmation is required.
It is suggested that 3 of 4 criteria
be met to establish the diagnosis of
typical CSD.
1. Cat or flea contact regardless of
scratch or bite.
2. Negative serologic test results for
other causes of adenopathy, sterile
lymph node aspirate, positive tissue
Bartonella PCR results, and/or
liver or spleen lesions.
3. Positive serologic test result for B
henselae with an IgG titer of 1:64
or greater.
4. Biopsy specimen with granulo-
matous inflammation or positive
index of suspicion
Warthin-Starry silver stain con-
sistent with CSD.
In general, titers of B henselae IgG
greater than 1:64 to 1:256 suggest
acute infection, but retesting 10 to
14 days later is recommended, with
titers greater than 1:256 strongly sug-
gestive of active or recent infection.
IgM is useful but known to increase
only briefly in response to infection.
PCR-based tests for B henselae are also
available commercially.
Culture of B henselae is not easily
achieved because of the fastidious,
slow-growing nature of the organ-
ism. However, B henselae can be vi-
sualized as pleomorphic bacilli in
chains, clumps, or filaments on
Warthin-Starry stain performed on
lymph node and cutaneous lesion
tissue specimens.
Management
The role of antimicrobial therapy in
CSD is unclear. Most patients with
typical CSD have gradual resolution
of symptoms within 2 to 6 months,
and antimicrobial therapy is not sug-
gested for uncomplicated disease.
Suppurative lymphadenopathy should
be aspirated if they are painful; how-
ever, incision and drainage are not
recommended because of potential
chronic sinus tract formation. Most
studies report no benefit to antibiotic
therapy in CSD. Given the natural res-
olution of uncomplicated CSD and
the risk of unnecessary antibiotic ex-
posures, antibiotics are not suggested
for typical CSD. In patients with ex-
tensive lymphadenopathy or who are
immunocompromised or severely ill,
especially patients with hepatosplenic
disease, antibiotic therapy may be
considered. The most commonly rec-
ommended therapy is azithromycin.
Other antibiotics suggested in-
clude trimethoprim-sulfamethoxa-
zole, gentamicin, ciprofloxacin, or
rifampin. Our patient was treated
Pediatrics in Review Vol.35 No.1 January 2014 45
index of suspicion
with azithromycin and experienced
rapid defervescence.
Lessons for the Clinician
• Cat scratch disease (CSD) is an in-
fectious disease typically charac-
terized by self-limited regional
lymphadenopathy.
• However, CSD should also be
considered in the differential diag-
nosis of acute fever without source
and, in particular, fever of un-
known origin in children.
• CSD is the third most common in-
fectious cause of fever of unknown
origin in children.
(Kavita Parikh, MD, Jessica Signoff,
MD, Roberta L. DeBiasi, MD, MS,
Children’s National Medical Center,
Washington, DC)
Case 3 Discussion
The patient was placed on nasogastric
tube feedings. The results of subse-
quent metabolic workup, including
anion gap, free thyroxine, thyrotropin,
sweat chloride test, stool elastase, a1-
antitrypsin phenotype, carnitine and
acylcarnitine profile, plasma amino
acid, organic acid, and succinyl acetone
from urine and serum, were normal.
Hepatitis B, human immunodeficiency
virus, CMV, Epstein-Barr virus, and
human herpesvirus 6 antibody panel
results were also negative. The re-
sults of electrocardiography and 2-
dimensional echocardiography were
normal. The underglycosylated trans-
ferrin level was slightly elevated but
not enough to make a diagnosis of
congenital disorder of glycosylation.
Plain microscopy of skeletal and ab-
dominal muscle revealed many ragged
red fibers on trichrome stain consistent
with the diagnosis of mitochondrial
myopathy. On electron microscopy,
liver and muscle tissue revealed ir-
regular, swollen mitochondria with
46 Pediatrics in Review Vol.35 No.1 January 2014
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reduced cristae. The results of ge-
netic studies for various mutations
(eg, POLG, COX10, SCO2, SCO1,
and SURF) were negative.
The Condition
Although the diagnosis of mitochon-
drial myopathies is primarily a clinical
one, molecular and biochemical eval-
uations are required to confirm the
specific diagnosis. All these disorders
may follow mendelian inheritance
(ie, nuclear DNA mutations) or ma-
ternal inheritance (ie, mitochondrial
and mitochondrial DNA [mtDNA]
mutations). Most pediatric mito-
chondrial diseases are caused by nu-
clear DNA mutations. Respiratory
chain dysfunction (ie, problems with
oxidative phosphorylation in the in-
ner mitochondrial membrane) are
conventionally termed mitochondrial
myopathies.
Clinical Presentation
Clinical presentation of mitochon-
drial myopathies is extremely vari-
able. Myopathies can present as an
incidental finding or in association
with multisystem illness. A detailed
family history of childhood muscle
or cardiac involvement, deafness, vi-
sion abnormality, diabetes, or devel-
opmental delay should be obtained.
In neonates the most common pre-
sentation is an encephalomyopathic
form of mitochondrial myopathy. In
one study the median survival of those
with infantile onset was 12 years. De-
fects in the respiratory chain invariably
impair energy production in skeletal
muscle. Potential defects can occur
in complex 1, 2, 3, or 4 of the respi-
ratory chain in mitochondria. Chil-
dren with mitochondrial myopathies
may have life-threatening complica-
tions during anesthesia due to under-
lying metabolic derangements.
The most lethal form of encepha-
lomyopathy of infancy and child-
hood presents at birth with severe
hypotonia and may have associated
brain, heart, kidney, or liver involve-
ment. This presentation is generally
secondary to mutation in the thymi-
dine kinase 2 or succinyl COA syn-
thase ligase 2 genes and is known
as the mitochondrial depletion syn-
drome. Sometimes tubular dysfunc-
tion, such as Fanconi syndrome, is
also associated with the mitochon-
drial depletion syndrome.
Mitochondrial disorders can also
present as various syndromes, such
as Barth syndrome (cardiomyopathy,
cyclic neutropenia, and mitochon-
drial myopathies), Leber hereditary
optic neuropathy, Leigh syndrome
(necrotizing encephalomyopathy), ma-
ternally inherited deafness and diabetes,
myoclonic epilepsy and ragged red
fibers, and Pearson syndrome (side-
roblastic anemia and pancreatic in-
sufficiency). Leigh syndrome and
mitochondrial encephalopathy with
lactic acidosis and strokelike episodes
are the most common mitochondrial
disorders.
Diagnosis
The diagnosis of mitochondrial dis-
ease can be made by family history,
particularly in the case of maternal
transmission. Sixty-two percent of
cases result from nuclear DNA muta-
tions and follow mendelian inheritance.
The evaluation generally includes com-
plete blood cell count, serum electrolyte
measurement, fasting glucose measure-
ment, glycosylated hemoglobin mea-
surement, renal and liver function
tests, creatine kinase measurement,
plasma and cerebrospinal fluid lactate
and pyruvate measurement, lactate to
pyruvate ratio, plasma amino acid mea-
surement, urine organic acid measure-
ment, plasma acylcarnitine analysis,
ammonia measurement, brain magnetic
resonance imaging, thyroid studies,
electromyography, nerve conduction
studies, hearing studies, electroenceph-
alography, and echocardiography. The

ratio of lactate to pyruvate differentiates
between pyruvate dehydrogenase defi-
ciency and primary respiratory chain
dysfunction. Because of defects in oxi-
dative phosphorylation, patients with
mtDNA disorders are dependent on
anaerobic metabolism, which results
in a shunt of pyruvate to lactate. Thus,
as demonstrated in our patient, a high
lactate level at rest and elevated lactate
to pyruvate ratio is suggestive of an
mtDNA disorder. Muscle biopsy is
the gold standard test for diagnosing
a mitochondrial disorder, and the classic
hallmark is ragged red fibers on Gomori
trichrome stain. Other stains that are
used are succinate dehydrogenase and
Cox stain. Overall, electron microscopy
does not provide any additional helpful
findings than plain microscopy but may
reveal hypoplastic or dystrophic cristae.
Treatment
The management of mitochondrial
disease is generally symptomatic and
includes respiratory support and con-
trol of cardiac, ophthalmic, and neu-
rocognitive problems. At this time
there is no well-researched pharma-
cologic treatment, but various agents
have been tried, including respiratory
Parent Resources From the AAP at HealthyChildren.org
Case 2
• English: http://www.healthychildren.org/English/health-issues/conditions/from-insects-animals/Pages/Cat-Scratch-
Disease.aspx
• Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/from-insects-animals/paginas/cat-scratch-
disease.aspx
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chain cofactors, antioxidants, agents
that correct secondary biochemical
deficits, and drugs that reduce lactic
acid accumulation. The current re-
search on gene therapy and approach
of gene shifting is still in the investi-
gational stages.
Lessons for the Clinician
• The clinical presentation of mito-
chondrial myopathies is variable
and ranges from very mild to fatal
disease. However, the most com-
mon neonatal presentation is ence-
phalomyopathy with or without
hypotonia.
• Mitochondrial dysfunction invari-
ably impairs energy production, pri-
marily affecting muscles, and can
lead to multiorgan dysfunction.
• An elevated lactate to pyruvate
ratio is the key to differentiating
mitochondrial disease from enzy-
matic deficiency in conjunction
with other biochemical, meta-
bolic, and genetic tests. Although
no specific reference range is id-
entified, generally a ratio of more
than 15 to 20 is considered sug-
gestive of mitochondrial respira-
tory chain defects.
Chronic Kidney Disease: 1. C; 2. C; 3. E; 4. 3; 5. C.
Acute Kidney Injury: 1. D; 2. C; 3. D; 4. B; 5. B.
index of suspicion
• The measurement unit for lactate and
pyruvate must be the same when cal-
culating the lactate to pyruvate ratio
because most laboratories commonly
report lactate and pyruvate levels in
entirely different units. (Lactate is re-
ported in millimoles per liter and py-
ruvate in milligrams per deciliter.)
• When testing lactate and pyruvate
levels, an arterial sample is prefera-
ble and must be collected without
use of a tourniquet; blood should
be free-flowing when sampled.
• Muscle biopsy with microscopy
remains one of the most valuable
diagnostic tests for determining
mitochondrial disorders.
• No definite treatment is available,
and the current standard of care
is supportive therapy.
(Dhiren Patel, MD, Anil Chhabra,
MD, H. Dele Davies, MD, MSc,
MHCM, Shraddha Patel, PhD, Re-
search Associate, Yakov Sigal, MD,
Michigan State University, Sparrow
Hospital, Lansing, MI)
To view Suggested Reading lists
for these cases, visit http://pedsinreview.
aappublications.org and click on the
“Index of Suspicion” link.
Answer Key for January 2014 Issue:
Fluoride: 1. D; 2. E; 3. B; 4. D; 5. A.
Pediatrics in Review Vol.35 No.1 January 2014 47
 Index of Suspicion
Karine Barseghyan, Kavita Parikh, Dhiren Patel, Eyal Ben-Isaac, Jessica Signoff,
Roberta L. DeBiasi, Anil Chhabra, H. Dele Davies, Shraddha Patel and Yakov Sigal
Pediatrics in Review 2014;35;42
DOI: 10.1542/pir.35-1-42

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