Differentiating PFAPA Syndrome From Monogenic Periodic Fevers
Marco Gattorno, Roberta Caorsi, Antonella Meini, Marco Cattalini, Silvia Federici,
Francesco Zulian, Elisabetta Cortis, Giuseppina Calcagno, Alberto Tommasini, Rita
Consolini, Gabriele Simonini, Maria Antonietta Pelagatti, Maurizia Baldi, Isabella
Ceccherini, Alessandro Plebani, Joost Frenkel, Maria Pia Sormani and Alberto Martini
Pediatrics 2009;124;e721; originally published online September 28, 2009;
DOI: 10.1542/peds.2009-0088
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/124/4/e721.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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ARTICLES
Differentiating PFAPA Syndrome From Monogenic
Periodic Fevers
AUTHORS: Marco Gattorno, MD,a,b Roberta Caorsi, MD,a,b
Antonella Meini, MD,c Marco Cattalini, MD,c Silvia
Federici, MD,a,b Francesco Zulian, MD,d Elisabetta Cortis,
MD,e Giuseppina Calcagno, MD,f Alberto Tommasini, MD,g
Rita Consolini, MD,h Gabriele Simonini, MD,i Maria
Antonietta Pelagatti, MD,a,b Maurizia Baldi, PhD,j Isabella
Ceccherini, PhD,k Alessandro Plebani, MD,c Joost Frenkel,
MD,l Maria Pia Sormani, PhD,m and Alberto Martini, MDa,b
aPediatric Unit II and kLaboratory of Molecular Genetics,
Giannina Gaslini Institute, Genoa, Italy; bDepartment of
Pediatrics and mBiostatistics Unit, Department of Health
Sciences, University of Genoa, Genoa, Italy; cDepartment of
Pediatrics, Pediatric Immunology and Rheumatology Unit,
Spedali Civili and University of Brescia, Brescia, Italy;
dDepartment of Pediatrics, University of Padua, Padua, Italy;
eDepartment of Medicine, Division of Rheumatology, Pediatric
Hospital of the Child Jesus, Rome, Italy; fDepartment of Medical
and Surgical Pediatric Sciences, Section of Pediatric
Rheumatology, Hospital Worker University Gaetano Martino,
Messina, Italy; gDepartment of Pediatrics, Scientiﬁc Institute for
Treatment and Research Burlo Garofolo, University of Trieste,
Trieste, Italy; hDepartment of Reproductive Medicine and
Development, University of Pisa, Pisa, Italy; iDepartment of
Pediatrics, Rheumatology Unit, Anna Meyer Children’s Hospital
and University of Florence, Florence, Italy; jDepartment of Human
Genetics, Galliera Hospital, Genoa, Italy; and lDepartment of
General Pediatrics, Wilhelmina Children’s Hospital, University
Medical Center Utrecht, Utrecht, Netherlands
KEY WORDS
periodic fever, aphthous stomatitis, pharyngitis, and cervical
adenitis syndrome, classiﬁcation, diagnostic score, molecular
analysis
ABBREVIATIONS
PFAPA—periodic fever, aphthous stomatitis, pharyngitis, and
cervical adenitis
FMF—familial Mediterranean fever
TNF—tumor necrosis factor
TRAPS—tumor necrosis factor receptor-associated periodic
syndrome
MKD—mevalonate kinase deﬁciency
www.pediatrics.org/cgi/doi/10.1542/peds.2009-0088
doi:10.1542/peds.2009-0088
Accepted for publication May 29, 2009
Address correspondence to Marco Gattorno, MD, UO Pediatria II,
G. Gaslini Institute, Largo G. Gaslini 5, 16146, Genova, Italy. E-mail:
[email protected]
WHAT’S KNOWN ON THIS SUBJECT: Inherited periodic fevers
should be differentiated from PFAPA syndrome. PFAPA syndrome
criteria are not able to distinguish genetically positive patients
from genetically negative patients.
WHAT THIS STUDY ADDS: The Gaslini diagnostic score
represents a useful tool to identify patients who meet PFAPA
syndrome criteria and are at low risk of carrying relevant
mutations of genes associated with periodic fevers.
abstract
OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulﬁlling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA)
syndrome criteria and to test the accuracy of the Gaslini diagnostic
score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers.
METHODS: Complete clinical and genetic information was available for
393 children with periodic fever; 82 had positive genetic test results, 75
had incomplete genetic test results, and 236 had negative results for
MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for
PFAPA syndrome were applied.
RESULTS: Of 393 children, 210 satisﬁed PFAPA syndrome criteria; 43
carried diagnostic mutations (mevalonate kinase deﬁciency: n ⫽ 33;
tumor necrosis factor receptor-associated periodic syndrome: n ⫽ 3;
familial Mediterranean fever: n ⫽ 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P ⬍ .001), vomiting (P ⫽ .006),
and cutaneous rash and arthralgia (P ⫽ .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P ⫽ .010).
Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic
score was able to identify 91% of genetically positive patients correctly,
with a global accuracy of 66%.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2009 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no ﬁnancial relationships relevant to this article to disclose.
PEDIATRICS Volume 124, Number 4, October 2009
CONCLUSION: The Gaslini diagnostic score represents a useful tool to
identify patients meeting PFAPA syndrome criteria and at low risk of
carrying relevant mutations in genes associated with periodic fevers.
Pediatrics 2009;124:e721–e728
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e721
The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis
(PFAPA) syndrome is a clinical entity
that was ﬁrst described in 1987.1 The
syndrome has its onset before 5 years
of age and is characterized by regularly (often clockwork-like) recurrent
episodes of high fever lasting 3 to 6
days.2,3 The diagnosis is established
on the basis of clinical criteria that
require the presence of a recurrent
fever of early onset (⬍5 years) and
ⱖ1 of the 3 associated symptoms
(aphthosis, cervical adenitis, and
pharyngitis), in the absence of upper
respiratory tract infections and cyclic neutropenia.4
It is now widely recognized that, to
make a diagnosis of PFAPA syndrome,
it is necessary to rule out the presence
of another group of diseases (monogenic periodic fevers) that are caused
by mutations of genes involved in regulation of the inﬂammatory response,
namely, familial Mediterranean fever
(FMF), tumor necrosis factor (TNF)
receptor-associated periodic syndrome (TRAPS), and mevalonate kinase deﬁciency (MKD). These disorders, which belong to the group of
autoinﬂammatory diseases,5 also are
responsible for recurrent fevers and
demonstrate clinical overlap with
PFAPA syndrome in childhood.6–9
In this respect, the current PFAPA syndrome diagnostic criteria have very
low speciﬁcity. We showed recently
that a relevant number of patients with
monogenic periodic fevers also meet
the diagnostic criteria for PFAPA syndrome.10 In that preliminary experience, 83% of patients with MKD, 57% of
patients with TRAPS, and 8% of patients with FMF satisﬁed the criteria
for PFAPA syndrome,10 which shows
that the criteria have limited utility in
differentiating PFAPA syndrome from
monogenic periodic fevers. However,
because PFAPA syndrome is a morefrequent cause of recurrent fever in
e722
GATTORNO et al
children, it would be important, to
avoid useless genetic testing, to be
able to identify, among patients who
meet PFAPA syndrome diagnostic criteria, those with a low probability of
carrying one of the mutations associated with monogenic periodic fever.
In this study, we analyzed the main clinical features that could distinguish patients who meet current PFAPA syndrome criteria with negative versus
positive genetic testing results. Furthermore, we tested the accuracy of a
set of variables in identifying patients
with higher probability of carrying relevant mutations of genes associated
with monogenic periodic fever (the
Gaslini diagnostic score).10
METHODS
Beginning in 2002, a national laboratory facility for the genetic diagnosis of
recurrent fevers in children was established at the Gaslini Institute, in collaboration with the Galliera Hospital
(Genoa, Italy). The extracellular region
(exons 1– 6) of the p55 TNF receptor of
the TNFRSF1A gene, the 10 coding exons (exons 2–11) of the MVK gene, and
exons 2, 3, 5, and 10 of the MEFV gene
were analyzed by means of denaturing
high-performance liquid chromatography and DNA sequencing of amplimers displaying anomalous chromatographic patterns, as described
previously.10
For each patient, detailed clinical information was collected consistently
with a unique questionnaire aimed at
recording the frequency (never, sometime, often, or always) of the clinical
manifestations associated with periodic fever.10 The inclusion criteria for
molecular analysis of genes associated with periodic fever were (1) periodic fever attacks (⬎38°C) of unknown
origin, with exclusion of recurrent infections, cyclic neutropenia, and other
immunodeﬁciencies; (2) age at onset
of ⬍18 years; (3) symptom-free inter-
720 patients screened for
autoinflammatory diseases
351 noneligible for
inclusion in the studya
369 Italian patients
+24 from other centers
Negative for PFAPA
criteria: 183 patients
Positive for PFAFA
criteria: 210 patients
Involved in the
elaboration of the
“Gaslini” diagnostic
score: 115 patients
Newly diagnosed
PFAPA-like
patients: 95
FIGURE 1
Flowchart showing the numbers of patients included in the study. aCriteria for exclusion from
the study were (1) not fulﬁlling the inclusion
criteria for periodic fever, (2) lack of complete
clinical information, and (3) recruitment and
screening for suspected cryopyrin-related disorders only.
vals characterized by general wellbeing and normal levels of acutephase reactants; and (4) ⱖ2 of the
following symptoms during fever attacks: lymphadenopathy, splenomegaly, chest pain, or gastrointestinal, mucocutaneous (including pharyngitis
and oral aphthosis), or musculoskeletal manifestations.
Up to July 2008, specimens from 720 consecutive patients with suspected autoinﬂammatory syndrome were received for
molecular diagnosis. Among them, 351
were excluded from the present study
for ⱖ1 of the following reasons: (1) not
fulﬁlling the inclusion criteria for periodic fever, (2) lack of complete clinical
information, or (3) recruitment and
screening for suspected cryopyrinrelated disorders.11,12 Results of genetic
analyses performed for all 3 genes involved in periodic fevers (MEFV,
TNFRSF1A, and MVK) and complete clinical information were therefore available
for 369 patients (Fig 1).
During the 6-year period, a total of 58
children with a history of recurrent fe-
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ARTICLES
ver were found to carry relevant mutations in the screened genes (29 were
compound heterozygous or homozygous for MVK, 21 were compound heterozygous or homozygous for MEFV,
and 8 were heterozygous for structural mutations of TNFRSF1A); moreover, 21 patients displayed lowpenetrance mutations of TNFRSF1A, 4
were heterozygous for MVK, and 50
were heterozygous for MEFV. Complete
clinical information on an additional
24 genetically positive patients (11 patients with MKD, 4 patients with TRAPS
with structural mutations, and 9 patients with complete FMF) from collaborating European centers also was
available.10 Clinical information for the
latter patients was collected by using
the same forms as were used for the
Italian patients.
Current PFAPA syndrome criteria2,4
were applied to all genetically positive
patients and genetically negative patients screened for all 3 genes. Patients were considered positive for
PFAPA syndrome criteria if their age at
disease onset was ⬍5 years and they
exhibited ⱖ1 of the 3 clinical manifestations (cervical lymphadenopathy, erythematous and/or exudative pharyngitis, and/or oral aphthosis) in all
febrile episodes. All 30 patients who
were compound heterozygous or homozygous and 26 of 50 patients who
were heterozygous for MEFV gene mutations were considered positive for
FMF criteria.13
The Gaslini diagnostic score was formulated on the basis of statistical
analysis of the clinical features of 173
children with periodic fever who were
analyzed for the 3 genes.10 A multivariate logistic regression analysis indicated a set of clinical predictors for
positive genetic test results. Age at onset, positive family history, thoracic
and abdominal pain, diarrhea, and
oral aphthosis were the variables included in the ﬁnal model that prePEDIATRICS Volume 124, Number 4, October 2009
TABLE 1 Mutations Found in Patients With Periodic Fever Fulﬁlling PFAPA Syndrome Criteria
Mutations (n)
MVK (N ⫽ 33)
I268T/V377I (8)
V377I/V377I (5)
L265R/V377I (2)
V310M/V377I (2)
L264F/V377I
R215Q/V377I
V132I/V377I
G211E/V377I
H20Q/V377I
c.16㛭34del/V377I
G171R/I268T
G336S/G336S
C367S/C367S
A148T/I268T
V337I/H20P
A334T/A334T
I268T/P167L
P228L/V377I
C972T/S314S
C886–1G⬎A/V377I
a
TNFRSF1A
(N ⫽ 10)
Structural (3)
C55Y (2)a
c.586㛭612del
Low penetrance (7)
R92Q (7)
MEVF
(N ⫽ 40)
Composite (7)
M694V/V726A
M680I/V726A
M694V/E148Q
L110P/L110P
V726A/E148Q
V726A/S108R
P369S/R408Q
Heterozygous (33)
E148Q (11)
K695R (5)
M694V (4)
A744S (3)
V726A (2)
P369S
V487M
R408Q
M680I
R717L
Individuals from 2 different families.
dicted independently the probability of
positive genetic test results. The diagnostic score was calculated by using
the linear combination of these variables weighted according to the coefﬁcients (logarithm of the odds ratios)
estimated with the logistic model and
was validated with an independent
data set (see www.printo.it/periodicfever). According to the diagnostic
score, a probability of ⬎15% identiﬁes
patients at high risk of carrying relevant mutations in the 3 genes.10 In this
study, the accuracy of the Gaslini diagnostic score in identifying patients at
high risk of carrying relevant mutations in any of the 3 genes was calculated for all patients with PFAPA
syndrome-like ﬁndings who were not
involved in the deﬁnition of the score.10
Differences in frequencies of symptoms were evaluated by using the ␹2
test, and differences between average
values of continuous variables were
evaluated by using the Mann-Whitney U
test. Logistic regression was used for
multivariate analysis, with positive genetic test results as the dependent
variable.
RESULTS
Differences in Clinical
Presentation Between Genetically
Positive and Genetically Negative
Patients Fulﬁlling PFAPA Syndrome
Criteria
Among the 369 Italian patients who
were screened for all 3 genes, 199 satisﬁed the PFAPA syndrome criteria (Fig
1); 130 of those patients tested negative for all 3 genes (group A; genetically
negative patients with PFAPA
syndrome-like ﬁndings), 32 (22 with
MKD, 3 with TRAPS, and 7 with FMF)
were affected by 1 of the inherited periodic fever syndromes (group B; genetically positive patients with PFAPA
syndrome-like ﬁndings), and 37 carried low-penetrance or incomplete
genotypes (group C; genetically undetermined patients with PFAPA syndromelike ﬁndings) (Table 1). Among the 24
patients who were evaluated at other
European centers, 11 patients with
MKD exhibited a PFAPA syndrome phenotype and were included in group B.
The prevalence of the main clinical
variables among the 210 patients who
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e723
TABLE 2 Prevalence of Main Clinical Manifestations During Fever Episodes for Patients With PFAPA Syndrome-like Phenotype, According to Genotype
Diagnosis
Group A
No. of patients
Positive family history, %
Periodicity, %
Oral aphthosis, %
Erythematous pharyngitis, %
Exudative pharyngitis, %
Enlargement of cervical lymph nodes, %
Pain in cervical lymph nodes, %
Rash, %
Genital aphthosis, %
Conjunctivitis, %
Periorbital edema, %
Thoracic pain, %
Pleurisy, %
Pericarditis, %
Abdominal pain, %
Diarrhea, %
Vomiting, %
Splenomegaly, %
Arthritis, %
Arthralgia, %
Myalgia, %
Headache, %
Age at onset, mean ⫾ SD, mo
Fever duration, mean ⫾ SD, d
MKD
Severe
TRAPS
FMF
Mild TRAPS
Heterozygous
MEFV
130
13.8
59.4
58.5
83.8
66.9
83.8
49.2
22.3
3.1
20.0
7.7
4.6
0
0
53.1
29.2
30.8
12.3
6.9
43.8
34.6
40.8
18.69 ⫾ 15.1
4.5 ⫾ 2.9
33
9.1
60.6
48.5
69.7
39.4
97.0
81.8
57.6
3.0
21.2
9.1
6.1
0
3.0
100
81.8
75.8
40.6
15.2
72.7
45.5
63.6
11.42 ⫾ 7.0
4.3 ⫾ 1.1
3
100
33.3
33.3
66.7
33.3
66.7
0
66.7
0
0
33.3
0
0
0
100
66.7
66.7
0
0
66.7
66.7
33.3
12.67 ⫾ 11.0
12.6 ⫾ 6.8
7
14.3
57.1
57.1
71.4
57.1
85.7
42.9
0
0
28.6
0
14.3
0
0
100
42.9
14.3
14.3
0
71.4
42.9
57.1
24.8 ⫾ 11.7
3.7 ⫾ 2.4
7
14.3
85.7
71.4
100
71.4
100
71.4
42.9
0
28.6
14.3
0
0
0
71.4
42.9
42.9
27.1
0
28.6
42.9
57.1
34.57 ⫾ 18.7
5.2 ⫾ 4.4
30
20.0
71.4
46.7
73.3
70.0
83.3
53.3
33.3
0
13.3
10.0
6.7
3.3
6.7
56.7
33.3
30.0
16.7
3.3
43.3
26.7
53.3
20.27 ⫾ 17.1
6.6 ⫾ 9.9
Approximately 14% of patients with
PFAPA syndrome had a positive family
history, a proportion similar to those
observed for MKD and FMF, which are
autosomal recessive disorders. Although no genetic basis for PFAPA syndrome has been discovered to date, it
may well be that the syndrome does not
represent a homogenous entity and may
include some yet-uncharacterized genetic disease.
Episodes recurring with clockwork
regularity were present for almost
60% of genetically negative patients
with PFAPA syndrome-like ﬁndings, a
proportion similar to that observed for
patients with MKD and for the few patients with genetically proven FMF who
fulﬁlled the PFAPA syndrome criteria
(Table 2). Therefore, clockwork periodicity does not seem to represent a distinguishing feature of PFAPA synGATTORNO et al
Group C
Genetically
Negative
fulﬁlled the PFAPA syndrome criteria is
shown in Table 2, according to the different disease groups.
e724
Group B
drome. Moreover, among genetically
negative patients with PFAPA syndrome, no evident clinical differences
were found between patients who exhibited periodicity of febrile episodes
and those who exhibited a moreirregular disease course (multivariate
analysis; data not shown).
Cardinal features of the PFAPA syndrome, such as oral aphthosis and enlargement of cervical lymph nodes,
were observed with similar frequencies in PFAPA syndrome-positive MKD
and FMF. Moreover, no meaningful differences in fever duration were observed between genetically negative
and genetically positive patients. Disease onset was observed earlier for
genetically positive patients with
PFAPA syndrome-like ﬁndings (mean:
13.7 months; range: 1–36 months),
compared with genetically negative
patients with PFAPA syndrome-like
ﬁndings (mean: 18.1 months; range:
1– 60 months) and genetically undeter-
mined patients with PFAPA syndromelike ﬁndings (mean: 22.9 months;
range: 1– 60 months; P ⫽ .02, analysis
of variance).
Clinical symptoms were compared by
taking into account not only their presence or absence but also their frequency (never, sometimes, often, or always). Heterogeneity among the 3
subgroups was observed for a limited
number of clinical variables. Genetically positive patients with PFAPA
syndrome-like ﬁndings had higher frequencies of abdominal pain and diarrhea (P ⬍ .001), vomiting (P ⫽ .006),
and cutaneous rash and arthralgia
(P ⫽ .01) (Fig 2). Genetically negative
patients with PFAPA syndrome-like
ﬁndings had a higher frequency of exudative pharyngitis, compared with
genetically positive patients (P ⫽
.010). Patients belonging to group C
showed the same pattern as observed
for genetically negative patients with
PFAPA syndrome-like ﬁndings (Fig 2).
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ARTICLES
% of patients
A
70
B 80
60
70
60
50
50
40
40
30
30
20
20
10
10
0
Never
Sometime
Often
Always
0
D 100
70
60
80
50
60
40
30
40
20
10
20
% of patients
C 80
0
E
Never
Sometime
Often
Often
Always
Never
Sometime
Often
Always
Never
Sometime
60
50
50
40
40
30
30
20
20
10
10
0
Sometime
F 70
70
60
% of patients
0
Always
Never
0
Never
Sometime
Often
Always
Often
Always
Genetically negative PFAPA-like patients (group A)
Genetically positive PFAPA-like patients (group B)
Genetically undetermined PFAPA-like patients (group C)
FIGURE 2
Frequencies of clinical manifestations in the 3 subgroups of patients. P values refer to the ␹2 heterogeneity test. A, abdominal pain (p ⬍ .001); B, diarrhea
(p ⬍ .001); C, vomiting (p ⫽ .006); D, rash (p ⫽ .01); E, arthralgia (p ⫽ .01); F, exudative pharyngitis (p ⫽ .01).
Accuracy of the Gaslini Diagnostic
Score for Patients With PFAPA
Syndrome Phenotype
As stated above, the Gaslini diagnostic
score was recently formulated on the basis of statistical analysis of the clinical
features of children with periodic fever.10
The aim of this part of the study was to test,
with an independent set of patients fulﬁlling the PFAPA syndrome criteria, the ability
of the score to classify genetically positive
and negative patients correctly.
The accuracy of the Gaslini diagnostic score10 was calculated for 95 conPEDIATRICS Volume 124, Number 4, October 2009
secutive patients who satisﬁed the
PFAPA syndrome criteria and were
not involved in the original deﬁnition
of the score (Fig 1); 65 patients belonged to group A, 22 patients belonged to group B (18 with MKD and 4
with FMF), and 8 belonged to group C
(2 with R92Q in TNFRSF1A and 6 heterozygous for MEFV). The diagnostic
score correctly identiﬁed 20 of 22 genetically positive patients with PFAPA
syndrome-like ﬁndings (sensitivity:
91%), whereas the speciﬁcity was
59%. Therefore, the global accuracy
of the Gaslini diagnostic score was
66% (Table 3).
DISCUSSION
This case-control study compared the
clinical features of genetically positive
and genetically negative patients fulﬁlling the clinical criteria for the PFAPA
syndrome, and we provided evidence
of high sensitivity of the Gaslini diagnostic score for the identiﬁcation of
patients with a PFAPA syndrome-like
phenotype with a high probability of
carrying relevant mutations in genes
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e725
TABLE 3 Performance of Gaslini Diagnostic Score for Patients With PFAPA Syndrome-like Findings
Diagnostic
Score
Low risk
High risk
Total
n (%)
Genetically
Negative
(Group A)
Genetically
Positive
(Group B)
Genetically
Undetermined
(Group C)
Total
38 (58.50)
27 (41.50)
65 (100)
2 (9.10)
20 (90.90)
22 (100)
5 (62.50)
3 (37.50)
8 (100)
45 (47.40)
50 (52.60)
95 (100)
associated with monogenic periodic
diseases. In 1987, Marshall et al1 ﬁrst
described a group of 12 children who
experienced periodic febrile episodes
typically associated with some cardinal symptoms (erythematous or exudative pharyngitis, oral aphthosis, and
cervical lymph node enlargement), in
the absence of signs of infection, immunodeﬁciency, or other immunemediated or neoplastic disorders. Elevations of acute-phase reactant levels
and white blood cell counts, with
complete normalization during the
symptom-free intervals, are characteristic. Febrile episodes generally are
responsive to oral steroid treatment.
Complete well-being in the intercritical
periods, with normal growth and development, also is typical.2,3,14,15 In
1989, the diagnostic criteria were
proposed.4
After the ﬁrst description, a number of
subsequent articles were devoted to
the analysis of different aspects of this
syndrome, including the incidence of
other clinical manifestations associated with febrile episodes, follow-up
ﬁndings, and responses to treatment
and/or tonsillectomy.16–18 The incidence of the clinical manifestations
possibly associated with the classic
triad during febrile episodes varied
widely in the different studies available to date, as summarized in Table
4.1–3,15 Neither the original4 and revised2 diagnostic criteria nor the
aforementioned studies took into account the possible clinical overlap between PFAPA syndrome and monogenic autoinﬂammatory syndromes
e726
GATTORNO et al
characterized by periodic fever (FMF,
MKD, and TRAPS).
The identiﬁcation of the molecular defects associated with monogenic periodic fevers from 1997 onward19–23 and
the widening of molecular analyses for
patients with periodic fever indicated
that these diseases are more frequent
than expected and can be observed in
populations not originally associated
with these disorders.8,10,24–30 Indeed, in
Western countries, the rates of detection of mutations in any of the aforementioned disease genes among patients with recurrent fever range from
10% to 20%.31–33
In our study, 52% of children (43 of 82
children) with recurrent fever attributable to monogenic autoinﬂammatory
diseases exhibited positive results for
PFAPA syndrome criteria. The proportion was greater for MKD (33 of 40 children) than for FMF (7 of 30 children) or
TRAPS (3 of 12 children). Therefore, because PFAPA syndrome is far more
prevalent than the aforementioned inherited periodic fevers, it is crucial to
identify, among patients with a PFAPA
syndrome phenotype, those with
higher probabilities of carrying mutations in genes associated with periodic
fever. The latter diseases often require
a different therapeutic approach and
are characterized by more-severe
long-term prognoses, compared with
PFAPA syndrome.34
Our ﬁndings show that PFAPA syndrome criteria alone are not able to
distinguish genetically positive from
genetically negative patients. To avoid
unnecessary genetic testing, it could
be useful to have additional clinical parameters that could predict positive
results. Therefore, we studied a large
population of patients who met the diagnostic criteria for PFAPA syndrome
and were fully characterized from the
molecular point of view, comparing for
the ﬁrst time the clinical ﬁndings for
patients with negative genetic testing
results and patients affected by a genetic autoinﬂammatory disease.
We found that some of the features
that are considered characteristic of
PFAPA syndrome, such as clockwork-
TABLE 4 Distribution of Clinical Manifestations Associated With Fever Episodes in Different Cohorts
of Patients With PFAPA
Symptoms
Proportion, %
1
Fever
Pharyngitis
Cervical adenopathy
Aphthous stomatitis
Malaise
Headache
Abdominal pain
Diarrhea
Arthralgia
Chills
Rhinorrhea
Cough
Rash
Marshall et al
(N ⫽ 12)
Thomas et al2
(N ⫽ 66)
Padeh et al3
(N ⫽ 28)
Tasher et al15
(N ⫽ 54)
100
75
67
75
100
NA
NA
NA
NA
NA
NA
NA
NA
100
65
77
67
NA
65
45
30
NA
80
18
20
15
100
100
100
68
100
18
18
NA
11
NA
NA
NA
NA
NA
96
61
39
NA
46
65
13
NA
61
33
28
4
NA indicates not available.
Downloaded from pediatrics.aappublications.org by guest on August 22, 2014
ARTICLES
like recurrence of febrile episodes,
oral aphthosis, and enlargement of
cervical lymph nodes, are present with
similar frequencies in MKD and also
may be present in some genetically
proven pediatric FMF cases. Our descriptive analysis showed that, although the presence alone of some
clinical manifestations is not able to
distinguish clearly the genetically positive and genetically negative patients
with PFAPA syndrome, evaluation of
their frequencies in all fever episodes
can be much more informative (Fig 2).
On the basis of these considerations,
we tested the accuracy of the Gaslini
score for identiﬁcation of patients with
PFAPA syndrome with a higher probability of carrying relevant mutations in
genes associated with periodic fevers.
Because the score was developed to
discriminate genetically positive and
genetically negative patients in a large
population of children presenting with
periodic fever,10 we analyzed its discriminative ability with a subset of pa-
tients fulﬁlling the PFAPA syndrome
criteria who were not involved in its
original deﬁnition.10 Our results
showed that the Gaslini score was able
to perform very well in distinguishing
genetically negative from genetically
positive patients with PFAPA syndrome; it identiﬁed correctly 20 of 22
genetically positive patients with
PFAPA syndrome-like ﬁndings.
CONCLUSIONS
We propose the use of the Gaslini diagnostic score for all patients with a
PFAPA syndrome phenotype. Patients
with low risk of carrying relevant mutations may be diagnosed as having
PFAPA syndrome without the need for
formal exclusion of inherited periodic
fever through molecular analysis or
other clinical or laboratory investigations. Conversely, patients with high
risk should be screened for the mostprobable gene according to their clinical phenotype (ie, positive FMF criteria for patients of Jewish, Arabic,
Turkish, or Armenian ethnicity) and/or
ancillary laboratory examinations (ie,
determination of urinary mevalonic
acid levels during fever episodes) and
should be classiﬁed as having PFAPA
syndrome only in the case of negative
genetic testing results. Further validation of the diagnostic score in children
with a PFAPA syndrome phenotype in
different populations is warranted, to
establish its accuracy in different ethnic groups.
ACKNOWLEDGMENTS
This work was supported in part by
Ricerca Corrente Ministeriale Telethon
(project GGP07236), EUROTRAPS (grant
agreement Health-F2-2008-200023),
and Fondazione C. Golgi (Brescia, Italy).
We thank Drs M. Cecconi and F. Caroli
for molecular screening, Prof Isabelle
Konè-Paut and Prof Patricia Woo for
sharing information on some PFAPA
syndrome-negative patients with FMF
and TRAPS, and Dr Michael Hofer for
critical reading of the manuscript.
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Differentiating PFAPA Syndrome From Monogenic Periodic Fevers
Marco Gattorno, Roberta Caorsi, Antonella Meini, Marco Cattalini, Silvia Federici,
Francesco Zulian, Elisabetta Cortis, Giuseppina Calcagno, Alberto Tommasini, Rita
Consolini, Gabriele Simonini, Maria Antonietta Pelagatti, Maurizia Baldi, Isabella
Ceccherini, Alessandro Plebani, Joost Frenkel, Maria Pia Sormani and Alberto Martini
Pediatrics 2009;124;e721; originally published online September 28, 2009;
DOI: 10.1542/peds.2009-0088
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