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Letters to the Editor
Association between neonatal hyperbilirubinemia and
UDP-glucuronosyltransferase 1A1 gene polymorphisms
Michael Kaplan1and Cathy Hammerman2
1Department of Neonatology, Shaare Zedek Medical Center and 2Faculty of Medicine, Hebrew University, Jerusalem, Israel
We read the meta-analysis by Long et al. in which the
association between neonatal hyperbilirubinemia and UDP-
glucuronosyltransferase (UGT) 1A1 gene polymorphisms was
analyzed, with great interest.1We were particularly surprised by
the authors’ conclusion that UGT1A1 TATA promoter polymor-
phisms were not associated with an increased risk of neonatal
hyperbilirubinemia in Asian subjects and that results from Cau-
casian populations were conflicting. Our surprise emanates from
the non-inclusion in the meta-analysis of a study in which
the interaction between glucose-6-phosphate dehydrogenase
(G-6-PD) deficiency and UGT1A1 (TA)6/(TA)7heterozygosity or
(TA)7/(TA)7homozygosity led to a dramatic and significant
increase in the incidence of neonatal hyperbilirubinemia.2
In that study, hyperbilirubinemia was defined as serum total
bilirubin (STB) ⱖ15.0 mg/dL (257 mmol/L) during the first week
of life. DNA from term neonates born to Sephardic Jewish
mothers was analyzed for the UGT1A1 TATA promoter polymor-
phism and for the G-6-PD Mediterranean mutation. The variant
(TA)7promoter allele frequency was similar among G-6-PD-
deficient (n=131) and normal neonates (n=240). Overall, 30
G-6-PD-deficient neonates (22.9%) developed hyperbilirubine-
mia versus 22 normal neonates (9.2%; P=0.0005). Among those
normal for G-6-PD, the UGT1A1 polymorphism had no signifi-
cant effect on the incidence of hyperbilirubinemia (normal
homozygotes, 9.9%; heterozygotes, 6.7%; variant homozygotes,
14.7%, NS). Furthermore, of those with the normal homozygous
UGT1A1 promoter genotype ((TA)6/(TA)6), the incidence of
hyperbilirubinemia was similar in G-6-PD-deficient neonates and
controls (9.7% and 9.9%). Among the G-6-PD-deficient infants,
however, between UGT1A1 promoter subgroups, the incidence of
hyperbilirubinemia increased in a stepwise fashion and was
greater in those with the heterozygous (31.6%; P=0.006) or
variant homozygous (50%; P=0.003) UGT1A1 promoter geno-
type compared with normal homozygotes. Furthermore, among
the G-6-PD-deficient neonates, within UGT1A1 promoter sub-
groups, those with the heterozygous or homozygous variant
UGT1A1 promoter genotype had a higher incidence of hyperbi-
lirubinemia than corresponding G-6-PD normal controls (hetero-
zygotes: 31.6% vs. 6.7%, P<0.0001; variant homozygotes: 50%
vs. 14.7%, P=0.02). Thus, neither G-6-PD deficiency alone nor
the variant UGT1A1 gene promoter alone, increased the inci-
dence of hyperbilirubinemia, but both in combination did.
We would like to bring this gene interaction, which may serve
as a paradigm of interaction of benign genetic polymorphisms in
the causation of disease, to the attention of readers who may have
received the wrong impression of the role of (TA)npromoter
polymorphism in the pathogenesis of neonatal hyperbilirubine-
mia from the meta-anaylsis.
References
1 Long J, Zhang S, Fang X, Luo Y, Liu J. Association
of neonatal hyperbilirubinemia with uridine diphosphate-
glucuronosyltransferase 1A1 gene polymorphisms: Meta-analysis.
Pediatr. Int. 2011; 53: 530–40.
2 Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A,
Beutler E. Gilbert syndrome and glucose-6-phosphate dehydroge-
nase deficiency: A dose-dependent genetic interaction crucial to
neonatal hyperbilirubinemia. Proc. Natl Acad. Sci. USA 1997; 94:
12128–32.
Severe post-streptococcal acute glomerulonephritis and periodic
fever, aphthous stomatitis, pharyngitis, and cervical
adenitis syndrome
Nao Chiba,1Shojiro Watanabe,1Tomomi Aizawa-Yashiro,1Kazushi Tsuruga,1Etsuro Ito,1Takashi Oda,3Kensuke Joh4and
Hiroshi Tanaka1,2
1Department of Pediatrics, Hirosaki University Hospital, 2Department of School Health Science, Faculty of Education,
Hirosaki University, Hirosaki, 3Department of Nephrology, National Defense Medical College, Tokorozawa, and 4Division of
Pathology, Sendai Shakaihoken Hospital, Sendai, Japan
Correspondence: Michael Kaplan, MB ChB, Department of Neonatol-
ogy, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031,
Israel. Email: kaplan@cc.huji.ac.il
Received 12 July 2012; accepted 18 December 2012.
doi: 10.1111/ped.12065
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Pediatrics International (2013) 55, 259–261
© 2013 The Authors
Pediatrics International © 2013 Japan Pediatric Society
Periodic fever, aphthous stomatitis, pharyngitis, and cervical
adenitis (PFAPA) syndrome is the most common periodic fever
disease in children.1,2 Although its cause remains to be elucidated,
non-genetic cyclic dysregulation of proinflammatory cytokine
secretion may be responsible,3and the long-term outcomes are
reported to be usually favorable.2However, thus far, there have
been few clinical reports about PFAPA syndrome complicated
with glomerular diseases.4,5 On the contrary, there has been no
report about how the presence of periodic fever episode influ-
ences the severity of glomerular diseases in children with PFAPA
syndrome. Recently, we experienced the case of a 7-year-old
Japanese boy with PFAPA syndrome who developed a severe
form of post-streptococcal acute glomerulonephritis (PSAGN).
When PSAGN occurred, he developed a periodic fever episode.
The severity of PSAGN may be modified, in part, by the sup-
posed proinflammatory hypercytokinemia during the periodic
fever episode.
The patient had a 6-year history of PFAPA syndrome and was
referred to our hospital because of macrohematuria, hyperten-
sion, oliguria, edema, and fever. Two weeks before presentation,
he experienced acute pharyngitis due to culture-proven group A
b-hemolytic streptococcal throat infection. On this occasion, he
visited a nocturnal emergency clinic and was given a single dose
of cefcapene pivoxil hydrochloride hydrate and acetamino-
phen for acute pharyngitis. On admission, the laboratory study
revealed a significant decrease in serum C3 level (15 mg/dl;
normal 65–135 mg/dl) and a significant elevation of serum
C-reactive protein (CRP) (4.3 mg/dl, normal <0.3 mg/dl),
without serum autoantibodies. Within 2 days, the fever disap-
peared and serum CRP decreased spontaneously. However, he
thereafter developed a rapid deterioration of renal function
(blood urea nitrogen [BUN], 84 mg/dl; serum creatinine,
2.93 mg/dl; serum cystatin C, 2.9 mg/l [normal <0.9 mg/l]),
which required the initiation of emergency hemodialysis (HD).
Ten days after the start of HD, his urine output gradually
increased as his general condition improved, and HD was dis-
continued after 14 days of therapy. Percutaneous renal biopsy
performed at day 16 of hospitalization revealed a typical picture
of endocapillary proliferative glomerulonephritis with tubu-
lointerstitial edema and mononuclear cell infiltration (Fig. 1).
Electron-microscopic analysis showed neutrophil infiltration and
massive hump formation. The positive result of glomerular
nephritis-associated plasmin receptor staining confirmed that the
patient had PSAGN.6Hypocomplementemia and renal function
recovered at day 30 of hospitalization (serum C3, 114 mg/dl;
BUN, 10 mg/dl; serum creatinine, 0.43 mg/dl). Although he
experienced a 2-day-long, self-limiting febrile attack associated
with transient gross hematuria at day 38 of hospitalization, his
renal function was preserved. At 20 months after our first obser-
vation, he was free from renal diseases except for occasional
febrile attacks.
Recently, Sugimoto et al.5reported the case of a 10-year-old
boy with PFAPA and immunoglobulin A nephropathy (IgAN),
and concluded that the concurrence of PFAPA and IgAN may be
a consequence of shared autoimmune mechanisms and systemic
and local increases in cytokine concentrations. To the best of our
knowledge, there are only two case reports describing PFAPA
syndrome complicated with biopsy-proven glomerular dis-
eases,4,5 suggesting that even though systemic proinflammatory
hypercytokinemia exists, the development of glomerular disease
is rarely seen in patients with PFAPA syndrome. Nevertheless,
PFAPA syndrome is reportedly the most common periodic fever
disease in children.1,2 Therefore, in the future, physicians may
encounter cases of occurrence of some glomerular diseases in
patients with pre-existing PFAPA syndrome. Indeed, we believe
that the occurrence of PSAGN in this patient was incidental
rather than a consequence of shared autoimmune mechanisms
between PSAGN and PFAPA syndrome. In addition, PFAPA can
be treated with oral steroids, which supports the theory that the
PSAGN was more severe due to the pro-inflammatory milieu
existing as a result of the PFAPA. Our patient developed a clini-
cally severe form of PSAGN in concurrence with a febrile attack.
Although PSAGN is one of the most common glomerulonephri-
tis diseases in children and its severity varies, severe acute renal
failure requiring emergency HD is relatively rare. As repeat
administration of cefcapene pivoxil hydrochloride hydrate and
acetaminophen did not worsen his clinical course, we think
superimposition of possible drug-induced tubulointerstitial
nephritis on PSAGN was unsuitable for this patient. Therefore,
we believe that due to the cyclic febrile attack of a pre-existing
PFAPA, some inflammatory conditions might modify PSAGN
lesions, such as unusual tubulointerstitial changes, thus resulting
in a clinically severe form of PSAGN; however, this remains
speculative.
Acknowledgment
No potential conflicts of interest were disclosed.
Correspondence: Hiroshi Tanaka, MD PhD, Department of Pediatrics,
Hirosaki University Hospital, Hirosaki 036-8563, Japan. Email:
hirotana@cc.hirosaki-u.ac.jp
Received 18 December 2012; revised 10 January 2013; accepted 18
February 2013.
doi: 10.1111/ped.12077
Fig. 1 Light microscopy shows endocapillary proliferative lesion
associated with tubulointerstitial edema and mononuclear cells infil-
tration (hematoxylin–eosin staining, ¥200).
260 Letters to the Editor
© 2013 The Authors
Pediatrics International © 2013 Japan Pediatric Society
References
1 Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA
(a periodic fever syndrome). Acta Paediatr. 2010; 99: 178–84.
2 Wurster VM, Carlucci JG, Feder HM, Edwards KM. Long-term
follow-up of children with periodic fever, aphthous stomoatitis,
pharyngitis, and cervical adenitis syndrome. J. Pediatr. 2011; 159:
958–64.
3 Stojanav S, Lapidus S, Chitkara P et al. Periodic fever, aphthous
stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate
immunity and Th1 activation responsive to IL-1 blockade. Proc.
Natl Acad. Sci. U.S.A. 2011; 108: 148–53.
4 Cazzato M, Neri R, Possemato N, Puccini R, Bombardieri S. A case
of adult periodic fever, aphthous stomatitis, pharyngitis, and cervical
adenitis (PFAPA) syndrome associated with endocapillary proli-
ferative glomerulonephritis. Clin. Rheumatol. doi 10.1007/s10067-
010-1420-8.
5 Sugimoto K, Fujita S, Miyazawa T, Okada M, Takemura T. Periodic
fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syn-
drome and IgA nephropathy. Pediatr. Nephrol. 2013; 28: 151–4.
6 Oda T, Yamakami K, Fujimoto O et al. Glomerular plasmin-like
activity in relation to nephritis-associated plasmin receptor in acute
poststreptococcal glomerulonephritis. J. Am. Soc. Nephrol. 2005;
16: 247–54.
Letters to the Editor 261
© 2013 The Authors
Pediatrics International © 2013 Japan Pediatric Society
