Congenital nephrotic syndrome (CNS) is defined as nephrot-
ic syndrome which manifests in utero or during the first 3
months of life (1). Although CNS may develop secondary to
underlying diseases such as various kinds of congenital infec-
tions, most of CNS is primary lesion of genetic origin. Recent
genetic studies disclosed four major causative genes impli-
catingCNS; the NPHS1gene encoding nephrin, the NPHS2
gene encoding podocin, the WT1 gene encoding the nucle-
ar transcriptional factor Wilms tumor suppressor gene 1, and
the LAMB2 gene encoding laminin β 2 chain (2).
CNS of Finnish type (CNF, OMIM #602716) is an auto-
somal recessive disease due to NPHS1 mutations. CNF is the
most common CNS in Finland with the incidence of 1 per
10,000 births. However, patients with CNF have also been
reported worldwide. Most of the patients develop nephrotic
syndrome at birth or soon after birth, which progresses rapid-
ly to end-stage renal disease. Kidney transplantation is the
only curative treatment modality currently (3-5).
In Korea, only few cases with rather typical clinicopatho-
logic findings of CNF have been reported (6, 7). However,
genetic study was done in none of those cases. Here we report
the two infants with CNF which was confirmed by molecu-
lar genetic study for the first time in our country.
A 2 months old male infant was admitted to a local hos-
pital due to generalized edema. On prenatal examination,
high α -fetoprotein (AFP) level (20.85 MoM) in the mater-
nal serum was detected at the 18th gestational week. The
baby was born at 36 weeks of gestational age with a birth
weight of 2.57 kg. The weight of placenta was reported to
be normal. Apgar scores at 1 and 5 min were 9 and 10 points,
respectively. However, he showed shortness of breath and
abdominal distension soon after the birth. He has normal
male external genitalia. Laboratory tests revealed markedly
hypoalbuminemia (serum albumin 1.2 g/dL), massive pro-
teinuria (urinary protein excretion 7,959 mg/m2/day), and
hypothyroidism. There was no evidence of congenital infec-
Beom Hee Lee*, Yo Han Ahn*,
Hyun Jin Choi*, Hee Kyung Kang*,
Kyung Chul Moon
Hae Il Cheong*
�, Byoung-Soo Cho
� ,�, Il Soo Ha*
,�, and Yong Choi*
Department of Pediatrics*, Seoul National University
Children’s Hospital, Seoul; East West Kidney Diseases
Research Institute, Department of Pediatrics
Kyung-Hee University Hospital, Seoul; Department of
Kidney Research Institute, Medical Research Center
Seoul National University College of Medicine, Seoul,
�, Seoul National University Hospital, Seoul;
Address for correspondence
Hae Il Cheong, M.D.
Department of Pediatrics, Seoul National University
Children’s Hospital, 28 Yeongeon-dong, Jongno-gu,
Seoul 110-744, Korea
Tel : +82.2-2072-2810, Fax : +82.2-743-3455
E-mail : email@example.com
*This study was supported by a grant (06-2008-192-9)
from Seoul National University Hospital.
J Korean Med Sci 2009; 24 (Suppl 1): S210-4
Copyright � The Korean Academy
of Medical Sciences
Two Korean Infants with Genetically Confirmed Congenital Nephrotic
Syndrome of Finnish Type
Congenital nephrotic syndrome is defined as nephrotic syndrome which manifests
in utero or during the first 3 months of life. The prototype of congenital nephrotic
syndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716),
which is caused by loss-of-function mutations of the nephrin gene (NPHS1). There
have been few clinical case reports of CNF in Korea, but none of which was con-
firmed by genetic study. Here, we report two children with congenital nephrotic syn-
drome. Genetic analysis of the NPHS1 gene revealed compound heterozygous
frame-shifting mutations (c.2156_2163 delTGCACTGC causing p.L719DfsX4 and
c.3250_3251insG causing p.V1084GfsX12) in one patient and a missense muta-
tion (c.1381G>A causing p.R460Q) and a nonsense mutation (c.2442C>G caus-
ing p.Y814X) in the other patient. The nonsense mutation was novel. The clinical
courses of the patients were typical of CNF. This is the first report of genetically
confirmed CNF in Korea to date. The early genetic diagnosis of CNF is important
for proper clinical management of the patients and precise genetic counseling of
Key Words : Congenital Nephrotic Syndrome; Congenital Nephrotic Syndrome of Finnish Type; NPHS1
Gene; Nephrin; Mutation
Received : 27 May 2008
Accepted : 29 July 2008
Infants with Congenital Nephrotic Syndrome of Finnish TypeS211
tion. The parents and his older brother are all healthy except
that his mother is a hepatitis B virus antigen carrier. Capto-
pril (0.1 mg/kg/day) and synthyroid (2.7 μ g/kg/day) were
started as well as intermittent albumin infusions. However,
generalized edema was aggravated with frequent need of
albumin infusion. At 2 months of age, he was transferred to
Seoul National University Children’s Hospital because of
intractable generalized edema and respiratory difficulty. On
admission, his body weight was 4.49 kg (3-10 percentile),
and height was 52 cm (<3 percentile). He showed mild chest
retraction, and breathing sound was coarse with crackles on
both lung fields. The serum albumin was 1.6 g/dL, serum
creatinine was 0.3 mg/dL, random urine protein/creatinine
ratio was 110 mg/mg, platelet count was 888×103/μ L, and
serum immunoglobulin G level was 64 mg/dL (normal range,
176-201 mg/dL). The nasopharyngeal aspirate was positive
for human respiratory syncytial virus A. Thus, in addition
to supportive lung care, intravenous immune globulin (0.5
g/kg) was given. He was medicated with indomethacin (4
mg/kg/day), captopril (4.7 mg/kg/day), dipyridamole (3 mg/
kg/day), warfarin, and synthyroid as well as high protein (up
to 4 mg/kg/day) and high calorie diet (120 Cal/kg/day). How-
ever, frequent albumin infusion (2 g/kg/day) had to be con-
tinued to control respiratory problem and generalized edema,
Fig. 1. Renal biopsy findings of both patients (A, Case 1; B, Case 2). The glomeruli showed mesangial hypercellularity in both cases, and
diffuse increase of mesangial matrix was noted in Case 2. Tubules revealed focal mild atrophy or loss with focal moderate infiltration of
mononuclear cells and mild fibrosis in interstitium in both patients (PAS staining. Magnification: ×400).
Fig. 2. Electron microscopic findings of the glomerulus in both cases (A, Case 1; B, Case 2). While the glomerular basement membrane
(GBM) measured normal in average thickness with relatively smooth inner and outer contours in Case 1, diffuse thinning of GBM (100 μ m)
was noted in Case 2. No electron-dense deposits were found. Epithelial foot processes exhibited wide effacement (Magnification: ×7,000
[A], ×10,000 [B]).
S212 B.H. Lee, Y.H. Ahn, H.J. Choi, et al.
and a Chemoport�was implanted into right atrium via right
external jugular vein to secure a central venous line. An open
renal biopsy was performed at 4 months of age, which showed
diffuse mesangial proliferation (Fig. 1A, 2A). Genetic anal-
ysis of the NPHS1 gene revealed compound heterozygous
frame-shifting mutations, 8-bp deletion in exon 16 (c.2156_
2163 delTGCACTGC causing p.L719DfsX4), and 1-bp
insertion in exon 24 (c.3250_3251insG causing p.V1084-
GfsX12) (Fig. 3A, B). The former mutation was inherited
from mother, and the latter from father. During follow-up,
he was admitted 2 more times due to central line infections.
Thus, at 8 months of age, Chemoport�removal and unilat-
eral nephrectomy were done to control the recurrent infec-
tions and to reduce the degree of proteinuria and the need
of albumin infusions, respectively.
A female newborn baby was admitted to neonatal inten-
sive care unit of Kyung Hee University Medical Center due
to respiratory difficulty, which was detected at birth. She
was born at 38 weeks of gestational age, and the birth weight
was 2,920 gm. Apgar scores at 1 and 5 min were 7 and 9
points, respectively. There was no abnormality on routine
prenatal examinations. She is the first baby of healthy par-
ents. On physical examination, she showed tachypnea and
generalized edema. The serum albumin was 1.5 g/dL, serum
creatinine was 0.3 mg/dL, random urine protein/creatinine
ratio was 64.4 mg/mg, platelet count was 377×103/μ L, and
serum immunoglobulin G level was 146 mg/dL. She has
normal female external genitalia. Captopril (1.5 mg/kg/day),
dipyridamole and synthyroid were started as well as daily
intravenous albumin infusions (1 g/kg/day). A kidney biop-
sy, which was done at 1 month of age, revealed diffuse mesan-
gial proliferation (Fig. 1B, 2B). Genetic analysis of the NPHS1
gene revealed compound heterozygote mutations, a missense
mutation in exon 11 (c.1381G>A causing p.R460Q) inherit-
ed from mother and a nonsense mutation in exon 18 (c.2442C>
G causing p.Y814X) inherited from father (Fig. 3C, D). At
1.5 months of age, she was discharged, and her family emi-
grated to Japan.
The cardinal clinical manifestation of nephrotic syndrome
is massive proteinuria due to impairments of the glomerular
filtration barrier, which is composed of 3 layers: the fenestrat-
ed endothelium, the glomerular basement membrane, and
the podocyte foot processes with bridging slit diaphragms.
Recent molecular genetic studies have identified several genes
involved in the pathogenesis of hereditary nephrotic syn-
dromes, and most of these genes encode proteins of the glo-
merular podocyte or the glomerular basement membrane or
nuclear transcription factors expressed in the podocytes (NP-
HS1, NPHS2, CD2AP, ACTN4, TRPC6, PLCE1, LAMB2,
The onset of nephrotic syndromes associated with genetic
Fig. 3. Results of the NPHS1 gene analysis of both patients. Case 1 has two frame-shifting deletions, c.2155_2162 delCTGCACTG in exon
16 (A) and c.3250_3251insG in exon 24 (B). The former was inherited from mother, and the latter from father (data not shown). Case 2 has
c.1381G>A mutation in exon 11 in one allele (C) and c.2242C>G in exon 18 in the other allele (D). The former was inherited from mother,
and the latter from father (data not shown).
C T A T C A G C C G C A C C G C T G A A G C T
T C G G G G G G G T C C C C C G G G A A
3′ >5′ complementary sequences
C A G C C T C A C C T G G G T C C C A G C
T G G C G C T T A C C A G T G C A T T G
Infants with Congenital Nephrotic Syndrome of Finnish TypeS213
defects differs from each other. The NPHS1 gene, which
encodes nephrin, a major component of the slit diaphragm,
is the first gene identified to be associated with hereditary
nephrotic syndrome, CNF (3). Mutations in NPHS1are exclu-
sively detected in patients with CNS (3). Podocin, which is
encoded by the NPHS2gene, is another essential component
of the slit diaphragm and a close interactor of nephrin. Genet-
ic defect of podocin is the cause of early-onset autosomal reces-
sive steroid-resistant nephrotic syndrome (OMIM #600995)
(8). The WT1gene functions both as a tumor suppressor and
a critical regulator of kidney and gonad development. Ger-
mline mutations in WT1 result in two clinical syndromes
with glomerular diseases, Denys-Drash syndrome (OMIM
#194080) and Frasier syndrome (OMIM #136680), as well
as isolated steroid-resistant nephrotic syndrome (9, 10). The
LAMB2 gene encodes laminin-β 2 chain, which is one of the
major components of the glomerular basement membrane.
Mutations in LAMB2 present with a spectrum of clinical
phenotypes from isolated early onset nephrotic syndrome to
the full syndromic phenotype of Pierson syndrome with CNS,
diffuse mesangial sclerosis, microcoria, and mental retarda-
tion (OMIM #609049) (11-13). Mutations in PLCE1, which
is also called as NPHS3and encodes phospholipase C epsilon,
can cause autosomal recessive early onset nephrotic syndrome
with rapid progression to end-stage renal disease (14). Muta-
tions of the ACTN4 (encoding α -actinin-4), TRPC6 (encod-
ing canonical transient receptor potential 6 ion channel) and
CD2AP(encoding CD2-associated protein) genes are primar-
ily associated with autosomal dominant focal segmental
glomerulosclerosis in adults (15-17).
A recent genetic study of a large number of European and
Turkish children with CNS disclosed that 84.8% of patients
with CNS (39 of 46 families) carried disease-causing muta-
tionsin one of the four genes; 18 (39.1%) in NPHS1, 18 (39.1
%) in NPHS2, 1 (2.2%) in WT1, and 2 (4.4%) in LAMB2
(2). In our country, the incidence of WT1 mutations in chil-
dren with steroid-resistant nephrotic syndrome is similar to
those of other countries (18), and cases with LAMB2 muta-
tions have also been reported (13). In contrast, NPHS2 muta-
tions appear to be very uncommon in Korea as same as in
other Far East Asian countries (China and Japan) (18). How-
ever, there has been no genetic study of CNS with NPHS1
mutations before this paper in Korea.
Precise diagnosis of CNF can be confirmed only by genet-
ic analysis of NPHS1. To date, about 100 different mutations
have been identified in the NPHS1 gene. Two founder muta-
tions, Finmajor (c.121delCT causing p.L41fsX90) and Finminor
(p.R1109X), account for nearly 90% all affected Finnish
patients (4, 5). On the other hand, most patients outside
Finland have individual mutations of different types (2, 4,
14, 19). Among the four mutations detected in this study,
one nonsense mutation (p.Y814X) is novel, and other three
are known mutation (3, 20).
Compared with many other genetic disorders, NPHS1
shows relatively little phenotypic variation (21). Most of the
patients with CNF are born prematurely with abnormally
enlarged placenta (the placental weight is over 25% of the
newborn weight). Proteinuria begins in utero and and full-
blown nephrotic syndrome follows soon after birth. The clini-
cal courses are commonly complicated by poor nutritional
status, growth delay, recurrent infections, thromboembolism,
and hypothyroidism, and progression to end-stage renal dis-
ease within 3-8 yr of life is inevitable (5).
Renal biopsy does not reveal the etiology of CNS, because
the pathologic findings overlap in different genetic entities.
The most characteristic renal pathologic findings of CNF
are expansion of glomerular mesangium and dilations of the
proximal and distal tubules. Effacement of podocyte foot pro-
cesses and disappearance of the filamentous image of podocyte
slit diaphragm are seen in electron microscopy, although
none of these findings are pathognomonic for CNF (5, 21).
However, immunohistochemistry for nephrin expression in
a biopsy sample is useful.
Steroids or other immunosuppressive drugs are not effective
at all in all forms of hereditary proteinuric diseases including
CNF, although rare exceptional cases have been reported (14).
Thus, successful kidney transplantation is the only curative
treatment. During infantile period with active nephrotic syn-
drome, several conservative managements are recommended
to control severe edema such as daily or every other day albu-
min infusion with intermittent gamma globulin replacement,
and low-salt diet. A combination treatment of angiotensin
converting enzyme inhibitor and indomethacin lowers intra-
glomerular pressure and, therefore, decreases urinary protein
excretion. It is also important to prevent and treat infectious
and thrombotic complications. Optimal nutrition includ-
ing vitamin and thyroid hormone should also be provided
for the patients to grow and develop as normally as possible.
However, unilateral or bilateral nephrectomy and early dial-
ysis before the development of renal failure may be required
in some patients to control massive protein loss. When the
patient reaches a body weight of 8 to 9 kg, renal transplan-
tation can be considered (1, 5).
Elevated AFP levels in amniotic fluid and maternal serum,
which reflects fetal proteinuria in utero, can be used as a pre-
natal diagnostic marker of CNF. However, because heterozy-
gous fetal carriers of NPHS1 mutations may have temporar-
ily elevated AFP levels, prenatal diagnosis should be based
on genetic testing whenever possible in high risk families.
Otherwise, repeated measurement of amniotic fluid AFP
before the 20th week of pregnancy is recommended (5). In
case of no family history or if the mutations in the affected
sibling(s) were not identified yet, prenatal diagnosis of CNF
may be based on high amniotic fluid AFP level only, because
whole sequencing the NPHS1 (total 29 exons) gene is time
consuming (5). Amniotic fluid AFP level can be elevated
fetal anencephaly or other malformations as well. Elevated
AFP levels in amniotic in maternal serum was detected in
S214 B.H. Lee, Y.H. Ahn, H.J. Choi, et al. Download full-text
Case 1 of this study, but nevertheless the prenatal diagnosis
of CNF was missed. It may be due to unfamiliarity of CNF
to clinicians in our country.
In conclusion, this is the first report of Korean children
with CNF, which was confirmed by molecular genetic stud-
ies. Precise genetic diagnosis is important for proper man-
agement of the patients and accurate genetic counseling of
the families. In addition to NPHS1, further molecular genet-
ic study of NPHS2, WT1, and LAMB2 will provide more
detailed information about the genetic background in the
Korean patients with CNS.
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