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CASE REPORT
Familial juvenile polyposis syndrome with a novelSMAD4 germline mutation
Yutaka Honda • Yuichi Sato • Junji Yokoyama • Masaaki Kobayashi •
Rintaro Narisawa • Yusuke Kawauchi • Takahiro Hoshi • Kazuhito Yajima •
Tatsuo Kanda • Yoichi Ajioka • Katsuyoshi Hatakeyama • Yutaka Aoyagi
Received: 17 September 2012 / Accepted: 30 July 2013 / Published online: 21 September 2013
� Springer Japan 2013
Abstract Juvenile polyposis syndrome (JPS) is a domi-
nantly inherited disorder characterized by the development
of numerous juvenile polyps (JPs) of the gastrointestinal
tract, and associated with a mutation of the SMAD4 or
BMPR1A gene. Here, we report a mother-daughter case of
familial JPS. A 29-year-old female patient with severe iron
deficiency anemia and hypoproteinemia had numerous
polyps in the stomach and a few polyps in the ileum and
colon that were detected endoscopically. Biopsy specimens
from the gastric polyps were diagnosed as JPs. The patient
underwent a laparoscopy-assisted total gastrectomy, and
her anemia and hypoproteinemia improved. Her mother
also had multiple JPs in the stomach, duodenum, jejunum,
and colon. We then diagnosed them as having familial JPS.
Moreover, germline mutation analysis of the 2 patients
presented a novel pathogenic SMAD4 variant.
Keywords Familial juvenile polyposis syndrome �SMAD4 germline mutation � Gastric polyp � Protein
losing gastropathy � Laparoscopy-assisted total
gastrectomy
Introduction
Juvenile polyposis syndrome (JPS) is a rare hamartomatous
condition characterized by the development of multiple
juvenile polyps (JPs) of the gastrointestinal (GI) tract [1,
2]. A germline mutation in the SMAD4 or BMPR1A gene is
found in about 50–60 % of JPS patients [3–5].
JPS features JPs of various sizes that appear spherical,
lobulated, and pedunculated. JPs are microscopically
characterized by an abundance of edematous lamina pro-
pria with inflammatory cells and cystically dilated glands
lined with cuboidal to columnar epithelium with reactive
changes [6–8]. The clinical signs of JPS include isolated GI
bleeding, anemia, abdominal pain, intussusceptions,
hypoproteinemia, and diarrhea [9].
Here we present a familial case (mother–daughter) of
stomach-predominant JPS with a novel SMAD4 germline
mutation complicated by intractable anemia and protein-
losing gastropathy that were successfully treated by lapa-
roscopy-assisted total gastrectomy.
Case report
Daughter
A 29-year-old Japanese woman with gastric polyps pre-
sented to our facility. She was treated for iron-deficiency
Y. Honda (&) � M. Kobayashi � R. Narisawa � Y. Kawauchi
Department of Endoscopy, Niigata University Medical and
Dental Hospital, 1-757 Asahimachi-dori, Chuo-ku,
Niigata City 951-8510, Japan
e-mail: [email protected]
Y. Sato � T. Hoshi � Y. Aoyagi
Division of Gastroenterology and Hepatology, Graduate School
of Medical and Dental Science, Niigata University,
1-757 Asahimachi-dori, Chuo-ku, Niigata City 951-8510, Japan
J. Yokoyama
Department of Gastroenterology, Niigata University Medical
and Dental Hospital, 1-757 Asahimachi-dori, Chuo-ku,
Niigata City 951-8510, Japan
K. Yajima � T. Kanda � K. Hatakeyama
Division of Digestive and General Surgery, Niigata University
Graduate School of Medical and Dental Sciences,
1-757 Asahimachi-dori, Niigata City 951-8510, Japan
Y. Ajioka
Division of Molecular and Diagnostic Pathology, Niigata
University Graduate School of Medical and Dental Sciences,
1-757 Asahimachi-dori, Chuo-ku, Niigata City 951-8510, Japan
123
Clin J Gastroenterol (2013) 6:361–367
DOI 10.1007/s12328-013-0413-y
anemia for 1 year, and an esophagogastroduodenoscopy
(EGD) was performed in response to her complaint of
epigastralgia. She had neither the hair loss nor skin lesions
that are indicative of Cronkhite–Canada syndrome or
Peutz–Jeghers syndrome (PJS), and no other systemic
abnormalities were observed. Her mother and maternal
grandfather had gastric polyps and her brother had colon
cancer (Fig. 1). Laboratory data showed iron deficiency
anemia (hemoglobin 8.0 g/dL; serum iron 19 lg/dL; fer-
ritin 12 ng/mL) and hypoproteinemia (serum total protein
5.3 g/dL; albumin, 3.1 g/dL). A double-contrast barium
study revealed numerous polyps in the gastric antrum and
corpus (Fig. 2). EGD revealed multiple edematous, red-
dish, and lustrous polypoid lesions, predominantly in the
gastric antrum (Fig. 3). Biopsy specimens from the gastric
polyps were histologically diagnosed as JPs. Helicobacter
pylori infection was not detected in the culture test of
gastric mucosa, urea breath test, and stool antigen.
Colonoscopy revealed a flat reddish elevated lesion in the
ascending colon measuring 6 mm in diameter that was
diagnosed as a JP by pathological examination. Video
capsule endoscopy (VCE) showed two reddish polypoid
lesions in the ileum measuring 2-3 mm in diameter that
also appeared to be JPs. We then diagnosed gastric-pre-
dominant JPS and the patient underwent laparoscopy-
assisted total gastrectomy to improve the anemia and
hypoproteinemia.
The resected specimen revealed numerous tall polypoid
lesions predominantly within the gastric antrum. Micro-
scopically, the gastric polyps consisted of an abundance of
edematous lamina propria and cystically dilated glands
lined with cuboidal to columnar epithelium with hyper-
plastic changes; no dysplasia or cancer was seen in any part
of the stomach (Fig. 4). There was no muscularis mucosa
branching that is characteristic of PJS.
There were no postoperative complications and hemo-
globin, total protein, and albumin levels returned to 12.5,
6.9, and 4.3 g/dL, respectively, after surgery. The patient
remains in excellent condition.
Mother
A 57-year-old Japanese woman with colon polyps pre-
sented to our facility. She had a history of endoscopic
resection of gastric and colon polyps (details unknown),
Sjogren syndrome, and lichen planus. Physical examination
revealed no abnormalities, and there were no remarkable
laboratory findings on arrival. Laboratory data showed no
abnormality. Anemia and hypoproteinemia were not
observed (hemoglobin 13.9 g/dL, serum total protein 7.4 g/
dL, albumin 3.9 g/dL). Colonoscopy revealed peduncu-
lated polyps in the lower rectum (Fig. 5), so an endoscopic
mucosal resection was performed. Pathological examina-
tion revealed that the polyps were JPs; however, she was
not diagnosed as having JPS at this time.
After her daughter was diagnosed as having JPS, we
requested her mother to undergo a general endoscopy at our
facility because it is an inherited condition. EGD revealed
reddish edematous semi-pedunculated polypoid lesions
measuring 7-8 mm in diameter in the gastric antrum,
reddish flat elevations around the greater curvature of the
gastric body and cardia, and pedunculated and semi-
pedunculated polyps in the duodenum (Fig. 6), all of which
were also histologically diagnosed as JPs. H. pylori infec-
tion was not detected in the culture test of gastric mucosa.
I
II
V
III
IV
1 y.o. 3 y.o. 1 y.o. 2 y.o.
29 y.o.
56 y.o.
35 y.o. 33 y.o.
61 y.o. 58 y.o.
case1
case2
d. 87 y.o.
Fig. 1 Family history
Fig. 2 Double-contrast barium study of daughter revealed numerous
gastric polyps, predominantly within the gastric antrum
362 Clin J Gastroenterol (2013) 6:361–367
123
VCE showed three reddish polyps in the jejunum mea-
suring 3-4 mm in diameter that also appeared to be JPs.
We then diagnosed the patient with generalized juvenile GI
polyposis.
Mutation analysis
Written informed consent was obtained from the patients
for SMAD4 and BMPR1A gene analysis. The patients
received standard genetic counseling in the Division of
Gene Therapy of the Bioscience Medical Research Center
of our hospital. Blood samples were collected and sent to
the GENDIA (for GENetic DIAgnostics) network through
the Orphan Net Japan (specified nonprofit corporation) to
analyze genomic mutations of the SMAD4 and BMPR1A
genes. Direct sequencing of the genomic DNA of the
mother and daughter showed that the SMAD4:
c.1421C [ G pathogenic variant was present in exon 11 of
the SMAD4 gene. This substitution is a nonsense variant
predicted to lead to a substitution of a serine by a
premature stop codon on position 474 (SMAD4:
p.Ser474X). This variant is a novel variant that has not
been previously described in other patients or controls, and
it is a truncating mutation. In addition, this is classified as a
pathogenic variant according to MutaDATABASE criteria
(www.MutaDATABASE.org). No BMPR1A gene muta-
tions were detected in the patients’ genomic DNA.
Discussion
JPS is characterized by the development of multiple JPs in
the GI tract [1, 2]. JPS occurs in *1 of every
100,000–160,000 individuals, and autosomal dominant
inheritance with variable penetrance has been observed
[10, 18]. JPS can be defined by any one of the following
clinical criteria—:5 JPs in the colorectum, multiple JPs
throughout the GI tract, or at least 1 JP and a positive
family history of JPS [11, 12]. JPS has 3 subtypes—juve-
nile polyposis of infancy (JPI), juvenile polyposis coli, and
Fig. 3 EGD of daughter revealed dozens of edematous, reddish, and lustrous polypoid lesions, predominantly within the gastric antrum (a, b).
Many small reddish elevated lesions were detected within the gastric corpus (c, d)
Clin J Gastroenterol (2013) 6:361–367 363
123
generalized juvenile polyposis [13]. JPI is a rare phenotype
of JPS that is diagnosed before the age of 2 years and is
characterized by massive polyposis throughout the GI tract,
severe bleeding, diarrhea, protein-losing enteropathy, ina-
nition, rectal prolapse and a poor prognosis. JPI is caused
by large microdeletions that include the BMPR1A and
PTEN genes [14, 15]. On the other hand, juvenile polyposis
coli is the most common type in which the JPs are limited
to the colon, and generalized juvenile polyposis is defined
as JPs in the stomach, small bowel, colon, and rectum [11].
However, these two forms appear to be variable expres-
sions of the same disease because patients of both forms
have been reported to segregate according to a dominant
mode in the same family [14, 16]. We classified the present
cases as gastric-predominant generalized juvenile polypo-
sis. These cases had no other features of this syndrome
such as CNS defects, Meckel’s diverticulum, gastric and
duodenal diverticula, malrotation, thoracic anomalies,
urogenital anomalies, osteoma, lymphangioma, hypertel-
orism, amyotonia congenita, or extra toes on the foot [17–
21]. In comparison, PJS is characterized by the presence of
hamartomatous polyps in the GI tract, and mucocutaneous
pigmentation which occurs almost universally on the lips,
as well as the buccal mucosa, hands and feet, and areas
around the mouth and nose. This syndrome also has auto-
somal dominant inheritance. Most of the polyps are found
in the small intestine, and to a lesser extent the rectum,
colon, stomach, and duodenum [22]. Histopathologically,
polyps are characterized by arborizing smooth muscle
proliferation, which represents the muscularis mucosa
branching in various directions. This characteristic micro-
scopic appearance of PJS polyps is the major difference
from juvenile polyps [23]. Patients with PJS usually pres-
ent symptoms include abdominal pain, rectal bleeding,
anemia, small intestinal intussusception, bowel obstruction,
and rectal prolapse of polyps [24]. PJS is associated with
Fig. 4 The resected specimen of daughter contained multiple tall
polypoid lesions, predominantly within the gastric antrum (a, b).
Microscopically, the gastric polyps consisted of an abundance of
edematous lamina propria and cystically dilated glands lined with
cuboidal to columnar epithelium with hyperplastic changes and no
evidence of dysplasia or cancer (c low-power view, d high-power
view of a square part of c; 940 objective lens)
364 Clin J Gastroenterol (2013) 6:361–367
123
germline mutations in the STK11 gene (LKB1 gene). It is
reported that there is a large deletion of the gene in about
30 % of families [25].
Heterozygous germline mutations in the SMAD4 and/or
BMPR1A gene has been found in 50–60 % of patients with
JPS [3–5]. Both SMAD4 and BMPR1A genes encode pro-
teins that are involved in the transforming growth factor-bsignaling pathway [26] that is an important modulator of
many cellular processes, including proliferation, differen-
tiation, migration, adhesion and death [27]. Most of the
mutations are point mutations or small base pair deletions
in the coding regions of SMAD4 or BMPR1A, and about
15 % of the germline genetic defects are larger deletions
which affect one or more exons, or the entire SMAD4 or
BMPR1A coding sequence [3, 5].
A correlation between SMAD4 mutation and significant
gastric polyposis in patients with JPS has been identified.
Friedl et al. [28] reported that individuals with SMAD4
mutations had far higher rates of gastric polyposis than
BMPR1A mutation carriers and that gastric polyposis was
more severe. Recent experimental evidence indicates that
the Smad4 ± mouse shows a phenotype that is similar to
that of human JPS, and develops multiple gastric and small
intestinal polyps that are histologically very similar to JPS
including coexisting adenocarcinoma, although no polyps
are seen in the colon [29, 30]. In contrast, heterozygous
Bmpr1a knockout mice appear grossly normal [31].
In our cases, the SMAD4 mutation contributed to the
predominant development of JPs in the stomach compared
to the rest of the GI tract. Interestingly, their severity dif-
fered between mother and daughter, although they had the
same mutation. Schwetz et al. [32] listed secondary factors
influencing JPS manifestations. They suggested that H.
pylori infection might have an influence on JPS manifes-
tations. However, both of our patients had no H. pylori
infection, and there is now uncertainty about this difference
between daughter and mother.
Meanwhile, mutations in the SMAD4 gene are also
associated with extra-GI tract abnormalities. SMAD4
mutations are reported to cause 1–4.2 % of hereditary
hemorrhagic telangiectasia (HHT) or Rendu-Osler-
Weber syndrome, which is characterized by vascular
malformations with mucocutaneous telangiectasia, arte-
riovenous malformations of the lungs, liver, and brain
leading to potentially life-threatening complications. Gal-
lione et al. [33, 34] reported families in which SMAD4
mutations caused both JPS and HHT. Therefore, screening
for vascular malformations is recommended for JPS
patients.
With regard to our presenting cases, we commissioned
the GENDIA (for GENtic DIAgnostics), which is a par-
ticipating laboratory of MutaDATABASE, to analyze
genomic mutations of SMAD4 and BMPR1A genes. Mu-
taDATABASE is a central database created by joint large
consortium of diagnostic testing laboratories in Europe, the
USA, Australia and Asia to provide a repository of DNA
variations and allows open access to the whole community.
JPS is associated with an increased risk of GI cancer. It
was recently reported that the cumulative risk of colorectal
and gastric cancers is 39–68 and 21 %, respectively, in
patients with JPS [32, 35, 36], and several cases of duo-
denal cancer in JPS have been described in the literature
[37]. In another report, the relative risk (95 % CI) of
colorectal cancer was 34.0 (14.4–65.7). Similar risks were
noted in both males (30.0, 9.6–68.6) and females (43.7,
8.8–125.0) [38].
Therefore, it is recommended that general endoscopy
including total colonoscopy (TCS) and EGD is started at 15
years of age or at the time of first symptoms for patients with
JPS. Screening endoscopy should be repeated annually if
polyps are found and every 2–3 years if no polyps are
identified [2, 13]. Polyps that are found in the GI tract should
be removed endoscopically. Patients with mild polyposis can
be managed by frequent endoscopic resection. However,
Fig. 5 Colonoscopy of mother revealing pedunculated polyps in the
lower rectum
Clin J Gastroenterol (2013) 6:361–367 365
123
when they cannot be managed endoscopically, surgery is
indicated (colectomy, gastrectomy, or small intestine
resection) [2, 32, 37, 39]. In particular, patients with severe
symptomatic gastric polyposis may need subtotal or total
gastrectomy, because of the difficulty of endoscopic treat-
ment. In addition, the gastric cancer risk is higher in patients
with JPS who develop multiple gastric polyps and have the
SMAD4 mutation [40]. Therefore, in the mother described
here, close endoscopic surveillance should be performed
despite the lack of cancer detected in the GI tract.
VCE and double-balloon endoscopy (DBE) are current
useful methods for the detection of small intestinal lesions.
The risk of small intestinal cancer in JPS remains unde-
fined. However, VCE was able to show many JPs in the
small intestine of our patients. Postgate et al. [41] dem-
onstrated that VCE showed small bowel polyps and duo-
denal polyps that were beyond the range of standard EGD.
Therefore, close follow-up using EGD, TCS, VCE, and
DBE is needed in the future for patients with JPS.
Here we reported gastric-dominant JPS occurring in a
mother and daughter bearing a novel SMAD4 mutation.
Acknowledgments The authors thank Dr. Sakurai (Department of
Medical Genetics, Shinshu University School of Medicine, Matsum-
oto, Japan) for his advice regarding the gene mutation analysis.
Conflict of interest The authors declare that they have no conflict
of interest.
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