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: yutakatheskywalker@gmail.com

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

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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

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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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