Xiao et al. BMC Pediatrics(2024) 24:544
https://doi.org/10.1186/s12887-024-04994-7

BMC Pediatrics

CASE REPORTOpen Access

Successful treatment of juvenile polyposisof infancy with sirolimus: a case reportPei Xiao1, Ting Zhang1, Yizhong Wang1, Yongmei Xiao1, Xiaolu Li1, Ruixue Wang1, Youran Li1 and Ting Song1*
Abstract
Background Infantile Juvenile polyposis of infantile (JPI) is a rare and aggressive form of juvenile polyposis syndrome(JPS) typically diagnosed in the first year of life. It often carries a poor prognosis due to chronic gastrointestinal
bleeding, protein-losing enteropathy, malnutrition and immune deficiency.
Case presentation We report a case of a girl initially presented with pallor at 7 months of age, which progressed
to gastrointestinal bleeding and protein-losing enteropathy. Endoscopic examination, which included both uppergastrointestinal endoscopy and enteroscopy, showed diffuse polyposis. Histopathology results indicated thepresence of juvenile polyps with no dysplasia in all removed polyps. Genetic testing identified a 2.1 Mb deletionon chromosome 10q23.2q23.31 involving the phosphatase and tensin homolog (PTEN) and bone morphogenetic
protein receptor type IA (BMPR1A) genes. Treatment with sirolimus initiated at 10 months of age led to a reductionin the need for blood and albumin infusions, improved patient growth, and quality of life. While the frequency
of endoscopic evaluations decreased with sirolimus, regular endoscopic polypectomy every 5 months remainednecessary. However, discontinuation of sirolimus resulted in polyp recurrence after 2 months due to pneumonia.
Conclusion This case highlights sirolimus treatment can alleviate many complications of JPI, it does not eliminate theneed for aggressive polypectomy.
Keywords JPI, PTEN, BMPR1A, Sirolimus

Background
Juvenile polyposis syndrome (JPS) is a rare autosomal
dominant condition characterized by the presence ofmultiple distinct juvenile polyps in the gastrointestinal
tract [1]. JPS occurs 1 in 100.000 people. JPS patientsdevelop multiple juvenile polyps of the gastrointestinal tract, especially in the colon/rectum (98%), stomach (14%), duodenum (7%) and small bowel (7%) [2]. It
has been clinically defined by the presence of 5 juvenile*Correspondence:
Ting Song
songt@shchildren.com.cn
1
Department of Gastroenterology, Hepatology and Nutrition, ShanghaiChildren’s Hospital, School of Medicine, Shanghai Jiao Tong University,
355 Luding Road, Shanghai 200062, China

polyps in the colon, juvenile polyps throughout the gastrointestinal tract, or any number of juvenile polyps anda family history of juvenile polyposis [1]. Patients with
JPS are typically asymptomatic, but when symptoms do
occur, rectal bleeding accompanied by anemia is the mostcommon presentation. This is often followed by abdominal pain, diarrhea, and potentially intussusception at thelocation of the largest polyps. It is important to note thatJPS can also manifest with additional symptoms outsideof the intestines, including cutaneous manifestations
such as telangiectasia and pigmented nevi, as well as
skeletal abnormalities like macrocephaly, hydrocephalus,
cleft palate, polydactyly, and hypertelorism. These extraintestinal manifestations are encountered in a significant
percentage of JPS cases, with cutaneous manifestations© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Xiao et al. BMC Pediatrics(2024) 24:544

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Fig. 1 A. Endoscopy pre sirolimus and colonoscopy are shown. B. Endoscopy post sirolimus and colonoscopy are shown. C. Endoscopy stop sirolimus
and colonoscopy are shown

Fig. 2 A. Small intestinal polyp with dialeted hyperplastic glands B. Colonic junuvial polyp with dilated hyperplastic colonic glands

seen in up to 56% of patients and skeletal stigmata in up
to 70% [3].
Juvenile polyposis Infantile (JPI) is an extremely raredisease with limited reported cases in the literature. In
contrast to other forms of juvenile polyposis, JPI typicallypresents early in life, leading to a severe clinical course
and reduced life expectancy. Key features of JPI include
disease onset in early childhood (often within the first 2
years of life) and severe gastrointestinal symptoms suchas diarrhea, significant intestinal bleeding, protein-losing
enteropathy, intussusception, rectal or polyp prolapse,
and inanition, ultimately resulting in death during earlychildhood. JPI is not linked to a family history and has
been associated with the deletion of a chromosomal
region containing the phosphatase and tensin homolog(PTEN) and bone morphogenetic protein receptor type
1A (BMPR1A) genes [4, 5].
This case study illustrates a positive clinical outcome
achieved through the early administration of sirolimus inpatients with JPI. While sirolimus shows promising benefits, it does not seem to replace the necessity of aggressive polypectomy.

Case presentation
A premature girl, delivered at 35 weeks’ gestation via
cesarean delivery with a weight of 2700 g, presented
at 7 months of age in June 2022 with severe anemia(hemoglobin of 3.4 g/dL). She had no family historyof gastrointestinal disease. One week later, she experienced gastrointestinal bleeding and protein-losing enteropathy. An upper gastrointestinal endoscopy showed
multiple polyps in the stomach. Colonoscopy revealed
multiple colorectal polyps, leading to multiple polypectomies being performed (Fig. 1A). Histopathology of theresected polyps showed characteristic features of juvenile
polyps with no dysplasia (Fig. 2A-B). Initially managedwith endoscopic polypectomies, she later required frequent blood transfusions and albumin due to recurrent
bleeding episodes causing severe anemia and hypoalbuminemia (Fig. 3A-B). Genetic testing through targeted
microarray analysis identified a 2.1 Mb deletion in chromosome 10q23.2q23.31 involving both the PTEN geneand BMPR1A gene.
At 10 months of age, specifically in September 2022, wecommenced treatment with sirolimus at an initial dose of
1.5 mg/m2 per day administered twice daily (0.4 mg bid),a mammalian target of rapamycin protein (mTOR) Inhibitor. Prior to starting sirolimus, an informed consent
was obtained from the parents, outlining details about
the medication, treatment objectives in JPI, associatedrisks, side effects, alternatives, and potential benefits.
The primary aim was to decelerate the proliferation ofgastrointestinal polyps, or ideally, promote their regression. Before sirolimus therapy, the patient had an average
albumin level of 2.5–2.9 g/dL and hemoglobin level of
3.4–7.1 g/dL, necessitating weekly albumin infusions andXiao et al. BMC Pediatrics(2024) 24:544

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Fig. 3 Albumin and heamoglobin level before and after sirolimus

RBC transfusions every 1–2 weeks. Following 1 month ofsirolimus treatment targeting a serum level of 6 to 8 ng/
mL, there was no longer a need for albumin infusions or
RBC transfusions. Albumin levels remained stable at 3.3–
3.5 g/dL and hemoglobin levels improved to 10.5–12.1 g/
dL.
At 14 months of age, following 4 months of sirolimus treatment, the patient experienced intussusception
approximately 10 cm into the small intestine. The patient
initially underwent gastroenteroscopy, revealing multiple polyps in the stomach and intestines, which significantly decreased compared to pre-sirolimus treatment.
Subsequently, endoscopic polypectomy was carried out.
The procedure then transitioned to the abdomen, wherelaparoscopic reduction of small intestinal intussusception
and further polypectomy were conducted, eliminating
the need for intestinal resection.

At 21 months of age, sirolimus was discontinued due
to pneumonia. Two months post-discontinuation, thepatient experienced aggravated intestinal bleeding, withstable hemoglobin levels but decreased albumin to 3.1 g/
dL. Gastrointestinal endoscopy revealed numerous polyps of varying sizes, leading to another round of endoscopic polypectomy. Subsequently, sirolimus treatment
was resumed. After a 15-month follow-up period, thepatient has remained stable without requiring transfusions or albumin supplementation. Post-treatment
growth improvement was observed, as well as enhanced
quality of life for the patient and their family.
Although there is intermittent blood in the stool andthe need for endoscopic polypectomy every 5 months,
the patient has not experienced the common side effects
associated with sirolimus use, such as lipid disorders,cytopenia, hepatotoxicity, nephrotoxicity, interstitial lungdisease, or thrombotic microangiopathy.

Xiao et al. BMC Pediatrics(2024) 24:544

Discussion and conclusions
JPS is a rare autosomal dominant disease characterizedby hamartomatous growths that develop throughout thegastrointestinal tract of affected children. Diagnosis of
JPS is based on the presence of ≥ 5 gastrointestinal polyps, or any polyps in a child with a family history of the
syndrome. Individuals with JPS face an increased risk ofcolorectal and gastric cancers in the long term, as wellas potential immediate impacts on health and development. The majority of patients with JPS exhibit a loss offunction variant in either mothers against decapentaplegic homolog 4 (SMAD4) or BMPR1A. Furthermore, casestudies have revealed a connection between chromosome
10q23 deletions involving BMPR1A and PTEN, and therare onset of various phenotypically diverse polyposis
syndromes [1].
JPI is a distinct and aggressive subtype of JPS characterized by severe gastrointestinal symptoms. JPI emerges
during early infancy and is often linked to a poorer prognosis due to gastrointestinal blood loss and protein-losing enteropathy, leading to additional health issues suchas malnutrition, severe anemia, and immune deficiency.
The presence of polyps also raises the risk of intussusception and gastrointestinal obstruction, which may require
urgent surgical intervention [6].
JPS has been associated with mutations in both
SMAD4 on chromosome band 18q21.2 and BMPR1A
on chromosome band 10q23.2, both integral components of the BMP/TGF-beta signaling pathway. BMPR1A
is situated in close proximity to PTEN on the chromosome, and cases of larger deletions affecting both genes
have been documented. Children carrying deletions inboth BMPR1A and PTEN genes may exhibit symptomsof JPI. Delnatte et al [4] initially suggested a cooperation
between PTEN and BMPR1A and the existence of a combined synergistic effect of the deletion of both PTEN and
BMPR1A, leading to a severe form of JPS, i.e. JPI. The
combined deletion of the PTEN and BMPR1A genes,
which are pivotal players in the regulation of cell proliferation, differentiation and apoptosis via PI3K/Akt and
BMP pathways, respectively, could lead to more aggressive polyposis and development of malignancies [4, 7, 8].
Morbidity associated with JPI is significant. The standard treatment involves repeated endoscopic surveillanceand polypectomy, often requiring red blood cell transfusions and albumin infusions. Advanced nutritional
support may be necessary in cases of severe growth
impairment. In the most severe instances, colectomy may
be necessary to reduce blood and protein losses. Previous case studies have shown some success with surgicalinterventions such as bowel resection and multi-organtransplantation. Busoni et al [9] documented a case ofdelayed JPI diagnosis at the age of 6, where a 3.34 Mb denovo deletion was found at 10q23.1q23.31, involving thePage 4 of 6

PTEN and BMPR1A genes. The disease progression was
severe, presenting symptoms like diarrhea, abdominal
pain, inanition, refractory anemia, rectal bleeding, hypoalbuminemia, and exudative enteropathy. A sub-total colectomy, along with intraoperative endoscopic removal of
ileal and rectal stump polyps, was necessary for palliative
disease management. Chandan et al [10] reported a caseof JPI diagnosed at 9 months of age, where the patientunderwent multiorgan transplantation, including liver,small bowel, pancreas, and colon transplants at 3.5 years
old. Unfortunately, the patient succumbed to an invasive
pneumococcal infection at the age of 5.
Frequent endoscopy poses a challenge for patients withgastrointestinal polyposis and other inherited gastrointestinal cancer syndromes. Moreover, many patients
exhibit hesitancy and reluctance towards surgical resection of the affected organ once endoscopic management
is no longer viable, despite guideline recommendations.
Given the significant impact on quality of life and thelack of disease-modifying treatment options, there is acompelling need to explore new mechanisms for treating these diseases effectively and safely. Rapamycin is an
inhibitor of mTOR, which shows strong expression inmouse small intestine polyps with APC defects, as well as
in human colorectal adenomas [11] and colorectal cancers [12]. In animal models, the effectiveness of sirolimus
to inhibit the formation of gastrointestinal polyps andincrease the time of progression to dysplasia in patientswith intestinal polyposis syndromes, including JPS [13].
In addition to animal models, an increasing numberof studies have documented the use of sirolimus in JPS.
Busoni, et al [14] initially reported a case of a patient who
presented with gastrointestinal bleeding and proteinlosing enteropathy at 4 months of age. A chromosomal
microarray revealed a single allele deletion in chromosome 10q23, involving both the PTEN and BMPR1A
genes. Despite undergoing subtotal colectomy with ileorectal anastomosis, the patient continued to experience
protein-losing enteropathy and bleeding, necessitating
ongoing blood transfusions and albumin infusions. Treatment with sirolimus was initiated at 20 months of age,and no further albumin infusions or red blood cell transfusions were required during the subsequent 27-monthfollow-up period. Another case report described an
11-year-old girl who had been monitored since birth formacrocephaly, mild hypotonia, motor and developmental
delay. At 18 months of age, she experienced rectal bleeding, and colonoscopy revealed numerous juvenile polyps,
some up to 3 cm in diameter. Genetic analysis identified a de novo germline deletion encompassing PTEN
and BMPR1A. The patient exhibited failure to thrive,
mild anemia, and protein-losing enteropathy. Following
a colonic perforation during the resection of large polyps at 5 years old, she underwent emergency transientXiao et al. BMC Pediatrics(2024) 24:544

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Table 1 Studies in which sirolimus has been used for the treatment of JPS(JPI)
Year
DiseaseAge of onset
Age oftreatment
Gene
Sirolimus
dose
Study
duration
Side effects
Results

Busoni, et al [14].
2019
JPS(JPI)
4 month
20 month

Quaranta et al [15].
2019
JPS(JPI)
18 month
6 years old

Martín-Masot et al [16].
2021JPS
6 years old
12 years old

Dillon Bell et al [17].
2022
JPS(JPI)
7 month
14 month

PTEN, BMPR1A
0.8 mg/m2/d

PTEN, BMPR1A-

SMAD4
0.8 mg/m2/d

PTEN, BMPR1A
1.5 mg/m2/d

27 month

6 years

12 month

4 years

No
Reduction in the number and size ofpolyps.
The patient did not require new transfusions of red blood cells or albumin.
Growth improvement and better life.

No
Decrease in the number
and size of polyps.
weight improvement
and normal serum
albumin and hemoglobin level.

No
Disappearance of almost all
the polypoid lesions.
laboratory test values were
within normal ranges. (including hemoglobin、ironand fecal calprotectin)

No
Improvement in protein-losing enteropathy, decreased intestinal blood
loss and improved weight gain.
The number of polyps resected perunit time and frequency of upperand lower endoscopic evaluationneeded dropped.

ileostomy. Sirolimus treatment was initiated at 6 years ofage, and after more than 4 years of follow-up, she demonstrated weight improvement and normal serum albumin
levels without recurrence of anemia or adverse events[15]. Our case aligns with those reported in the literature,
involving deletions of the PTEN and BMPR1A genes, andsuggests that sirolimus treatment can ameliorate proteinlosing gastrointestinal disease. In our case, sirolimus
therapy commenced at 10 months of age, just 3 months
after diagnosis, marking the youngest reported use of thetreatment in a child. Table 1 provides an overview of the
key studies on sirolimus in the pediatric treatment of JPS
available in the current literature.
Adverse effects of sirolimus that are clinically significant and require specific treatment, or have the potential to impact both short- and long-term patient health,include high levels of cholesterol and triglycerides, pneumonia (both infectious and non-infectious), anemia, formation of lymphoceles, and impaired healing of wounds.
Less severe complications of sirolimus treatment can
include temporary reductions in platelets and whiteblood cells, as well as gastrointestinal issues and ulcerations in the mucosal lining [18]. mTOR inhibitors, suchas sirolimus, have a limited range of effective doses, withabsorption rates that vary widely among individuals andwithin the same person over time. Due to this variability, it is essential to monitor sirolimus levels in the bloodto ensure effective treatment. In our case, following theinitiation of sirolimus administration, weekly monitoring of drug concentration was implemented, with subsequent dose adjustments based on the concentrationlevels. Once the blood drug concentration reached a stable state, the monitoring interval was gradually extended
to 2 weeks, 4 weeks, and eventually 8 weeks. It wasobserved that sirolimus concentration typically ranged
between 6-10ng/ml.
The increasing evidence supporting the use of sirolimus
suggests it could be a viable alternative to endoscopic
treatment for patients with JPS, potentially preventing
the need for colectomy. We present a successful caseof treating a girl with severe infantile juvenile polyposis using sirolimus, marking the first reported case from
China. While sirolimus shows promising benefits, it does
not seem to replace the necessity of polypectomy.
Abbreviations
JPI	Juvenile Polyposis of Infantile
JPS	Juvenile Polyposis Syndrome
PTEN	Phosphatase and Tensin Homolog
BMPR1A	Bone Morphogenetic Protein Receptor type IA
SMAD4	Mothers Against Decapentaplegic Homolog 4mTOR	Mammalian Target of Rapamycin Protein
Acknowledgements
We thank the patient and her parents for permitting us to present the caseand data.
Author contributions
PX involved in the patient care, helped with collecting case information anddrafting the initial manuscript, and critically revised the manuscript. YMX,TZ and YRL critically reviewed and revised the manuscript for important
intellectual content. YZW and RXW conceptualized the case presentation,
drafted the manuscript, carried out the finalization of the manuscript, andcritically reviewed and revised the manuscript. TS was directly involved in
the diagnostic process, conceptualized the case presentation, drafted themanuscript, and critically reviewed and revised the manuscript. All authors
approved the final manuscript as submitted and agree to be accountable for
all aspects of the work.
Funding
No external funding.
Data availability
All relevant data is included in the case report. Further information areavailable from the corresponding author on reasonable request.

Xiao et al. BMC Pediatrics(2024) 24:544

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Declarations

8.

Ethics approval and consent to participate
Not applicable.

9.

Consent for publication
Written informed consent to anonymously publish this case report has beenobtained from the child’s parents.

10.

Competing interests
The authors declare no competing interests.
Received: 24 April 2024 / Accepted: 6 August 2024

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