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Successful Treatment of Juvenile Polyposis of Infancy with Sirolimus Veronica B

Successful Treatment of Juvenile Polyposis of Infancy with Sirolimus Veronica B

Successful Treatment of Juvenile Polyposis of Infancy With Veronica B. Busoni, MD,a Marina Orsi, MD,a Pablo A. Lobos, MD,a Daniel D’Agostino, MD,a Marta Wagener, MD,b Paola De la Iglesia, MD,a Victor L. Fox, MDc

Juvenile polyposis syndrome is a rare autosomal dominant condition abstract characterized by multiple hamartomatous polyps throughout the . Juvenile polyposis of infancy is a generalized severe form of juvenile polyposis syndrome associated with a poor prognosis. A 47- month-old female infant presented initially with gastrointestinal bleeding and -losing enteropathy at 4 months of age. At the age of 12 months, the condition worsened, requiring albumin infusions every 24 to 48 hours and aHospital Italiano de Buenos Aires, Buenos Aires, Argentina; red cell transfusions every 15 days. Upper gastrointestinal endoscopy, bHospital de Niños Dr Alassia, Santa Fe, Argentina; and cBoston Children’s Hospital, Boston, Massachusetts colonoscopy, and small-bowel enteroscopy revealed diffuse polyposis that was treated with multiple endoscopic polypectomies. Despite subtotal Dr Busoni conceptualized and designed the study, collected, analyzed, and interpreted data, and colectomy with ileorectal anastomosis, protein-losing enteropathy and drafted the initial manuscript; Dr Fox conceptualized bleeding persisted, requiring continued blood transfusions and albumin and designed the study and analyzed and infusions. A chromosomal microarray revealed a single allele deletion in interpreted data; Drs Orsi, Lobos, D’Agostino, De la chromosome 10q23, involving both the PTEN and BMPR1A genes. Loss of Iglesia, and Wagener analyzed and interpreted data; and all authors revised and critically reviewed the PTEN function is associated with an increased activation of the protein manuscript for important intellectual content, B (AKT)/mammalian target of rapamycin (mTOR) pathway involved in cell approved the final version to be published as proliferation. Treatment with sirolimus, an mTOR inhibitor, was initiated with submitted, and agreed to be accountable for all aspects of the work in ensuring that questions the aim of inhibiting polyp growth. Soon after initiation of treatment with related to the accuracy or integrity of any part of the sirolimus, blood and albumin infusions were no longer needed and resulted in work are appropriately investigated and resolved. improved patient growth and quality of life. This case represents the first DOI: https://doi.org/10.1542/peds.2018-2922 detailed report of successful drug for life-threatening juvenile Accepted for publication May 1, 2019 polyposis of infancy. Address correspondence to Veronica B. Busoni, MD, Pediatric , and Liver Intestinal Transplantation Division, Department of , Hospital Italiano de Buenos Aires, Potosi Juvenile polyposis syndrome (JPS) is (cumulative lifetime risk: 39%; 4135, Buenos Aires CP 1199, Argentina. E-mail: [email protected] a rare autosomal dominant condition relative risk: 34%).1,3,4 characterized by the presence of PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, JPI is a generalized form of JPS that 1098-4275). multiple distinct juvenile polyps in the develops during the first months of life gastrointestinal tract. It has been Copyright © 2019 by the American Academy of with polyps in stomach, small bowel, Pediatrics clinically defined by the presence of and colon. JPI is the most severe form FINANCIAL DISCLOSURE: $5juvenilepolypsinthecolon, The authors have indicated of JPS and is associated with a poor they have no financial relationships relevant to this juvenile polyps throughout the prognosis. This syndrome is article to disclose. gastrointestinal tract, or any number characterized by gastrointestinal FUNDING: No external funding. of juvenile polyps and a family history bleeding, diarrhea, protein-losing POTENTIAL CONFLICT OF INTEREST: of juvenile polyposis.1 In 1975, The authors have enteropathy, , rectal prolapse, indicated they have no potential conflicts of interest Sachatello and Griffen2 defined 3 and intestinal intussusception in to disclose. types: juvenile polyposis coli, infants and young children.5 Severe generalized juvenile polyposis, and protein-losing enteropathy can lead to To cite: Busoni VB, Orsi M, Lobos PA, et al. juvenile polyposis of infancy (JPI). growth retardation, emaciation, Successful Treatment of Juvenile Polyposis of Patients with JPS are at an increased cachexia, and death. JPI has rarely been Infancy With Sirolimus. Pediatrics. 2019;144(2): risk of gastric and colorectal e20182922 reported in the medical literature, and

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 144, number 2, August 2019:e20182922 CASE REPORT the scarcity of this condition and its high rate of mortality have limited the study of its molecular basis in the past.6 of the BMPR1A and PTEN genes are responsible for JPS and Cowden syndrome, respectively. The development of polyposis is a typical feature of both disorders. Microdeletions in chromosome 10q23 involving both contiguous genes are associated with aggressive polyposis in childhood.6 PTEN are associated with several hamartomatous syndromes, including juvenile polyposis, Cowden syndrome, and Bannayan-Riley- Ruvalcaba syndrome, collectively named the PTEN tumor syndrome.7 Associated extraintestinal manifestations include congenital heart disease, developmental delay, and macrocephaly.8 Morbidity associated with polyposis in JPI is significant. Standard treatment includes repeated endoscopic surveillance and polypectomy, with frequent need of red blood cell (RBC) transfusions and albumin infusions. Advanced nutritional support may be necessary in cases of severe growth impairment. In the most severe cases, colectomy may be necessary to reduce blood and protein losses. FIGURE 1 A, Endoscopy pre sirolimus and gastroscopy are shown. B, Endoscopy pre sirolimus and duode- noscopy are shown. C, Endoscopy pre sirolimus and colonoscopy are shown. D, Endoscopy post CASE DESCRIPTION sirolimus and gastroscopy are shown. E, Endoscopy post sirolimus and duodenoscopy are shown. F, A term (38 weeks’ gestation) girl endoscopy post sirolimus and colonoscopy are shown. delivered by cesarean delivery (weight 3300 g, length 49.5 cm, endoscopic procedures (Table 1). performed with no later cephalic circumference 35.5 cm) Histopathology revealed complications. presented at age 5 months with characteristic features of juvenile At the age of 12 months, the condition gastrointestinal bleeding and protein- polyps with no in all worsened, requiring albumin losing enteropathy. Endoscopic resected polyps. Biopsies of grossly infusions every 24 to 48 hours to examination, including upper normal gastrointestinal mucosa maintain an average albumin level of gastrointestinal endoscopy, showed normal histology (Fig 2). 1.4 g/dL. RBC transfusions were colonoscopy, and small-bowel During laparotomy-assisted required every 15 days. enteroscopy, revealed diffuse enteroscopy performed at 8 months polyposis (Fig 1 A–C). Repeated RBC of age, a major laceration of the At 17 months of age, a subtotal transfusions and intravenous mesentery was produced by traction colectomy with ileorectal infusions of albumin were required during manipulation of the small anastomosis was performed during despite multiple polypectomies bowel. A 15-cm jejunal resection with an emergent laparotomy for an performed during a series of end-to-end anastomosis was ileocolonic intussusception. After this

Downloaded from www.aappublications.org/news by guest on October 2, 2021 2 BUSONI et al FIGURE 2 Histology: A, Colonic juvenile polyp with dilated hyperplastic colonic glands, inflammatory infiltrate, and surface erosion. B, Gastric juvenile polyp composed of hyperplastic foveolar epithelium with formation and edematous stroma. C, Colonic mucosa with preserved histoarchitecture. procedure, protein-losing decided to initiate treatment with of treatment with sirolimus with enteropathy persisted and sirolimus, an inhibitor of mTOR and a target serum level of 6 to 8 ng/mL, requirements of blood transfusions the molecular pathway known to be albumin infusions and RBC and albumin infusion remained activated in patients with PTEN transfusions were no longer required. unchanged, presumably as a result of mutations. An informed consent with Albumin levels remained steadily persisting protein exudation and detailed information about sirolimus .3.8 to 4 g/dL and hemoglobin levels bleeding from the gastric, small- and its uses in organ transplant, over 12 g/dL. a-1 antitrypsin bowel, and rectal polyps. Placement vascular anomalies, and PTEN clearance also improved to near- of a central venous catheter was disorders; the goal of therapy in JPI; normal levels at 13.3 mL/day (Fig 3). required because of frequent blood and monitoring, risks, side effects, Endoscopic evaluations showed sampling and albumin infusions. alternatives, and potential benefits was adefinite change in polyp growth, signed by the parents and . with scarce distribution and smaller The patient also had congenital Our goal was to slow gastrointestinal size (Fig 1 D–F). At 47 months of age, abnormalities, including macrocephaly polyp proliferation or, at least, favor after 27 months of treatment with (head circumference .97th percentile) their involution. Before starting sirolimus, the patient remains stable and complex congenital heart disease treatment with sirolimus, the patient with no transfusion requirements. consisting of pulmonary stenosis and had an average albumin level of 1.5 g/ a ventricular septal defect. dL, requiring albumin infusions every Congenital heart disease was treated a A chromosomal microarray was 24 to 48 hours. The clearance of -1 through cardiac catheterization after performed, which revealed a 3078- antitrypsin measuring protein gastrointestinal disease was under Mb deletion in chromosome exudation by fecal material was control at 22 months of age. 10q23.2q23.31 involving both the 176 mL/24 hours at initiation Valvuloplasty was performed for PTEN gene and BMPR1A gene. of treatment (normal value: pulmonary stenosis, with a residual ,12.5 mL/day). gradient of 30 mm Hg. The Given the difficulty to stabilize our interventricular communication was patient and discharge her from the The initial dose was 0.8 mg/m2 per closed with a device with minimum hospital, at 20 months of age, we day taken twice daily. After 1 month residual shunt.

TABLE 1 Endoscopic Procedures Before and After Sirolimus Age in Mo, Endoscopic Procedure No. Stomach Polyps No. Duodenum Polyps No. Jejunum Ileum Polyps No. Colon Polyps No. Performed (mean (mean (mean size, mm) (mean Resected size, mm) size, mm) size, mm) Polyps 8 No 5 (15) 70 30 (15) 10 12 6 (5) 10 (15) Not explored 49 (15) 38 17, subtotal colectomy (ileorectal anastomosis) performed 19 6 (8) 42 (15) Terminal ileum 80 (7) Rectum 20 (7) 65 20, sirolimus treatment initiated 25 4 (4) 14 (5) Terminal ileum 56 (3) Rectum 1 (2) 9 46 1 (3) 1 (3) Terminal ileum 7 (3) None 5

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 144, number 2, August 2019 3 Since initiation of treatment with DISCUSSION malformations11 and different types sirolimus, the magnitude of the We believe that this is the first of cancer, hoping that it will act on the enteropathy was reduced, and the detailed report of successful drug abnormal development of blood patient could be discharged from the therapy of this devastating and life- vessels (). As an inhibitor hospital without the need for central threatening condition. The child’s of the mTOR pathway, an important venous access 1 month post initiation pretreatment and improved post- regulator of cell proliferation and of treatment. Edema resolved, and no treatment clinical findings survival, sirolimus and its analogs albumin infusion or RBC transfusion (laboratory values, growth have an expanding role in the was needed in the last 27-month fi treatment of tumors associated with parameters, and endoscopic ndings) 12,13 follow-up interval. Post-treatment demonstrate a dramatic change in the complex, growth improvement was also lymphoproliferative disease, and natural evolution of this disease. The 14,15 evident (Fig 4). The patient and genetic defect underlying our autoimmune cytopenias. family’s quality of life improved by patient’s condition is well defined by The etiologic basis for the subset of allowing the child to return home a deletion in chromosome 10q23 that juvenile polyposis termed JPI is (300 miles from the hospital). includes the PTEN gene. The potential a contiguous PTEN and BMPR1A gene mechanism by which sirolimus works deletion.16 PTEN is a tumor can be explained by its known suppressor gene whose function is inhibitory effect on the frequently lost through genetic and phosphatidylinositol 3-kinase/AKT/ epigenetic mechanisms. Loss of PTEN mTOR pathway involved in cell increases the activation of the AKT/ proliferation and regulated by PTEN. mTOR pathway, which increases cell proliferation and survival and is 9 As reported by Oliveira et al, patients associated with subsequent with JPI are offered subtotal development of various tumors. colectomy combined with intraoperative endoscopic removal of There is some preliminary evidence on polyps as a palliative disease control. the effect of sirolimus on cell It is remarkable that despite multiple proliferation in conditions with polyp resection or even subtotal generalized polyposis. Hardiman 17 colectomy, we were unable to obtain et al reported experimental evidence a decrease in the magnitude of of an inhibitory effect of rapamycin in protein loss. Sirolimus treatment a transgenic adenomatous polyposis improved severe protein-losing coli mutation–dependent colon enteropathy in our patient and polyposis mouse model. The effect on reduced the need for frequent polyps included a decrease in infusions of albumin, with an evident proliferation, an increase in improvement in her quality of life. differentiation, and prolonged time to development of dysplasia, resulting in Sirolimus (originally named increased animal survival. rapamycin) is an approved drug for Authors of several case reports have suppression of the suggested a potential role in the after organ transplant and evidence treatment of patients with PTEN suggests that use of mTOR inhibitors – hamartoma tumor syndrome,18 21 in children undergoing solid organ and there is emerging experimental transplant is efficacious and safe.10 Its and clinical evidence for role in the effect is produced by the inhibition of treatment of adenomatous a protein called mTOR, a Ser/Thr polyposis17,22 and Peutz-Jeghers , which regulates cell – syndrome.23 25 growth and proliferation and is involved in the regulation of the Although we are encouraged by the immune system and the development dramatic beneficial effect of sirolimus of blood vessels and tissue growth. in our patient over a period of time FIGURE 3 a1 antitrypsin (AT) clearance and albumin and Sirolimus (and other mTOR exceeding 2 years, we remain cautious hemoglobin levels before and after sirolimus. inhibitors) are currently being used about predicting the long-term effects. Hb, hemoglobin. for the treatment of complex vascular The development of drug resistance

Downloaded from www.aappublications.org/news by guest on October 2, 2021 4 BUSONI et al FIGURE 4 Growth improvement: length-for-age chart. WHO, World Health Organization. remains a possibility, although this is similarly affected by this condition. editor that was published after not well described when used to treat Given the rareness of the disease, our manuscript was submitted other benign conditions. We also multicenter studies should gather for review. The authors reported acknowledge that we are reporting experiences with multiple patients to a 5-year sustained positive a clinical response to sirolimus explore the safety and long-term response to sirolimus in a child without direct evidence of its effectiveness of this drug therapy. This with JPI.26 molecular effect on cells or tissue in report contributes to the growing our patient. Such evidence is beyond knowledge and experience of using the scope of this report. inhibitors of the mTOR pathway for ABBREVIATIONS various conditions associated with tumor formation and cellular AKT CONCLUSIONS : proliferation. JPI: juvenile polyposis of infancy We report successful treatment of JPS: juvenile polyposis syndrome a child suffering from complications of ACKNOWLEDGMENTS mTOR: mammalian target of severe infant juvenile polyposis using rapamycin sirolimus. This treatment should be We acknowledge a recent brief RBC: red blood cell considered for other children who are report in the form of a letter to the

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 6 BUSONI et al Successful Treatment of Juvenile Polyposis of Infancy With Sirolimus Veronica B. Busoni, Marina Orsi, Pablo A. Lobos, Daniel D'Agostino, Marta Wagener, Paola De la Iglesia and Victor L. Fox Pediatrics 2019;144; DOI: 10.1542/peds.2018-2922 originally published online July 31, 2019;

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Successful Treatment of Juvenile Polyposis of Infancy With Sirolimus Veronica B. Busoni, Marina Orsi, Pablo A. Lobos, Daniel D'Agostino, Marta Wagener, Paola De la Iglesia and Victor L. Fox Pediatrics 2019;144; DOI: 10.1542/peds.2018-2922 originally published online July 31, 2019;

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