Successful Treatment of Juvenile Polyposis of Infancy With Sirolimus

Abstract

Juvenile polyposis syndrome is a rare autosomal dominant condition characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. 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 protein-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 red blood cell transfusions every 15 days. Upper gastrointestinal endoscopy, colonoscopy, and small-bowel enteroscopy revealed diffuse polyposis that was treated with multiple endoscopic polypectomies. Despite subtotal colectomy with ileorectal anastomosis, protein-losing enteropathy and bleeding persisted, requiring continued blood transfusions and albumin infusions. A chromosomal microarray revealed a single allele deletion in chromosome 10q23, involving both the PTEN and BMPR1A genes. Loss of PTEN function is associated with an increased activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway involved in cell proliferation. Treatment with sirolimus, an mTOR inhibitor, was initiated with the aim of inhibiting polyp growth. Soon after initiation of treatment with sirolimus, blood and albumin infusions were no longer needed and resulted in improved patient growth and quality of life. This case represents the first detailed report of successful drug therapy for life-threatening juvenile polyposis of infancy.

mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion

“…In familial adenomatous polyposis (FAP), chemoprevention strategies using combined cyclo-oxygenase and epidermal growth factor inhibitors show promise in clinical trials, but they are not in routine clinical use ( 22–24 ). Case reports have described clinical benefit from mammalian target of rapamycin (mTOR) inhibitors in JPI ( 25 , 26 ), PHTS ( 27 ) and FAP ( 23 ), but their efficacy has not previously been demonstrated in controlled studies.…”

Polygenic Infantile Juvenile Polyposis Syndrome Managed With Sirolimus and Endoscopic Polypectomy

“…Previous case reports have demonstrated some success in treating juvenile polyposis with multi-organ transplantation, colectomy with endoscopic polypectomy, and even sirolimus with subtotal colectomy and sirolimus alone [4][5][6][7]. Our case report characterizes the complete clinical course of one patient with this rare disease entity.…”

“…Some short-term and long-term potential risks associated with sirolimus therapy include immunosuppression, dyslipidemia, pulmonary toxicity, nephrotoxicity, and impaired wound healing [ 8 - 10 ]. Even still, it was determined that the desired benefits of improved weight gain, reduced dependence on PN, reduced frequency of albumin and red blood cell transfusions, and avoidance of GI surgery, outweighed the risks of initiating sirolimus therapy [ 6 , 11 ].…”

“…Without intervention, infantile JPS is often associated with detrimental health sequelae such as protein losing enteropathy (PLE), blood loss, malabsorption, malnutrition, and intussusception. Extensive medical and surgical interventions are needed to mitigate the sequelae of the disease, including parenteral nutrition (PN) support, frequent transfusions of red blood cells and albumin, endoscopic polypectomies, and bowel resection [ 4 - 6 ].…”

Sirolimus for the Treatment of Juvenile Polyposis in Childhood

“… 16 On the other hand, the loss of function at the level of PTEN, another of the genes that is related to this disease, is associated with greater activation of the protein kinase B pathway (mammalian target of rapamycin [mTOR]), which is also involved in cell proliferation. 7 Although these are different mutations, both pathways are related because m-TOR interacts with the transforming growth factor-beta pathway, blocking it and, therefore, further promoting the inhibition of cell apoptosis. 16 This justifies the use of sirolimus, an mTOR inhibitor drug, in patients with JPS with mutations in the SMAD4 gene, not only if there are mutations in the PTEN (Figure 3 ).…”