Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.

Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort.

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.

The c.386A>C p.(Asn129Thr) variant in SMAD4 is likely to be pathogenic, causing Juvenile Polyposis Syndrome. A case report of a mosaic variant.

BACKGROUND: Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple hamartomatous gastrointestinal polyps. Here, we present a case of JPS with a mosaic variant in SMAD4. METHODS: Exome sequencing TRIO analysis, using germline DNA from the biological mother and father along with the index case (IC). RESULTS: A 46-year-old male with no family history of cancer presented with chronic iron deficiency anemia and was diagnosed with massive gastric polyposis (≥100 polyps). At the age of 59, he underwent a total gastrectomy, revealing numerous polyps occupying the entire gastric mucosa, including a 5 cm gastric hyperplastic polyp with high-grade dysplasia and focal adenocarcinoma. TRIO analysis identified the c.386A>C p.(Asn129Thr) variant in the SMAD4 gene at an allele frequency (AF) of 22%, suggesting its mosaic origin. Subsequently, the variant was found in heterozygosity in the IC's son, who exhibited two subcentimeter polyps in the colon and seven inflammatory gastric polyps with gastric inflammatory areas and hyperplasia, suggesting that the c.386A>C p.(Asn129Thr) variant in SMAD4 segregated with the phenotype. CONCLUSION: Our study provides evidence supporting the classification of the c.386A>C p.(Asn129Thr) variant in SMAD4 as a likely pathogenic variant. This finding contributes to improved accuracy in the diagnosis and genetic counseling of JPS.

Will previous antimicrobial therapy reduce the positivity rate of metagenomic next-generation sequencing in periprosthetic joint infections? A clinical study.

Background: Metagenomic next-generation sequencing (mNGS) is a culture-independent massively parallel DNA sequencing technology and it has been widely used for rapid etiological diagnosis with significantly high positivity rate. Currently, clinical studies on evaluating the influence of previous antimicrobial therapy on positivity rate of mNGS in PJIs are rarely reported. The present study aimed to investigate whether the positivity rate of mNGS is susceptible to previous antimicrobial therapy. Methods: We performed a prospective trial among patients who undergone hip or knee surgery due to periprosthetic joint infection (PJI) to compare the positivity rate of culture and mNGS between cases with and without previous antimicrobial therapy, and the positivity rates between cases with different antimicrobial-free intervals were also analysed. Results: Among 131 included PJIs, 91 (69.5%) had positive cultures and 115 (87.8%) had positive mNGS results. There was no significant difference in the positivity rate of deep-tissue culture and synovial fluid mNGS between cases with and without previous antimicrobial therapy. The positivity rate of synovial fluid culture was higher in cases with previous antimicrobial therapy. The positivity rates of mNGS in synovial fluid decreased as the antimicrobial-free interval ranged from 4 to 14 days to 0 to 3 days. Conclusion: mNGS is more advantageous than culture with a higher pathogen detection rate. However, our data suggested that antimicrobial agents may need to be discontinued more than 3 days before sampling to further increase the positivity rate of mNGS for PJIs.

Juvenile polyposis syndrome: An overview.

Juvenile polyposis syndrome (JPS) is a rare precancerous condition that confers an increased risk of developing gastrointestinal cancers. The inheritance pattern is autosomal dominant. JPS should be clinically suspected when the other hamartomatous polyposis syndromes are excluded (i.e., Peutz- Jeghers and Cowden), in presence of numerous juvenile polyps in the colorectum or in other GI locations. Among the syndromic features, JPS can present with concomitant extra-intestinal manifestations, above all cutaneous manifestations such as telangiectasia, pigmented nevi, and skeletal stigmata. Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. In JPS a cumulative risk of CRC of 39-68% has been estimated. The oncological risk justifies and imposes prevention strategies that aim at the cancer risk reduction through endoscopic screening, as recommended by international scientific societies. The aim of this review is to summarize clinical and genetic features of JPS and to elucidate the steps of the clinical management from diagnosis to surveillance.

Juvenile polyposis: Focus on less described manifestations.

Juvenile polyposis represents an heterogeneous disease as different genetic dominant backgrounds have been evidenced leading to different clinical presentations. It is associated in some patients with a different syndrome, Hereditary Hemorragic Telangiectasia, justifying a complementary and different management. Recent international recommendations help in managing this very rare disease, and this management should probably be restricted to expert centers able to take care of the multiple manifestations and risks of these patients and families. This paper will focus on the poorly known and evaluated aspects of juvenile polyposis, excluding the colonic involvement and epidemiology that are addressed in a different article of this issue.

A case of early gastric cancer in a patient with gastric juvenile polyposis diagnosed by magnifying endoscopy and resected by endoscopic submucosal dissection.

Gastric juvenile polyposis (GJP) is frequently associated with the development of gastric cancer. However, there are no reports of gastric cancer in patients with GJP diagnosed using magnifying endoscopy with narrow-band imaging (M-NBI) and successfully treated by endoscopic submucosal dissection (ESD). A 50-year-old woman was referred to our hospital. Conventional white-light endoscopy revealed numerous aggregated polyps with reddish and whitish areas in the gastric cardia. M-NBI revealed a regular microvascular pattern (MVP) and regular microsurface pattern (MSP) in the reddish area of the lesion, and they were diagnosed as non-cancerous polyps. There was a clear demarcation line between the reddish and whitish areas, with irregular MVP plus irregular MSP in the whitish area, which was diagnosed as early gastric cancer. The horizontal extent of the cancer was precisely identified using M-NBI, and the en bloc resection of cancerous lesions was performed using ESD. Histopathological examination of the resected specimen showed that the reddish area comprised a hyperplastic foveolar epithelium. Conversely, the whitish area was diagnosed as a well-differentiated adenocarcinoma. The cancer was limited to the mucosa, lymphovascular invasion was negative, and horizontal and vertical margins were free from cancerous tissue. According to surveillance endoscopy, there has been no recurrence 11 years after ESD. This is the first report demonstrating that M-NBI is useful for making a precise diagnosis of cancer in juvenile polyposis and that ESD can be an option for the treatment of such a cancer.

An additional patient with SMAD4-Juvenile Polyposis-Hereditary hemorrhagic telangiectasia and connective tissue abnormalities: SMAD4 loss-of-function and gain-of-function pathogenic variants result in contrasting phenotypes.

Loss-of-function pathogenic variants in somatic and germline cells in SMAD4 may cause cancer and juvenile polyposis-Hereditary Hemorrhagic Telangiectasia (SMAD4-JP-HHT), respectively. In a similar manner, gain-of-function somatic and germline pathogenic variants in SMAD4 can cause various forms of cancer as well as Myhre syndrome. The different SMAD4 molecular mechanisms result in contrasting clinical phenotypes demonstrated by SMAD4-JP-HHT and Myhre syndrome. We report an additional patient with SMAD4-JP-HHT and aortopathy, and expand the phenotype to include severe valvulopathy, cutaneous, ophthalmologic, and musculoskeletal features consistent with an inherited disorder of connective tissue. We compared this 70-year-old man with SMAD4-JP-HHT to 18 additional literature cases, and also compared patients with SMAD4-JP-HHT to those with Myhre syndrome. In contrast to aorta dilation, hypermobility, and loose skin in SMAD4-JP-HHT, Myhre syndrome has aorta hypoplasia, stiff joints, and firm skin representing an intriguing phenotypic contrast, which can be attributed to different molecular mechanisms involving SMAD4. We remind clinicians about the possibility of significant cardiac valvulopathy and aortopathy, as well as connective tissue disease in SMAD4-JP-HHT. Additional patients and longer follow-up will help determine if more intensive surveillance improves care amongst these patients.

[A case of juvenile gastric polyposis with gastric cancer successfully treated by laparoscopic total gastrectomy -review of 36 reported cases in Japan].

A 43-year-old woman was suffering from epigastric pain. Her gastroscopy revealed polyposis of the stomach, and her biopsy revealed a hyperplastic polyp. During the 18-month follow-up, the polyps proliferated, and the patient was referred to our institute for further investigation and treatment. A juvenile gastric polyposis diagnosis was made. She refused to have the surgery despite the fact that it was necessary due to the anemia and hypoalbuminemia she was experiencing. Endoscopic biopsy results revealed gastric cancer at a follow-up visit 2 years and 3 months later; thus, a laparoscopic total gastrectomy was performed. Pathological examination revealed adenocarcinomas that were scattered and well-differentiated, with hyperplastic polyps in the background. No lymph node metastasis was found. Despite the fact that juvenile gastric polyposis is a pathologically benign disease, there have been numerous case reports of surgery being performed due to anemia, hypoalbuminemia, or gastric cancer associated with the disease. When gastric cancers are discovered in cases of juvenile gastric polyposis, they are usually in an early stage, making them a good candidate for laparoscopic total gastrectomy.

FOCAD Indel in a Family With Juvenile Polyposis Syndrome.

Juvenile polyposis syndrome (JPS) is a childhood polyposis syndrome with up to a 50% lifetime risk of gastrointestinal cancer. Germline pathogenic variants in BMPR1A and SMAD4 are responsible for around 40% of cases of JPS, but for the majority of individuals, the underlying genetic cause is unknown. We identified a family for which polyposis spanned four generations, and the proband had a clinical diagnosis of JPS. Next-generation sequencing was conducted, followed by Sanger sequencing confirmation. We identified an internal deletion of the FOCAD gene in all family members tested that altered the reading frame and is predicted to be pathogenic. We conclude that inactivation of the FOCAD gene is likely to cause JPS in this family.

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S. Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

A novel BMPR1A mutation affects mRNA splicing in juvenile polyposis syndrome.

BACKGROUND: Juvenile polyposis syndrome (JPS) is one of the hereditary polyposis syndromes caused by abnormal regulation of transforming growth factor ß signaling because of mutations in BMPR1A and SMAD4. Juvenile polyposis syndrome patients with SMAD4 mutations develop cardiovascular events, whereas those with BMPR1A usually do not. Analysis of genetic mutations in JPS patients can be helpful in devising suitable strategies for medical management. In this study, we demonstrate the pathogenicity of a novel intronic mutation in BMPR1A using mRNA extracted from colonic mucosa of a boy with JPS. METHODS: Genomic DNA extracted from peripheral blood and total RNA isolated from the colonic mucosa were used for DNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively. RESULTS: A 13-year-old boy, with no previous medical history, presented to the hospital complaining of bloody stools. Colonoscopy revealed multiple polyps in the colon, and the resected polyps were compatible with juvenile polyps. Sequencing analysis revealed a novel intronic mutation (c.778+5G>C) in BMPR1A. Reverse transcription polymerase chain reaction analysis of RNA extracted from the colonic mucosa showed an aberrant splicing form of BMPR1A. Trio analysis showed that his mother also had the same BMPR1A mutation. She was diagnosed with cancer of the cecum and polyposis of the colon at the age of 41. CONCLUSION: We demonstrate the presence of a novel BMPR1A intronic mutation that exhibits splicing abnormality in a family with JPS. Further research and development will help elucidate the genotype-phenotype relationship in JPS.

Digital Clubbing in Hereditary Hemorrhagic Telangiectasia/Juvenile Polyposis Syndrome.

Hereditary hemorrhagic telangiectasia (HHT) (Osler-Weber-Rendu Syndrome) is a rare autosomal dominant vascular disorder characterized by the presence of multiple arteriovenous malformations (AVMs) and recurrent bleeding episodes. The diagnosis is based on the Curacao criteria: (i) spontaneous recurrent epistaxis, (ii) mucocutaneous telangiectasia, (iii) AVMs of visceral organs, and (iv) first degree relatives with a similar condition (1). Due to a common genetic pathway and SMAD4 gene mutation, juvenile polyposis syndrome (JPS) may coexist with HHT (2). The disease burden is high in overlapping HHT/JPS, but digital clubbing may be the only physical finding. Continuous meticulous management may improve the quality of life and reduce the risk of complications. In 2000, a 15-year-old female patient was diagnosed with HHT based on epistaxis, multiple pulmonary AVMs, and a father who had similar symptoms. Other visceral AVMs were excluded. No telangiectasia was noted. On several occasions, pulmonary AVMs were managed with coil embolization (Figure 1), which successfully led to the resolution of dyspnea and cyanosis. Recurrent gastrointestinal bleedings led to severe transfusion-dependent anemia. Multiple polyps in the stomach, small intestine, and colon were repeatedly endoscopically removed, confirming the coexisting JPS. Genetic testing was not performed. Proctocolectomy was performed to prevent malignant transformation in the digestive tract. Telangiectasias are the dermatological hallmark of the HHT and occur in up to 90% of patients with the typical onset in childhood, becoming more apparent with increasing age. They are most frequently found on the face, with highest incidence on the nose, lips, tongue, and ears, followed by the fingertips, trunk, and feet; telangiectasia is recognized as the most common of the three criteria required for the diagnosis of HHT (1). Interestingly, no cutaneous telangiectasia developed in our patient during years of follow-up. However, pulmonary AVMs led to digital clubbing of her both fingers and toes (Figure 2). Digital clubbing is the focal enlargement of the connective tissue in the terminal phalanges, consequently changing the shape of nails, which become abnormally curved and shiny. It is associated with various infectious, neoplastic, inflammatory, and vascular conditions (3). Despite its well-known prevalence in certain conditions, the pathogenesis of this phenomenon remains elusive. Vascular, neural, and hormonal mechanisms have been considered, implicating the role of a wide range of substances, such as prostaglandins, bradykinin, estrogen, platelet-derived growth factor, hepatocyte growth factor, and growth hormone, however, none of these mechanisms provide a unifying explanation (4,5). In digital clubbing, the increased vascularity in the nail-bed leads to hyperplasia of fibrous tissue and edema, resulting in a loss of the hyponychial angle, fluctuance of the nail-bed, and an abnormal phalangeal depth ratio (5). The clinical assessment of the clubbing is based on the measurement of the distal phalangeal depth (DPD) of the finger (at the nail base) and the interphalangeal depth (IPD). A DPD/IPD ratio >1 is defined as clubbing, while a DPD/IPD ratio <1 is defined as normal (3). Clubbing is a potentially reversible phenomenon provided that the underlying condition is cured (4,5). In the context of pulmonary AVMs, abnormal communication between the pulmonary artery and pulmonary vein outside the capillary bed leads to right-to-left shunt physiology that clinically presents as dyspnea, cyanosis, and clubbing. Embolization of AVMs as the first-line therapy resolved systemic symptoms in our patient, and therefore no other treatment options were pulmonary considered further. However, 20 years later, despite the treatment, the severe clubbing of her both fingers and toes remained (Figure 2). Based on our findings, HHT should be considered in differential diagnosis of patients with digital clubbing resulting from AVMs, in particular when no skin telangiectasia is present.

SMAD4 Germline Pathogenic Variant-Related Gastric Juvenile Polyposis with Adenocarcinoma Treated with Laparoscopic Total Gastrectomy: A Case Report.

BACKGROUND Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases. CASE REPORT A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing. CONCLUSIONS JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

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

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.