Peutz-Jeghers Research Articles

Distinct promoter methylation patterns of LKB1 in the hamartomatous polyps of Peutz-Jeghers syndrome and its potential in gastrointestinal malignancy prediction

BackgroundPeutz-Jeghers Syndrome (PJS) is known as a rare inherited polyposis due to the malfunction of serine/threonine kinase gene LKB1. However, not all of PJS patients carry LKB1 germline mutation. Previous researches have observed the elevated DNA methylation level in PJS polyps. Nevertheless, the mechanism of such abnormal and its impact on PJS patients remains to be fully described.ResultsThe results proved a significant increase on the methylation level of LKB1 promoter in PJS polyps compared with normal colon biopsies through bisulfite PCR followed by Sanger sequencing. Moreover, the methylation pattern in PJS polyps could be further categorized as three different scenarios: hypermethylated, hemimethylated and hypomethylated pattern. Furthermore, immunohistochemistry of DNMT1/3a/3b suggested the up-regulation of DNMT1 and 3a might participate the epigenetic alternation of LKB1 in PJS polyps. Logistic regression suggested hypomethylated LKB1 promoter in PJS polyps as a risk factor for gastrointestinal malignancies in PJS patients.ConclusionsThe promoter methylation level of LKB1 gene in PJS polyps is generally elevated compared with normal colon mucosa. Yet not all of PJS polyps carry hypermethylated LKB1 promoter. Hypomethylation in this region has linked to malignant tumors in PJS patients. Given the rarity of PJS, this work together with previous researches, have proved the importance of LKB1 promoter methylation in PJS development and prognosis.

A case of jejunal solitary Peutz–Jeghers polyp with intussusception identified by double-balloon enteroscopy

Solitary Peutz-Jeghers polyp is a rare hamartomatous polyp that has similar histologic characteristics with those of polyps in Peutz-Jeghers syndrome, without associated mucocutaneous hyperpigmentation and a family history. Previous reports indicated that solitary Peutz-Jeghers polyp is rarely found in the small intestine. We experienced a rare case of jejunal solitary Peutz-Jeghers polyp. A 29-year-old man was admitted to our hospital with a 6-month history of upper abdominal pain. He had no hyperpigmentation or a family history of Peutz-Jeghers syndrome. Abdominal computed tomography showed a 3-cm tumor-like structure at the tip of a mildly intussuscepted jejunum. Per oral double-balloon enteroscopy revealed a 3-cm pedunculated polyp in the jejunum. The patient underwent partial jejunal resection under laparotomy. Macroscopically, the surgical specimen showed a pedunculated polyp, measuring 30 × 15 × 10mm in size, with lobulated head. Histopathologic examination revealed irregular aggregation of hyperplastic crypts with branching muscular bundles originating from the muscularis mucosae. Based on these histologic findings, we finally diagnosed the patient as a solitary Peutz-Jeghers polyp in the jejunum. The present case indicated that solitary Peutz-Jeghers polyp should be considered in a patient with solitary hamartomatous polyp in the gastrointestinal tract.

Effect of Nonsteroidal Anti-inflammatory Agents on Small Intestinal Injuries as Evaluated by Capsule Endoscopy.

Currently, because the population is aging, use of medications has been increasing, including use of nonsteroidal anti-inflammatory drugs (NSAIDs) and antithrombotic agents. This study aims to investigate whether NSAIDs can cause damage to the small bowel (SB) mucosa. Endoscopic videos of subjects who had undergone capsule endoscopy (CE) were evaluated by three experts in order to identify SB injury. All medications taken within 2weeks from the time of CE were investigated. Cases with a final diagnosis of intestinal tuberculosis, inflammatory bowel disease, Behcet's disease, Peutz-Jeghers syndrome, small bowel lymphoma, or Henoch-Schönlein purpura were excluded from the analysis. Among the 273 subjects, 125 (45.8%) had SB erosions or ulcers (erosion group) and the remaining 148 (54.2%) did not (no erosion group). SB erosions or ulcers were more common in females, patients aged > 60years, and subjects taking NSAIDs (p = 0.048, 0.032, and < 0.001, respectively). No statistically significant differences were found between the two groups in the following variables: history of cancer and GI surgery, reasons for the test, comorbidities, and use of anticoagulants and antiplatelet agents. Multivariate analysis showed that use of NSAIDs [OR 4.191 (95% CI 1.858-9.458), p < 0.001] was an independent risk factor for SB erosions or ulcers. Use of NSAIDs is the only independent risk factor for SB injury identified in this study. Antithrombotic agents do not cause or exacerbate damage to the SB, according to our results. KCT0004795.

Abstract PR03: YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis

Abstract Hamartomatous polyposis syndromes (HPS) are rare genetic syndromes, including Peutz-Jeghers syndrome (PJS) and PTEN hamartoma tumor syndrome (Cowden and Bannayan-Riley-Ruvalcaba syndromes), which are caused by germline mutations of STK11 (LKB1) and PTEN genes, respectively. HPS is characterized by the development of hamartomatous polyps in the GI tract; however, the cellular origins and molecular mechanism underlying hamartomatous polyposis remain poorly understood. Here we demonstrate that specific disruption or deletion of Stk11 or Pten in mouse GI mesenchyme, but not in the epithelium, generates hamartomatous polyps histologically resembling GI polyps observed in PJS and Cowden syndrome patients. Genetically, we show that mTOR activity is essential for Pten but not Stk11 deletion-driven hamartomatous polyposis. Furthermore, we show that AMPK1/2 deletion is not able to initiate PJS polyp formation. However, we find significant upregulation of mesenchymal YAP/TAZ activity in PJS polyps and demonstrate that YAP/TAZ in gut mesenchyme are required for Stk11 deletion-induced PJS hamartomatous polyposis. Our studies suggest a mesenchymal origin of GI polyps in HPS and reveal the distinct roles of YAP/TAZ and mTOR in gut mesenchyme during hamartomatous polyposis, which likely have important therapeutic implication for treating these HPSs. This abstract is also being presented as Poster A06. Citation Format: Jennifer L. Cotton, Kyvan Dang, Qi Li, Randy L. Johnson, Y. Tony Ip, Xu Wu, Junhao Mao. YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr PR03.

Roles of Capsule Endoscopy and Device-Assisted Enteroscopy in the Diagnosis and Treatment of Small-Bowel Tumors.

With the development of capsule endoscopy (CE) and device-assisted enteroscopy (DAE), the incidence of small-bowel tumors has increased and the characteristics of these tumors have changed. In addition, the diagnostic and therapeutic approaches for small-bowel tumors have diversified. CE is a simple, noninvasive method that aid in the visualization the entire small bowel. CE is considered the initial approach for small-bowel tumors. DAE can be used to perform endoscopic procedures such as bleeding control, polypectomy, stent insertion, and tattooing, as well as for diagnosis through visualization or tissue sampling. Therapeutic intervention with DAE is particularly useful in polyposis syndromes such as familial adenomatous polyposis and Peutz-Jeghers syndrome. This review will discuss the roles of CE and DAE in the diagnosis and treatment of small-bowel tumors.

LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin.

Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.

Peutz-Jeghars’ syndrome, a rare genetic disorder: A case report

Abstract:&#x0D; Hamartomatous polyposis syndromes or Peutz-Jeghers syndrome (PJS) is a hereditary autosomal dominant disease characterized by benign hamartomatous polyps and mucocutaneous pigmentation in the digestive tract. It occurs mostly in the small intestine during first decade of life but frequently in the colon and stomach. Only a few cases have been reported in the duodenum1. Polyposis syndromes are common cause of adult intussusceptions, with polyps acting as lead points. Adult intussusceptions are rare and is almost always associated with that lead point2. Although hamartomatous polyps are not pre-malignant, there is an increased risk of gastrointestinal and non-gastrointestinal malignancy, commonly involving the small bowel. Most patients of PJS presents with acute abdomen and diagnosed as intussusceptions, commonly entero-enteric type but colo-colic intussusceptions are rare in Peutz-Jeghers syndrome3. To the best of our knowledge, synchronous colo-colic intussusception association in Peutz-Jeghers syndrome has not been previously reported.

Secondary Prevention in Hereditary Breast and/or Ovarian Cancer Syndromes Other Than BRCA.

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndromes are among the best-known and most extensively studied hereditary cancer syndromes. Nevertheless, many patients who proved negative at BRCA genetic testing bring pathogenic mutations in other suppressor genes and oncogenes associated with hereditary breast and/or ovarian cancers. These genes include TP53 in Li–Fraumeni syndrome, PTEN in Cowden syndrome, mismatch repair (MMR) genes in Lynch syndrome, CDH1 in diffuse gastric cancer syndrome, STK11 in Peutz–Jeghers syndrome, and NF1 in neurofibromatosis type 1 syndrome. To these, several other genes can be added that act jointly with BRCA1 and BRCA2 in the double-strand break repair system, such as PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D. Management of primary and secondary cancer prevention in these hereditary cancer syndromes is crucial. In particular, secondary prevention by screening aims to discover precancerous lesions or cancers at their initial stages because early detection could allow for effective treatment and a full recovery. The present review aims to summarize the available literature and suggest proper screening strategies for hereditary breast and/or ovarian cancer syndromes other than BRCA.

Telescoping intestines intussusception in adults

Introduction: Intussusception in adults is a rare entity. Being one of the most common causes of intestinal obstruction in children, it accounts for only 5% of all cases of intussusceptions and about 1%-5% of bowel obstruction in adults. A minority of cases are idiopathic, without a lead point lesion. Postoperative adhesions, meckel’s diverticulum, inflammatory bowel disease, benign and malignant tumors, metastatic neoplasms or even iatrogenic presence of intestinal tubes, jejunostomy feeding tubes or after gastric surgery account for the various causes of secondary intussusception in 70%-90% of cases. Computerized tomography (CT) is often considered as one of the most useful, sensitive imaging modality in the diagnosis of intussusception. AIM: To study and describe the different pathological causes, clinical features and management of intussusception in adults. Materials & methods: A retrospective study was conducted to evaluate the various causes of intussusception. All patients above the age of 18yrs presenting with a clinical diagnosis of intussusception, between Jan 2008 and June 2015 were included in the study. Results: There were 15 cases of adult intussusception. A male predominance was noted and the mean age was 41.7 years. Majority of the patients presented with abdominal pain, abdominal distension, nausea and vomiting. The commonest site of intussception was the ileo-colic junction (46.7%, 7cases). There were four jejuno-jejunal cases (26.7%) and two ileo-ileal cases (13.3%). There were also two other cases of colonic intussusception, not involving the ileo-colic junction (13.3%). Among the pathological causes of intussusception, four cases were secondary to diffuse large B cell lymphoma (DLBCL), four due to submucosal lipomas, two cases secondary to peutz jegher polyps, one case of carcinoid involving the appendix, three cases due to inflammatory causes and one being idiopathic. All cases were treated surgically. Conclusion: Malignant lesions account for majority of causes of adult intussusception involving the colon. Adult intussusception is a challenging condition for the surgeon and is very often a preoperative diagnostic problem when compared to that in children. Because of the high incidence of malignancy in colonic intussusceptions, a segmental bowel resection is generally undertaken.

Jejunal Polyps that Lead to Small Bowel Intussusception in Adults: A Rare Case Report

Small intestine polyps are very rare in adults. Incidental finding of those polyps; sending them for histopathology that comes out to be Peutz-Jeghers syndrome (PJS) is extremely rare. PJS is an inherited disease characterized with typical hamartomas polyps in intestine along with distinctive skin pattern and mucocutaneous pigmentation. Gene mutation is responsible for 93% of PJS cases, among which majority of cases occur due to mutation in STK11 gene. PJS patients have 15-fold higher risk of developing cancer, including intestinal, extra-intestinal, breast, lung, pancreatic and colorectal cancer. Although PJS incidence is very low but its early recognition is very important for lowering morbidity and mortality. In this study, we have reported a very rare case of PJS in adults that was operated for small bowel obstruction secondary to intussusception. These cases are very rare in literature.

Emerging Therapeutic Implications of STK11 Mutation: Case Series.

STK11 was first recognized as a tumor suppressor gene in the late 1990s based on linkage analysis of patients with Peutz-Jeghers syndrome. STK11 encodes LKB1, an intracellular serine-threonine kinase involved in cellular metabolism, cell polarization, regulation of apoptosis, and DNA damage response. Recurrent somatic loss-of-function mutations occur in multiple cancer types, most notably in 13% of lung adenocarcinomas. Recent reports indicate that KRAS-mutant non-small cell lung cancers harboring co-mutations in STK11 do not respond to PD-1 axis inhibitors. We present three patients with STK11-mutated tumors and discuss the proposed mechanisms by which germline and somatic alterations in STK11 promote carcinogenesis, potential approaches for therapeutic targeting, and the new data on resistance to immune checkpoint inhibitors. KEY POINTS: STK11 is a tumor suppressor gene, and loss-of-function mutations are oncogenic, due at least in part to loss of AMPK regulation of mTOR and HIF-1-α. Clinical trials are under way, offering hope to patients whose STK11-mutated tumors are refractory and/or have progressed on chemotherapeutic regimens. Whether gastrointestinal cancers with STK11 loss of function will show the same outcome and potential refractoriness to immune therapy that were reported for lung cancer is unknown. However, physicians managing such patients should consider the experience in lung cancer, particularly outside the context of a clinical trial. In the CheckMate-057 trial lung tumors harboring co-mutations in KRAS and STK11 had an inferior response to PD-1 axis inhibitors. Coupled with the observation that STK11-mutated tumors were found to have a cold immune microenvironment regardless of KRAS status, the conclusion could extend to KRAS wild-type tumors with STK11 mutation. Current data suggest that the use of PD-1 axis inhibitors may be ill advised in the presence of STK11 mutation.

Two cases of somatic STK11 mosaicism in Danish patients with Peutz–Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is a hereditary polyposis syndrome characterized by hamartomatous Peutz-Jeghers polyps in the gastrointestinal tract, mucocutaneous pigmentations, and increased risk for intestinal and extraintestinal cancer. In more than two-third of patients it is possible to detect pathogenic variants in the serine/threonine kinase 11 (STK11) gene, but so far is knowledge about genetic causes in the remaining part of patients limited. Reports of STK11 mosaicism are rare but may be an explanation in some patients without initial findings of pathogenic variants in STK11. We report two Danish patients with STK11 mosaicism detected in blood when using Next-Generation Sequencing. This is only the sixth and seventh patient reported in the literature, and we compare phenotypes of the reported cases. The results indicate that STK11 mosaicism is more frequent than anticipated and highlight that mosaicism should be considered in patients with clinical suspicion of PJS or patients fulfilling the diagnostic criteria.

Urgent double-balloon enteroscopy for reduction of jejuno-jejunal intussusception and polypectomy in Peutz-Jeghers syndrome

A 13-year-old girl presented with sudden-onset colicky abdominal pain and biliary vomiting. She was diagnosed with Peutz-Jeghers syndrome 2 months previously based on mucocutaneous pigmentation and hamartomatous polyposis. On diagnosis of Peutz-Jeghers syndrome, in addition to colonoscopy and esophagogastroduodenoscopy, antegrade and retrograde double-balloon enteroscopies were performed, and >10 hamartomas were resected. She was scheduled for additional elective double-balloon enteroscopy for total small-bowel observation. On visiting the emergency unit, enhanced abdominal computed tomography showed jejuno-jejunal intussusception with a polyp. There were no ischemic signs in the invaginated bowel. Urgent antegrade double-balloon enteroscopy performed 5 hours after onset of acute abdominal symptoms revealed a large polyp with intussusception stalk in the jejunum, and simultaneous reduction of intussusception and endoscopic mucosal resection of the polyp were performed successfully. There were no endoscopy-related complications, and emergent laparotomy was avoided. The patient has been asymptomatic, and total gastrointestinal screening is scheduled every 2 years. This is the first case in which emergent laparotomy was avoided by urgent double-balloon enteroscopy in an adolescent with symptomatic jejuno-jejunal intussusception. Non-surgical management of small-bowel polyps in pediatric patients with Peutz-Jeghers syndrome is beneficial as laparotomy can cause bowel adhesion and increases risk of incomplete balloon-assisted enteroscopy.

Abstract A049: Program for the identification, management and monitoring of patients and families at high risk of cancer in a Colombian National Cancer Reference Institution

Abstract Cancer is the second cause of mortality due to noncommunicable diseases in Colombia. In 2015 incident cases of breast (BC), gastric (GC), colorectal (CRC), and ovarian cancer (OC) attended at the Colombian National Cancer Institute (NCI) were 685, 498, 470, and 127, respectively. Although hereditary cancer syndromes are the minority of all cancer cases, the precise identification of individuals and relatives at high risk is a key aspect to the implementation of surveillance/screening, chemoprevention, and preventive surgery strategies for affected and unaffected carriers. In our country there are few studies conducted on hereditary cancer, and little is known about the spectrum of syndromes affecting Colombian families. In the Colombian NCI, we have designed and develop a comprehensive program for the registration, identification, diagnosis, management, and surveillance of cancer cases at high risk. Two main strategies where defined within this pilot program: 1) adjustment of the international protocols to the institutional context for identification and referral criteria of cancer patients with suspected syndrome to genetic counseling, genetic testing criteria, management, and surveillance, and 2) implementation of an institutional registry of patients with hereditary cancer, among other strategies. Also, first-degree relatives (FDR) of the affected carriers are offered to be tested and followed through the Center for Cancer Prevention and Early Detection (CPRED), recently established by the Colombian NCI. This Institutional ongoing program is providing genetic risk assessment to an average of 20 cancer patients per week since April 2018. The most frequent cancer we have attended is BC (56%), followed by CRC (10.5%), OC (6%), GC (5.5%), and others (22%). The average age at diagnosis was 47.3 for BC, 50.6 for CRC, 33.6 for OC, 39.4 for GC, and 47.8 years old (yo) for other cancers. Genetic testing has been offered to the patients according to the international guidelines. From all BC cases, the following fulfilled the Hereditary Breast and Ovarian Cancer (HBOC) criteria: i) 44.3% were diagnosed ≤ 45 yo, ii) 24% were diagnosed with triple-negative breast cancer (TNBC) at ≤ 60 yo, iii) 4% were TNBC cases diagnosed at &amp;gt; 60 yo + ≥ 1 FDR/second-degree relative with BC at &amp;lt; 50 yo, iv) 8% were patients with bilateral BC, v) 4% had a second primary tumor, and vi) 1.3% had Ashkenazi Jewish ancestry. From CRC cases, 50% were diagnosed at &amp;lt; 50 yo regardless of family history of gastrointestinal cancers and 30% were diagnosed at ≥ 50 yo and fulfilled criteria for Lynch or Li Fraumeni syndromes. In the case of GC, 60% of the patients had diffuse gastric cancer subtype at &amp;lt; 50 yo. Finally, all OC cases were submitted for genetic testing since all were diagnosed at &amp;lt; 50 yo; 43% were tested for HBOC since they corresponded to papillary serous subtype and 29% fulfilled criteria for Peutz Jeghers syndrome. To our knowledge, this is the first genetic cancer risk assessment program in the country, based in the largest Colombian cancer hospital. Citation Format: María Carolina Sanabria-Salas, Gonzalo Guevara-Pardo, Antonio Huertas, Vilma Medina, Ana Lucía Rivera-Herrera, Juan Carlos Mejía, Jesús Acosta, Carolina Wiesner-Ceballo. Program for the identification, management and monitoring of patients and families at high risk of cancer in a Colombian National Cancer Reference Institution [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A049.

AGA Clinical Practice Update on Pancreas Cancer Screening in High-Risk Individuals: Expert Review

The purpose of this American Gastroenterological Association Institute Clinical Practice Update is to describe the indications for screening for pancreas cancer in high-risk individuals. The evidence reviewed in this work is based on reports of pancreas cancer screening studies in high-risk individuals and expert opinion. BEST PRACTICE ADVICE 1: Pancreas cancer screening should be considered in patients determined to be at high risk, including first-degree relatives of patients with pancreas cancer with at least 2 affected genetically related relatives. BEST PRACTICE ADVICE 2: Pancreas cancer screening should be considered in patients with genetic syndromes associated with an increased risk of pancreas cancer, including all patients with Peutz-Jeghers syndrome, hereditary pancreatitis, patients with CDKN2A gene mutation, and patients with 1 or more first-degree relatives with pancreas cancer with Lynch syndrome, and mutations in BRCA1, BRCA2, PALB2, and ATM genes. BEST PRACTICE ADVICE 3: Genetic testing and counseling should be considered for familial pancreas cancer relatives who are eligible for surveillance. A positive germline mutation is associated with an increased risk of neoplastic progression and may also lead to screening for other relevant associated cancers. BEST PRACTICE ADVICE 4: Participation in a registry or referral to a pancreas Center of Excellence should be pursued when possible for high-risk patients undergoing pancreas cancer screening. BEST PRACTICE ADVICE 5: Clinicians should not screen average-risk individuals for pancreas cancer. BEST PRACTICE ADVICE 6: Pancreas cancer screening in high-risk individuals should begin at age 50 years, or 10 years younger than the initial age of familial onset. Screening should be initiated at age 40 years in CKDN2A and PRSS1 mutation carriers with hereditary pancreatitis and at age 35 years in the setting of Peutz-Jeghers syndrome. BEST PRACTICE ADVICE 7: Magnetic resonance imaging and endoscopic ultrasonography (EUS) should be used in combination as the preferred screening modalities in individuals undergoing pancreas cancer screening. BEST PRACTICE ADVICE 8: The target detectable pancreatic neoplasms are resectable stage I pancreatic ductal adenocarcinoma and high-risk precursor neoplasms, such as intraductal papillary mucinous neoplasms with high-grade dysplasia and some enlarged pancreatic intraepithelial neoplasias. BEST PRACTICE ADVICE 9: Screening intervals of 12 months should be considered when there are no concerning pancreas lesions, with shortened intervals and/or the performance of EUS in 6-12 months directed towards lesions determined to be low risk (by a multidisciplinary team). EUS evaluation should be performed within 3-6 months for indeterminate lesions and within 3 months for high-risk lesions, if surgical resection is not planned. New-onset diabetes in a high-risk individual should lead to additional diagnostic studies or change in surveillance interval. BEST PRACTICE ADVICE 10: Decisions regarding therapy directed towards abnormal findings detected during screening should be made by a dedicated multidisciplinary team together with the high-risk individual and their family. BEST PRACTICE ADVICE 11: Surgical resection should be performed at high-volume centers. BEST PRACTICE ADVICE 12: Clinicians should consider discontinuing pancreas cancer screening in high-risk individuals when they are more likely to die of non-pancreas cancer-related causes due to comorbidity and/or are not candidates for pancreas resection. BEST PRACTICE ADVICE 13: The limitations and potential risks of pancreas cancer screening should be discussed with patients before initiating a screening program.

Clinical and Genetic Analyses of 38 Chinese Patients with Peutz-Jeghers Syndrome.

Background Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease caused by a germline mutation in the STK11 gene. It is characterized by mucocutaneous pigmentation, gastrointestinal hamartomatous polyps, and cancer predisposition. Aims We aimed to summarize the main clinical and genetic features of Chinese PJS patients and assessed the genotype-phenotype correlations. Methods Thirty-eight patients clinically diagnosed with Peutz-Jeghers syndrome were included in this study from 2016 to 2019. Combined direct sequencing and multiplex ligation-dependent probe amplification tests were used to detect germline heterogeneous STK11 mutations. RNA sequencing was performed in polyps of PJS patients and control groups to evaluate the difference in expression of STK11. The genotype-phenotype correlations were calculated by Kaplan-Meier analyses. Results All 26 probands and 12 affected relatives had germline heterogeneous STK11 mutations among which 8 variants were novel. Individuals with missense mutations had their first surgery and other symptoms significantly later than individuals with null mutations. Conclusion This study expanded the spectrum of STK11 gene mutations and further elucidated individuals with null mutations of STK11 typically had an earlier onset of PJS symptoms and needed earlier management.

SUN-940 Carney Complex: A Case of a Rare Multiple Endocrine Neoplasia Misdiagnosed as Peutz-Jeghers Syndrome

Carney Complex (CNC) is an extremely rare multiple endocrine neoplasia caused by germline inactivating mutation in protein kinase A type I-alpha regulatory subunit (PRKAR1A gene). Mode of inheritance is mostly autosomal dominant; 25% of cases are due to de novo mutations. Only 750 world-wide cases have been reported. Most patients are diagnosed in the second or third decade. Clinical features include cutaneous myxomas, angiomyxoid nodules, lentiginous skin pigmentation, cardiac myxomas, and benign and rare malignant endocrine tumors. These endocrine tumors include and are not limited to prolactinomas, thyroid tumors, primary pigmented nodular adrenocortical disease (PPNAD), and large cell-calcifying Sertoli cell tumors (LCCSCT). Diagnosis is often challenging as disease manifestations can occur sporadically over a large span of time, and patients may present with various conditions such as Cushing syndrome, like our case. We present a case that demonstrates the importance of early recognition of this rare disorder.A 28-year-old Caucasian male with PMH of HFrEF, HTN, Sertoli cell tumor status post orchiectomy, vertebral fractures, and surgical removal of lip angiomyxoma presented to clinic for hypogonadism. Physical examination revealed marked Cushingoid features and facial lentigines above his eyes and on his lips. His eclectic medical history and unique exam findings lead to finding of a unifying diagnosis. His labs revealed severe Cushing syndrome, and computed tomography (CT) of his abdomen was performed due to ACTH independent hypercortisolism, demonstrating a bilateral lobular appearance of the adrenal glands.Combination of labs and physical exam findings of lentigines, skin myxomas, cushingoid features, rare angiomyxoma, LCCSCT and hypercortisolism lead to diagnosis of Carney Complex. He was misdiagnosed with Peutz-Jeghers in his adolescence due to LCCSCT and mucosal lentigines; therefore, hormonal screening was not routinely performed. Untreated Cushings led to severe osteoporosis with vertebral fractures and heart failure. Treatment included bilateral adrenalectomy. Pathology report confirmed rare PPNAD. PPNAD and LCCSCT are extremely rare tumors almost exclusively linked to Carney Complex. Interestingly, family history did not reveal endocrine disorders, cancers, or severe illnesses. Genetic testing returned positive for the PRKAR1A gene mutation. Given the consequences of untreated hormonal aberrations seen in this disorder, an early and accurate diagnosis is imperative.

Ovarian sex cord tumour with annular tubules in a 13-year-old female: a case report.

Sex cord tumour with annular tubules (SCTAT) is uncommon and distinctive type of sex cord-stromal tumours of the ovary which develops from sex cord cells. Most of SCTATs are strongly associated with Peutz–Jeghers syndrome (PJS) and have low malignancy potential; however, 20% of non-PJS-associated SCTATs have been reported to have high malignancy potential. Herein, we present a 13-year-old female who presented with severe abdominal pain localized in the right lower side, associated with nausea. Based on histopathological and immunohistochemical findings, the diagnosis was confirmed to be SCTAT. SCTAT of the ovary is extremely rare in the paediatric population as compared to the general population. Its occurrence among paediatrics as it was the case in the patient described in this paper may pose diagnostic challenges due to lack of clinical suspicion and therefore resulting in delay of diagnosis.

Mutation analysis of related genes in hamartoma polyp tissue of Peutz-Jeghers syndrome

BACKGROUNDPeutz-Jeghers syndrome (PJS) is a rare disease with clinical manifestations of pigmented spots on the lips, mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors. The clinical heterogeneity of PJS is obvious, and the relationship between clinical phenotype and genotype is still unclear.AIMTo investigate the mutation status of hereditary colorectal tumor-associated genes in hamartoma polyp tissue of PJS patients and discuss its relationship with the clinicopathological data of PJS.METHODSTwenty patients with PJS were randomly selected for this study and were treated in the Air Force Medical Center (former Air Force General Hospital) PLA between 2008 and 2017. Their hamartoma polyp tissues were used for APC, AXIN2, BMPR1A, EPCAM, MLH1, MLH3, MSH2, MSH6, MUTYH, PMS1, PMS2, PTEN, SMAD4, and LKB1/STK11 gene sequencing using next-generation sequencing technology. The correlations between the sequencing results and clinical pathological data of PJS were analyzed.RESULTSFourteen types of LKB1/STK11 mutations were detected in 16 cases (80.0%), of which 8 new mutations were found (3 types of frameshift deletion mutations: c.243delG, c.363_364delGA, and c.722delC; 2 types of frameshift insertions: c. 144_145insGCAAG, and c.454_455insC; 3 types of splice site mutations: c.464+1G>T, c.464+1G>A, and c.598-1G>A); 9 cases (45.0%) were found to have 18 types of heterozygous mutations in the remaining 13 genes except LKB1/STK11. Of these, MSH2: c.792+1G>A, MSH6: c.3689C>G, c.4001+13C>CTTAC, PMS1: c.46C>t, and c.922G>A were new mutations.CONCLUSIONThe genetic mutations in hamartoma polyp tissue of PJS are complex and diverse. Moreover, other gene mutations in PJS hamartoma polyp tissue were observed, with the exception of LKB1/STK11 gene, especially the DNA mismatch repair gene (MMR). Colorectal hamartoma polyps with LKB1/STK11 mutations were larger in diameter than those with other gene mutations.

Cierre de perforación de intestino delgado posterior a polipectomía de pólipo hamartomatoso

Single balloon enteroscopy allows a non-surgical therapeutic approach in patients with small bowel polyps. In patients with Peutz Jeghers Syndrome (SPJ) resection of hamartomatous polyps with this method is safe and effective. Although complications are rare, if they occur, they can be managed conservatively. We present a 16-year-old patient with a history of PJS who underwent an enteroscopy for small bowel polyps. Endoscopic resection of a 3 cm jejunum polyp was performed, and a full thickness intestinal perforation was immediately noticed after the resection. We were able to close the gap with hemo clips. The patient had an excellent clinical outcome.