Introduction

The lactulose breath test (L-BT) is a non-invasive method to assess small intestinal bacterial overgrowth (SIBO). However, diagnostic criteria for intestinal methanogenic overgrowth (IMO) differ among experts, and international guidelines lack a definition. Methanogenic flora is linked to slower gut transit in irritable bowel syndrome (IBS), but the effects of methane-targeting treatments on methanogens, colonic transit, and stool form remain unclear.

Aims & Methods

To examine relationships between methanogenesis, constipation, pain and bloating in healthy volunteers and patients with and without IBS. METHODS: Cross-sectional study on adults with L-BT between 2016–2024 at a single center. Each patient completed a Rome IV questionnaire, sociodemographic and medical data and Bristol stool scale. IMO was diagnosed if there were more than 3 measurements of CH₄ over 10 ppm over 180 minutes. We examineded 3 alternate diagnostic thresholds: (A) 10 ppm at any time (American criteria or C1); (B) 10 ppm over baseline before 90 minutes (C2); and (C) 10 ppm over baseline before 60 minutes (C3), We considered “high producers” of CH₄ those that had 2 measurements over 60 ppm. Statistical analysis with Mann-Whitney and Kruskal Wallis test.

Results

We included 5,053 subjects who underwent L-BT (mean age 49 years, 81% women). Of these, 10% were exclusive H2 producers, 2% CH4 producers, and 2.7% were non H2/CH4 producers. CH4 producers had a higher frequency of constipation (p<0.001) and greater total CH4 production in the Bristol 1-2 group. CH4 production over 180 minutes was lower in IBS-D patients, though the overall methane production rate was similar to healthy volunteers. Based on diagnostic thresholds, 92.6% of constipated patients met C1, 52.3% C2, and 18.1% C3, with significant differences (p=0.001). Stricter IMO criteria were associated with greater bloating and pain intensity.

Conclusion

The high proportion of methane production in our asymptomatic controls, compared to previous series, may reflect demographic differences. Methane producers had a higher frequency of constipation. The IMO diagnosis rate varied depending on the criteria used, with stricter criteria identifying patients with more frequent constipation, bloating, and abdominal pain.

Disclosure

None

Introduction

Emerging epidemiologic evidence suggested that moderate-to-vigorous physical activity (MVPA) was associated with a lower risk of steatotic liver disease (SLD).¹ However, several issues remain unanswered. First, prospective association between PA and hepatic steatosis was less investigated, with few studies mainly in Western populations,^{2, 3} but not in Chinese populations. Second, since sedentary behavior and PA are interrelated and may jointly affect the health outcomes,⁴ a key concern is whether moderate-to-vigorous physical activity (MVPA) can mitigate the detrimental link between sedentary time and SLD. Moreover, PA was shown to affect the gut microbiome by altering the bile acid profile and promoting the production of metabolites such as short-chain fatty acids^5,6 with benefit to SLD in animal models.⁷ However, PA-related gut microbes and metabolites, as well as their associations with SLD risk were rarely investigated at the population level.

Aims & Methods

We investigated the association between PA and the SLD risk in a cohort of 2,942 adults from the Anhui Liver Disease Study (ALDS), in which PA and SLD were measured using a validated self-reported questionnaire and transient elastography, respectively. In a subset of ALDS (n=330), we further identified gut microbial changes and serum metabolites related to MVPA assessed by accelerometer, and examined their associations with SLD risk. Fecal samples for 16S ribosomal RNA sequencing were collected twice (1-year apart) to evaluate 1-year microbial changes, targeted metabolomics analysis of baseline serum samples was performed using liquid chromatography tandem mass spectrometry, while PA was measured using a wrist-worn accelerometer for 3 consecutive days at baseline. Cox and Logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs) with 95%CIs, respectively.

Results

From 2020 to 2025, 565 SLD cases were newly diagnosed. MVPA levels were inversely (per 1-SD increase HR=0.91, 95%CI: 0.83–0.99) and sedentary hours were positively associated with the risk of SLD (HR=1.13, 95%CI: 1.03–1.24). Relative to long-low group (i.e., participants with long sedentary time and low MVPA level), HRs (95%CIs) for SLD risk were 1.00 (0.78–1.28), 0.93 (0.73–1.19), and 0.75 (0.58–0.97) for long-high, short-low, and short-high group, respectively. The α-diversity decreased in the low MVPA group (p=0.024) and the β-diversity changed in both low and high MVPA groups (all p=0.001). We identified 14 microbial genera whose relative abundance significantly changed in low or high MVPA group (all p_FDR<0.05). Among these genera, Proteus and Synergistes were associated with both low and high MVPA but in opposite directions, and were associated with SLD with ORs (95%CIs) of 1.15 (1.01–1.32) and 0.91 (0.78–1.06), respectively. Targeted metabolomics showed an inverse association between MVPA and serum L-Valine (β=-0.068, p_FDR=0.031), which was positively related to SLD risk (OR=16.40, 95%CI: 2.67–111.94). Significant correlations were also found between PA-associated microbial genera and L-Valine.

Conclusion

MVPA may modify gut microbial diversity and composition, as well as serum metabolite levels, and is associated with lower SLD risk, whereas sedentary behavior is associated with higher SLD risk.

References

[1] European Association for the Study of the Liver . Electronic address eee, European Association for the Study of D, European Association for the Study of O, et al. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.
[2] McDonough DJ, Mathew M, Pope ZC, et al. Aerobic and Muscle-Strengthening Physical Activity, Television Viewing, and Nonalcoholic Fatty Liver Disease: The CARDIA Study. Journal of Clinical Medicine 2023;12.
[3] Liu M, Ye Z, Zhang Y, et al. Accelerometer-derived moderate-to-vigorous physical activity and incident nonalcoholic fatty liver disease. BMC Medicine 2024;22.
[4] Ekelund U, Tarp J, Steene-Johannessen J, et al. Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis. Bmj 2019;366:l4570.
[5] Penney N, Barton W, Posma JM, et al. Investigating the Role of Diet and Exercise in Gut Microbe-Host Cometabolism. mSystems 2020;5.
[6] Campaniello D, Corbo MR, Sinigaglia M, et al. How Diet and Physical Activity Modulate Gut Microbiota: Evidence, and Perspectives. Nutrients 2022;14.
[7] Chen J, Vitetta L. Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications. Int J Mol Sci 2020;21.

Introduction

Small intestinal bacterial overgrowth (SIBO) is characterized by the presence of excessive gram-negative aerobic and anaerobic colonic bacteria in the small intestine^1,2, leading to increased carbohydrate fermentation and gas production. Symptomatology frequently overlaps with other gastrointestinal disorders³. This study aimed to identify factors associated with test positivity and improve patient selection for diagnostic evaluation.

Aims & Methods

Retrospective, unicentric study. A cohort of 34 patients underwent glucose hydrogen and methane breath testing for SIBO. Demographic, clinical, laboratory data and test results were analyzed.

Results

The cohort included 21 females (61.8%) and 13 males (38.2%), with a mean age of 46.5 ± 15.9 years. Chronic diarrhea was the leading indication for testing (82.4%), followed by abdominal pain (8.8%). Tests results were positive in 4 cases (11.8%). Positive patients had a higher mean age (56.0 ± 10.8 vs. 46.1 ± 15.8 years, p = 0.236) and a comparable gender distribution. Among positive patients, diarrhea was reported in 100% of cases, followed by abdominal distension (75%) and abdominal pain (50%). Folic acid levels were higher in the positive group (11.65 vs. 6.54 ng/mL, p = 0.074), while fecal calprotectin levels were significantly elevated (480 vs. 44.26 µg/g, p = 0.027). Altered small intestine anatomy due to prior surgical interventions was strongly associated with test positivity (p = 0.012), while systemic disorders affecting gastrointestinal motility showed a non-significant trend (p=0.136). Proton pump inhibitor use was not associated with test positivity (p = 1.0). Rifaximin treatment led to symptom improvement in all positive cases, but with no significant difference compared to negative patients (p = 0.444).

Conclusion

Elevated serum folate and fecal calprotectin levels may serve as indicators of underlying SIBO in the appropriate setting. Altered small intestine anatomy was strongly associated with test positivity, and could indicate SIBO under adequate intestinal transit time. These findings highlight the need for larger studies to refine patient selection and improve diagnostic strategies.

References

1. UpToDate. Small intestinal bacterial overgrowth: Etiology and pathogenesis. Available at: https://www.uptodate.com/contents/small-intestinal-bacterial-overgrowth-etiology-and-pathogenesis. Accessed January 19, 2025.
2. Pimentel M, Saad RJ, Long MD, Rao SSC. ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol. 2020;115(2):165-178. doi:10.14309/ajg.0000000000000501.
3. Sachdev AH, Pimentel M. Antibiotics for irritable bowel syndrome: Rationale and current evidence. Curr Gastroenterol Rep. 2012;14:439–45.

Introduction

Functional dyspepsia (FD) is a chronic gastrointestinal disorder characterised by meal-related symptoms, which a subset of patients attribute to the consumption of gluten-containing foods [1]. Recent evidence suggests that subtle duodenal immune activation is a feature of FD, as evidenced by elevated eosinophils [2] and impaired epithelial barrier function [3]. FD patients also exhibit an altered duodenal mucosa-associated microbiota (d-MAM) when compared to controls [4]. Given the microbiome’s involvement in the digestion of gluten, we hypothesised that the d-MAM determines the capacity for gluten to disrupt the epithelium and drive immune responses in FD patients.

Aims & Methods

Duodenal biopsies were collected from 10 FD patients and 7 asymptomatic controls. The d-MAM was cultured from biopsies in a habitat simulating media [5] containing 1% wheat-gluten, for up to 48hrs. Microbial cell pellets were frozen for future microbiome sequencing and the cell-free supernatants, containing d-MAM-digested gluten, were collected. Caco2 cells were challenged with the d-MAM-digested gluten, in a Transwell model of the intestinal epithelium (n=3, 2 technical replicates). Transepithelial electrical resistance (TEER) and protein expression of markers of epithelial integrity were measured in Caco2 cells and compared between treatments. Peripheral blood mononuclear cells (PBMCs) from FD patients (n=20) and controls (n=20) were stimulated with pooled samples of FD or control d-MAM-digested gluten, or left untreated, for 44 hours. For comparison to host enzymatic breakdown of gluten, matched PBMCs were also treated with α-chymotrypsin digested, deaminated gluten (CT gluten). The T cell phenotype and presence of activation-induced markers was assessed in PBMCs by flow cytometry.

Results

Challenge of Caco2 cells with gluten digested by the FD d-MAM resulted in a significant increase in Zonula occludens-1 (p=0.007), and reduction in Myd88 (p=0.03), compared to Caco2 cells challenged with control d-MAM-digested gluten. However, TEER readings were not altered between treatment groups in Caco2 experiments. In PBMC experiments, in response to stimulation with FD or control d-MAM-digested gluten, both FD and control PBMCs exhibited heightened expression of activation markers (CD4⁺OX40⁺CD25⁺), when compared to their respective unstimulated cells (p<0.05). When assessing the T-cell phenotype we observed that FD d-MAM-digested gluten promoted an increase in T-helper (Th) 2 cells in both FD (p=0.007) and control (p=0.0001) PBMCs. Meanwhile, control d-MAM-digested gluten stimulation resulted in elevated Th17.1 cells in FD (p<0.0001) and control (p=0.02) PBMCs, when compared to unstimulated cells. Alternatively, CT gluten stimulation did not alter any of the assessed lymphocyte populations in FD or control PBMCs when compared to unstimulated cells, suggesting host digestion of gluten isn’t sufficient to induce immune responses in FD.

Conclusion

Our findings suggest that the d-MAM of FD patients digest gluten in a way that promotes epithelial barrier remodelling and altered immune responses compared to the d-MAM from asymptomatic individuals. The promotion of a Th2 T-cell phenotype by the FD d-MAM is consistent with reports of increased Th2-associated cells, such as eosinophils, in FD patients [6]. These results highlight the likely role of microbiome-gluten interactions in FD, indicating the potential for novel dietary therapies and microbial approaches to management.

References

1. Potter, M., et al., Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia. Med J Aust, 2020. 212(3): p. 126-131.
2. Shah, A., et al., Duodenal Eosinophils and Mast Cells in Functional Dyspepsia: A Systematic Review and Meta-Analysis of Case-Control Studies. Clinical Gastroenterology and Hepatology, 2022. 20(10): p. 2229-2242.e29.
3. Puthanmadhom Narayanan, S., et al., Duodenal Mucosal Barrier in Functional Dyspepsia. Clin Gastroenterol Hepatol, 2022. 20(5): p. 1019-1028.e3.
4. Shanahan, E.R., et al., Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia. Gut, 2023. 72(5): p. 929-938.
5. Schooth, L., Defining the Role of the Mucosa-Associated Microbiota in Digestive Health and Disease Using Novel ex-vivo Combinations of Microbe Culture with Metagenomics. 2024 [Doctoral thesis, The University of Queensland], UQ eSpace.
6. Burns, G.L., et al., Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia. Front Immunol, 2022. 13: p. 1051632.

Disclosure

JP, EH, CN, SS, SR, MS, KH, GB, and KD have no disclosures to report.
NT: Financial support from: BluMaiden (microbiome advisory board) (2021), Comvita Mānuka Honey (2021) (digestive health), Biocodex (functional dyspepsia tool), Microba (microbiome advisory board) outside the submitted work. In addition, Dr. Talley has a patent Nepean Dyspepsia Index (NDI) 1998, Biomarkers of IBS licensed, a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley, a patent issued, “Diagnostic marker for functional gastrointestinal disorders” Australian Patent Application WO2022256861A1via the University of Newcastle and UniQuest (University of Queensland) and ”Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis” US Application No. 63/537,725. Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre for Research Excellence in Digestive Health and he holds an NHMRC Investigator grant.
SK: Grants from National Health and Medical Research Council (Ideas Grant and Centre for Research Excellence), grants from Viscera Labs (Research contract), grants from Microba Life Science (Research contract), personal fees from Gossamer Bio, personal fees from Anatara Lifescience, personal fees from Immuron, personal fees from Microba Life Science.

Clinical Case Summary

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive non-Hodgkin lymphoma with poor prognosis. We present a case of colonic T-cell lymphoma diagnosed in a patient with refractory chronic diarrhoea.
A 60-year-old Chinese female with a family history of colon cancer had recurrent admissions with extensive workup for a 4-month history of chronic watery non-bloody diarrhoea and 12-kg weight loss. Initial blood tests showed normochromic normocytic anaemia and hypokalaemia. Stool studies were negative for infections but demonstrated elevated calprotectin and low elastase. Coeliac and autoimmune workup returned negative. A Computed Tomography scan showed prominent nonspecific central mesenteric abdominal nodes without pancreas or small bowel abnormalities.
Initial colonoscopy revealed a 2mm descending colon polyp and normal looking colonic mucosa. Random terminal ileum and colonic biopsies were unremarkable. Polyp histology showed focally increased intraepithelial lymphocytes insufficient to diagnose microscopic colitis.
Working differentials included pancreatic insufficiency, small intestinal bacterial overgrowth and irritable bowel syndrome. She was treated with various drugs including Rifaximin, Pancrelipase and Nortriptyline. However, her symptoms persisted with increasing stool calprotectin levels. A repeat colonoscopy performed 2 months after the initial endoscopy, showed normal colonic mucosa again. However, random colonic biopsies histology demonstrated florid intraepithelial lymphocytosis and immunohistochemistry stains confirming MEITL. Systemic chemotherapy was initiated and her diarrhoea resolved.
Though MEITL classically involves the small bowel, our case demonstrated florid colonic involvement. This patient’s indolent presentation illustrated the diagnostic pitfall of a normal looking colon during colonoscopy, raising the importance of random colonic biopsies and repeat evaluation in persistent unexplained diarrhoea.

References

Illustrative material: Endoscopic images showing normal-appearing colonic mucosa. Histological sections demonstrating intraepithelial lymphocytosis on initial colon biopsy. Subsequent biopsy on repeat colonoscopy with immunohistochemistry showing CD3, CD8, CD56, granzyme B, and TIA-1 positivity
References:
Ozaka S, Inoue K, Okajima T, et al. Monomorphic epitheliotropic intestinal T-cell lymphoma presenting as melena with long-term survival: A case report and review of literature. World J Gastroenterol. 2021;27(38):6501-6510. doi:10.3748/wjg.v27.i38.6501
Afzal A, Esmaeili A, Ibrahimi S, Farooque U, Gehrs B. Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma With Extraintestinal Areas of Peripheral T-Cell Lymphoma Involvement. Cureus. 2020;12(8):e10021. Published 2020 Aug 25. doi:10.7759/cureus.10021
Tian S, Xiao SY, Chen Q, Liu H, Ping J. Monomorphic epitheliotropic intestinal T-cell lymphoma may mimic intestinal inflammatory disorders. Int J Immunopathol Pharmacol. 2019;33:2058738419829387. doi:10.1177/2058738419829387
Shin SY. A Rare Case of Intestinal T-cell Lymphoma with Multiple Complications. JDCR 2023;11:114-118. doi.org/10.52927/jdcr.2023.11.2.114
Sun ZH, Zhou HM, Song GX, Zhou ZX, Bai L. Intestinal T-cell lymphomas: a retrospective analysis of 68 cases in China. World J Gastroenterol. 2014;20(1):296-302. doi:10.3748/wjg.v20.i1.296

Introduction

Dyspepsia is a prevalent clinical syndrome with a broad differential diagnosis. Functional dyspepsia is the most frequent aetiology, followed by peptic ulcer disease, gastro-oesophageal reflux, and biliary disorders. Less commonly, it may be due to chronic pancreatitis, malignancy, or coeliac disease.
Coeliac disease may present with dyspepsia, malabsorptive diarrhoea, and weight loss. Laboratory findings often reveal protein malnutrition, iron deficiency, and occasional hypocalcaemia due to duodenal atrophy. Thus, excluding coeliac disease is essential when such features are present. Initial assessment should include serological testing and nutritional profiling.
In routine practice, due to celiac iceberg theory, there is a growing tendency to obtain duodenal biopsies during endoscopy for dyspepsia, regardless of macroscopic findings or clinical suspicion, aiming to rule out atrophic pathology.

Aims & Methods

We hypothesised that routine duodenal biopsies in dyspepsia without pathological signs or symptoms are inefficient, both clinically and economically.
We performed a retrospective, observational, descriptive study analysing 403 duodenal biopsies taken between January 2023 and January 2024. All cases had “dyspepsia” as the endoscopic indication and were requested by gastroenterologists.
We assessed histological and macroscopic duodenal atrophy, positivity for anti-transglutaminase (tTG) and anti-DGP antibodies, and clinical and laboratory features suggestive of coeliac disease. “Clinical suspicion” was defined as symptoms or abnormal tests; “serological suspicion” as antibody positivity. A high pre-test probability was defined as the presence of either.

Results

Mean age was 48.7 ± 15.9 years, with a female predominance (77.2%). Clinical features and laboratory findings suggesting coeliac disease are detailed in Table 1. Clinical suspicion was present in 31.5% of patients. Only one patient had both clinical and serological suspicion and was the sole case (1/403) with Marsh 3A changes in relation with coeliac disease.
Although serology is recommended in low pre-test probability cases, only 67.4% (271/403) underwent antibody testing; of these, 2.2% (6/271) were positive.
Three patients (0.007%) had endoscopic signs of atrophy. Nine biopsies showed non-specific lymphocytic infiltration (Marsh 1).
In 400 macroscopically normal duodenums, 127 patients (31.7%) had a high pre-test probability. The other 273 (68.3%) had no clinical suspicion yet underwent biopsy. At our centre, each biopsy costs about €50 and requires 30 minutes of staff time. Based on our data, €20,100 and over 25 labour working days could have been saved.

Conclusion

Of 403 duodenal biopsies performed for dyspepsia, only one case of coeliac disease was detected. Routine biopsies in low pre-test probability patients appear not to be cost-effective. Notably, one third of patients underwent gastroscopy without prior antibody determination—highlighting the need to align clinical practice with diagnostic guidelines.

References

- Ebell MH. British Society of Gastroenterology Guidelines for the Evaluation and Management of Dyspepsia. Am Fam Physician. 2023 Jul;108(1):Online. PMID: 37440724.

- Ahmed YH, Mohammed RA, Alghamdi IK, Alqahtani MF, Alhelali SN, Sultan I, Badawy MI, Barakat MM, Abozeid HE, Mohammed HL. Histopathological Findings in Adult Patients With Dyspepsia and Their Association With Helicobacter pylori Infection. Cureus. 2023 Dec 23;15(12):e50981. doi: 10.7759/cureus.50981. PMID: 38259413; PMCID: PMC10801451.

- ASGE Standards of Practice Committee; Shaukat A, Wang A, Acosta RD, Bruining DH, Chandrasekhara V, Chathadi KV, Eloubeidi MA, Fanelli RD, Faulx AL, Fonkalsrud L, Gurudu SR, Kelsey LR, Khashab MA, Kothari S, Lightdale JR, Muthusamy VR, Pasha SF, Saltzman JR, Yang J, Cash BD, DeWitt JM. The role of endoscopy in dyspepsia. Gastrointest Endosc. 2015 Aug;82(2):227-32. doi: 10.1016/j.gie.2015.04.003. Epub 2015 May 29. PMID: 26032200.

- Feld L, Cifu AS. Management of Dyspepsia. JAMA. 2018 May 1;319(17):1816-1817. doi: 10.1001/jama.2018.3435. PMID: 29715342.

Introduction

PTEN Hamartoma Tumor Syndrome (PHTS) is a rare condition caused by PTEN disease-causing variants and characterized by a complex phenotype including gastrointestinal-hamartomas and an increased lifetime risk for malignancies. Current genetic testing enables carriers identification and cascade testing

Aims & Methods

To describe a large cohort of PHTS carriers including unique clinical presentation, genetic diagnosis and treatment approach.
We conducted a retrospective, comprehensive review of medical charts was conducted for individuals with PHTS who were under surveillance at specialized high-risk clinics in Israel. The diagnosis of PHTS was based on the revised diagnostic criteria, which include identification of disease-causing variants in the PTEN gene mutation and/or a combination of major and minor clinical features *.

Results

A total of 53 individuals were included in the study (43% female; median age at diagnosis: 38 years, IQR 29, range 25-75). Pathogenic or likely pathogenic variants in the PTEN gene were identified in 40 individuals (75%), (52% missense, 17% nonsense, and 25% frameshift mutations). Common clinical presentations included gastrointestinal polyps, observed in 75% (n = 40), with five patients having adenomas and one presenting with a ganglion cell polyp. Malignancies were reported in 62% (n = 33), most commonly breast cancer (20%) and thyroid cancer (9%). Macrocephaly was observed in 35% (n = 20), and developmental delay, including autism spectrum disorder, in 8 patients (15%). There were three cases of soft tissue tumors (5.6%): One individual with abdominal desmoid tumor at age 18, one individual with axillary osteosarcoma followed by bilateral chest liposarcoma and one case with a rare soft tissue sarcoma, at the base of the skull.
One case of PHTS with PTEN mosaicism was identified through sequencing of endometrial, salivary, and thyroid tissue samples, following a negative result from blood-based genetic testing. Five individuals (9.4%) received Sirolimus for severe clinical manifestations (multiple thyroid nodules, colonic polyps, gastrointestinal symptoms, and early-onset malignancies). Of them, two patients had substantial reduction in polyp burden and improvement in gastrointestinal symptoms.

Conclusion

In this substantial series we found that PTHS exhibits a wide range of phenotypic presentations, high overall cancer rates and a relatively high prevalence of soft tissue malignancies, which have been rarely described in PHTS. Constitutional mosaicism should be sought in a clinical picture suggestive of PHTS with negative germline genetic testing.

References

* Pilarski R et al: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013
1. Hendricks LAJ et al: PTEN Study Group; Mensenkamp AR, Vos JR. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. Eur J Med Genet. 2022 Dec;65(12):104632. doi: 10.1016/j.ejmg.2022.104632. Epub 2022 Oct 18. PMID: 36270489.
2. Dhawan A et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.
3.Dhawan A, et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.