Superior mesenteric arteriovenous fistula as a rare manifestation of Cowden syndrome: A case report and review of literature

Abstract

BACKGROUND

Cowden syndrome (CS) is a rare autosomal dominant disorder primarily attributed to germline mutations in the PTEN gene, and is characterized by multiple systemic hamartomas and an increased lifetime risk of various malignancies. Despite the broad clinical spectrum of CS, gastrointestinal and hepatic vascular anomalies are infrequent manifestations. Notably, the association between CS and superior mesenteric arteriovenous fistula (SMAVF) remains poorly characterized and has not been previously reported.

CASE SUMMARY

A 50-year-old woman presented with progressive abdominal distension, fatigue, and anorexia for 6 months. Contrast-enhanced magnetic resonance imaging revealed splenomegaly, massive ascites, portal vein dilatation (18 mm), and subtle cirrhosis-like changes, without evidence of alcoholic hepatitis, viral hepatitis, or autoimmune liver disease. Liver function tests were within normal limits and ascitic fluid analysis revealed a transudative pattern. Digital subtraction angiography uncovered extensive SMAVFs. Given that the extensive lesions made surgical resection infeasible and embolization likely to cause bowel necrosis, a transjugular intrahepatic portosystemic shunt (TIPS) procedure was performed as a safer and more viable alternative to achieve symptomatic relief. Liver biopsy showed hepatic fibrosis without cirrhosis, which is compatible with a diagnosis of non-cirrhotic portal hypertension. Hematemesis occurred following TIPS, and endoscopy demonstrated gastric fundic gland polyps. Whole-exome sequencing confirmed CS in light of the patient history regarding multiple tumors and a lower-extremity hemangioma (PTEN mutation: C.80A>G,p.Tyr27Cys).

CONCLUSION

SMAVF is a rare gastrointestinal vascular manifestation associated with CS. Our findings suggest a potential link between PTEN germline mutations and mesenteric vascular anomalies, further broadening the phenotypic spectrum of CS.

Key Words: Cowden syndrome; PTEN mutation; Superior mesenteric arteriovenous fistula; Transjugular intrahepatic portosystemic shunt; Vascular malformation; Case report

Core Tip: We report the first documented case of Cowden syndrome (CS) complicated by a superior mesenteric arteriovenous fistula. A systematic review of the literature identified 13 cases, in addition to the present case, of CS associated with gastrointestinal and hepatic vascular anomalies. These findings suggest that these lesions may be linked to the imbalance of angiogenesis and vascular remodeling induced by PTEN mutations, thereby expanding the known vascular phenotypic spectrum of CS.

INTRODUCTION

Cowden syndrome (CS) is a rare autosomal dominant disorder within the PTEN hamartoma tumor syndrome spectrum (PHTS), primarily driven by germline mutations in the tumor suppressor gene PTEN[1]. Dysregulation of the PI3K/AKT/mTOR signaling pathway increases susceptibility to mucocutaneous lesions and significantly elevates the lifetime risk of multiple malignancies in affected individuals[2]. Although the mucocutaneous and neoplastic hallmarks of CS are well defined, the syndrome also exhibits a propensity for vascular anomalies. Previous literature has documented the occurrence of developmental venous anomalies, hemangiomas, and arteriovenous malformations (AVMs) in extraintestinal sites among patients with CS, underscoring the systemic impact of PTEN dysfunction on vascular development and integrity[3].

The clinical relevance of visceral vascular anomalies in CS, particularly those involving the gastrointestinal tract and portal circulation, remains poorly characterized. Vascular abnormalities are acknowledged as non-neoplastic features of CS, yet high-flow mesenteric fistulas such as superior mesenteric arteriovenous fistula (SMAVF) are exceedingly rare. Although isolated reports describe hepatic and gastrointestinal vascular malformations in patients with CS, a comprehensive synthesis of these observations is currently absent from the literature. Consequently, a substantial knowledge gap remains regarding the clinical presentation, diagnostic challenges, and optimal management strategies for patients with CS who present with vascular malformations.

To address this gap, we report a novel case of CS presenting with SMAVF and conduct a literature review of gastrointestinal and hepatic vascular malformations associated with CS. This investigation delineates the clinical manifestations of the vascular malformations and examines the link to PTEN-related vascular dysregulation. It highlights the importance of early diagnostic imaging and integrated management strategies to improve outcomes in these rare patient populations.

CASE PRESENTATION

Chief complaints

A 50-year-old female patient was evaluated for progressive abdominal distension that had persisted for over six months.

History of present illness

Abdominal distension began insidiously six months prior to presentation and worsened progressively. Concurrent fatigue and marked anorexia resulted in a substantial decline in the patient’s capacity for activities of daily living.

History of past illness

The patient presented with a medical history significant for multiple neoplasms and vascular anomalies. Specifically, she had been previously diagnosed with endometrioid adenocarcinoma, thyroid carcinoma, uterine leiomyoma, and bilateral benign breast tumors, alongside vascular malformations including lower-extremity hemangiomas.

Personal and family history

Alcoholic hepatitis was excluded, as the patient reported no history of long-term alcohol consumption. No CS-associated malignancies were reported among her first-degree relatives based on the available family history. As the parents died before the diagnosis was established and lacked comprehensive medical evaluation, vascular imaging, or PTEN genetic testing, potential vascular anomalies or hereditary PTEN-related manifestations could not be retrospectively evaluated in the parental generation. The children appeared healthy at the time of evaluation and showed no evidence of CS-associated tumors or vascular anomalies. Nevertheless, they have not yet undergone systematic vascular screening or PTEN genetic testing.

Physical examination

Physical examination demonstrated a distended abdomen and positive shifting dullness, which indicated the presence of massive ascites. Other vital signs were stable, and cardiopulmonary auscultation showed no significant abnormalities.

Laboratory examinations

Liver function tests, autoimmune serologies, and screenings for various hepatotropic viruses were unremarkable. The transudative nature of the ascitic fluid suggested that autoimmune and viral etiologies were not the underlying causes. To further clarify the hepatic pathological status, the patient underwent a transjugular liver biopsy. Histopathological examination revealed fibrous tissue hyperplasia and sporadic fibrous septa formation. However, no typical features of cirrhosis were identified. After a transjugular intrahepatic portosystemic shunt (TIPS) procedure, the patient presented with hematemesis. Upper gastrointestinal endoscopy revealed multiple gastric lesions, and histological analysis confirmed fundic gland polyps. Ultimately, whole-exome sequencing provided critical genetic evidence, revealing a c.80A>G/p.Tyr27Cys missense mutation in the PTEN gene (Figure 1).

Figure 1 Three-dimensional structural model of the mutant PTEN protein. α-helices are shown in light pink and β-sheets in light cyan. The inset provides a magnified view of the mutation site, displaying the spatial arrangement and side-chain conformations of the affected residues, with tyrosine (Tyr) shown in blue and cysteine (Cys) in yellow.

Imaging examinations

Non-contrast and contrast-enhanced abdominal magnetic resonance imaging revealed significant splenomegaly, massive ascites, and an atypical hemangioma in the left hepatic lobe. The portal vein showed significant dilation and measured 18 mm at its greatest diameter. The liver exhibited a slightly reduced volume, widened fissures, and scalloped margins (Figure 2). Subsequent digital subtraction angiography (DSA), including superior mesenteric arteriography combined with indirect portography, confirmed the presence of extensive SMAVFs (Figure 3). Gastroscopy performed following the TIPS procedure revealed esophagogastric varices and multiple polypoid lesions within the stomach (Figure 4).

Figure 2 Upper abdominal magnetic resonance imaging. The liver is slightly reduced in volume, with a wavy contour and widened fissures. A roundish lesion with hypointense T1-weighted and hyperintense T2-weighted signals is observed in the left hepatic lobe adjacent to the falciform ligament (orange arrow), measuring approximately 1.3 cm in diameter and demonstrating nodular enhancement on contrast-enhanced imaging. The portal vein is dilated, with a maximum diameter of 1.8 cm. Splenomegaly is present, with heterogeneous signal intensity and an irregular contour.

Figure 3 Digital subtraction angiography of the superior mesenteric artery with indirect portal venography. The main trunk of the superior mesenteric artery appears thickened and tortuous. A distinct arteriovenous malformation is visible in the distal branches (orange arrow). No filling defects are observed within the vessels, and blood flow velocity is rapid, resulting in early visualization of the mesenteric and portal veins.

Figure 4 Upper gastrointestinal endoscopy. Moderate turbid gastric fluid is present in the gastric body. Multiple scattered polypoid lesions measuring 0.5-1.2 cm in diameter were observed, with hyperemic surfaces. A biopsy specimen was obtained from a larger polyp located along the greater curvature. Histopathological examination confirmed a fundic gland polyp.

FINAL DIAGNOSIS

The combination of clinical manifestations, history of multiple primary neoplasms, and whole-exome sequencing results supported a definitive diagnosis of CS. The elevated portal venous pressure was attributed to idiopathic non-cirrhotic portal hypertension, triggered by hyperdynamic circulation secondary to the SMAVF.

TREATMENT

Due to the extensive distribution and high volume shunting of the SMAVF, conventional fistula ligation or embolization under DSA guidance carried a substantial risk of inducing widespread intestinal necrosis. Consequently, the clinical team opted for a TIPS procedure to manage ascites and prevent variceal bleeding by reducing portal venous pressure. On postoperative day 9, the patient experienced hematemesis, which necessitated emergency gastroscopy and endoscopic hemostasis.

OUTCOME AND FOLLOW-UP

One month later, the patient developed recurrent progressive abdominal distension and died of thromboembolism, which may have been linked to non-adherence to the prescribed oral antiplatelet regimen.

DISCUSSION

CS is a rare autosomal dominant disorder primarily attributed to germline mutations in the PTEN gene and represents a subset of the PHTS. The syndrome was first reported in 1963 (named after the index patient Rachel Cowden), and its association with the PTEN gene was subsequently confirmed in 1996[1]. The PTEN gene is located on the long arm of human chromosome 10 (10q23.31) and encodes a tumor suppressor protein with lipid phosphatase activity[4]. This protein negatively regulates the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, thereby inhibiting cell proliferation, promoting apoptosis, and maintaining cell cycle homeostasis. Germline mutations in PTEN result in the dysregulation of these signaling pathways, promoting the formation of hamartomas across multiple tissues and organs, and significantly increasing cancer susceptibility. CS follows an autosomal dominant inheritance pattern, where carriers have a 50% probability of transmitting the mutation to their offspring.

The global prevalence ranges from approximately 1 in 200000 to 1 in 250000[5]. Although the incidence rate is comparable between sexes, female patients are more prone to presenting with tumor-related symptoms[2]. Clinical manifestations of CS are highly variable and involve tissues derived from the ectoderm, mesoderm, and endoderm. Pathognomonic features include mucocutaneous lesions, such as trichilemmomas (often in the trigeminal nerve distribution), oral papillomatous fibromas, palmoplantar keratosis, and facial papules. Macrocephaly occurs in more than 90% of patients and generally manifests during childhood. Furthermore, patients may develop thyroid nodules, adenomas, or carcinomas (lifetime risk 25%-35%), breast cancer in women (lifetime risk 25%-50%), and endometrial cancer (5%-10%), as well as renal and colorectal cancers[2]. Non-neoplastic manifestations include intellectual disability, autism spectrum disorder, and vascular conditions, such as AVMs and developmental venous anomalies[3]. Among these, SMAVF represents an exceptionally rare but clinically significant manifestation that warrants further investigation.

SMAVF is an infrequent vascular disorder characterized by an abnormal connection between the superior mesenteric artery and vein, resulting in direct arterio-venous shunting and secondary portal hypertension[6,10]. Aside from a small minority of congenital cases, acquired forms account for over 90% of instances and typically stem from abdominal trauma, inflammatory conditions such as Crohn’s disease, or iatrogenic factors following abdominal surgery[8,9]. Pathologically, abnormal shunting significantly elevates portal venous pressure, potentially inducing high-output heart failure or local tissue ischemia[6]. Patients typically advance from an asymptomatic latent stage to symptomatic portal hypertension, characterized by clinical signs such as ascites, splenomegaly, and severe esophagogastric variceal hemorrhage[7].

Diagnostic assessment utilizes comprehensive imaging findings. Multidetector computed tomography angiography or magnetic resonance angiography are the preferred modalities for delineating fistula location, characterizing blood flow dynamics, and demonstrating portal vein dilation. DSA remains the gold standard, facilitating dynamic assessment and guiding therapeutic interventions[6,7]. Effective treatment necessitates early fistula closure to mitigate progression and associated complications. Open surgery, including fistula ligation, vascular reconstruction, and bowel resection, is associated with considerable risk and perioperative mortality rates of 5% to 10%. Consequently, endovascular therapy has emerged as the preferred approach, yielding success rates exceeding 90% and providing a minimally invasive alternative for high-risk or emergent patients[6,7,10]. Nevertheless, long-term follow-up remains indispensable after intervention. Postoperative monitoring enables the early detection of complications such as portal vein thrombosis and intestinal ischemia, as well as recurrence, which occurs in approximately 5% of cases. Early identification combined with individualized minimally invasive interventions typically leads to improved patient prognosis[7].

Against the clinical backdrop of SMAVF as a complex vascular entity, we report a case of CS associated with gastrointestinal vascular malformations, representing the first documented instance of SMAVF. PTEN normally antagonizes the PI3K/AKT/mTOR signaling pathway via its lipid phosphatase activity, whereas deleterious PTEN variants promote pathway overactivation and pro-angiogenic signaling[11,12]. Genetic testing of the patient identified the PTEN c.80A>G(p.Tyr27Cys) variant, which is currently classified as “likely pathogenic” for PHTS by the ClinGen PTEN Expert Panel in ClinVar. The mutation affects a highly conserved tyrosine residue in the N-terminal phosphatase domain and has been previously described in patients with PTEN-related phenotypes, including at least one presumed de novo case[13,14]. Functional evidence indicates that p.Tyr27Cys reduces PTEN protein abundance and significantly impairs lipid phosphatase activity, consistent with a hypomorphic allele with reduced capacity to restrain downstream PI3K/AKT/mTOR signaling[14-16]. In the present case, the molecular defect likely fostered a hyper-angiogenic environment that disturbed normal vascular remodeling and stimulated aberrant endothelial proliferation, offering a potential molecular mechanism for the development of high-flow vascular anomalies like SMAVF[11,12,17].

To further contextualize our findings, we conducted a literature review of PubMed, Web of Science, and China National Knowledge Infrastructure from database inception to February 23, 2026 using terms related to CS, gastrointestinal or hepatic involvement, and vascular anomalies. Eligible studies included those reporting patients with a confirmed diagnosis of CS and gastrointestinal or hepatic vascular lesions, where sufficient individual clinical data were documented. Reviews, conference abstracts, duplicate reports, inaccessible full texts, and studies describing other PHTS or isolated lymphatic malformations were excluded. Clinical data encompassing patient characteristics, genetic findings, vascular lesions, therapeutic approaches, and outcomes were documented. Thirteen previously reported cases were identified and analyzed together with the present case (Tables 1 and 2)[18-30]. Considering the rarity of the condition and the prevalence of isolated reports in existing literature, the summary provides a comprehensive characterization of the clinical spectrum. Analysis revealed a high detection rate of PTEN mutations (78.6%), supporting their role as a significant molecular basis for these vascular lesions, which is consistent with the findings of Pilarski et al[31]. Among the various types of digestive vascular malformations, AVMs were the most common (34.8%), primarily involving the small intestine (43.5%) and the liver (26.1%), with a frequent multifocal distribution (56.5%). Clinical manifestations were primarily characterized by chronic gastrointestinal bleeding (35.7%). Despite its rarity, acute bleeding posed a significant risk. Abdominal pain and intestinal obstruction were also observed in a subset of patients.

Table 1 Summary of clinical characteristics of patients with Cowden syndrome associated with gastrointestinal and hepatic vascular malformations, mean ± SD.

Variable category	Specific item	By patients, n = 14	By lesion, n = 23	Percentage
Demographics	Sex-male	7	NA	50.0
	Sex-female	7	NA	50.0
	Age at diagnosis in years	48.1 ± 18.0	NA	NA
	Age at diagnosis in years, median	Stillbirth-65	NA	NA
Genetics	PTEN mutation-positive	11	NA	78.6
	PTEN mutation-negative/not tested	3	NA	21.4
Lesion type	Hemangioma	NA	3	13.0
	AVM	NA	8	34.8
	VM	NA	5	21.7
	Varices	NA	1	4.3
	Vein dilatation	NA	1	4.3
	Others	NA	2	8.7
Lesion location	Esophagus	NA	2	8.7
	Jejunum/ileum (small intestine)	NA	10	43.5
	Colorectum	NA	1	4.3
	Liver	NA	6	26.1
	Others	NA	2	8.7
Extent of involvement	Single lesion	NA	7	30.4
	Multiple lesions: ≥ 2 sites	NA	13	56.5
Clinical presentation	Asymptomatic	1	NA	7.1
	Chronic hemorrhage	5	NA	35.7
	Acute hemorrhage	2	NA	14.3
	Abdominal pain/obstruction	2	NA	14.3
	Others	5	NA	35.7
Treatment	Conservative management	2	NA	14.3
	Endoscopic therapy	1	NA	7.1
	Interventional radiology (embolization)	3	NA	21.4
	Surgery	3	NA	21.4
Follow-up and outcome	Improved/stable	6	NA	42.9
	Death	2	NA	14.3

AVM: Arteriovenous malformation; NA: Not applicable; VM: Venous malformation.

Table 2 Clinical data of patients with Cowden syndrome associated with gastrointestinal and hepatic vascular malformations.

Ref.	Sex	Age	PTEN mutation status	Lesion site 1	Lesion type 1	Lesion site 2	Lesion type 2	Multifocal	Extraintestinal vascular lesions	Main symptom	Treatment	Follow-up (months) and outcome	Notes
Takaya et al[18], 1999	Male	22	PTEN 10q22–23	Liver	AVMs	Liver	Hemangiomas	Yes	Pelvis AVMs, the fifth cervical vertebra AVMs, right supraclavicular area AVMs, right hip and leg hemangiomas, right chest subcutaneous hemangiomas	High output heart failure; pain and weakness in the right upper extremity	Not mentioned	Death	NA
Suphapeetiporn et al[19], 2006	Male	48	PTEN c.511C>T/p.Gln171Ter	Liver	Large AVM	Esophagus	Varices	Yes	Centrifugal superficial vein dilatation	Chronic blood loss, Acute painless hematochezia	Performed embolization three times	Improved	NA
Pan et al[20], 2011	Female	45	PTEN exon 8 c.1003C>T/p.Arg335Ter	Liver	Hemangioma	NA	NA	No	Not mentioned	Epigastric distension and pain	Not mentioned	Not mentioned	NA
Nakayama et al[21], 2013	Male	54	Not mentioned	Jejunum	AVMs	Ileum	AVMs	Yes	Not mentioned	Chronic blood loss	Partial resection of the small intestine	Improved	NA
Toya et al[22], 2016	Female	65	Not mentioned	Jejunum	VMs	Ileum	VMs	Yes	Not mentioned	Chronic blood loss	Conservative	Improved	NA
Harada et al[23], 2018	Female	65	PTEN c.1003C>T/p.Arg335Ter	Jejunum	VMs	Ileum	VMs	Yes	Skin of the trunk and the limbs; several small hemangiomas	Not mentioned	Not mentioned	Not mentioned	Small varices-like lesions in the esophagus
Inukai et al[24], 2018	Male	48	Not mentioned	Sigmoid colon	AVM	NA	NA	No	Not mentioned	Chronic blood loss, shortness of breath	Sigmoidectomy	Improved, no recurrence was observed 1 year post-surgery	NA
Duhaut et al[25], 2021	Female	56	PTEN c.71A>G/p.Asp24Gly	Liver	AVM	NA	NA	No	Not mentioned	Refractory ascites, Portal hypertension, Esophageal varices	TIPS, LT	Not mentioned	NA
Zhang et al[26], 2022	Male	44	PTEN	Small intestine	Possible vascular malformation	NA	NA	No	Intermuscular space of the left chest wall; vascular malformation; A1 segment of the right anterior cerebral artery; aneurysm	Increased frequency of defecation, unformed stool, occasional fresh blood in stool	Not mentioned	Not mentioned	NA
Piazzolla et al[27], 2022	Female	62	PTEN c.1003C>T/p.Arg335Ter	Jejunum	VMs	NA	NA	No	Shoulder-upper arm region AVM	Chronic blood loss	Conservative	Improved	NA
Saiki et al[28], 2024	Male	66	PTEN c.1003C>T/p.Arg335Ter	Small intestine	VMs	NA	NA	No	Trunk (ventral and dorsal); multiple hemangiomas	Asymptomatic (only positive fecal occult blood test, no subjective symptoms)	Not mentioned	Not mentioned	NA
Zhu et al[29], 2024	Male	Stillbirth	PTEN c.193T>G/p.Tyr65Asp	Subcapsular of the liver	Hemangioma (giant, 96 mm × 64 mm)	Intra-abdominal umbilical vein	vein dilatation	Yes	Striped blood flow signals were seen in the mass below the liver	Congestive cardiac insufficiency	Not mentioned	Termination of pregnancy by induced labor	NA
Woller et al[30], 2025	Female	48	PTEN	Jejunum	AVM	NA	NA	No	Not mentioned	Acute bleeding	Conservative + endoscopic therapy + embolization + surgery	Improved,	NA
Present study	Female	50	PTEN c.80A>G/p.Tyr27Cys	Superior mesenteric artery	AVM	Liver	Hemangiomas	Yes	Not mentioned	Progressive abdominal distension	TIPS (lesion 1)	Death	Esophageal and gastric varices

AVM: Arteriovenous malformation; LT: Liver transplantation; NA: Not applicable; PTEN: Phosphatase and tensin homolog; TIPS: Transjugular intrahepatic portosystemic shunt; VM: Venous malformation.

Available treatment modalities encompass conservative, endoscopic, interventional, and surgical approaches. The relatively high proportions of interventional and surgical treatments (21.4% each) reflect the necessity for active intervention in some cases. In the present case, the extensive and diffuse nature of the SMAVF precluded conventional aggressive therapeutic approaches. Surgical resection was contraindicated as it would necessitate extensive bowel removal, potentially leading to severe complications such as short bowel syndrome. Likewise, conventional interventional therapy was considered unsafe because multi-site embolization within the diffuse lesion network carried an unacceptably high risk of extensive intestinal necrosis. Furthermore, as clinical and pathological evaluations excluded liver cirrhosis, the patient’s portal hypertension was classified as non-cirrhotic and primarily attributed to the high-flow vascular shunt. Liver transplantation was therefore deemed inappropriate. TIPS was adopted as a palliative measure to manage intractable ascites caused by non-cirrhotic portal hypertension, lowering portal pressure to relieve symptoms without compromising intestinal viability. However, the subsequent fatal outcome warrants cautious interpretation and should not be ascribed solely to TIPS. As autopsy findings were unavailable, the fatal outcome was likely multifactorial. Primary contributing factors included advanced high-flow SMAVF, rapidly progressive portal hypertension, esophageal variceal hemorrhage, and refractory ascites, alongside a heightened risk of thrombosis attributable to inconsistent antiplatelet therapy (Table 3).

Table 3 Timeline of clinical presentation, diagnosis, and management.

Time point	Clinical presentation and diagnostic/therapeutic interventions	Key findings and clinical decisions
Day 0	A 50-year-old woman presented with progressive abdominal distension for more than 6 months	Physical examination revealed a markedly protuberant abdomen, with positive shifting dullness, consistent with massive ascites
Day 1	Laboratory testing for liver function, hepatotropic viruses, autoantibodies, and ascitic fluid analysis	All markers (viral, autoimmune, and biochemical) were within normal limits. Ascites was confirmed as transudate; alcoholic and viral hepatitis were excluded
Day 2	Initial physical examination and contrast-enhanced abdominal MRI	Findings suggested possible early-stage liver cirrhosis, splenomegaly, ascites, and portal vein dilatation (18 mm)
Day 4	DSA with superior mesenteric artery angiography combined with indirect portography	Thickened and tortuous superior mesenteric artery with a distinct arteriovenous malformation; rapid flow with early visualization of mesenteric and portal veins
Day 10	TIPS and transjugular liver biopsy	Liver biopsy showed fibrous hyperplasia but no definitive evidence of cirrhosis
Day 21	Acute hematemesis followed by emergency gastroscopy	Esophagogastric varices and multiple gastric polyps identified; biopsy confirmed fundic gland polyps
Day 22	WES	PTEN mutation identified (c.80A>G/p.Tyr27Cys)
Retrospective review	Detailed retrospective analysis of past medical history	History of multiple neoplasms (endometroid adenocarcinoma, thyroid cancer, uterine leiomyoma, bilateral breast tumors) and vascular malformations (lower-extremity hemangiomas)
Final diagnosis	Integration of clinical, imaging, pathological, and genetic data	Diagnosis of CS established

DSA: Digital subtraction angiography; MRI: Magnetic resonance imaging; TIPS: Transjugular intrahepatic portosystemic shunt; WES: Whole-exome sequencing.

Future research should further explore pathway-directed therapies for PTEN-related vascular manifestations. In this context, mTOR inhibitors such as sirolimus do not correct PTEN function but instead suppress the downstream PI3K/AKT/mTOR pathway overactivation resulting from PTEN deficiency. Preliminary clinical data from patients with PHTS, including CS, indicate that sirolimus offers biological and clinical benefits for specific manifestations of PTEN-related disease[32]. In addition, prospective studies have demonstrated the efficacy of sirolimus in patients with complex vascular anomalies, supporting its application as a targeted therapeutic strategy[33,34]. However, evidence supporting its effectiveness in extensive high-flow vascular lesions including SMAVF is limited, and its potential utility in these cases requires rigorous evaluation in future studies.

Follow-up data from all available cases including the present one indicate that 42.9% of patients experienced stable or improved health status. The recorded mortality rate of 14.3% emphasizes the significant prognostic risks linked to these lesions in individuals diagnosed with CS. Due to the limited sample size and variable follow-up periods, further long-term prognostic data need to be collected. Considering the fetal death cases reported by Zhu et al[29] and our observations, gastrointestinal vascular malformations associated with PTEN mutations may manifest early and progress rapidly to severe clinical states. Therefore, we recommend prompt, systematic imaging evaluation and multidisciplinary management at the time of diagnosis to enable timely intervention, prevent irreversible damage and complications, and improve long-term outcomes. Furthermore, relatives of the first degree of affected individuals should undergo genetic counseling and targeted PTEN testing, followed by regular surveillance for malignancies and vascular malformations associated with CS within a structured familial monitoring program.

Although gastrointestinal vascular malformations are uncommon in patients with CS, they carry substantial clinical significance due to frequent associations with hemorrhage, ischemia, and nutritional impairment, particularly within the small intestine and liver. The present case of extensive SMAVF underscores the critical role of the PTEN pathway in the regulation of angiogenesis. Loss-of-function mutations in PTEN may promote overactivation of PI3K/AKT signaling, leading to abnormal vascular endothelial proliferation, arteriovenous fistula formation, and secondary portal hypertension.

Clinical management should integrate genetic testing with proactive imaging screening (e.g., annual computed tomography angiography) for early identification, followed by the formulation of individualized treatment strategies and long-term surveillance. The conclusions of this report are limited by the small sample size, which restricts external validity. Therefore, while the PTEN mutation might contribute to SMAVF pathogenesis, a causal association cannot be confirmed through this report alone. Moreover, reliable long-term follow-up data remain rom extended clinical observation are currently insufficient in both routine clinical practice and the current literature. Future large scale cohort studies and multicenter registries are required to standardize data collection, elucidate the pathobiology of visceral vascular malformations, and assess targeted therapies including mTOR inhibition to optimize patient outcomes.

CONCLUSION

This report describes a rare case of CS associated characterized by SMAVF and non-cirrhotic portal hypertension. Incorporating a review of 13 earlier reports, the present study extends the identified range of gastrointestinal and hepatic vascular manifestations observed in disorders related to PTEN. This study demonstrates that visceral vascular malformations represent an underrecognized source of severe complications in patients with CS. Achieving optimal clinical outcomes requires early recognition and comprehensive vascular imaging supported by multidisciplinary management.

ACKNOWLEDGEMENTS

The authors acknowledge the cooperation of the patient and the family and thank them for their consent to publish this report and the associated clinical data.