Chronic enteropathy associated with solute carrier organic anion transporter family member 2A1 gene: A case report and review of literature

Abstract

BACKGROUND

Chronic enteropathy associated with solute carrier organic anion transporter family member 2A1 (SLCO2A1) (CEAS) is a rare autosomal recessive hereditary disease characterized by anemia, hypoproteinemia, abdominal pain, diarrhea, and multiple shallow ulcers in the small intestine. Genetic analysis for SLCO2A1 mutations has identified more than 10 variant types, including the mostly reported c.940+1G>A splice site mutation.

CASE SUMMARY

Herein, we described a 33-year-old female patient who was admitted for anemia, edema, and a positive fecal occult blood test, unaccompanied by abdominal pain and diarrhea. She was diagnosed with CEAS due to compound heterozygous variants, c.940+1G>cA (splice-5) and c.1658T>A (p.Ile553Asn) in SLCO2A1, which had not been previously reported. Importantly, we reviewed 132 reported CEAS patients, which showed that anemia (87.3%) and hypoproteinemia (81%) were the most common symptoms. Nearly 25.8% of patients only had a positive result of fecal occult blood, without any symptoms of gastrointestinal bleeding.

CONCLUSION

In conclusion, fecal tests should be repeated in patients with anemia and edema to find clues for chronic enteropathy, including the rare cause-CEAS.

Key Words: Chronic enteropathy; Solute carrier organic anion transporter family member 2A1; Small intestinal ulcer; Anemia; Edema; Prostaglandin transporter; Organic anion transporting polypeptide 2A1; Case report

Core Tip: We present a 33-year-old female patient who was admitted for anemia, edema, and a positive fecal occult blood test. She was diagnosed with chronic enteropathy associated with solute carrier organic anion transporter family member 2A1 (SLCO2A1) due to heterozygous mutations, c.1658T>A (p.Ile553Asn) and c.940+1G>A (splice-5) in SLCO2A1, which had not been previously reported. Chronic enteropathy associated with SLCO2A1 should be considered in patients with anemia and edema to avoid inappropriate therapies.

INTRODUCTION

Chronic enteropathy associated with solute carrier organic anion transporter family member 2A1 (SLCO2A1) (CEAS) is a rare autosomal recessive hereditary disease, characterized by intractable small bowel ulcers, which has been reported in nearly 132 cases[1-5]. The most common symptom is chronic persistent anemia and hypoproteinemia, due to the loss of protein from intractable small bowel ulcers, followed by abdominal pain, diarrhea, blood in the stool, and hematochezia[1,3,6]. Studies of Japanese and Korean CEAS patients show SLCO2A1 mutations associated with chronic enteropathy predominantly affect females, while those associated with primary hypertrophic osteoarthropathy (PHO) are more predominant in males[1,7]. The majority of CEAS cases previously were from Asian countries like Japan, Korea, and China, while the French patients with CEAS were reported recently, suggesting CEAS may be more prevalent[8,9].

The diagnosis of CEAS requires the genetic analysis, which has identified more than 10 variant types in SLCO2A1[1,5]. SLCO2A1 encodes the transmembrane prostaglandin transporter, which mediates prostaglandin reuptake into cells[6]. In addition to CEAS, mutations in SLCO2A1, resulting in elevated levels of prostaglandin E2 (PGE2), were also associated with PHO, featuring digital clubbing, pachydermia, and periostosis[7]. Recently, heterozygous SLCO2A1 was also detected in very early-onset inflammatory bowel diseases (IBD) and monogenic IBD, which still need further research[10]. CEAS patients did not respond to some drugs for IBD, such as mesalazine, glucocorticoids, immunosuppressants, and biological agents, and mainly received supportive and symptomatic treatment[4]. Herein, we describe a 33-year-old female patient who was admitted for anemia, edema, and a positive fecal occult blood test, unaccompanied by abdominal pain and diarrhea. She was diagnosed with CEAS due to compound heterozygous variants, c.1658T>A (p.Ile553Asn) and c.940+1G>A (splice-5) in SLCO2A1, which had not been previously reported.

CASE PRESENTATION

Chief complaints

Anemia and edema for 3 years.

History of present illness

A 33-year-old female presented with fatigue for 3 years, occasionally accompanied by a positive fecal occult blood test. She was diagnosed with iron deficiency anemia at a local hospital, with a hemoglobin level of 89 g/L. She underwent gastroduodenoscopy and colonoscopy, but these procedures did not find any abnormalities. Although the anemia responds temporarily to iron supplementation, the hemoglobin level remains unstable, fluctuating between 66 and 120 g/L. One year ago, she developed pitting edema of the lower extremity with no typical renal manifestations, like frequent urination, urgency, dysuria, hematuria, foam urine, and lumbago. After evaluation by Nephrologists and Rheumatologists, peripheral edema was suggested to be caused by hypoalbuminemia (albumin 26-29 g/L). There were no symptoms of abdominal pain, diarrhea, melena, mucus in the stools, or menorrhagia. Additionally, there were no specific indications of IBD, such as intestinal obstruction, perforation, fissure, fistula formation, oral ulcers, arthralgia, or skin lesions.

History of past illness

The patient had suffered from adenomyosis and underwent surgery for an ovarian cyst.

Personal and family history

She was born to non-related parents of Chinese origin, and her sister had a history of duodenal stricture. She had occasionally taken nonsteroidal anti-inflammatory drugs due to menstrual cramps and had no history of smoking or alcohol consumption.

Physical examination

No positive signs.

Laboratory examinations

On admission, the hemoglobin was 103 g/L, the albumin was 28.7 g/L (immunoglobulin G was also decreased), the C-reactive protein was 2.3 mg/L, the erythrocyte sedimentation rate was 5 mm/hour, the fecal calprotectin was 316.8 μg/g, and the fecal occult blood test was 3+. No abnormalities were found in the Clostridium difficile or tuberculosis T-cell spot test results.

Imaging examinations

Gastroduodenoscopy showed the esophagus, stomach, and duodenum mucosa appeared normal. Colonoscopy showed lymphoid follicular hyperplasia in the terminal ileum, with no abnormalities in the rectal mucosa. The pathology indicated chronic inflammation in the ileum. Considering the patency capsule had been blocked in the small bowel in the reported CEAS patient[11], we preferred gastrointestinal ultrasound and computed tomography enterography (Figure 1), which showed multiple segments of the small intestine in the lower left abdomen and pelvic area were thickened and enhanced, with ulcer formation. The enteroscopy (Figure 1) revealed multiple circular and tape-like shallow ulcers in the ileum (about 150-200 cm from the ileocecal valve), and the enteroscopy could not pass through due to intestinal stenosis (about 200 cm from the ileocecal valve). The pathology indicated chronic inflammation in the ileum, with scattered lymphocytes, plasma cells, and eosinophils.

Figure 1 Endoscopic features and radiographic findings of patients diagnosed with chronic enteropathy associated with the solute carrier organic anion transporter family member 2A1 gene. A and B: Enteroscopy revealed multiple circular, tape-like, shallow ulcers and intestinal stenosis in the ileum; C and D: Computed tomography enterography showed multiple segments of the small intestine in the lower left abdomen, and the pelvic area was thickened and enhanced, with ulcer formation. Arrows indicate ulcers; dashed lines indicate intestinal stenosis.

FINAL DIAGNOSIS

As CEAS was highly suspected, we conducted a further investigation using a genetic analysis. We observed the compound heterozygous variants c.1658T>A (p.Ile553Asn) and c.940+1G>A (splice-5) in SLCO2A1. Genetic data were analyzed with gnomAD, Clinvar, and Online Mendelian Inheritance in Man to estimate the pathogenicity of the variants. The Human Gene Mutation Database was used to search for mutation-related information. The splice site mutation (c.940+1G>A) was previously reported to be pathogenic[3], whereas the missense variant (c.1658T>A) was predicted as “probably damaging” and had not yet been reported.

TREATMENT

After the diagnosis of CEAS, iron preparations were given regularly.

OUTCOME AND FOLLOW-UP

The condition is stable.

DISCUSSION

Here, we present a female case of CEAS secondary to the newly identified SLCO2A1 variant. CEAS is a rare autosomal recessive hereditary disease, which was first reported in 2015 by Umeno et al[5]. CEAS is mainly reported in Asian populations, especially Japan, China, and Korea. Recently, three cases of CEAS were detected in France, suggesting CEAS may be more prevalent[8,9]. We reviewed 132 reported patients with CEAS from the previous studies within a time range from January 2015 to April 2025 (Table 1). The results showed a higher frequency in females (60.3%) and a median age at diagnosis of 30 years (range 4-75 years). Anemia (87.3%) and hypoproteinemia (81%) were the most common symptoms of CEAS, followed by abdominal pain (69.3%), diarrhea (26.2%), and hematochezia/melena (18.7%). Importantly, 25.8% of CEAS patients only had a positive result of fecal occult blood, without any symptoms of gastrointestinal bleeding. Similarly, our patient had anemia, hypoproteinemia, and positive fecal occult blood, without classic gastrointestinal symptoms. Fecal tests should be repeated in patients with anemia and edema to find clues for chronic enteropathy, including the rare cause-CEAS, which may be due to chronic, insidious bleeding, malabsorption related to bowel inflammation, or chronic inflammation[1]. About one-third of CEAS had symptoms of PHO, such as pachydermia, digital clubbing, and periostosis. CEAS can involve any part of the digestive tract, including the ileum (88.2%), duodenum (40.4%), jejunum (32.5%), stomach (29.0%), colon (19.3%), and esophagus (16.7%). 59.4% of the CESE patients underwent surgery due to intestinal stenosis. Another fact that catches our attention is that our patient had suffered from adenomyosis and the surgery for an ovarian cyst. Prostaglandins and Prostaglandin transporters play important roles in the menstrual cycle, suggesting SLCO2A1 may potentially affect the endometrium in females, which still needs to be tested with carefully designed experiments[12] (Table 1)[13-30].

Table 1 Clinical features of chronic enteropathy associated with solute carrier organic anion transporter family member 2A1 in the 132 published cases, n (%).

Ref.	Country	Number	Age	Female	Clinical presentation					Hb (g/L)	Alb (mg/L)	Endoscopic features							Consanguinity1	PHO
					Anemia	Hypoproteinemia	Abdominal pain	Diarrhea	Gastro intestinal Bleeding			Esophagus	Stomach	Duodenum	Jejunum	Ileum	Colon	Surgery
Hamon et al[8], 2023; Ricard et al[9], 2024; Sun et al[11], 2018; Ariake et al[13], 2022; Chen et al[14], 2025; Dönger et al[15], 2022; Eda et al[16], 2018; Fang et al[17], 2020; Hu et al[18], 2019; Huang et al[19], 2021; Jimbo et al[20], 2020; Kumar et al[21], 2025; Lin et al[22], 2023; Long et al[23], 2022; Prasad et al[24], 2025; Saura et al[25], 2024; Sonoda et al[26], 2020; Sun et al[27], 20212; Tsuzuki et al[28], 2020; Uchida et al[29], 2017; Wang et al[30], 2019	/	31	24.5, (IQR: 4-75)	48.4	93.5	70.9	61.3	25.8	41.9	77.6 (IQR: 25-126)	27.7 (IQR: 14-40)	-	9.7	16.1	35.5	77.4	9.7	45.2	19.4	29.0
Shang et al[1], 2024	China	12	32 (IQR: 29-40)	41.7	66.7	75	100.0	41.7	33.3	67 (IQR: 49-81)	28 (IQR: 22-33)	16.7	50.0	33.3	16.7	91.7	33.3	75.0	33.3	58.3
Lim et al[2], 2024	Korea	11	16 (IQR: 11~20)	36.4	72.7	/	81.8	9.1	18.2	95 (IQR: 72-111)	31 (IQR: 30-37)	-	45.5	63.6	36.4	63.6	-	45.5	/	27.3
Hong et al[3], 2022	Korea	14	44.5 (IQR: 30-50)	85.7	92.9	100.0	100.0	50.0	21.4	96 (IQR: 79-100)	27 (IQR: 21-30)	-	14.3	35.7	42.9	92.9	14.3	50.0	/	35.7
Umeno et al[4], 2018	Japan	46	40 (IQR: 7-69)	71.7	97.8	/	39.1	4.3	4.3	96 (IQR: 23-137)	Serum protein 52 (IQR: 27-82)	-	26.0	48.0	31.0	98.0	-	63.0	28.0	11.0
Umeno et al[5], 2015	Japan	18	41.2 (IQR: 7-66)	77.8	100.0	77.8	33.3	/	/	87.5 (IQR: 48-112)	Serum protein 55.5 (IQR: 38-82)	-	27.8	44.4	-	100	-	77.8	44.4	12.5
Total		132	30 (IQR: 4-75)	60.3	87.3	81.0	69.3	26.2	25.8	86.5 (IQR: 23-137)	28.4 (IQR: 14-40)	16.7	29.0	40.4	32.5	88.2	19.3	59.4	31.3	29.0

¹Consanguinity: The parents of the patient are united by ties of consanguinity.

-: Negative: +: Positive; /: Not provide; Hb: Hemoglobin; Alb: Albumin; PHO: Primary hypertrophic osteoarthropathy; IQR: Interquartile range.

The types of SLCO2A1 mutations include missense, frame shift, etc. Among CEAS patients, a splice-site mutation c.940+1G>A and homozygous variants c.1807C>T were commonly reported in SLCO2A1 mutations[4]. Sanger sequencing revealed that 11 of the 15 homozygous or heterozygous variants in Chinese CEAS patients had not been reported previously, suggesting the high diversity of SLCO2A1 variants in CEAS patients[1]. In this case, we interestingly identified the new SLCO2A1 variants in Chinese CEAS patients, the compound heterozygous variants c.1658T>A (p.Ile553Asn) and c.940+1G>A (splice-5) in SLCO2A1. The splice site mutation (c.940+1G>A) was previously reported to be pathogenic[3], whereas the missense variant (c.1658T>A) was predicted as “probably damaging” and had not yet been reported. Regrettably, the novel genetic variants still need to be confirmed in designed experiments for the loss-of-function of the prostaglandin transporter and accumulation of PGE2.

Human SLCO2A1 is located on chromosome position 3q22.1-q22.2 and encodes the prostaglandin transporter organic anion transporting polypeptide 2A1 protein, which is located at the cell membrane of endothelial cells[6]. The defection of organic anion transporting polypeptide 2A1 caused by SLCO2A1 mutations lessens intracellular uptake of PGE2 in CEAS[5]. The elevated levels of PGE2 cause neutrophil infiltration, mast cell activation, high vascular permeability, and epithelial barrier disruption[6]. Therefore, CEAS patients, who developed a chronic inflammation, did not respond to some drugs for IBD, such as mesalazine, glucocorticoids, immunosuppressants, and biological agents[4]. The current medications of CEAS are mainly for supportive and symptomatic treatment, while surgery remains the primary treatment for half of the patients. Further studies are still needed to explore the pathogenesis of CEAS, which may lead to a rational treatment for CEAS. This study had several limitations. First, we lacked functional validation to support the pathogenicity of the novel variants, which needed to be confirmed in designed experiments. Second, due to the relatively short follow-up period, we could not obtain the long-term clinical course after the CEAS diagnosis. However, the levels of hemoglobin and albumin are stable currently. Finally, we only reported one patient, which limits generalizability.

CONCLUSION

In summary, it’s worth noting that CEAS should be considered in the differential diagnosis of chronic iron deficiency anemia and hypoproteinemia, which may lack gastrointestinal symptoms. Genetic testing for SLCO2A1 is crucial for diagnosis. Further accumulation of cases and mechanism research is necessary to explore the disease pathogenesis and establish effective treatments.