Chronic Enteropathy Associated with SLCO2A1 Gene

Abstract

Background

Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare hereditary disorder characterized by multiple small intestinal ulcers, chronic anemia, and hypoproteinemia. Initially reported by Okabe et al. [J Jpn Soc Gastroenterol. 1968;65:1114–7] in 1968 as chronic nonspecific multiple ulcers of the small intestine, the condition was later identified as a genetic disorder caused by mutations in the SLCO2A1 gene, which encodes a prostaglandin (PG) transporter. Unlike typical autosomal recessive disorders, CEAS predominantly affects females and is frequently present with extraintestinal manifestations such as digital clubbing, pachydermia, and periostosis.

Summary

This review provides a comprehensive summary of the epidemiology, pathogenesis, clinical features, diagnostic criteria, and management of CEAS, with an emphasis on newly established diagnostic protocols in Japan. CEAS is characterized by multiple shallow circumferential or oblique ulcers in the small intestine, often resembling NSAID-induced enteropathy. Laboratory findings typically include iron deficiency anemia and hypoproteinemia, while urinary PG metabolite levels are significantly elevated. Genetic testing for SLCO2A1 mutations, particularly the c.940 + 1G>A splice site mutation, confirms the diagnosis. While symptomatic management with enteral nutrition, iron supplementation, blood transfusions, and albumin infusion is the mainstay of therapy, definitive treatments remain unavailable. Endoscopic balloon dilation may be useful in cases of intestinal strictures, but surgical intervention is frequently required.

Key Messages

(i) CEAS should be considered in cases of chronic iron deficiency anemia and hypoproteinemia with unexplained small intestinal ulcers. (ii) Genetic testing for SLCO2A1 mutations, combined with assessment of small intestinal morphology, is essential for accurate diagnosis. (iii) Current treatment options are limited to symptomatic management and surgical intervention, highlighting the need for further research to develop effective therapies.

Introduction

In 1968, Okabe et al. [1] identified a group of diseases distinct from Crohn’s disease, characterized by multiple small intestinal ulcers that lacked specific histopathological features such as granulomas or eosinophilic infiltration. They proposed the term chronic nonspecific multiple ulcers of the small intestine (CNSU) to define this condition. This refractory disease is characterized by persistent occult bleeding from small intestinal ulcers, resulting in anemia and hypoproteinemia, and is considered a subtype of inflammatory bowel disease in a broad sense. Although the endoscopic and histopathological findings of CNSU clearly differ from those of Crohn’s disease and other ulcerative diseases of the small intestine [2, 3], diagnosing small intestinal lesions remains challenging and is frequently misdiagnosed.

Recently, it was revealed that this disorder is a hereditary disease caused by mutations in the SLCO2A1 gene, which encodes a prostaglandin (PG) transporter. Consequently, the disease is now referred to as chronic enteropathy associated with SLCO2A1 gene (CEAS) [4]. Unlike typical autosomal recessive disorders, CEAS is more prevalent in females, while male patients frequently present with extraintestinal manifestations. However, many aspects of its clinical picture remain unclear. This review summarizes the epidemiology, pathophysiology, and gastrointestinal characteristics of CEAS, along with an introduction to the newly established diagnostic criteria currently used in Japan.

Disease Concept

CNSU was proposed as a distinct disease entity within a group of small intestinal ulcerative diseases characterized by the absence of specific inflammatory findings, such as granulomas, based on pathological examination of surgical specimens [1]. Clinically, it was considered different from Crohn’s disease or intestinal tuberculosis. However, confusion arose due to the misclassification of numerous nonspecific small intestinal ulcers as this condition.

Yao [5] proposed the alternative term chronic hemorrhagic ulcerative enteropathy based on the persistent bleeding and resultant anemia from small intestinal ulcers. Yet, due to challenges in establishing a definitive diagnosis and the rarity of the disease, the disease concept was not fully established.

At Kyushu University, long-term case accumulation revealed consanguinity in 6 of 13 patients, suggesting a hereditary basis [6]. Family-based analyses using next-generation sequencing (whole-exome sequencing) subsequently identified SLCO2A1 mutations as the cause, confirming CEAS as a distinct genetic disorder [4]. The gastrointestinal lesions are characterized by multiple shallow ulcers arranged circumferentially or obliquely in the small intestine, resembling NSAID-induced enteropathy (Fig. 1) [2, 7, 8]. These features are thought to be associated with impaired tissue transport of PGs.

Fig. 1.

Endoscopic findings of CEAS (reproduced from reference 8). a–d Small intestine. e Stomach. f, g Duodenum. a Shallow ring-shaped ulcer in the lower ileum, located approximately 30 cm from the ileocecal valve. b Pseudodiverticulum and narrowing of the central ileum caused by the fusion of longitudinal and oblique ulcers. c Shallow ulcer with a longitudinal orientation. d Severe stenosis of the central ileum (intraoperative endoscopic findings) observed approximately 4 weeks after treatment with central venous nutrition. e Scarring and open ulceration in the antrum of the stomach. The lesser curvature is shortened. f Narrowing of the lumen in the superior duodenal angle due to a ring ulcer scar, with a shallow and oblique ulcer toward the anal side. g Mucosal defect observed above the folds in the third part of the duodenum.

Epidemiology

According to a survey conducted by a Ministry of Health, Labour and Welfare research group in Japan, the estimated prevalence of CEAS in the country is approximately 150–200. A nationwide mail-based survey of hospitals in Japan conducted in 2017 estimated the number of patients with CEAS to be 388 (95% confidence interval: 289–486), with a prevalence rate of 3.1 per 1,000,000 population. This prevalence is lower than that of intestinal Behcet’s disease and considered to be comparable to that of Cronkhite-Canada syndrome [9]. Most reported cases are Japanese [8, 10–15], although reports from Korea, China, and other parts of Asia are increasing [16–29]. Conversely, reports from Western countries are extremely rare [30, 31], likely due to both lack of awareness and racial genetic differences – particularly the c.940 + 1G>A splice site mutation, which is common in Asian patients but nearly absent in Caucasians.

The latest nationwide survey in Japan (Table 1) shows a male-to-female ratio of approximately 1:2, indicating a female predominance. Although hereditary, the age of onset varies widely from 1 to 69 years (median: 19 years). The median duration from symptom onset to diagnosis is 12 years, likely reflecting difficulty in diagnosis. In women and children, CEAS is often misdiagnosed as iron deficiency anemia without sufficient gastrointestinal evaluation. Parental consanguinity and familial clustering were observed in 27% and 26% of cases, respectively, though most cases are sporadic.

Table 1.

Clinical features of CEAS patients (n = 70)

Sex, male/female	25/45
Age at diagnosis, years	7–79 (median 43)
Age at onset, years	1–69 (median 19)
Parental consanguinity	19 (27%)
Family history	18 (26%)
Symptoms
Anemia	64 (91%)
Abdominal pain	29 (41%)
Edema	14 (20%)
Diarrhea	5 (7%)
Hypoproteinemia	3 (4%)
Hematochezia	2 (3%)
Hematemesis	1 (1%)
Laboratory data at diagnosis
Hemoglobin, g/dL	2.3–14.4 (median 9.7)
Serum protein, g/dL	2.7–8.2 (median 5.3)
CRP, g/dL	0–37 (median 2.9)
Surgery	38 (54%)
Skeletal manifestations
Digital clubbinga	18 (26%)
Periostosisa (by X-ray evaluation)	17 (25%)b
Acro-osteolysis (by X-ray evaluation)	3 (4%)b
Arthralgia of large joints	12 (17%)
Knee-joint effusions	5 (7%)
Skin manifestations
Hyperhidrosis	7 (10%)
Pachydermiaa	14 (20%)
Seborrhea	6 (9%)
Acne	7 (10%)
Flushing	9 (13%)
Developmental manifestations
Patent ductus arteriosus	1 (1%)
Delayed cranial suture closure	0 (0%)

Clinical information was available for 70 patients.

^aThese manifestations are included in the major clinical criteria for PHO.

^bX-ray was examined in 67 patients.

Etiology and Pathophysiology

The PG transporter encoded by SLCO2A1 is a transmembrane protein expressed on cell membranes, responsible for intracellular PG uptake and subsequent degradation [32]. Interestingly, mutations in this gene cause both CEAS and primary hypertrophic osteoarthropathy (PHOAR2, OMIM 614441), also known as pachydermoperiostosis [33]. This entity is listed in the Online Mendelian Inheritance in Man (OMIM) database as “PHOAR2-enteropathy syndrome.” Similarly, mutations in HPGD, encoding a PG-degrading enzyme, cause PHOAR1 (OMIM 259100) [34]. In both PHOAR1 and PHOAR2, elevated systemic PG levels are reflected in high urinary levels of PG metabolites and are thought to cause secondary changes such as digital clubbing, pachydermia, and periostosis.

In CEAS, urinary PG metabolites are significantly elevated compared to healthy controls and patients with Crohn’s disease [4], and extraintestinal manifestations such as clubbing, pachydermia, and periostosis are observed in some patients [35]. These systemic features are thought to result from impaired PG degradation due to SLCO2A1 dysfunction, leading to excessive circulating PGs. Thus, these findings are consistent with PG-related systemic effects. Although CEAS is caused by SLCO2A1 mutations, some patients with PHOAR2 do not exhibit gastrointestinal lesions, suggesting incomplete penetrance.

The gastrointestinal lesions of CEAS resemble NSAID-induced enteropathy, which results from impaired mucosal PG production. In CEAS, a similar state of impaired PG availability at the mucosal level is assumed. Among the various PGs, PGE2 is known to exert mucosal protective effects in the small intestine by stimulating the secretion of mucus and bicarbonate, maintaining mucosal blood flow, promoting epithelial cell turnover and repair, and preserving intercellular tight junctions [36, 37]. A dysfunction or reduction in PGE2 activity is presumed to contribute to ulcer formation in CEAS. However, since previously reported SLCO2A1-knockout mice did not exhibit any histological signs of enteritis in the ileum or colon up to 24 weeks of age [38], it is believed that additional factors, such as gastric acid secretion and gut microbiota, contribute to ulcer formation. Moreover, it has been shown that increased PGE2 levels in SLCO2A1-deficient mice can activate the NLRP3 inflammasome in macrophages and exacerbate dextran sulfate sodium-induced colitis [38]. The detailed mechanism of disease onset remains unclear and requires further investigation.

Clinical Features and Laboratory Findings

Persistent bleeding from ulcerative lesions leads to anemia and hypoproteinemia, which are hallmark features of CEAS (Table 1). While temporary symptomatic relief can be achieved through iron supplementation, albumin infusion, blood transfusion, or total parenteral nutrition, these treatments are not curative, and symptoms often recur after discontinuation. Clinical manifestations may include abdominal pain, peripheral edema due to hypoalbuminemia, and fatigue, but overt hematochezia is uncommon [35]. When the disease occurs in childhood, growth retardation, including delayed puberty, is observed, and amenorrhea may occur in females. More than half of the patients eventually require surgical intervention due to intestinal strictures (Table 1). However, some cases exhibit symptom onset at an older age, and the severity and age of onset vary widely among individuals. Factors associated with the age of onset remain unknown.

Nearly all patients exhibit iron deficiency anemia and hypoproteinemia at the initial visit (Table 1). Although inflammatory markers such as elevated CRP and ESR may be present, they are generally milder than those observed in Crohn’s disease. Urinary levels of the primary PGE2 metabolite (PGE-MUM) are significantly higher in CEAS patients than in healthy controls or Crohn’s disease patients, making this a useful screening test (positive if >30 μg/g.Cr) [39].

Extraintestinal features such as digital clubbing, pachydermia, and periostosis are observed in approximately 20% of patients and should prompt consideration of CEAS (Table 1). Orthopedic consultation is recommended, and plain radiographs of the limbs are useful for detecting periostosis (Fig. 2) [40]. A recent nationwide survey revealed that 10 patients (14%) exhibited the full triad of hypertrophic osteoarthropathy, all of whom were male. A comparison by sex revealed that digital clubbing, pachydermia, and periostosis were significantly more frequent in male patients (Table 2) [35]. Bone marrow fibrosis has also been reported in some cases [41].

Fig. 2.

Bone plain X-ray findings (reproduced from Nakata et al. [38]. a Bone hypertrophy extending from the metaphysis to the diaphysis of the tibia and fibula, with cortical thickening and irregular periosteal reaction. b Hypertrophy of the diaphysis observed around the first metatarsal of the foot.

Table 2.

Comparison of clinical findings of CEAS patients by sex (n = 70)

​	Male (n = 25)	Female (n = 45)	p valuea
Age at diagnosis (median), years	46	43	NS
Age at onset (median), years	18	19	NS
Consanguinity	6 (24%)	13 (29%)	NS
Family history	7 (28%)	11 (24%)	NS
Symptom
Abdominal pain	10 (40%)	19 (42%)	NS
Laboratory data at diagnosis	​	​	​
Hemoglobin (median), g/dl	10.2	9.5	NS
Serum protein (median), g/dl	5.6	5.0	0.040
CRP (median), g/dl	4.0	2.0	0.057
Disease site
Stomach	2 (8%)	14 (31%)	0.037
Duodenum	12 (48%)	18 (40%)	NS
Jejunum†	7 (29%)	10 (22%)	NS
Ileum (except for terminal ileum)b	23 (96%)	42 (93%)	NS
Surgery	11 (44%)	27 (60%)	NS
c.940+1G>A homozygous mutation	9 (36%)	12 (27%)	NS
Extraintestinal manifestations
Digital clubbing	14 (56%)	4 (9%)	<0.0001
Periostosisc	13 (54%)	4 (9%)	<0.0001
Acro-osteolysisc	1 (4%)	2 (5%)	NS
Arthralgia of large joints	5 (20%)	7 (16%)	NS
Knee-joint effusions	3 (12%)	2 (4%)	NS
Hyperhidrosis	4 (16%)	3 (7%)	NS
Pachydermia	14 (56%)	0	<0.0001
Seborrhea	6 (24%)	0	0.0014
Acne	3 (12%)	4 (9%)	NS
Flushing	7 (28%)	2 (4%)	0.0081
Patent ductus arteriosus	1 (4%)	0	NS
Delayed cranial suture closure	0	0	NS

NS, not significant.

^aFisher’s exact test or Mann-Whitney U test. Significant p values are indicated in bold.

Data are available for ^b69 and ^c67 patients.

Endoscopic and Radiological Findings

CEAS lesions are diverse but are characterized by multiple shallow ulcers arranged circumferentially or obliquely, along with frequent strictures (Fig. 1a–c) [3, 7, 8, 42]. In contrast to Crohn’s disease, which often features longitudinal ulcers located on the mesenteric side, CEAS lesions do not exhibit a consistent spatial relationship with the mesentery. In long-standing cases or those treated with total parenteral nutrition, severe intestinal deformation and strictures may obscure the typical findings (Fig. 1d). These lesions closely resemble those observed in NSAID-induced enteropathy. In our comparative analysis of CEAS and NSAID-induced enteropathy, CEAS was characterized by more active ulcerative lesions, whereas NSAID-induced enteropathy was typically presented with ulcers in the healing phase [7, 43]. Although written in Japanese, an image atlas containing numerous endoscopic and gross surgical photographs of CEAS-related findings has been compiled and published by a Japanese national research group (http://ibdjapan.org/pdf/doc06.pdf).

CEAS lesions are most frequently observed in the ileum, excluding the terminal ileum (94%, Fig. 3), although the terminal ileum and colon may also be involved. The most recent data indicate that upper gastrointestinal lesions occur in 23% (stomach) and 43% (duodenum) of cases, sometimes mimicking peptic ulcers (Fig. 1e). Gastric lesions are more common in females (Table 2). Unique findings in CEAS include deep stenotic lesions in the distal descending duodenum and multiple ring-shaped mucosal defects (Fig. 1f, g).

Fig. 3.

Distribution of lesion frequency by site in CEAS patients.

Capsule endoscopy or balloon-assisted enteroscopy is typically used to evaluate the small intestine. However, in patients with multiple strictures or those who have undergone surgery, small bowel contrast radiography remains a valuable alternative due to the limitations of endoscopic access and the risk of capsule retention. Despite concerns regarding radiation exposure, contrast radiography offers valuable insights into lesion distribution and progression over time (Fig. 4).

Fig. 4.

Small bowel X-ray findings. a Multiple asymmetric deformities and strictures observed in the mid to lower small intestine (yellow arrows). Some areas show the formation of a small pocket (red arrows). b Additional compression reveals a transversely oriented open ulcer more clearly.

Histopathology

Gross examination of resected specimens reveals shallow circumferential or oblique ulcers, short longitudinal ulcers, and map-like erosions. Unlike Crohn’s disease, findings such as cobblestone appearance, inflammatory polyps, transmural thickening, adhesions, or fistula formation are absent. A notable feature is the presence of “islands of normal mucosa,” where unaffected mucosa remains between lesions [44]. Although Crohn’s disease typically presents with skip lesions, ulcerative lesions surrounding areas of normal mucosa in a circumferential manner are not characteristic of the disease.

Microscopically, ulcers typically remain within the mucosa or submucosa and rarely extend to the muscularis propria (classified as UL-I or UL-II) [45]. Mild infiltration of lymphocytes and plasma cells, fibroblast proliferation, and capillary proliferation and dilation are observed. Granulomas are absent, and inflammatory changes are considered nonspecific.

The SLCO2A1 protein is expressed in various organs and shows strong expression in vascular endothelial cells of the lamina propria and submucosa of the small intestine. Immunohistochemical staining for SLCO2A1 protein is negative in most CEAS patients, making it a useful screening tool [46].

Diagnosis

The diagnostic criteria currently used in Japan (Table 3) include three major categories: clinical features, gastrointestinal lesions, and genetic testing for SLCO2A1. A definitive diagnosis requires the presence of at least two of these three criteria and the exclusion of other diseases. In cases where chronic anemia and hypoproteinemia are present without identifiable causes on upper or lower gastrointestinal endoscopy, CEAS should be suspected, and small bowel lesions should be actively investigated.

Table 3.

Diagnostic criteria for CEAS

Key findings
A. Clinical findings
Long-standing iron deficiency anemia and hypoproteinemia
B. Gastrointestinal lesions (duodenum to ileum, predominantly ileum)
Findings include either (1) and (3), or (2) and (3)
(1) Multiple asymmetric deformities and strictures, including annular (ring-like) strictures
(2) Sharply demarcated, oblique, or transverse shallow ulcers, with map-like or band-like (tape-like) appearances
(3) No specific inflammatory findings such as granulomas observed in histopathological examination of biopsy tissue or resected specimens
C. SLCO2A1 genetic testing
Presence of pathogenic variants
D. Differential diagnoses
Intestinal tuberculosis (including suspected cases), Crohn’s disease, intestinal Behçet’s disease/simple ulcer, drug-induced enteritis, eosinophilic gastroenteritis, radiation enteritis, ischemic enteritis of the small intestine, familial Mediterranean fever-related enteritis, small intestinal tumors such as lymphoproliferative disorders, infectious enteritis, etc.
Additional findings
(1) Decreased expression of SLCO2A1 protein in vascular endothelial cells within gastrointestinal biopsy tissue or resected specimens
(2) Elevated urinary levels of PG metabolites (PGE-MUM)
(3) Findings consistent with hypertrophic osteoarthropathy

Definite: Diagnosis is made when two or more of the three key findings (A to C) are present and differential diagnoses (D) are excluded. Possible: Diagnosis is considered when either key finding A or B is present, and at least one of the additional findings is observed, and differential diagnoses (D) are excluded.

While capsule endoscopy or contrast radiography is useful for small bowel evaluation, capsule endoscopy may be contraindicated in patients with strictures, and contrast studies require experience for accurate interpretation. In pediatric cases or in patients with advanced strictures, complete evaluation may be difficult. In such cases, extraintestinal findings, urinary PG metabolite levels, or SLCO2A1 immunostaining on biopsy specimens can guide decisions regarding genetic testing.

The types and frequencies of SLCO2A1 mutations in Japanese CEAS patients are shown in Table 4. The most common mutation is the splice site mutation c.940 + 1G>A, which causes exon 7 skipping and has an allele frequency of approximately 0.001 in the Asian population [4]. Other variants likely produce truncated or dysfunctional proteins. Of 72 cases analyzed, 70 carried pathogenic variants in homozygous or compound heterozygous states, while two had only a single heterozygous mutation. Ito et al. [14] reported a case with downregulated SLCO2A1 mRNA and protein due to promoter methylation, undetectable by standard Sanger sequencing.

Table 4.

Identified SLCO2A1 mutations

No.	Nucleotide change	Predicted effect		Mutant allele frequency (n = 72)a
1	c.940+1G>A	SS (R288Gfs*7)	Truncated	66/144
2	c.1807C>T	R603X	Truncated	35/144
3	c.664G>A	G222R	Deleteriousb	9/144
4	c.830dupT	F277Ffs*19	Truncated	9/144
5	c.1149delA	G383Gfs*5	Truncated	4/144
6	c.1475G>A	C492Y	Deleteriousb	3/144
7	c.421G>T	E141X	Deleteriousb	2/144
8	c.1372G>T	V458F	Deleteriousb	2/144
9	c.1461+1G>C	SS (I488Lfs*11)	Truncated	2/144
10	c.97G>C	V33L	Deleteriousb	1/144
11	c.101T>C	F34S	Deleteriousb	1/144
12	c.310G>A	G104R	Deleteriousb	1/144
13	c.547G>A	G183R	Deleteriousb	1/144
14	c.770G>A	W257X	Deleteriousb	1/144
15	c.830delT	F277Sfs*8	Truncated	1/144
16	c.1279_1290del	E427_P430del	Truncated	1/144
17	c.1530_1531del	F510Ffs*67	Truncated	1/144
18	c.1624C>T	R542C	Deleteriousb	1/144
19	c.1647G>T	K549N	Deleteriousb	1/144

SS, splice site.

^aIncludes two cases in which only one allele mutation was identified.

^bMutation pathogenicity according to SIFT, PolyPhen-2, and PROVEAN.

Treatment

At present, there is no definitive treatment for CEAS, and the management primarily focuses on symptomatic relief. Medical management includes enteral nutrition, iron supplementation, albumin infusion, and blood transfusions. In severe cases, repeated intravenous albumin infusions and total parenteral nutrition may be necessary. Oral PG analogs have not proven effective, and drugs commonly used for Crohn’s disease (e.g., corticosteroids, 5-ASA, anti-TNF agents) are ineffective.

Some case reports describe successful treatment with thiopurines [47] or the JAK1 inhibitor ruxolitinib in patients with concurrent bone marrow fibrosis [41]. Due to frequent progression to intestinal strictures, surgical intervention is often required (Table 1). However, postoperative recurrence is almost inevitable. Endoscopic balloon dilation may be effective in selected cases with accessible strictures.

Conclusion

This review provided an overview of the clinical features, pathogenesis, and diagnostic criteria of CEAS based on current evidence in Japan. Although rare, CEAS should be considered in the differential diagnosis of chronic iron deficiency anemia and hypoproteinemia. Morphological assessment of small intestinal lesions is essential, along with evaluation of upper gastrointestinal involvement and extraintestinal findings. Genetic testing for SLCO2A1 is useful for definitive diagnosis. Further accumulation of cases and research are necessary to elucidate the disease pathogenesis and establish effective treatments.

Acknowledgments

We would like to express our sincere gratitude to the members of the CEAS study group for their invaluable assistance in collecting clinical information. We extend our thanks to the following doctors: Daiki Abukawa, Masano Akamatsu, Kunihiko Aoyagi, Katsuya Endo, Shigeru Furukawa, Yoki Furuta, Yuta Fuyuno, Kuniko Gomi, Akira Harada, Naohiko Harada, Toshifumi Hibi, Aiichiro Higure, Fumihito Hirai, Atsushi Hirano, Sakiko Hiraoka, Tadakazu Hisamatsu, Naoki Hosoe, Shuhei Hosomi, Mitsuo Iida, Hiroyuki Imaeda, Toshihiro Inokuchi, Takeaki Ishii, Fumihiko Kakuta, Kazuya Kitamura, Takanari Kitazono, Hiroyuki Kobayashi, Shuji Kochi, Reiko Kunisaki, Toshiyuki Matsui, Tatsuki Mizuochi, Manabu Nagayama, Masanao Nakamura, Haruhiko Ogata, Soh Okano, Eiko Okimoto, Naoki Omiya, Kei Onodera, Hidehisa Ooi, Noriyoshi Sagihara, Satowa Seki, Akira Sonoda, Teruyuki Takeda, Tomoyuki Tsujikawa, Yoshitaka Ueno, Kenji Watanabe, Takashi Watanabe, Hironori Yamamoto, Tsuyoshi Yamatou, Shunichi Yanai, Tsuneyoshi Yao, Shigeyoshi Yasukawa, and Masashi Yoshida.

Conflict of Interest Statement

Motohiro Esaki was a member of the journal’s editorial board at the time of submission. The other authors disclose no conflicts of interest.

Funding Sources

This work was supported in part by Health and Labor Sciences Research Grants for research on intractable diseases from the Ministry of Health, Labour and Welfare of Japan.

Author Contributions

Conceptualization: T.M. and J.U.; literature search and data curation: J.U. and K.U.; writing – original draft: J.U.; writing – review and editing: M.E., K.U., and T.M., and supervision: T.M. All authors have read and approved the final manuscript.

Funding Statement

This work was supported in part by Health and Labor Sciences Research Grants for research on intractable diseases from the Ministry of Health, Labour and Welfare of Japan.