In this article, we reported a young woman patient with CEAS and PHO, a type of disease caused by a mutation in the SLCOA21 gene. The patient has gastrointestinal symptoms as the first symptom accompanied by skeletal symptoms.
CEAS
CEAS was initially referred to as chronic nonspecific multiple ulcers of the small intestine (CNSU)[12, 13], which is an intestinal disease characterized by ring-shaped ulcers and concentric stenosis. Its main clinical feature is chronic persistent gastrointestinal blood and protein loss caused by long-term recurring small intestinal ulcers. Most patients will have symptoms of anaemia and hypoalbuminemia[1, 2, 12–14]. In 2015, Umeno et al. identified seven candidate mutations in the SLCO2A1 gene through whole-exome sequencing of CNSU patients, which encodes a prostaglandin transporter. In contrast to the vague name of CNSU, a more suitable nomenclature of CEAS has been suggested and CEAS has been defined as a rare genetic disease characterized by multiple, circular, longitudinal or eccentric ulcers of the ileum[2]. CEAS principally occurs in women, with a male to female ratio of 1:2.5–4:14[1, 2]. It often presents in adolescence, and the median age of onset is 16.5 years; however, the age of onset ranges from 1 to 69 years old, and 28% of patients are the offspring of close relatives[1]. The main clinical manifestations of the patients are oedema, anaemia, hypoproteinemia or abdominal pain, and most patients have anaemia (98%), while diarrhoea, blood in the stool and fever are relatively rare[1, 2, 14]. This patient's parents were close relatives and she presented to the doctor with oedema of both lower limbs. She had severe anaemia and hypoproteinemia, which were consistent with the symptoms of CEAS previously reported. However, the faecal occult blood test in this case was positive, with severe diarrhoea and occasional bloody stool, which were slightly different from previous reports.
With the promotion and application of balloon-assisted enteroscopy (BAE), the diagnosis rate of intestinal ulcerative diseases has been greatly improved. However, because the endoscopic manifestations of ileal ulcers caused by CEAS are very similar to nonsteroidal anti-inflammatory drug-induced bowel disease (NSAID-bowel disease), Crohn’s disease (CD), Behçet's disease (BD), cryptogenic multifocal ulcerative stenotic enteritis (CMUSE) and other intestinal ulcerative diseases, misdiagnoses and missed diagnoses often occur in the clinic. It has been reported that glucocorticoids and immunosuppressants are ineffective for CEAS[12–14]. Therefore, it is vital to identify and diagnose CEAS and select appropriate treatment. CEAS cases are easily misdiagnosed as Crohn’s disease clinically, so they should be rigorously differentiated from CD initially. Both diseases share some common clinical features, such as a pubertal predisposition, persistent anaemia and hypoproteinaemia, ileal involvement and with or without stenosis. The patient in this case was considered to have Crohn's disease at the first diagnosis. However, there are also differences. The morphological characteristics of small intestinal ulcers are different. Unlike Crohn’s disease, there are multiple intestinal ulcers in CEAS (usually >20)[14]. The depth of CEAS ulcers is limited to the mucosa or submucosa and does not reach the muscle layer, so small intestinal lesions will not form transmural inflammation leading to fissures and fistulas or have a cobblestone appearance and granuloma manifestations. Furthermore, previous reports have confirmed that serum and urine prostaglandin E2 (PGE2) and prostaglandin E metabolite (PGE-M) levels in CEAS patients are increased[1, 2, 15]. Because PGE-M are more stable in urine, Matsuno et al.[16] confirmed that prostaglandin E-major urinary metabolite (PGE-MUM) measurement is a noninvasive and convenient detection method to distinguish CEAS from CD. In addition, in most CEAS patients, SLCO2A1 gene mutations result in the loss of SLCO2A1 protein expression in the vascular endothelial cells of the small intestinal mucosa and submucosa, whereas its expression is normal in healthy individuals and CD and BD patients[17, 18]. Moreover, CD patients are mainly male, while BD and CEAS patients are mainly female[14]. In Western countries and South Korea, a disease similar to CEAS called CMUSE has also been reported[19]. This enteropathy has been proven to be an autosomal recessive genetic disorder caused by a PLA2G4A gene mutation[20]. Patients with CEAS and CMUSE have similar clinical features, including anaemia and abdominal pain. Pathologically, they both show multiple mucosal and submucosal superficial ulcers and are prone to ulcerative stenosis of the small bowel[12–15, 19]. However, intestinal ulcers in CEAS patients mainly occur in the ileum, while CMUSE mainly occurs in the jejunum and can be accompanied by extraintestinal symptoms, including obstructive pulmonary disease, oral aphthae, arthralgia, Sjogren’s syndrome, Raynaud’s sign, and neuropathy[19, 21]. However, these comorbidities are rare in patients with CEAS[12, 13]. The symptoms can be improved by corticosteroid therapy, but this is not effective in CEAS[2, 12–14, 19, 21]. Combining these differences, CMUSE and CEAS can be distinguished, but the distinction between the two is mainly achieved through genetic testing.
NSAID enteropathy is also an important differential diagnosis of CEAS. Most patients with NSAID enteropathy have a history of a long-term history of using NSAIDs, and their symptoms are dramatically improved after drug withdrawal, while there is no significant improvement in the symptoms of CEAS patients. In short, gene analysis of SLCO2A1 is the key to the diagnosis of CEAS. In this case, the female patient had an onset in adolescence of refractory oedema, hypoproteinemia, and anaemia. Colonoscopy revealed ileocecal valve and terminal ileum stenosis ulcers. Finally, a homozygous mutation c.664G>A in SLCO2A1 exon 5 was found by gene sequencing and thus a conclusive diagnosis was reached.
PHO
Mutations in the SLCO2A1 gene cause not only CEAS but also a subtype of PHO[3, 8–10, 22]. Hypertrophic osteoarthropathy (HO) can be divided into primary and secondary according to its aetiology. PHO is an autosomal genetic disease, accounting for only 3%-5% of HO[10]. Secondary hypertrophic bone arthropathy (SHO) is more common clinically, accounting for approximately 95%-97%, and is mainly secondary to cardiopulmonary diseases[23]. In addition to the typical clinical triad of digital clubbing, periostosis, and pachydermia, PHO can also manifest as symptoms such as hyperhidrosis, seborrhoea, acroosteolysis, arthritis, joint pain and other symptoms[3, 9, 10]. In addition to the above clinical manifestations, PHO is often associated with some nonspecific complications: (1) Gastrointestinal diseases, including chronic gastritis, CNSU, peptic ulcer, gastric cancer, Crohn’s disease, and CMUSE[4, 5, 24]; (2) anaemia, (3) hypoproteinemia, (4) and myelofibrosis [3, 9, 10, 22, 24, 25]. The clinical manifestations of primary hypertrophic osteoarthropathy are diverse. In 2013, Zhang et al.[3] reported that diarrhoea was a common symptom of PHO patients, and 6 out of 7 PHO patients had diarrhoea. In the report of Wang et al.[5], PHO patients with gastrointestinal involvement mainly showed diarrhoea (46.2%), gastric or duodenal ulcers (19.2%/11.5%) and chronic gastritis (7.7%). In a research report involving 43 Chinese PHO patients, more than half of the patients had watery diarrhoea[24]. Hou et al.[9] confirmed that diarrhoea is the most common complication among the digestive tract symptoms. Different patients have different causes of diarrhoea, such as eating spicy food or taking cold drinks, or even sexual intercourse[3]. Sethuraman et al.[25] reported for the first time that PHO was associated with protein-losing enteropathy, indicating that lymphatic infiltration into the abdominal cavity or intestinal cavity was caused by dilatation and rupture of the intestinal mucosa and submucosal lymphatic vessels, resulting in protein loss. Anaemia is also a common comorbidity in PHO associated with SLCO2A1 mutations.
There are many factors that cause anaemia, including myelofibrosis and gastrointestinal bleeding [22, 24, 26]. Patients with SLCO2A1 mutations have a high frequency of severe anaemia due to myelofibrosis[4, 26]. Previous studies have shown that PGE2 is necessary for the formation of haematopoietic stem cells (HSCs), but the dose of PGE2 is very important. High-dose PGE2 can inhibit the differentiation of stem cells, and anaemia in PHO patients may be caused by an increased level of PGE2[3, 24, 27]. Zhang et al.[3] reported 2 cases of female PHO patients with c.855delA homozygous mutations. Their clinical symptoms were severe anaemia and hypoalbuminemia, rather than skin and bone manifestations. Combining the patient symptoms and gene test results, we consider these two cases to be CEAS. A case of PHO associated with a SLCO2A1 mutation in a postmenopausal elderly women was previously reported, but the patient did not present with the typical skin and bone manifestations[28]. Hou et al.[9] is by far the largest cohort study report of SLCO2A1 mutations in China, in which all PHO patients with SLCO2A1 mutations were male.
The patient in this paper with hyperhidrosis since childhood, when she was 15 years old, her lower limbs suddenly suffered from pain and formed hallux valgus. The X-ray of the lower limbs showed that the tibia and fibula periosteum was thickened, showing typical onion skin-like changes, and this was combined with severe diarrhoea, consistent with the clinical characteristics of PHO. A homozygous mutation of the SLCO2A1 gene was detected by gene sequencing, which is consistent with the PHO diagnosis. The patient was mainly treated for oedema, accompanied by watery diarrhoea and severe anaemia. She liked spicy food; in severe cases, she had diarrhoea episodes 10 times per day, and the causes of her diarrhoea and protein loss are still worth exploring.
Diseases associated with SLCO2A1
The SLCO2A1 gene is located on chromosome 3q21.1-q22.2 and consists of 14 exons, encoding a prostaglandin transporter (PGT). When mutation of the SLCO2A1 gene causes abnormal synthesis of PGT, abnormal prostaglandin metabolism leads to disease[10]. The degradation of prostaglandins in the human body is divided into two steps. First, PGT, including SLCO2A1, actively transports extracellular prostaglandin into the cells, and the prostaglandins are degraded to 15-OXO-PGE2 by 15-hydroxyprostaglandin dehydrogenase encoded by HPGD and then by prostaglandin reductase to PGE-M[29]. In 2008, Uppal et al.[30] revealed an HPGD (MIM 606188) gene mutation in a PHO family. In 2012, Zhang et al.[10] demonstrated another pathogenic gene of PHO, SLCO2A1 (MIM 601460). Previous molecular discoveries divided PHO into two types: PHOAR1 (MIM259100) with a HPGD gene mutation and PHOAR2 (MIM614441) with a SLCO2A1 gene mutation[24]. The mutated HPGD and SLCO2A1 genes inhibited the removal of prostaglandins, leading to local accumulation of prostaglandins, especially PGE2, a key factor in PHO pathogenesis[3, 10, 30]. The detection of PGE2 and PGE-M in urine can contribute to distinguishing between the two types: the levels of urine PGE2 and PGE-M in patients with PHOAR2 are increased. In PHOAR1 patients, urine PGE2 is increased and PGE-M is decreased[3, 9, 10, 24]. It has been previously reported that the level of PGE2 in PHOAR1 patients is significantly higher than that in PHOAR2 patients[24]. Since PGE2 levels in both PHO and CEAS are increased, we consider that PGE2 may be the main regulator of the clinical phenotype of the diseases associated with SLCO2A1. Although PGE2 is an important component of the intestinal mucosal defence barrier and is considered to be a protective factor of gastrointestinal tissue via the prostaglandin receptor EP3/EP4[31], patients with CEAS still develop multiple intestinal ulcers, and the mechanism of how prostaglandins play a role in the pathogenesis of CEAS has not yet been clarified. Based on the results of previous studies, we speculate that PGE2 levels in an appropriate range may be a necessary factor to maintain intestinal mucosal homeostasis.
In 2015, Umeno found that the SLCO2A1 gene is the cause of CEAS. Among the 7 different mutation sites detected, the splice site mutation c.940+1G>A is the most common in patients with CEAS[1, 2]. Mutation sites c.664G>A, c.940+1G>A, and c.1807C>T were also reported as pathogenic mutations of PHO[3, 9, 10, 26, 28]. PHOAR1 can have an onset within 1 year after birth, but the symptoms of PHOAR2 usually appear after puberty[10, 30]. In terms of complications, the incidence of anaemia, hypoproteinemia, and gastrointestinal lesions in the PHOAR2 type is higher than that for PHOAR1[3, 5, 9, 24]. In addition, there are also significant differences between males and females. In PHOAR1, the ratio of males to females is approximately 1:1; PHOAR2 patients are mainly male, and female patients are very rare[3, 9, 10, 24, 30]. Wang et al.[5] reviewed 158 PHO patients reported in China in the past 18 years (January 2000 to April 2018). That article reviewed and reported the first symptoms of 138 patients, and only a few patients (3.6%, 5/138) had gastrointestinal disease as their first symptom, but as the disease progressed, 17.2% (26/151) of patients had gastrointestinal complications. Among PHO patients with gastrointestinal involvement, peptic ulcers and chronic gastritis only occurred in patients with SLCO2A1 gene deficiency[9], and gastrointestinal complications in PHO patients are more closely related to SLCO2A1[5]. Previous studies have shown that CEAS and PHOAR2 share a common pathogenic gene[1, 2, 8, 14]. CEAS mainly occurs in women and it mainly manifests as anaemia and hypoproteinemia, without clubbing, periostosis, or pachydermia[1, 2]. PHOAR2 mainly occurs in men, and all reported PHO patients with gastrointestinal involvement are men[5]. All CEAS patients who met the main diagnostic criteria of PHO were male, and no female CEAS patients have developed PHO[1, 2].
Our patient was female and was finally diagnosed with CEAS with light PHO. In retrospect, this is a rare case, and the patient was in her youth and could not be excluded from developing skeletal and skin tissue changes or other systemic symptoms in the future. The relationship between PHO and CEAS is very close, and some of their clinical symptoms overlap, and the relationship between the two is worth exploring. Sun et al.[32] believed that CEAS and PHO may be different manifestations of the same pathological process, and they are two sides of a coin. These findings indicate that the clinical characteristics of SLCO2A1-related diseases are influenced by other factors. We consider that sex-related modifier genes or sex hormones may play a potential role in the occurrence and development of the disease, finally leading to differences in clinical symptoms.
After the patient was discharged from the hospital in November 2020, we followed her closely to seek a good treatment plan to control the progression of the disease. Currently, no effective drug treatment strategy has been reported for CEAS. This disease is characterized by chronic and refractory clinical characteristics, and its clinical course is characterized by postoperative recurrence and stenosis with small intestinal ulcers[2, 3, 12–14]. When small bowel stenosis occurs, the patient must undergo surgery. Balloon expansion under colonoscopy is the method used to treat this complication[14]. There is also currently no effective cure for PHO, and drugs are mainly used to relieve symptoms and plastic surgery is applied to improve the facial skin thickening for cosmetic purposes [22, 33]. Drug treatments mainly use nonsteroidal anti-inflammatory drugs (NSAIDs) that reduce prostaglandin synthesis. Previous studies have reported that NSAIDs are effective for both PHOAR1 and PHOAR2 patients and they can effectively alleviate the bone and skin symptoms of patients by inhibiting the production of PGE2[34]. Li SS et al. reported that etoricoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has a significant effect on reducing urinary PGE2 levels and it can be used to improve symptoms of finger clubbing, joint pain and swelling, and pachydermia. However, NSAIDs are often ineffective in PHO patients with gastrointestinal involvement[4]. At present, the diagnosis and treatment of CEAS and PHO are still difficult problems for clinicians, and they require further study. We need to make more clinicians aware of CEAS and PHO, which are a class of diseases associated with SLCO2A1 mutations that are characterized by multiple intestinal ulcers and abnormal bone and skin tissue. This case report is intended to provide valuable information for the diagnosis of CEAS and PHO and to shed new light on diseases associated with SLCO2A1 mutations.