A novel variant in the SLCO2A1 gene in a Chinese patient with chronic gastroenteropathy and primary hypertrophic osteoarthropathy.

BACKGROUND: Chronic enteropathy associated with SLCO2A1 gene (CEAS) results from loss-of-function variants in SLCO2A1, which encodes the prostaglandin transporter (PGT). CEAS follows an autosomal recessive inheritance pattern. To date, approximate 30 pathogenic variants have been reported in CEAS. METHODS: We performed whole exome sequencing (WES) to screen for potential pathogenic variants in a patient suspected of having CEAS, and confirmed a variant in SLCO2A1 using Sanger sequencing. We established an in vitro minigene model to compare splicing between wild type (WT) and mutant transcripts. Quantitative polymerase chain reaction (qPCR) was used to evaluate SLCO2A1 transcription in the stomach and colon tissues from the patient and a healthy control (HC). The transcripts were further cloned and sequenced. RESULTS: The patient had a novel, homozygous, recessive c.929A > G variant in exon 7 of SLCO2A1, which has not been previously reported in CEAS or PHO. This variant altered splicing, resulting in an exon 7-truncated transcript lacking 16 bases. No normal transcript was detected in the patient's stomach or colon tissue. qPCR also showed significantly decreased SLCO2A1 transcription compared to HC. CONCLUSION: A previously unreported variant caused defective SLCO2A1 splicing and reduced mRNA levels in a patient with CEAS and PHO. This research enhances understanding of CEAS and PHO pathophysiology and aids genetic counseling and diagnosis.

Genotype and phenotype characterization of primary hypertrophic osteoarthropathy type 2 and chronic enteropathy associated with SLCO2A1: Report of two cases and literature review.

Autosomal recessive type 2 primary hypertrophic osteoarthropathy (PHOAR2) and chronic enteropathy associated with SLCO2A1 (CEAS) are two entities caused by pathogenic variants (PVs) in the SLCO2A1 gene that can coexist or occur independently from one another. We report two cases of PHOAR2 in Mexico with concomitant CEAS and conducted a review of the literature of the reported cases of PHOAR2 and/or CEAS to analyze the relationship between their genotype and phenotype presentation. The patients from our Institution with classical PHOAR2 phenotype and CEAS, harbored SLCO2A1 c.547G > A and c.1768del variants. We reviewed 232 cases, of which 86.6% were of Asian origin, and identified 109 different variants in SLCO2A1. Intron 7, exon 13, and exon 4 were predominantly affected. The two most common PVs were c.940 + 1G > A and c.1807C > T. We found a statistically significant association between SLCO2A1 variants located in intron 7, exons 12, and 13 and the development of CEAS. Missense variants were more frequent in isolated PHOAR2, while a greater proportion of protein-truncating variants (PTVs) were found in CEAS. Further investigation is imperative to elucidate the underlying pathophysiological mechanisms associated with CEAS, thereby facilitating the identification of effective therapeutic interventions.

A Case Report of Primary Hypertrophic Osteoarthropathy / 罕见病研究

Primary hypertrophic osteoarthropathy(PHO) is a rare disease also known as pachydermoperiostosis. We reported a painless case whose diagnosis was confirmed by genetic test. A 24-year-old male presented a series of symptoms that first began at 14. He suffered from progressive clubbed-fingers accompanied by swelling of the wrist and ankle joints. Facial skin concentric thickening and alar nose broadening appeared simultaneously and increased progressively. He was also prone to acne and hyperhidrosis. X-rays showed thickening of the metacarpal and phalangeal bones, as well as symmetrical periosteal ossification of both the tibia and fibula. Clinical diagnosis of PHO is difficult because of the variable features. With acromegaly excluded, the diagnosis was confirmed by a genetic test. Whole exome sequencing revealed a heterozygous SLCO2A1 c.611C > T(p.Ser204Lue) and SLCO2A1 c.1602C > A(p.Asn534Lys) mutation from each parent. It suggests that primary hypertrophic osteoarthropathy should be considered for young limb hypertrophic patients especially when periosteal thickening signs were showed in X-ray. A confirmatory diagnosis can be made through the genetic test.

Primary hypertrophic osteoarthropathy: genetics, clinical features and management.

Primary hypertrophic osteoarthropathy (PHO) is a genetic disorder mainly characterized by clubbing fingers, pachydermia and periostosis. Mutations in the HPGD or SLCO2A1 gene lead to impaired prostaglandin E2 (PGE2) degradation, thus elevating PGE2 levels. The identification of the causative genes has provided a better understanding of the underlying mechanisms. PHO can be divided into three subtypes according to its pathogenic gene and inheritance patterns. The onset age, sex ratio and clinical features differ among subtypes. The synthesis and signaling pathways of PGE2 are outlined in this review. Cyclooxygenase-2 (COX-2) is the key enzyme that acts as the rate-limiting step for prostaglandin production, thus COX-2 inhibitors have been used to treat this disease. Although this treatment showed effective results, it has side effects that restrain its use. Here, we reviewed the genetics, clinical features, differential diagnosis and current treatment options of PHO according to our many years of clinical research on the disease. We also discussed probable treatment that may be an option in the future.

Touraine-Solente-Gole syndrome: pathogenic variant in SLCO2A1 presented with polyarthralgia and digital clubbing.

BACKGROUND: Primary Hypertrophic Osteoarthropathy (PHO), also known as Touraine-Solente-Gole Syndrome, is a rare, multisystemic autosomal recessive disorder caused by pathogenic variants in the 15-hydroxyprostaglandin dehydrogenase (HPGD) or Solute Carrier Organic Anion Transporter Family Member 2A1 (SLCO2A1) genes. However, autosomal dominant transmission has also been described in some families with incomplete penetrance. PHO usually starts in childhood or adolescence, presenting with digital clubbing, osteoarthropathy, and pachydermia. We described a complete form of the syndrome in a male patient with a homozygous variant in the SLCO2A1 gene (c.1259G > T). CASE PRESENTATION: A 20-year-old male was referred to our Pediatric Rheumatology Clinic with a five-year history of painful and swollen hands, knees, ankles and feet, prolonged morning stiffness and relief with non-steroidal antiinflammatory drugs. He also reported late onset facial acne and palmoplantar hyperhidrosis. Family history was irrelevant and parents were non-consanguineous. On clinical examination, he presented clubbing of the fingers and toes, moderate acne and marked facial skin thickening with prominent scalp folds. He had hand, knee, ankles and feet swelling. Laboratory investigations showed elevated inflammatory markers. Complete blood count, renal and hepatic function, bone biochemistry were normal, as well as immunological panel. Plain radiographs revealed soft tissue swelling, periosteal ossification and cortical thickening of the skull, phalanges, femur and toe acroosteolysis. Due to the absence of other clinical signs suggesting a secondary cause, we suspected PHO. A genetic study revealed a likely pathogenic variant, c.1259G > T(p.Cys420Phe), in homozygosity in the SLCO2A1 gene, thus confirming the diagnosis. The patient started oral naproxen with significant clinical improvement. CONCLUSIONS: PHO should be kept in the differential diagnosis of inflammatory arthritis affecting children, often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). To the best of our knowledge, this is the second genetically confirmed case of PHO in a Portuguese patient (first variant c.644 C > T), both made at our department.

Case report: Novel homozygous HPGD variant leads to primary hypertrophic osteoarthropathy with intussusception and acro-osteolysis in a Chinese family.

Objective: To perform molecular genetic analysis of a patient diagnosed with primary hypertrophic osteoarthropathy (PHO) with malnourishment, intussusception, and acro-osteolysis. Case presentation: At the age of 7 years, a boy born to a consanguineous couple was diagnosed with PHO attributed to delayed closure of the cranial suture, eczema, clubbing of fingers, and swelling of the knee and ankle. Clinical characteristics and follow-up data for 3 years were collected and analyzed. Trio whole-exome sequencing (WES) and copy number variant sequencing were used to screen for causative genetic variants. Candidate variants of the patient and his parents were confirmed by Sanger sequencing. When he was 7 years old, trio WES found that he had biallelic novel variants c.498 + 1G > A, inherited from his parents, in the HPGD gene. The patient was markedly malnourished. Ultrasonography and computed tomography showed intussusception with a gradual expansion of the duodenum, localized intestinal wall thickening, and acro-osteolysis. Cross-sectional blood tests showed that the patient had continuously decreased levels of serum 25-hydroxy vitamin D and serum ferritin at the age of 7and 10 years. Conclusion: PHO due to HPGD defects is rare in pediatric patients, and finding homozygous novel c.498 + 1G > A has expanded the spectrum of causative variants of HPGD and provided a clue for genotype-phenotype correlation analysis. Similar to mouse model results, human HPGD deficiency may also cause abnormal digestive tract development, and related secondary vitamin D deficiency and acro-osteolysis should be considered in HPGD-related PHO.

Novel pathogenic variants in SLCO2A1 causing autosomal dominant primary hypertrophic osteoarthropathy.

Primary hypertrophic osteoarthropathy (PHO), or pachydermoperiostosis, is characterized by a clinical association including digital clubbing, periostosis and pachydermia. SLCO2A1 and HPGD genes are both responsible for PHO. The pathology is classically defined as an autosomal recessive disorder with clinical variability ranging from a mild to more severe phenotype. However, the hypothesis for an autosomal dominant form suggested for a long time was only demonstrated for the first time in 2021 for SLCO2A1. We aimed to detect a second pathogenic variant by a deep sequencing of the entire SLCO2A1 and HPGD genes, associated with functional transcription analysis in PHO patients harboring only one heterozygous variant. Among 10 PHO patients, 4 presented a single pathogenic or probably pathogenic novel variant in SLCO2A1 in heterozygous status (NM_005630.3: c.234+1G > A, c.1523_1524delCT, c.1625G > A and c.31delC), and the others carried homozygous pathogenic variants. For heterozygous forms, we found no additional pathogenic variant in HPGD or SLCO2A1. PHO can be a dominant form with age at disease onset later than that for the recessive form. This dominant form is not exceptional in young adults. In conclusion, both modes of inheritance of PHO explain the clinical variability and the difference in age at disease onset. Molecular analysis is especially required in the incomplete form to distinguish it from secondary hypertrophic osteoarthropathy.

Etoricoxib as a treatment of choice for patients with SLCO2A1 mutation exhibiting autosomal recessive primary hypertrophic osteoarthropathy: A case report.

We reported a 22-year-old Emirati male with autosomal recessive primary hypertrophic osteoarthropathy caused by a possibly pathogenic homozygous non-synonymous variant in the SLCO2A1 gene (NM_005630.3: c.289C>T, p. Arg97Cys) presenting with joint swelling, forehead furrowing, and significant clubbing in all fingers and toes. Currently, no standard treatments are approved for this disease; medical care is palliative and includes non-steroidal anti-inflammatory drugs, corticosteroids, tamoxifen, retinoids, and risedronate. Colchicine may be helpful for the pain due to subperiosteal new bone formation. Our patient was treated with etoricoxib 60 mg once daily and showed a significant clinical improvement at the 6-month mark that was reversed upon the withdrawal of this medication. This case report highlights the importance of placing etoricoxib among first-line therapy recommendations for cases with confirmed primary hypertrophic osteoarthropathy diagnosis. To the best of our knowledge, this is the only case of primary hypertrophic osteoarthropathy from the Middle Eastern population of Arab ethnicity that has responded to non-steroidal anti-inflammatory drug therapy.

Clinical and biochemical characteristics of 12 Chinese primary hypertrophic osteoarthropathy patients with HPGD mutations.

Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disease mainly affecting the skeletal and skin. Two genes involved in prostaglandin degradation are known to be responsible for PHO: HPGD and SLCO2A1. HPGD gene mutation can cause PHO autosomal recessive 1 (PHOAR1). The purpose of the present study is to analyze the clinical and biochemical characteristics and HPGD gene mutations of 12 Chinese PHOAR1 patients. Twelve PHOAR1 patients from eleven families, including eleven males and one female, were enrolled in this study. Digital clubbing and periostosis came out to be the most common features, which always occur in the early childhood. We performed HPGD gene analysis and identified six novel (c.1A>G, c.34G>T, c.317T>A, c.475G>T, c.548C>T and c.421+1G>T) and one known (c.310_311delCT) HPGD mutations. The recurrent mutation c.310_311delCT were found in all eleven patients, suggesting it is a hotspot mutation. PHOAR1 patients are considered to have an autosomal recessive inheritance pattern. Here, in addition to nine compound heterozygous patients and two homozygous patients, we found one heterozygous patient and reviewed two heterozygous patients reported in other studies. In terms of biochemical characteristics, our PHOAR1 patients have elevated urinary prostaglandin E2 (PGE2) levels (P<0.001) and decreased urinary prostaglandin E metabolite (PGE-M) levels (P=0.04) compared with healthy controls. The patients' PGE2/PGE-M (E/M) ratio came out to be lower than normal subjects (P<0.001). This study provides a comprehensive description of the clinical phenotypes of Chinese PHOAR1 patients and expands the genotypic spectrum of the disease.

Primary hypertrophic osteoarthropathy - a rare cause of pain and arthritis in children. Description of 5 cases.

Primary hypertrophic osteoarthropathy (PHOA) is a very rare disease. The typical triad of symptoms, i.e. digital clubbing, periosteal bone formation with bone and joint deformities and skin hypertrophy, may be accompanied by other specific conditions. In the majority of patients, the picture of the disease is incomplete. The dominant clinical symptom may be osteoarticular complaints. Moreover, the final confirmation of the diagnosis of the primary form of hypertrophic osteoarthropathy requires the analysis of much more frequent secondary causes of the disease. Diagnosing primary osteoarthropathy in children is particularly difficult. Some children report joint pain before the onset of the other symptoms of osteoarthropathy, while the physical and imaging examinations show features of arthritis. This can lead to misdiagnoses including the diagnosis of juvenile idiopathic arthritis (JIA) and the unnecessary use of immunosuppressive treatment. The present description of five patients from the Paediatric Rheumatology Department indicates diagnostic difficulties in children with PHOA. All of them were examined due to pain and features of arthritis. We observed an incomplete clinical picture of the disease. One patient required a revision of the previous diagnosis of JIA and discontinuation of ineffective treatment with disease-modifying antirheumatic drugs (DMARDs). PHOA should always be considered in the differential diagnosis of arthritis in children, due to the slow and often atypical development of symptoms, including the presence of pain and arthritis as the predominant symptom of the disease.

Bone Geometry, Density, Microstructure, and Biomechanical Properties in the Distal Tibia in Patients With Primary Hypertrophic Osteoarthropathy Assessed by Second-Generation High-Resolution Peripheral Quantitative Computed Tomography.

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L1 -L4 ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E2 (PGE2 ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (ß-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE2 , biomarkers of bone resorption (ß-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE2 level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR).

Monoallelic mutations in SLCO2A1 cause autosomal dominant primary hypertrophic osteoarthropathy.

Primary hypertrophic osteoarthropathy (PHO) is a rare disease inherited as a recessive or irregular dominant trait and characterized by digital clubbing, pachydermia, and periostosis. Biallelic mutations in HPGD and SLCO2A1, disturbing prostaglandin E2 (PGE2 ) catabolism and leading to increased circulating PGE2 level, cause PHO autosomal recessive 1 (PHOAR1) and PHO autosomal recessive 2 (PHOAR2), respectively. However, no causative genes have been reported for PHO autosomal dominant (PHOAD). Here, we performed Sanger sequencing and whole-genome sequencing (WGS) on DNA samples from seven Chinese PHOAD families; after excluding other single-nucleotide variants (SNVs), structural variations (SVs), and copy number variations (CNVs) in the genomes, we reported six SLCO2A1 monoallelic mutations (c.1660G>A [p.G554R], c.664G>A [p.G222R], c.1106G>A [p.G369D], c.1065dupA [p.Q356TfsX77], c.1293delT [p.S432AfsX48], and c.1807C>T [p.R603X]) in the probands and affected family members. Then, in five other PHO families with probands carrying SLCO2A1 biallelic mutations, we verified that parents with SLCO2A1 monoallelic mutations also displayed PHO manifestations, which further confirmed the pathogenicity of SLCO2A1 monoallelic mutations and illustrated the allelic nature of PHOAD and PHOAR2. Subsequently, through comparison of seven PHOAD probands and 50 PHOAR2 patients, we found onset age in puberty and skewed penetrance rate were similar in both PHO types, but symptoms and signs of PHOAD were milder, including less severe pachydermia (p = .027) and periostosis (p = .005), and less frequent cutis verticis gyrata (p = .011), acne (p = .005), arthralgia (p = .037), and anemia (p = .023). The median urinary PGE2 level in PHOAD probands was almost half that in PHOAR2 patients (PHOAD 277.58 ng/mmoL creatinine, PHOAR2 473.19 ng/mmoL creatinine; p = .038). Moreover, through the 3-month trial of oral administration of etoricoxib, an effective response similar to that we reported previously in PHOAR2 patients was observed in PHOAD probands. In conclusion, our findings confirm that SLCO2A1 monoallelic mutations are the cause of PHOAD and broaden phenotypic spectrum of PHO. © 2021 American Society for Bone and Mineral Research (ASBMR).

Primary hypertrophic osteoarthropathy with severe arthralgia identified by gene mutation of SLCO2A1.

Male, 41 years old (yo) had been complaining of severe arthralgia. Past History indicated obstruction of intestinal tract at 12 yo and gastric ulcer at 13 yo. He had been suffered from polyarthralgia especially at PIP and MP joints of both hands from 38 yo. Finally, he complained severe arthralgia at PIP and MP joints with clubbed fingers without swelling. Biochemical finding indicated negative rheumatoid factor and anti-CCP antibody and normal MMP-3 level, but slightly increased CRP and ESR levels. Radiological finding indicated periostosis of　long bone without bone erosion and osteoporosis. His facial appearance was acromegalic with cutaneous manifestation of pachydermia and cutis vertices gyrate without abnormal growth hormone response. Histological findings of skin indicated oedema and hyperplasia of sebaceous glands with infiltration of lymphocytes around small blood vessels compatible with pachydermoperiostosis. In this case mutation of SLCO2A1 gene, which coded prostaglandin transport protein, was identified. The mutation c.940 + 1G > A of SLCO2A1 gene results in deletion of exon 7 and truncation of PG transporter (p.Arg288Glyfs*7). We suggest that severe arthralgia was originated from over production of prostaglandin E2. Further studies will be required.

The mask of furrow: A case of a 28-year-old Filipino male with pachydermoperiostosis

@#Pachydermoperiostosis (PDP) or primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder that affects mainly skin and bones. Its main clinical features are pachyderma (thickening of the skin), periostosis ~excessiv~ bone formation) and clubbing of fingernails. The d1sea~e is more common among males with a 7:1 ratio, starts during adolescence and stabilize and cease progression after 5 - 20 years.@*OBJECTIVE@#To discuss the summary of the case, new management options, and outcomes of the management options.@*CASE SUMMARY (METHODS)@#A 28-year-old male presents with a 9-year history of wrinkling of his facial skin. Other associated symptoms were seborrhea, acne, clubbed fingers, and occasional minimal knee joint pain. Histopathology results showed thickened dermis, fibrosis of the papillary dermis and around the folliculosebaceous units, hyalinized collagen bundles involving the fibrous trabeculae of the subcutis, and prominence of sebaceous and eccrine glands. The patient was given oral isotretinoin at 0.5 mg/kg/day, underwent fractional CO~ laser f?r rhytides and large pores, and given botuhnum toxin A injection (total of 16 U) on 5 sites at the glabellar region. The patient was referred to plastic surgery for frontal rhytidectomy, and orthopedic surgery for management of joint pains.@*RESULTS@#The patient noted 80% improvement from baseline.@*CONCLUSION@#Treatment of pachydermoperiostosis is mainly symptomatic and requires a multi-spec~alty approach. Because of its rarity, treatment options for pachydermoperiostosis have yet to_ be standardized. In this particular case, all available options in the institution were utilized which led to satisfaction of the patient of the outcome.

Characteristic Facial Appearance Was the Key to Diagnosing Chronic Enteropathy Associated with SLCO2A1-associated Primary Hypertrophic Osteoarthropathy.

Patients with chronic enteropathy associated with SLCO2A1 (CEAS) develop multiple circular, longitudinal, or eccentric ulcers in the ileum. It is sometimes difficult to distinguish CEAS from Crohn's disease. CEAS and primary hypertrophic osteoarthropathy (PHO) are together known to be caused by a mutation of SLCO2A1 gene. The case of a 65-year-old man whose characteristic appearance due to pachydermia of the forehead folds led to the diagnosis of CEAS with PHO is presented.

Impaired bone microarchitecture in distal interphalangeal joints in patients with primary hypertrophic osteoarthropathy assessed by high-resolution peripheral quantitative computed tomography.

This study aimed to investigate the bone impairment in finger joints in PHO patients by HR-pQCT. Results showed distinguished differences in bone architecture and biomechanics parameters at DIPs between PHO patients and healthy controls using HR-pQCT assessment. Besides, serum PGE2, hsCRP and ESR levels were found negatively correlated with total vBMD. INTRODUCTION: This study aimed to investigate the bone impairment in finger joints in primary hypertrophic osteoarthropathy (PHO) patients firstly by high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Fifteen PHO patients and 15 healthy controls were enrolled in this study. Bone erosions in hands at distal interphalangeal joints (DIPs) in both PHO patients and controls were evaluated by X-ray. Bone geometry, vBMD, microstructure parameters, and size of individual bone erosion were also measured at the 3rd DIP by HR-pQCT as well. Blood biochemistry levels between the two groups were also compared. RESULTS: Compared to X-ray, HR-pQCT assessment were more sensitive for detection of bone erosions, with 14 PHO patients by HR-pQCT versus ten PHO patients by X-ray judged at the 3rd DIP. The average depth, width, and volume of erosions size in PHO patients were 1.38 ± 0.80 mm, 0.79 ± 0.27 mm, and 1.71 ± 0.52 mm3, respectively. The bone cross-areas including total area (+ 25.3%, p ≤ 0.05), trabecular area (+ 56.2%, p ≤ 0.05), and cortical perimeter (+ 10.7%, p ≤ 0.05) at the defined region of interest of 3rd DIP was significantly larger than controls. Total vBMD was 11.9% lower in PHO patients compared with the controls (p ≤ 0.05). Biochemical test results showed the increased levels of inflammatory cytokines, bone resorption markers, and joint degeneration markers in PHO patients. Serum prostaglandin PGE2, high-sensitive C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR) levels were found negatively correlated with total vBMD. CONCLUSIONS: This study demonstrated higher sensitivity of the HR-pQCT measurement at DIPs by showing the differences in architecture and biomechanics parameters at DIPs between the PHO patients and healthy controls, which would be of interest clinically to investigate bone deterioration in PHO patients.

Primary hypertrophic osteoarthropathy related gastrointestinal complication has distinctive clinical and pathological characteristics: two cases report and review of the literature.

BACKGROUND: Primary hypertrophic osteoarthropathy (PHO) is a rare disease related to HPGD and SLCO2A1 gene mutation. Gastrointestinal involvement of PHO is even rarer with unknown pathogenesis. Clinical features of GI complication in PHO mimics other auto-immune based bowel entities, such as inflammatory bowel diseases and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). We aimed to analyze the clinical, genetic, radiological and pathological features of Chinese patients with PHO and determine the difference between PHO patients presenting with and without GI involvement. METHODS: We reported two PHO cases with gastrointestinal involvement and reviewed all the studies of PHO in Chinese population published from January 1, 2000, to April 30, 2018. Clinical and genetic presentations of PHO in Chinese patients were analyzed. We compared the characteristics of those patients with gastrointestinal involvement against those without. RESULTS: The two patients were both males with complete-form PHO for more than 10 years. GI related symptoms included diarrhea, chronic gastrointestinal hemorrhage, incomplete intestinal obstruction, anemia, and edema, which were unresponsive to etoricoxib treatment. Radiological examinations revealed segmental intestinal stenosis and thickened intestinal wall. Endoscopic findings included multiple ulcers and mucosal inflammation. Both patients had mutations of SLCO2A1 according to sequence analysis. The surgical pathology revealed chronic inflammation involving the intestinal mucosa and submucosa, similar to histological changes in CMUSE. According to the systemic review of 158 Chinese patients with PHO, 17.2% had gastrointestinal involvement, including peptic ulcer, gastric polyps, hypertrophic gastritis, and segmental intestinal stenosis. Patients with gastrointestinal involvement were more likely to have anemia (40.0% vs. 4.5%, P < 0.001), hypoalbuminemia (16.7% vs. 0.9%, P = 0.003), and myelofibrosis (19.0% vs. 0.9%, P = 0.002) than those without. Most patients with gastrointestinal complication had SLCO2A1 mutation (86.7%, 13 /15). CONCLUSIONS: Digestive tract involvement is uncommon in patients with PHO and often presents with anemia, and hypoalbuminemia resulted from intestinal inflammation. The intestinal pathologic characteristics are distinct from Crohn's disease but similar to CMUSE. Mutations in SLCO2A1 might be the pathogenic cause of GI involvement of PHO. NSAIDs may not be effective for PHO patients with gastrointestinal complications.