The CXCL10-CXCR3 axis plays an important role in Kawasaki disease.

The precise pathogenesis of Kawasaki disease remains unknown. In an attempt to elucidate the pathogenesis of KD through the analysis of acquired immunity, we comprehensively examined the immunophenotypic changes in immune cells such as lymphocytes and monocytes along with various cytokines, focusing on differences between pre- and post- treatment samples. We found high levels of CXCL9 and CXCL10 chemokines that decreased with treatment, which coincided with a post-treatment expansion of Th1 cells expressing CXCR3. Our results show that the CXCL10-CXCR3 axis plays an important role in the pathogenesis of KD.

Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy.

WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug-resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice-site mutation with uniparental isodisomy. A 1-year and 7-month-old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole-exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted.

Non-conditioned cord blood transplantation for infection control in athymic CHARGE syndrome.

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144 days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/µL naïve T cells with balanced repertoire 1 month post transplant, and survived more than 12 months with home care. Twelve patients including the index cases received HCT at a median 106 days after birth (range: 70-195 days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p = .02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

Effect of maturation at birth on the clinical features of neonatal cow's milk protein allergy: A retrospective study.

Neonatal immune regulation transitions from fetal immunity and varies with maturation status, but its role in neonatal cow's milk protein allergy (CMPA) remains unknown. We studied the association between maturation status at birth and neonatal CMPA. Clinical and laboratory data of neonates presenting with CMPA symptoms were retrospectively collected from two tertiary hospitals. Patients were assessed according to gestational age at birth: preterm, late-preterm, and full-term. Fifty-five infants (26 females, 14 preterm, 15 late-preterm, and 26 full-term) were included; 44 were negative for milk-specific immunoglobulin E. Neonatal CMPA was common during moderately premature periods. Preterm infants exhibited longer latency from initial CM exposure to disease onset, lower incidence of bloody stool, and absence of elevated monocyte counts. However, immunoreactivity to CM antigens was retained in all infants. Neonatal CMPA features varied with infant maturation status at birth. Our results improve the understanding of intestinal immunity development, fetal/neonatal immune regulation, and CMPA pathogenesis.

Effectiveness of ultrasound-guided peripheral arterial cannulation in neonates, including very low birth weight infants who are conventionally difficult-to-cannulate: a case series.

The effectiveness of ultrasound-guided peripheral arterial cannulation (UGPAC) in children has been increasingly been reported. However, to the best of our knowledge, there have been no reports of UGPAC in neonates, including very low birth weight infants (VLBWIs). In this study, we aimed to retrospectively review the results of UGPAC in neonates, including VLBWIs, and assess its effectiveness. This case series was conducted in a tertiary neonatal intensive care unit (NICU) in Japan. We included neonates aged below 28 days who underwent UGPAC in our NICU between April 2021 and October 2022. We extracted the following data from medical records and analysed it retrospectively: patient age (days), postconceptional age, patient weight at the time of cannulation, number of punctures using the conventional technique before ultrasound guidance was performed and number of punctures with the ultrasound-guided technique until successful cannulation. A total of 27 UGPACs were performed in 19 neonates, including 14 cannulations in 10 VLBWIs. In infants weighing > 1500 g and VLBWIs, the success rate within the first three punctures was 100% (13/13) and 79% (11/14), respectively. Overall, 41% (11/27) of UGPACs were performed following failed punctures using conventional methods, with a 100% success rate within the first three attempts. In all cases, no apparent adverse events, such as hypothermia, were noted.  Conclusions: Our results suggest that UGPAC had a high success rate in neonates, including VLBWIs. Further studies are required to compare the effectiveness of UGPAC with conventional methods in neonates. What is Known: • The use of ultrasound guidance for arterial cannulation is recommended in children. • Ultrasound-guided peripheral arterial cannulation (UGPAC) in neonates, including very low birth weight infants (VLBWIs), has not been reported. What is New: • UGPAC in neonates, including VLBWIs, was performed with a high success rate; approximately 40% of UGPACs were performed after the failure of the conventional methods. • This study suggested the effectiveness of UGPAC in neonates, including VLBWIs.

Gut microbiota of one-and-a-half-year-old food-allergic and healthy children.

BACKGROUND: Intestinal bacteria may play a role in the development of food allergies. This study aimed to analyze and compare the gut microbiota of food-allergic children with that of healthy children of the same age. METHODS: Stool samples were collected from one-and-a-half-year-old food-allergic (FA group, n = 29) and healthy controls (HC group, n = 19). A questionnaire was provided to examine the children's birth, dietary, medical, and social histories. The gut microbiota was profiled by 16S rRNA sequencing. Differences in taxonomic composition were assessed using linear discriminant analysis effect size (LEfSe), and microbial functional profiles were predicted with Tax4Fun2. RESULTS: No significant difference in the alpha diversity index between the two groups; however, a negative correlation was observed between the Shannon diversity index and the relative abundance of Bacteroides. A significant difference was observed in beta diversity (permutational multivariate analysis of variance) in the bacterial composition between the FA and HC groups (P < 0.05). The FA group had a higher abundance of Escherichia and Anaeromassilibacillus and a lower abundance of Bacteroides, Oscillibacter, Ruminococcus, Hungateiclostridium and Anaerotaenia than the HC group (LEfSe: linear discriminant analysis score >2). The FA group showed a predicted increase in the expression levels of genes associated with intestinal pathogenicity compared with that in the HC group. CONCLUSIONS: The gut microbiota of food-allergic children has a higher abundance of bacteria involved in intestinal inflammation and a lower abundance of bacteria involved in immune tolerance than that of healthy children. This dysbiosis may also be associated with food allergies.

Antigen-specific T cell balance reveals Why patients with atopic dermatitis fail to achieve immune tolerance.

The number of regulatory T cells (Tregs) and how they behave in the pathogenesis of atopic dermatitis (AD) are still controversial. We identified and quantified Tregs, mite-specific Tregs, and mite-specific effector T cells (Teffs) in patients with AD and healthy controls (HCs). We collected peripheral blood and analyzed the cells using flow cytometry after stimulation with mite antigens. Mite-specific Tregs and mite-specific Teffs were recognized by the expression of CD137 and CD154, respectively. Patients with AD had more Tregs than HCs; however, when focusing on a single antigen, the ratio of mite-specific Tregs/Teffs was lower in patients with AD than in HCs. Furthermore, the mite-specific Teffs in patients with AD were more likely to produce proinflammatory cytokines interleukin (IL)-4 and IL-13. This Teff-dominant imbalance is thought to be the cause of development of atopic status in patients with AD without immune tolerance.

Initial manifestations in Patients with Inborn Errors of Immunity Based on Onset Age: a Study from a Nationwide Survey in Japan.

PURPOSE: Patients with inborn errors of immunity (IEI) manifest various initial symptoms; however, those that are critical for the early diagnosis of IEI have not been identified. Also, the significance of the ten warning signs of primary immunodeficiency (PID) among infants has not been established. This study aimed to conduct a nationwide survey of IEI in Japan and investigated the initial manifestations based on onset age. METHODS: Among 1298 patients, data regarding the initial manifestation were available from 505 patients. Patients with autoinflammatory diseases, complement deficiency, and phenocopies of IEI were excluded. RESULTS: The ten warning signs were positive in 67.3% of the cases. The positivity rate was low (20.5%) in patients with immune dysregulation. Although the positivity rate was low (36.6%) in patients aged less than 3 months, they were highly positive for family history of IEI (26.8%). Infectious symptoms were the most commonly observed in all age groups and in all disease categories. Symptoms of "immune dysregulation" were present in approximately 15% of the patients. Regarding the anatomical category, almost all initial symptoms were "systemic" infections in patients with X-linked severe combined immunodeficiency. Moreover, "respiratory" symptoms were the most common in patients with IEI aged ≥ 1 year and accounted for more than 50% in all age groups in patients with common variable immunodeficiency. CONCLUSION: These results highlight the significance of the 10 warning signs and may serve as clinical indicators for early diagnosis, considering the initial presentation of IEI.

A novel de-novo RB1 mutation identified in a patient with bilateral retinoblastoma.

Retinoblastoma manifests as ocular malignancy due to mutations in the RB1 gene. A 17-month-old girl with bilateral retinoblastoma having no family history was admitted to our hospital. The right eye was enucleated but the other was preserved with systemic chemotherapy and topical treatment. The patient has been tumor-free for over 7 years since diagnosis. All exons of RB1 were sequenced and a novel 1-base pair deletion (NM_000321.2:c.2409del, p.Asn803Lysfs*7) was detected.

Gastrointestinal bleeding/ulcer among paediatric cancer patients after proton beam therapy.

BACKGROUND: The details of gastrointestinal bleeding/ulcer in paediatric cancer patients treated with proton beam therapy have not been reported previously. METHODS: Patients aged 15 years or younger at the time of proton beam therapy and whose gastrointestinal tract was included in the irradiated field participated. RESULTS: A total of 124 patients participated in the study; their median age at irradiation was 5.4 years. Concurrent chemotherapies were vincristine-cyclophosphamide (16 patients), irinotecan-based treatment (16 patients), vincristine-cyclophosphamide-ifosfamide-etoposide (14 patients), other chemotherapy (27 patients) and no chemotherapy (51 patients). Gastrointestinal bleeding/ulcer occurred in four patients (3.2%), with no death due to the bleeding/ulcer. The sites of the gastrointestinal bleeding/ulcer were the stomach (two patients) and the duodenum (two patients). The ages of the four patients at PBT were 5.3, 13.8, 14.2 and 14.8 years, which were significantly older than those of patients without GI bleeding/ulcer (p = 0.017). The maximum irradiated doses to the GI tract in the four patients were 43.2, 45, 50.4 and 50.4 gray equivalent, respectively. The concomitant chemotherapy was vincristine-cyclophosphamide-ifosfamide-etoposide 3 and vincristine-cyclophosphamide 1. Weeks from proton beam therapy to bleeding/ulcer were 15, 20, 22 and 264. DISCUSSION AND CONCLUSIONS: Patients who developed gastrointestinal bleeding/ulcer were treated concurrently with vincristine-cyclophosphamide-ifosfamide-etoposide or vincristine-cyclophosphamide, and their ages were older than those of patients without gastrointestinal bleeding/ulcer. Bleeding occurred in the upper gastrointestinal tract in all the cases, and most cases occurred early and during chemotherapy. Upper gastrointestinal irradiation in older children undergoing intensive chemotherapy may increase the risk of developing gastrointestinal complications.

Longitudinal health-related quality of life analysis in childhood cancer survivors after proton beam therapy.

PURPOSE: Whilst proton beam therapy (PBT) for children with cancer is expected to reduce their comorbidities, to date only a limited number of studies have been published. To analyze the long-term comorbidity and health-related quality of life (HRQoL) of childhood cancer survivors (CCSs) after PBT, we conducted a questionnaire-based study. METHODS: Questionnaires were sent to CCSs who underwent PBT at the University of Tsukuba Hospital during the period from 1984 to 2020. Scores from 41 CCSs who did not undergo PBT (noPBT-CCSs) and from the general population were used for comparison. RESULTS: In total, 110 individuals who underwent PBT participated in the study. Among them, 40 individuals were longitudinally analyzed. The range of change in the scores was significantly greater in the CCSs whose initial scores were low. Although the comorbidity levels were more severe, HRQoL tended to be better in the PBT-CCSs than in the noPBT-CCSs with central nervous system (CNS) or solid tumors, respectively. When compared with the general population, the psychosocial health summary scores and its components were not different in the noPBT-CNS-CCSs. On the other hand, the psychosocial health summary scores and/or at least one of the scores of emotional, social, and school functioning were significantly higher in the other CCSs groups. CONCLUSIONS: The HRQoL scores of CCSs with low initial scores can be greatly changed over time. Appropriate psychosocial support for this population is warranted. PBT may avoid reduction in HRQoL in terms of the psychosocial functioning of CCSs with CNS tumors.

Time course of peripheral immunophenotypes of multisystem inflammatory syndrome in children.

The etiology of multiple inflammatory syndrome in children (MIS-C) remains poorly understood. As clues to elucidate the pathogenic condition, several characteristic peripheral immunophenotypes have been reported in MIS-C. However, no report has demonstrated the time course of the peripheral immunophenotype along with the clinical course in the same patient. Herein, we clarified the immunological characteristics of a Japanese patient with MIS-C. There was an initial cytokine storm followed by T-cell activation, especially of CD8+ T cells, with the expansion of T-cell receptor Vß 21.3-expressing cells, which suggests superantigen-mediated T-cell activation. In addition, we also found an increase in IgG-producing cells (plasmablasts and switched memory B cells), which were accompanied by elevated serum levels of anti-SARS-CoV-2 spike antigen-specific IgG antibodies. These time course of peripheral immunophenotypes support that immunological activation against SARS-CoV-2 spike protein plays a central role in the etiology of MIS-C.

Immunological characteristics of severe acute hepatitis of unknown origin in a child post SARS-CoV-2 infection.

Recent studies have reported that pediatric acute liver failure of unknown origin is immune-mediated, with CD8+ T cells playing a key role. Moreover, investigation of superantigen-mediated T-cell activation by the SARS-CoV-2 spike protein in pediatric severe acute hepatitis is needed in the context of the proposed mechanism of multisystem inflammatory syndrome in children (MIS-C). We investigated the immunological characteristics of a Japanese pediatric patient with severe acute hepatitis post SARS-CoV-2 infection. The patient demonstrated autoimmune hepatitis-like liver histology with CD8+ lymphocyte-predominant infiltration. There was Th1-type immune skewing, including remarkable peripheral CD8+ T-cell activation and a skewed T cell receptor repertoire. We also found elevated plasma levels of the anti-SARS-CoV-2 spike-specific IgG antibody, and the titer peaked after treatment, as seen with MIS-C. These findings support that immunological activation involving SARS-CoV-2 spike protein plays a crucial role in a pediatric patient with acute severe hepatitis post SARS-CoV-2 infection.

Vaccination for Patients with Inborn Errors of Immunity: a Nationwide Survey in Japan.

We conducted a nationwide survey of inborn errors of immunity (IEI) in Japan for the second time in 10 years, focusing on protective measures for IEI patients against infectious diseases. Questionnaires were sent to various medical departments nationwide, and a total of 1307 patients were reported. The prevalence of IEI was 2.2 patients per 100,000 population, which was comparable with the previous nationwide study. The most common disease category was autoinflammatory disorders (25%), followed by antibody deficiencies (24%) and congenital defects of phagocyte number or function (16%). We found that a significant number of patients received contraindicated vaccines, principally because the patients were not diagnosed with IEI by the time of the vaccination. Regarding diseases for which BCG vaccination is contraindicated, 43% of patients had actually received BCG, of which 14% developed BCG-related infections. BCG-related infections were mainly observed among patients with CGD and MSMD. In order to prevent IEI patients from receiving inadequate vaccines, continuous education to parents and physicians is needed, along with the expansion of newborn screening, but efforts to screen IEI at the site of vaccination also remain important.

Cancer predisposition genes in Japanese children with rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children. Germline mutations in cancer-predisposition genes have been detected in approximately 10% of pediatric cancers. However, the genetic background of RMS is still unclear, especially in Asian children. DNA was extracted from the peripheral blood of children with RMS and cancer-associated genes analyzed using targeted re-sequencing. Twenty patients participated in this study. There were three deaths due to RMS. One patient developed a second neoplasm. Nine patients had long-term co-morbidities. Six pathogenic variants were found in five patients: one nonsense variant of DICER1, one exon deletion of TP53, and three missense variants of BUB1B, LIG4, and MEN1. Two of the five patients had a family history of cancer. Two patients with missense variants of LIG4 had long-term co-morbidities of drug-induced cardiomyopathy. The missense variants of LIG4, essential for DNA double-strand break repair, were detected in two unrelated patients. While this is the first report of the germline genetic analysis of Japanese children with RMS with detailed clinical information, the frequency of the variant was almost equivalent to that of previous reports from western countries. Unbiased exon sequencing may be useful to clarify the pathogenesis of RMS in children and in predicting the clinical course of these patients.

Cancer-Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan.

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer-predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients' peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

Effect of Germline MEFV Polymorphisms on the Prognosis of Japanese Children with Cancer: A Regional Analysis.

INTRODUCTION: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. MATERIALS AND METHODS: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. RESULTS: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. DISCUSSION/CONCLUSION: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.

Managing bleeding risk after cold snare polypectomy in patients receiving direct-acting oral anticoagulants.

BACKGROUND AND AIMS: The best strategy to manage direct-acting oral anticoagulants (DOACs) for patients undergoing cold snare polypectomy remains unclear. This study compared the effect of continuing versus stopping DOACs only on the day of the procedure on bleeding after cold snare polypectomy. METHODS: This prospective, observational, single-center cohort study enrolled consecutive patients receiving antithrombotic agents and undergoing cold snare polypectomy of colorectal polyps ≤10 mm in diameter. During period 1 (2017 and 2018) antithrombotic agents including DOACs were not discontinued (DOAC continued group). In period 2 (2019 and 2020) DOACs were withheld only on the day of the procedure (DOAC withheld group) and restarted the next day after the procedure. The primary outcome was delayed bleeding requiring endoscopic treatment occurring within 2 weeks after cold snare polypectomy. Secondary outcomes were immediate bleeding and the number of hemostatic clips used. RESULTS: For the 2 groups, 204 (DOAC continued group; 34% women; mean age, 75 years) and 264 (DOAC withheld group; 36% women; mean age, 74 years) patients were enrolled. Clinical features were similar between the 2 groups. Delayed bleeding after cold snare polypectomy occurred in 4 of 47 patients (8.5%) in the DOAC continued group versus 0 of 66 (0%) in the DOAC withheld group (P < .001). Immediate postpolypectomy bleeding occurred in 12 of 47 patients (25.5%) in the DOAC continued group versus 4 of 66 (6.1%) in the DOAC withheld group (P < .008). CONCLUSIONS: Cold snare polypectomy may be safely preformed if DOACs are withheld only on the day of the procedure. (Clinical trial registration number: NCT02594813.).

Effectiveness of Water Jelly Ingestion for Both Rehabilitation and Prevention of Aspiration Pneumonia in Elderly Patients With Moderate to Severe Dysphagia.

BACKGROUND AND AIMS: We evaluated the effectiveness of water jelly ingestion for both rehabilitation and the prevention of aspiration pneumonia in a retrospective analysis of elderly patients with moderate to severe dysphagia. PATIENTS AND METHODS: Study 1: consecutive patients with borderline ingestion in an endoscopic swallowing evaluation were enrolled (n=36, 18 men and 18 women: mean age 82±9 y) and categorized into a group with water jelly (50 to 100 mL) ingestion training 3×/day or an untrained control group. Their food intake levels were then compared using a Food Intake Level Scale. Study 2: consecutive patients who were hospitalized because of aspiration pneumonia were enrolled (n=64, 35 men and 29 women: mean age 81±9 y) and categorized into a group with cyclic ingestion of water jelly immediately after each meal or a control group. The incidence of aspiration pneumonia that was newly developed during hospitalization was compared between the groups. RESULTS: In study 1, 36 patients with a Hyodo-Komagane score of 8 were enrolled. Three of the 12 (25%) patients who underwent water jelly ingestion training were able to eat a pureed diet (level 5, 2 patients; level 6, 1 patient) while none of the 24 patients (0%) who did not undergo this training were able to eat any form of diet (levels 5 and 6, no patients) (P=0.011). In study 2, 64 patients were enrolled. No newly developed aspiration pneumonia was observed in the 34 patients (0%) who received cyclic water jelly ingestion, whereas 17% (5/30) of patients not receiving water jelly after meals newly developed aspiration pneumonia during hospitalization (P=0.031). CONCLUSIONS: Water jelly ingestion was effective for both rehabilitation and the prevention of aspiration pneumonia in elderly patients with moderate to severe dysphagia.

A novel BMPR1A mutation affects mRNA splicing in juvenile polyposis syndrome.

BACKGROUND: Juvenile polyposis syndrome (JPS) is one of the hereditary polyposis syndromes caused by abnormal regulation of transforming growth factor ß signaling because of mutations in BMPR1A and SMAD4. Juvenile polyposis syndrome patients with SMAD4 mutations develop cardiovascular events, whereas those with BMPR1A usually do not. Analysis of genetic mutations in JPS patients can be helpful in devising suitable strategies for medical management. In this study, we demonstrate the pathogenicity of a novel intronic mutation in BMPR1A using mRNA extracted from colonic mucosa of a boy with JPS. METHODS: Genomic DNA extracted from peripheral blood and total RNA isolated from the colonic mucosa were used for DNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively. RESULTS: A 13-year-old boy, with no previous medical history, presented to the hospital complaining of bloody stools. Colonoscopy revealed multiple polyps in the colon, and the resected polyps were compatible with juvenile polyps. Sequencing analysis revealed a novel intronic mutation (c.778+5G>C) in BMPR1A. Reverse transcription polymerase chain reaction analysis of RNA extracted from the colonic mucosa showed an aberrant splicing form of BMPR1A. Trio analysis showed that his mother also had the same BMPR1A mutation. She was diagnosed with cancer of the cecum and polyposis of the colon at the age of 41. CONCLUSION: We demonstrate the presence of a novel BMPR1A intronic mutation that exhibits splicing abnormality in a family with JPS. Further research and development will help elucidate the genotype-phenotype relationship in JPS.