Diagnosis Of PCD Research Articles

P946 Real life management of patients with active perianal fistulizing Crohn’s disease (ALERT-CD study)

Abstract Background The multitude of medical and surgical treatment options for perianal fistulizing Crohn’s disease (pCD) impels differences in management. This study aimed to assess management of pCD in current clinical practice in the Netherlands. Methods Patients with active pCD (i.e. visible external fistula opening or patent fistula tract on imaging) were included in a prospective multicenter cohort study in 41 Dutch academic and non-academic hospitals from September 2022 to March 2023. pCD-related clinical, radiological and surgical data were prospectively collected during a follow-up period of 6 months and retrospectively collected from pCD diagnosis until inclusion. Primary outcome of the study was adherence to the international guidelines on pCD management during the disease course (from pCD diagnosis until end of follow-up). Adequate adherence was defined as (I) imaging for pCD diagnosis using magnetic resonance imaging (MRI) and/or endo-anal ultrasound (EUS), (II) endoscopic evaluation of concomitant proctitis, (III) use of antibiotics for symptomatic response, (IV) initiation of an anti-tumour necrosis factor (TNF) agent for maintenance therapy, (V) fistula surgery aiming at fistula closure in case of surgically amendable disease and (VI) decision making by a multidisciplinary team (gastroenterologist and surgeon)(Figure 1). Results 449 patients with active pCD (52% female) were included(Table 1). At inclusion, median age and median pCD duration were 37.2 years (IQR 28.8–49.4) and 3.1 years (IQR 1.1–7.1). 54% of patients were treated in a non-academic hospital. 89% of patients were treated with CD medication, which concerned anti-TNF agents in 82% of these patients. As recommended by guidelines, a MRI (99%) and/or EUS (9%) were performed in the vast majority of patients (97%) for pCD diagnosis. Following diagnosis, endoscopy was performed in 81% of patients. During the disease course, antibiotics were initiated in 55% of patients and at least one anti-TNF agent(s) was started in 84% of patients for maintenance therapy (73% infliximab, 53% adalimumab, 26% both agents). Surgery aiming for fistula closure was performed in 38% of patients during the disease course. 60% of patients were discussed in a multidisciplinary team (MDT). Conclusion This study demonstrated a high adherence to international guidelines on pCD management concerning imaging at diagnosis, endoscopic evaluation for concomitant proctitis and treatment with anti-TNF agents. Adherence to use of antibiotics for symptoms, performance of fistula surgery aiming at fistula closure and decision making in a MDT is moderate and standardization may optimize pCD management.

P611 Relation between AntiTNF levels during the induction and clinical and radiological outcomes in perianal Crohn´s disease

Abstract Background Perianal Crohn's disease(PCD) significantly impacts quality of life with poor long-term prognosis. Anti-tumor necrosis factor(anti-TNF) therapy improves fistula closure rates. However, achieving permanent closure remains challenging. Our aim is to evaluate the relation between antiTNF(infliximab (IFX) and adalimumab(ADA) serum concentrations at induction(w2 and 6), and clinical and radiological outcomes at w24 and w52 Methods We conducted a single tertiary center, retrospective, cohort study including patients with an established diagnosis of PCD treated with antiTNF because of perianal activity. Variables related to their PCD(phenotype, location, fistulas type) were collected. Regarding treatment, we collected serum levels at week 2,6,24 and 52, concomitant treatment and setons presence. We defined clinical response as the absence of drainage on physical examination and clinical remission as the absence of external fistula openings. Radiological response was defined as the absence of T2 hypersignal, gadolinium enhancement, abscess and proctitis in pelvic MRI Results 65 patients were included, baseline characteristics are in Table1. None of the demographic characteristics collected were statistically significant related to clinical or radiological response although non smokers(p=0.01), ileal(p=0.02) and non-stricturing disease(p=0.01) had statistically significant higher drug levels. Taking into account the clinical response at w52, IFX mean levels at w2 were 25.8µg/mL(SD 4.1) in non responders and 30.9µg/mL(SD 14) in responders(p=0.39). At w6 they were 17.2µg/mL(SD 12.2) and 19.4µg/mL(SD 13.8) respectively(p=0.7). ADA mean levels at w2 were 13.3µg/mL(SD 7.7) in non responders and 14µg/mL(SD 6.3) in responders(p=0.87). At w6 they were 10.1µg/mL(SD 3.3) and 12µg/mL(SD 6.1) respectively(p= 0.59). For radiological response at w52 IFX mean levels at w2 were 27µg/mL(SD 15.3) in non responders and 32.7µg/mL(SD 14.5) in responders(p=0.45). At w6 the mean levels were 15.9µg/mL(SD 6.7) and 23.7µg/mL(SD 14.8) respectively(p=0.27). In ADA group the mean levels at w2 were 14.8µg/mL(SD 7.6) in responders and only one patient did not respond. At w6 ADA mean levels were 12.3µg/mL(SD 5.9) in non responders and 12.7µg/mL(SD 6.2) in responders(p=0.94). Early response at w24 was related with a long-term response at w52, 89.9% of the patients who responded at w52, had already responded at w24. Conclusion In our study we observed that almost 90% of the patients who had an early response also responded at w52, so trying to achieve an early response should be an aim in clinical practice. Despite the limited number of patients, our study shows a trend in the relationship between higher antiTNF levels and clinical and radiological response rates

Clinical and Genetic Characterization of Patients with Primary Ciliary Dyskinesia in Southwest Saudi Arabia: A Cross Sectional Study.

Primary ciliary dyskinesia (PCD, MIM 244400) is an inherited ciliopathy disorder characterized by recurrent sinopulmonary infections, subfertility, and laterality defects. The true incidence of PCD in Saudi Arabia is not known, but it is likely underdiagnosed due to the high prevalence of consanguineous marriages. In this study, we aim to study the clinical and genetic characteristics of PCD patients in the southwestern region of Saudi Arabia to provide guidance to clinicians and researchers studying PCD. This was a cross-sectional study conducted between 2019 and 2023 in Abha Maternity and Children's Hospital. Twenty-eight patients with clinically diagnosed PCD were recruited. The diagnosis of PCD was confirmed via whole-exome sequencing. A total of 28 patients from 20 families were identified and recruited for this study. The median age of patients was 7.5 years (IQR = 3, 13 years). The people of different sexes were evenly distributed, and 18 patients (64%) had neonatal respiratory distress (NRD). The median age of diagnosis was 5.5 years (IQR = 2, 11 years), while the age when the first symptoms appeared was 3 months old (IQR = 1, 6 months). The prevalence of a chronic wet cough, chronic rhinosinusitis, ear infections were 100% (n = 28), 78.6% (n = 22), and 67.9% (19), respectively. The most common gene in our study was DNAH5, which represented 17.9% (five out of twenty-eight) of the cases. Furthermore, the remaining pathogenic variants included: 14.3% with RSPH9 in four individuals (three families), 14.3% with DNAI2 in four individuals (two families), and 10.7% with LRRC56 in three individuals (one family). The most common findings on the chest CT scans were consolidation (seen in all patients), mucus plugging (seen in 95%), and bronchiectasis (seen in 77%). In the patients with bronchiectasis, the most commonly affected lobes were the right lower lobe (88%) and left lower lobe (76%). The patients with PCD and situs inversus were more likely to experience NRD than the patients with PCD and situs solitus. The median PICADAR score in the patients with PCD and situs inversus (median: 11.5; Q1: 10-Q3: 12.5) was significantly higher compared to those with PCD and situs solitus (median: 7.5; Q1: 5.8-Q3: 8) (U = 10.5; p < 0.001). This study provides preliminary data on the clinical and genetic characteristics of PCD patients in the southwestern region of Saudi Arabia. We found that DNAH5 and RSPH9 genes were the most common genes among the studied population. Furthermore, PCD should be considered for each child with early NRD and laterality defects, and further confirmatory tests are recommended. These findings also highlight the need for greater awareness of the disease in daily clinical practice to facilitate early diagnosis and avoid irreversible lung damage.

Airway microbiota correlated with pulmonary exacerbation in primary ciliary dyskinesia patients.

Primary ciliary dyskinesia (PCD) is characterized by symptoms such as productive cough, rhinitis, and recurrent infections in both the upper and lower airways, which can lead to chronic infection, bronchiectasis, and decreased pulmonary function. Our study aimed to analyze the diversity and composition of the microbiota in the respiratory tract and investigate the correlation of the microbiota with pulmonary exacerbation in PCD patients. This study employed 16S rRNA amplicon sequencing to explore the microbiota present in both bronchoalveolar lavage fluid (BALF) and sputum samples collected from PCD patients. Eighty-five airway samples (17 BALF and 68 sputum samples) were collected from 72 patients aged 2 months to 60 years. Significantly lower sputum microbiota diversity and richness were found in the pulmonary exacerbation group than in the pulmonary stabilization group; additionally, the relative abundance of Pseudomonas increased when pulmonary exacerbation occurred. There was a positive correlation between pulmonary exacerbation and the relative abundance of Pseudomonas, while Streptococcus, Moraxella, and Haemophilus showed a negative correlation. Although there was no significant difference in the sputum microbiota diversity and composition in children aged 6-18 years with pulmonary exacerbation, Pseudomonas increased during pulmonary exacerbation. BALF samples of pediatric patients with pulmonary exacerbation had a lower microbiota diversity and richness; furthermore, Pseudomonas had a higher abundance and a moderate distinguishing effect. We found that microbiota beta diversity and dominance were decreased during pulmonary exacerbation. Additionally, Pseudomonas had a higher abundance and moderate distinguishing effect in pediatric patients with pulmonary exacerbation. IMPORTANCE PCD is a rare disease characterized by productive cough, rhinitis, and recurrent infections of the upper and lower airways. Because the diagnosis of PCD is often delayed, patients receive more antibiotics, experience a heavier financial burden, and have a worse prognosis; thus, it is very important to identify the pathogeny and use the correct antibiotic. In this large single-center study of PCD microbiota, we identified an outline of the bacterial microbes from the respiratory tract; furthermore, we found that the microbiota diversity in pediatric sputum was richer than that in pediatric BALF through sequencing, indicating a heterogeneous community structure. The microbiota diversity and richness were lower during pulmonary exacerbation than during pulmonary stabilization. A significantly higher abundance of Pseudomonas had a moderate distinguishing effect for lung exacerbation, which attracted more attention for the study of Pseudomonas therapy in pediatric patients with PCD.

Primary ciliary dyskinesia

Background and objectivesPrimary ciliary dyskinesia (PCD, ORPHA:244) is a group of rare genetic disorders characterized by dysfunction of motile cilia. It is phenotypically and genetically heterogeneous, with more than 50 genes involved. Thanks to genetic, clinical, and functional characterization, immense progress has been made in the understanding and diagnosis of PCD. Nevertheless, it is underdiagnosed due to the heterogeneous phenotype and complexity of diagnosis. This review aims to help clinicians navigate this heterogeneous group of diseases. Here, we describe the broad spectrum of phenotypes associated with PCD and address pitfalls and difficult-to-interpret findings to avoid misinterpretation. MethodReview of literature ConclusionPCD diagnosis is complex and requires integration of history, clinical picture, imaging, functional and structural analysis of motile cilia and, if available, genetic analysis to make a definitive diagnosis. It is critical that we continue to expand our knowledge of this group of rare disorders to improve the identification of PCD patients and to develop evidence-based therapeutic approaches.

Epidemiology, Disease Course, and Clinical Outcomes of Perianal Fistulas and Fissures Crohn's Disease: A Nationwide Population-Based Study in Taiwan.

Population-based data on the course of perianal disease in East Asian populations with Crohn's disease (CD) are limited. This study examined the prevalence, clinical course, and compared the outcomes of CD patients with perianal CD (pCD) versus without pCD in Taiwan. A nationwide population-based study was implemented from 2000 to 2017 by using the Taiwan National Health Insurance Research Database. Of 2424 patients with CD, 358 (14.8%) patients with pCD were identified. Most patients with CD and pCD were men (79.3%). The mean age at CD diagnosis was lower in patients with pCD (33.7 years) than in those without pCD (44.9 years). Approximately half the patients with pCD received the pCD diagnosis at least 6 months before receiving a CD diagnosis. Approximately one-third (121/358) of patients with pCD had recurrent fistula; the median recurrence interval was 239 days. Compared with patients without pCD, patients with pCD had higher mean incidences of hospitalization (7.0 vs 3.8, P < .01), outpatient visits (13 vs 2.9, P < .01), and emergency room visits (10.3 vs 4.4, P < .01) over a 15-year period. Although patients with pCD had higher rates of healthcare utilization, their 15-year mortality rate was lower than that of those without pCD (6.1% vs 17.3%, P < .01). The period prevalence of pCD in Taiwanese patients with CD was 14.8%. Although patients with pCD required more intensive care and had greater healthcare utilization, they did not have inferior survival outcomes compared with those without pCD.

Rates and Predictors of Long-term Clinical Outcomes in Patients With Perianal Crohn's Disease on Biologic Therapy.

Perianal Crohn's disease (pCD) represents an aggressive phenotype with limited studies on long-term outcomes. We evaluated 5-year outcomes of these patients on biologic therapies. We performed a retrospective analysis of patients with pCD at a tertiary medical center. We used Kaplan-Meier curves to estimate rates and multivariate logistic regression to identify predictors of long-term outcomes. We included 311 patients with pCD of which 168 patients were started on biologics [138 anti-tumor necrosis factor (TNF) α, 14 vedolizumab, 16 ustekinumab] at the time of diagnosis. Anti-TNF use at the time of diagnosis was associated with decreased rates of perianal abscess recurrence [hazard ratio (HR)=0.48, 95% confidence interval (CI): 0.32-0.74], whereas ustekinumab use was associated with increased rates of perianal fistula closure (HR=3.58, 95% CI: 1.04-12.35) and decreased rates of perianal abscess recurrence (HR=0.20, 95% CI: 0.07-0.56) at follow-up. Among patients who failed their first anti-TNF, switching to another anti-TNF was associated with decreased rates of colectomy (HR=0.20, 95% CI: 0.04-0.90) and permanent diversion (HR=0.16, 95% CI: 0.03-0.94) compared with ustekinumab, whereas vedolizumab use was associated with decreased perianal fistula closure (HR=0.22, 95% CI: 0.05-0.96) compared with ustekinumab. Predictors of colectomy included colonic disease (odds ratio=2.71, 95% CI: 1.36-5.38) and anal stenosis (odds ratio=4.44, 95% CI: 1.59-12.43). Type of biologic use at the time of pCD diagnosis or after first anti-TNF failure may be associated with long-term outcomes in patients with pCD.

Lack of sensitivity and specificity for PCD diagnosis when ciliary videomicroscopy is performed at room temperature

Lack of sensitivity and specificity for PCD diagnosis when ciliary videomicroscopy is performed at room temperature

P561 Risk of stoma formation in patients with Crohn’s perianal fistulas over a two decades period. A cohort study from a tertiary referral center.

Abstract Background Optimal management of perianal Crohn’s disease (pCD) consists of combined medical (preferentially anti-TNF) and surgical treatment. However, it is still unclear if this has improved outcomes. This study aimed to described outcome and prognosis of pCD patients at a referral center over almost two decades. Methods All pCD patients referred for active perianal fistulas between 2000-2018 at our center were considered eligible for this retrospective study. Patients were divided into two groups according to the date of pCD diagnosis: period A (2000-2006) and period B (2006-2018). The complement of Kaplan-Meier estimates were used to visualize the time since pCD diagnosis until temporary and definitive fecal diversion. Clinically important outcomes such as need for temporary or permanent fecal diversion, and factors associated to these outcomes were evaluated by Cox regressions models. Results A total of 336 patients with active pCD were identified. The mean interval between the diagnosis of CD and the perineal fistulizing disease was 4.9 years (+-7.64). Mean follow up was 10.83 years (SD ± 4.5). The two groups were similar for demographic and clinical characteristics, except for the cumulative exposure to biologicals prior to pCD diagnosis [27.8% vs 46.9% in period A and B, respectively (p&amp;lt;0.001)]. (Table 1) The risk for temporary and definitive fecal diversion was higher for group B, at 5- [temporary stoma: 10.8 CI (6.7%-17.3%) vs 27.3% CI (21.1%-34.9%), p&amp;lt;0.001; definitive stoma: 0.7% CI (0.1%-4.8%) vs 13.1% CI (8.7%-19.5%), p=0.002] and 10-years follow-up [temporary stoma: 23.3% CI (17%-31.5%) vs 39.0% CI (31.1%-48.1%), p&amp;lt;0.001; definitive stoma: 11.7% CI (7.2%-18.7%) vs 19.9% CI (13.9-28.0%), p=0.002], respectively. (Figure 1 and Figure 2). At multivariate analysis, the presence of extraintestinal manifestations [HR 2.55 CI (1.40-4.62)], B2 stricturing disease [HR 4.43 CI (1.46-13.4)], B3 penetrating disease [HR 7.10 CI (2.37-21.27)], and diagnosis of pCD diagnosis after 2006 (period B) [HR 2.20 CI (1.16-4.17)], were independent risk factors for need for permanent ileostomy. (Table 2) Conclusion This retrospective analysis spanning almost twenty years shows that prognosis of CD patients affected by anal fistulas remains poor and has not much changed over time, despite the introduction of biologicals and new surgical techniques. The observed increase in definitive fecal diversion in more recent years can be partially explained by referral bias and/or a more aggressive clinical management of the most severe cases. Extraintestinal manifestations and synchronous complicated luminal disease increased the risk of definitive stoma in the long-term.

Primary ciliary dyskinesia diagnosis management in low-resource setting, a practical approach

Abstract Primary ciliary dyskinesia (PCD) is a congenital disorder with genetic determinism, characterized by chronic infections of the upper and lower respiratory tract. The triad of situs inversus, chronic sinusitis and bronchiectasis is called Kartagener Syndrome. PCD is a predominantly autosomal recessive disease, involving more than 40 mutations of genes. Abnormal cilia movement leads to defective mucociliary clearance resulting in chronic cough, nasal congestion, recurrent otitis, chronic sinusitis, male infertility and other rare conditions. First presented case is one of a 17-year-old girl with chronic treatment for asthma for the last 5 years. Respiratory functional tests were performed: the patient didn’t present variable airflow obstruction. The diagnosis of PCD was suspected because of chronic respiratory infections in a situs-inversus patient. The second case is a 4-year-old patient with a clinical history highly suggestive of ciliary dyskinesia, who received a recommendation for genetic testing to confirm the diagnosis. The third case is an 8-year-old boy with wet cough from neonatal period, bronchiectasis and sinusitis. Both his symptoms and the fact that his adult brother presented situs inversus, chronic sinusitis and bronchiectasis led us to raise suspicion of PCD. These case reports aim to highlight the real-life difficulties in a rather low-resource setting in diagnosing PCD, a genetic syndrome with long term impact on airways. The second objective was outlining the clinical manifestations that are highly suggestive of PCD and also to develop a diagnostic algorithm for a real-life scenario involving a pulmonologist with reduced access to high-performance tools like TEM (transmission electron microscopy) and complex genetic tests. Because not all PCD cases have known genetic mutations and some don’t have ultrastructural abnormalities we could still rely on the old saccharin test in order to select patients that are candidates for nasal NO. A high index of suspicion for PCD should be present in any patient with non-cystic fibrosis bronchiectasis patient. PCD remains a rare and underdiagnosed genetic syndrome in real-life paediatric setting in countries with limited neonatal screening programs. Increasing awareness of this condition and accessible diagnostic tools are desirable in order to find patients with high-likelihood of PCD and to refer these selected patients to specialized centres. Authors provide an age-dependent approach of PCD patients in a low resource setting.

Clinical and genetic features of primary ciliary dyskinesia in a cohort of consecutive clinically suspect children in western China

BackgroundPrimary ciliary dyskinesia (PCD) is a rare, inherited disorder of the motile cilia that exhibits genetic and clinical heterogeneity among different populations. PCD diagnosis remains challenging owing to the heterogeneity of associated clinical features and lack of a gold standard diagnostic test.ObjectiveThe aim of this study was to analyze the clinical and genetic characteristics of a group of children with clinically suspected PCD in one region of China, with the goal of providing a more robust knowledge base regarding the genetic stratification underlying this disease in Chinese populations.MethodsWe retrospectively analyzed the data from 38 patients with clinically suspected PCD who had undergone next-generation sequencing (NGS) between November 2016 and March 2021 in the respiratory department of a tertiary Children‘s hospital in Western China. The genetic features of the confirmed cases were summarized by reviewing data associated with other cohorts of Chinese children.ResultsOverall, 16 patients were ultimately diagnosed with PCD with a median age of 8.5 years. All patients presented with a chronic wet cough, 93.75% exhibited chronic or recurrent sinusitis/rhinitis, 43.75% experienced recurrent wheezing, 56.25% reported respiratory symptoms present since infancy, 31.25% had a history of neonatal respiratory distress (NRD), and 25% exhibited otitis media. Only 18.75% of these patients exhibited laterality defects. High frequencies of DNAH11 mutations were detected by integrating data from PCD patient cohorts in China.ConclusionThe high frequency of DNAH11 mutations may limit the utility of transmission electron microscopy (TEM) as a first-line approach to diagnosing PCD in China in the absence of other indicators.

Analysis of the clinical features of Japanese patients with primary ciliary dyskinesia

ObjectivePrimary ciliary dyskinesia (PCD) is a rare hereditary disease. Most reports of PCD in Japan are case reports, and clinical analysis has not been performed. Differences in the causative genes might affect the clinical features in different ethnic groups. The purpose of this study was to clarify the clinical features of Japanese patients with PCD. MethodsWe performed a retrospective chart review of PCD patients seen at Mie University Hospital and patients whose blood samples were sent to us for genetic analysis from 2011 to 2020. Data on the following items were collected and analyzed: age at first visit to the hospital, age at diagnosis of PCD, process of referral to our facility, chief complaint, situs status, PrImary CiliARy DyskinesiA Rule (PICADAR) score, nasal nitric oxide concentration, otoscopic findings, rhinoscopic findings, and paranasal computed tomography scan findings. ResultsSixty-seven patients (24 male, 43 female) were diagnosed with PCD during the study period. Age at diagnosis ranged from 2 months to 69 years (median, 17 years). Respiratory symptoms (77%) were the most common complaint, followed by nasal (15%) and aural (8%) symptoms. Situs inversus was present in 17 (25%) cases. Only 2 cases had congenital cardiac anomalies. The mean PICADAR score was 7.3 (range, 3–14) points. Approximately 50% of tympanic membranes showed retraction, suggesting otitis media with effusion. The mean Lund-Mackay score was 12.8 (range, 7–17) points, suggesting that the radiographic findings were not always severe. There was no significant difference in the total Lund-Mackay score between patients with and without situs inversus (12.7 vs. 12.6, respectively). ConclusionSitus inversus was present in 25% of Japanese PCD patients, which is much lower than observed in other countries. This is a result of differences in the major disease-causing genes. The general rule that “situs inversus is observed in approximately 50% of PCD patients” cannot be applied, at least, in Japanese PCD patients.

Primary Carnitine Deficiency and Autism Spectrum Disorder is there a Relationship?

Carnitine plays essential role in energy metabolism .Systemic primary carnitine deficiency is a genetic disorder caused by decreased or absent organic cation transporter type 2 (OCTN2) carnitine transporter activity, resulting in low serum carnitine levels and decreased carnitine accumulation inside cells. The decrease carnitine results in impaired fatty acid oxidation. Primary carnitine deficiency presents a hypoketotic, hypoglycemia and hepatic encephalopathy. Recently, primary carnitine deficiency has been associated with neurodevelopmental disorders including autism spectrum disorders. A seven year-old schoolgirl with intellectual deficit, autistic features and primary carnitine deficiency has been reported. A significant decrease in carnitine levels has been shown in patients with autism and this has been related to the existence of a mitochondrial disease and more severe autism. The early identification of patients with low levels of carnitine or primary carnitine deficiency, with the different methods of measuring free carnitine, including tandem mass spectrometry could help to identify these patients early and achieve an early treatment and better neurological prognosis, because autism spectrum disorders may be preventable in this subgroup. We hope that this paper is useful to neurologists and pediatricians, and may give them more reason to suspect a diagnosis of PCD and autism.

Clinical characteristics and genetic spectrum of 26 individuals of Chinese origin with primary ciliary dyskinesia

BackgroundPrimary ciliary dyskinesia (PCD) is a rare, highly heterogeneous genetic disorder involving the impairment of motile cilia. With no single gold standard for PCD diagnosis and complicated multiorgan dysfunction, the diagnosis of PCD can be difficult in clinical settings. Some methods for diagnosis, such as nasal nitric oxide measurement and digital high-speed video microscopy with ciliary beat pattern analysis, can be expensive or unavailable. To confirm PCD diagnosis, we used a strategy combining assessment of typical symptoms with whole-exome sequencing (WES) and/or low-pass whole-genome sequencing (WGS) as an unbiased detection tool to identify known pathogenic mutations, novel variations, and copy number variations.ResultsA total of 26 individuals of Chinese origin with a confirmed PCD diagnosis aged 13 to 61 years (median age, 24.5 years) were included. Biallelic pathogenic mutations were identified in 19 of the 26 patients, including 8 recorded HGMD mutations and 24 novel mutations. The detection rate reached 73.1%. DNAH5 was the most frequently mutated gene, and c.8383C > T was the most common mutated variant, but it is relatively rare in PCD patients from other ethnic groups.ConclusionThis study demonstrates the practical clinical utility of combining WES and low-pass WGS as a no-bias detecting tool in adult patients with PCD, showing a clinical characteristics and genetic spectrum of Chinese PCD patients.

DOP72 Perianal Crohn’s Disease in the biologic era: A population-based cohort study

Abstract Background Peri-anal Crohn’s disease (pCD) significantly affects quality of life in patients with CD. The natural history of pCD in the era of biologic therapy is poorly understood. Perianal surgery includes examination under anaesthesia (EUA), drainage of peri-anal sepsis, seton instertion and fistula manipulation. EUA forms part of the standard of care at diagnosis of pCD and therefore can be used as a proxy for incidence of pCD. Methods CD patients were identified from the Lothian IBD registry, a physician validated registry of all IBD cases within Lothian which has been shown to be 94.3% complete. Prospectively collected coding data was used to identify peri-anal surgery, which was validated by review of the electronic health record. Biologic prescription data was extracted from the Lothian biologics database; a physician validated, prospectively collected registry. Time trend analysis was performed for the period 2000 to 2017 by 1) calculating annual incidence rates of peri-anal interventions for all patients with CD and estimating annual percentage change and 2) by calculating cumulative incidence of pCD and biologic prescription in newly diagnosed CD and 3) stratifying by era of diagnosis (Cohort 1: 2000–2008 and Cohort 2: 2009–2017. Results 2937 patients with CD were identified in the study period, with 1108 operations for pCD performed on 381 patients. Rates of surgery fell from 5.1 to 2.0 operations per 100 CD patients per year between 2000 and 2017 (p&amp;lt;0.001) giving an annual percentage change of -3.4% (-4.9% to -1.9% 95% CI) (fig 1). 1753 new diagnoses of CD were made of whom 247 developed pCD. 5 year risk of pCD was 12.8% (9.5–16.6%) with no significant difference identified between cohort 1 (11.5%) and cohort 2 (13.8%) (p=0.116) (fig 2). The 5 year incidence of biologic prescription for patients with pCD increased from 11.2% in cohort 1 to 58.1% in cohort 2 (p&amp;lt;0.001) (fig 3). Figure 1: Number of peri-anal interventions per 100 CD patients per year (multiple procedures per patient included). Figure 2: Kaplan Meier curves showing cumulative incidence of pCD stratified by era of diagnosis. Figure 3: Kaplan Meier curves showing cumulative incidence of biologic prescription in patients with CD stratified by era of diagnosis and presence of pCD. Conclusion The incidence of pCD remains unchanged over time. Although we cannot ascribe causality, the overall decrease in surgery for pCD has been paralleled by a marked increase in the use of biologic medication.

Implementation of a gene panel for genetic diagnosis of primary ciliary dyskinesia

IntroductionPrimary ciliary dyskinesia (PCD) is characterized by an alteration in the ciliary structure causing difficulty in the clearance of respiratory secretions. Diagnosis is complex and based on a combination of techniques. The objective of this study was to design a gene panel including all known causative genes, and to corroborate their diagnostic utility in a cohort of Spanish patients. MethodsThis was a multicenter cross-sectional study of patients with a high suspicion of PCD according to European Respiratory Society criteria. We designed a gene panel for massive sequencing using SeqCap EZ capture technology that included 44 genes associated with PCD. ResultsWe included 79 patients, 53 of whom had a diagnosis of confirmed or highly probable PCD. The sensitivity of the gene panel was 81.1%, with a specificity of 100%. Candidate variants were found in some of the genes of the panel in 43 patients with PCD, 51.2% (22/43) of whom were homozygotes and 48.8% (21/43) compound heterozygotes. The most common causative genes were DNAH5 and CCDC39. We found 52 different variants, 36 of which were not previously described in the literature. ConclusionsThe design and implementation of a tailored gene panel produces a high yield in the genetic diagnosis of PCD. This panel provides a better understanding of the causative factors involved in these patients and lays down the groundwork for future therapeutic approaches.

A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report

BackgroundPrimary ciliary dyskinesia (PCD) is a highly heterogeneous genetic disorder caused by defects in motile cilia. The hallmark features of PCD are the chronic infections of the respiratory tract, moreover, clinical manifestations include also laterality defects and risk of male infertility.Clinical phenotypes of PCD are the result of mutations in genes encoding components of axonema or factors involved in axonemal assembly. Recent studies have identified over 45 PCD-associated genes, therefore, molecular analysis represents a powerful diagnostic tool to confirm and uncover new genetic causes of this rare disease.Case presentationHere, we describe a female infant of Moroccan origin with normal pressure hydrocephalus (NPH) in addition to most common PCD symptoms. Transmission Electron Microscopy (TEM) and molecular tests, such as a Next generation Sequencing panel and a custom array CGH, were performed for diagnosis of PCD. TEM revealed outer dynein arm (ODA) defects, whilst molecular analyses detected a novel 6,9 kb microdeletion in DNAI2 gene.ConclusionsSince DNAI2 mutations are very rare, this case report contributes to better delineate the important role of DNAI2 as causative of PCD phenotype, suggesting, furthermore, that the variations in DNAI2 may be as a new genetic risk factor for NPH. Indeed, although the association of hydrocephalus with PCD has been well documented, however, only a small number of human patients show this defect.Furthermore, this study highlights the importance of high-throughput technologies in advancing our understanding of heterogeneous genetic disorders.

Implementación de un panel de genes para el diagnóstico genético de la discinesia ciliar primaria

IntroductionPrimary ciliary dyskinesia (PCD) is characterized by an alteration in the ciliary structure causing difficulty in the clearance of respiratory secretions. Diagnosis is complex and based on a combination of techniques. The objective of this study was to design a gene panel including all known causative genes, and to corroborate their diagnostic utility in a cohort of Spanish patients. MethodsThis was a multicenter cross-sectional study of patients with a high suspicion of PCD, according to European Respiratory Society criteria, designed around a gene panel for massive sequencing using SeqCap EZ capture technology that included 44 genes associated with PCD. ResultsWe included 79 patients, 53 of whom had a diagnosis of confirmed or highly probable PCD. The sensitivity of the gene panel was 81.1%, with a specificity of 100%. Candidate variants were found in some of the genes of the panel in 43 patients with PCD, 51.2% (22/43) of whom were homozygotes and 48.8% (21/43) compound heterozygotes. The most common causative genes were DNAH5 and CCDC39. We found 52 different variants, 36 of which were not previously described in the literature. ConclusionsThe design and implementation of a tailored gene panel produces a high yield in the genetic diagnosis of PCD. This panel provides a better understanding of the causative factors involved in these patients and lays down the groundwork for future therapeutic approaches.

Skin bioengineering in the diagnosis of occupational protein contact dermatitis

Protein contact dermatitis (PCD) often presents as chronic hand eczema (CHE) with an immediate hypersensitivity to protein proved by a positive skin prick test or by the presence of specific immunoglobulin E. This is frequently induced by occupational exposure to proteins in food workers, farmers, animal breeders, veterinarians and healthcare professionals. While skin barrier impairment is crucial in the pathogenesis of PCD, methods to assess skin barrier function such as trans-epidermal water loss and stratum corneum hydration are not widely used in clinical settings. We describe the diagnostic workup of occupational PCD due to Argentinean shrimps and discuss how the use of skin bioengineering methods including assessment of corneocytes morphology by Scanning Electron Microscopy provides with insightful information on skin barrier function. Diagnosis of PCD is time-consuming and a multidisciplinary team contributes to early diagnosis and proper occupational rehabilitation.

Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort

BackgroundPrimary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests.MethodsThe diagnostic utility...