Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV1)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.

Galectin-3 levels in children with cystic fibrosis.

Cystic fibrosis (CF) is a multisystemic disease in which airway obstruction, infection, and inflammation play a critical role in the pathogenesis and progression of CF lung disease. The carbohydrate-binding protein Galectin-3 is increased in several inflammatory and fibrotic diseases and has recently been forwarded as a biomarker in these diseases. We aimed to define the role of serum Galectin-3 in children with CF by comparison with healthy subjects. This is a cross-sectional, case-control study. 143 CF and 30 healthy subjects were enrolled in the study. Peripheral blood and sputum concentrations of Galectins-3, interleukin (IL)-17A, IL-8, and neutrophil elastase (NE) were determined with commercial ELISA kits. There was no significant difference between the groups in age and gender (p = 0.592, p = 0.613, respectively). Serum Galectin-3 and NE concentrations were higher in the patient group than in healthy controls (p = 0.002, p < 0.001, respectively). There were no significant differences between groups according to IL-17A and IL-8 concentrations. Serum Galectin-3 was correlated with age (r = 0.289, p < 0.001) and body mass index (BMI) (r = 0.493, p < 0.001) in children with CF. Sputum Galectin-3 levels are negatively correlated with percent predictive forced expiratory volume in 1 s (FEV1) (r = - 0.297, p = 0.029), FEV1 z-score, (r = - 0.316, p = 0.020), percent predictive forced vital capacity (FVC) (r = - 0.347, p = 0.010), and FVC z-score (r = - 0.373, p = 0.006).   Conclusion: The study shows that serum Galectin-3 levels increased in clinically stable CF patients, and serum Galectin-3 response may depend on age, gender, and BMI. The sputum Galectin-3 was found to be negatively correlated with patients' lung functions. What is known: • Galectin-3 is a key regulator of chronic inflammation in the lung, liver, kidney, and tumor microenvironment. What is new: • Children with cystic fibrosis (CF) have higher serum Galectin-3 concentrations than healthy children. • Serum Galectin-3 expression influenced by age, BMI, and gender in children with CF.

Childhood interstitial lung disease in Turkey: first data from the national registry.

The childhood interstitial lung diseases (chILD) Turkey registry (chILD-TR) was established in November 2021 to increase awareness of disease, and in collaboration with the centers to improve the diagnostic and treatment standards. Here, the first results of the chILD registry system were presented. In this prospective cohort study, data were collected using a data-entry software system. The demographic characteristics, clinical, laboratory, radiologic findings, diagnoses, and treatment characteristics of the patients were evaluated. Clinical characteristics were compared between two main chILD groups ((A) diffuse parenchymal lung diseases (DPLD) disorders manifesting primarily in infancy [group1] and (B) DPLD disorders occurring at all ages [group 2]). There were 416 patients registered from 19 centers. Forty-six patients were excluded due to missing information. The median age of diagnosis of the patients was 6.05 (1.3-11.6) years. Across the study population (n = 370), 81 (21.8%) were in group 1, and 289 (78.1%) were in group 2. The median weight z-score was significantly lower in group 1 (- 2.0 [- 3.36 to - 0.81]) than in group 2 (- 0.80 [- 1.7 to 0.20]) (p < 0.001). When we compared the groups according to chest CT findings, ground-glass opacities were significantly more common in group 1, and nodular opacities, bronchiectasis, mosaic perfusion, and mediastinal lymphadenopathy were significantly more common in group 2. Out of the overall study population, 67.8% were undergoing some form of treatment. The use of oral steroids was significantly higher in group 2 than in group 1 (40.6% vs. 23.3%, respectively; p = 0.040).   Conclusion: This study showed that national registry allowed to obtain information about the frequency, types, and treatment methods of chILD in Turkey and helped to see the difficulties in the diagnosis and management of these patients. What is Known: • Childhood interstitial lung diseases comprise many diverse entities which are challenging to diagnose and manage. What is New: • This study showed that national registry allowed to obtain information about the frequency, types and treatment methods of chILD in Turkey and helped to see the difficulties in the diagnosis and management of these patients. Also, our findings reveal that nutrition should be considered in all patients with chILD, especially in A-DPLD disorders manifesting primarily in infancy.

Minimal important difference in childhood interstitial lung diseases.

BACKGROUND: Monitoring disease progression in childhood interstitial lung diseases (chILD) is essential. No information for the minimal important difference (MID), which is defined as the smallest change in a parameter that is perceived as important prompting a clinician to change the treatment, is available. We calculated MIDs for vital signs (respiratory rate, peripheral oxygen saturation in room air, Fan severity score) and health-related quality of life (HrQoL) scores. METHODS: This study used data from the Kids Lung Register, which is a web-based management platform that collects data of rare paediatric lung disorders with a focus on chILD. Data of vital signs and HrQoL scores (Health Status Questionnaire, chILD-specific questionnaire and PedsQL V.4.0) were collected. MIDs were calculated according to distribution-based (one-third SD) and anchor-based methods (using forced expiratory volume in 1 s and forced vital capacity) as anchors. RESULTS: Baseline data of 774 children were used to calculate the following MIDs: respiratory rate 1.3 (z-score), O2 saturation in room air 3.0%, Fan severity score 0.2-0.4, Health Status Questionnaire 0.4-0.8, chILD-specific questionnaire 4.4%-8.2%, physical health summary score 7.8%-8.9%, psychosocial health summary score 3.4%-6.9% and total score 5.1%-7.4%. Results of the responsiveness analysis generally agreed with the MIDs calculated. CONCLUSIONS: For the first time, we provide estimates of MIDs for vital signs and HrQoL scores in a large cohort of chILD using different methods.

Evaluation of polysomnography findings in children with genetic skeletal disorders.

Children with genetic skeletal disorders have variable conditions that can lead to sleep-disordered breathing, and polysomnography is the gold standard for diagnosing this condition. We aimed to review polysomnography findings, to assess the severity of sleep apnea, and to investigate the clinical variables predictive of sleep-disordered breathing in these patients. We retrospectively collected the medical records of patients with genetic skeletal disorders who underwent polysomnography for 5 years. Twenty-seven children with various genetic skeletal disorders, including achondroplasia (14), Crouzon syndrome (3), acromesomelic dysplasia Maroteaux type (3), Apert syndrome (2), osteopetrosis (1), Jeune dysplasia (1), Desbuquois dysplasia (1), acrodysostosis (1), and spondyloepiphyseal dysplasia (1) were enrolled. The median age at the first polysomnography was 58 (1st-3rd quartile: 31-113) months. The overall sleep-disordered breathing results were: 19 (70.3%) had obstructive sleep apneas (OSA) (4 mild, 6 moderate, 9 severe), 2 (7.4%) had central apneas, 4 (14.8%) had nocturnal hypoventilation. There was a significant correlation between non-ambulatory status with both total AHI and OSA (p < 0.001, rho: -0.66/p = 0.04, rho: 0.38, respectively). Nine patients received positive airway pressure titration, and the oAHI values of all returned to the normal range. These patients were started with positive airway pressure treatment. Our cohort showed that the majority of the patients with skeletal dysplasia had sleep apnea syndrome characterised mainly by OSA, highlighting the importance of polysomnography screening for sleep disorders. Positive airway pressure therapy represents an effective treatment for sleep-disordered breathing in those patients.

The role of flexible bronchoscopy in the diagnostic pathway of children with unexplained peripheral eosinophilia.

BACKGROUND: Many possible underlying causes can be seen in children with unexplained peripheral eosinophilia (UPE) with suspected pulmonary involvement. Here, we aimed to demonstrate the clinical characteristics and diagnoses of children evaluated for UPE who underwent diagnostic bronchoscopy. METHODS: Thirty-one children who underwent diagnostic bronchoscopy for UPE between 2006-2018 were included. Demographic characteristics, bronchoscopy findings and final diagnosis, and treatments were evaluated. RESULTS: The median age at the time of diagnosis was 5 (0.25-17.5) years. The final diagnoses of 26 patients were as follows: immunodeficiency (n = 6); hyper-IgE syndromes (n = 4), DOCK8 deficiency + HES (idiopathic hypereosinophilic syndrome; n = 1), and severe combined immunodeficiency (n = 1), HES (n = 3), idiopathic chronic eosinophilic pneumonia (ICEP; n = 3), idiopathic pulmonary hemosiderosis (n = 1), B cell lymphoma (n = 1). In one child, an integrin α3 mutation + cytomegalovirus (CMV) pneumonia was detected. Congenital pneumonia was found in one patient, and parasitic infection in another. In two, eosinophilia was attributed to underlying asthma and atopy. In four, the underlying reasons could not be elucidated. Two children with HES and one with ICEP were lost to follow-up. There was no significant relationship between the peripheral eosinophil count at the time of diagnosis and the percentage of bronchoalveolar lavage eosinophils (BAL). Bronchoscopy contributed to the management of 14 (53.9%) patients. CONCLUSIONS: Bronchoscopy has potential diagnostic contribution in patients with UPE suspected of having pulmonary involvement. Numerous various underlying causes may be present in this patient group. There is no relation between peripheral eosinophil count and BAL eosinophil percentage.

Healthcare resource utilisation and medical costs for children with interstitial lung diseases (chILD) in Europe.

BACKGROUND: No data on healthcare utilisation and associated costs for the many rare entities of children's interstitial lung diseases (chILD) exist. This paper portrays healthcare utilisation structures among individuals with chILD, provides a pan-European estimate of a 3-month interval per-capita costs and delineates crucial cost drivers. METHODS: Based on longitudinal healthcare resource utilisation pattern of 445 children included in the Kids Lung Register diagnosed with chILD across 10 European countries, we delineated direct medical and non-medical costs of care per 3-month interval. Country-specific utilisation patterns were assessed with a children-tailored modification of the validated FIMA questionnaire and valued by German unit costs. Costs of care and their drivers were subsequently identified via gamma-distributed generalised linear regression models. RESULTS: During the 3 months prior to inclusion into the registry (baseline), the rate of hospital admissions and inpatient days was high. Unadjusted direct medical per capita costs (€19 818) exceeded indirect (€1 907) and direct non-medical costs (€1 125) by far. Country-specific total costs ranged from €8 713 in Italy to €28 788 in Poland. Highest expenses were caused by the disease categories 'diffuse parenchymal lung disease (DPLD)-diffuse developmental disorders' (€45 536) and 'DPLD-unclear in the non-neonate' (€47 011). During a follow-up time of up to 5 years, direct medical costs dropped, whereas indirect costs and non-medical costs remained stable. CONCLUSIONS: This is the first prospective, longitudinal study analysing healthcare resource utilisation and costs for chILD across different European countries. Our results indicate that chILD is associated with high utilisation of healthcare services, placing a substantial economic burden on health systems.

Acute exacerbations in children's interstitial lung disease.

INTRODUCTION: Acute exacerbations (AEs) increase morbidity and mortality of patients with chronic pulmonary diseases. Little is known about the characteristics and impact of AEs on children's interstitial lung disease (chILD). METHODS: The Kids Lung Register collected data on AEs, the clinical course and quality of life (patient-reported outcomes - PRO) of rare paediatric lung diseases. Characteristics of AEs were obtained. RESULTS: Data of 2822 AEs and 2887 register visits of 719 patients with chILD were recorded. AEs were characterised by increased levels of dyspnoea (74.1%), increased respiratory rate (58.6%) and increased oxygen demand (57.4%). Mostly, infections (94.4%) were suspected causing an AE. AEs between two register visits revealed a decline in predicted FEV1 (median -1.6%, IQR -8.0 to 3.9; p=0.001), predicted FVC (median -1.8%, IQR -7.5 to 3.9; p=0.004), chILD-specific questionnaire (median -1.3%, IQR -3.6 to 4.5; p=0.034) and the physical health summary score (median -3.1%, IQR -15.6 to 4.3; p=0.005) compared with no AEs in between visits. During the median observational period of 2.5 years (IQR 1.2-4.6), 81 patients died. For 49 of these patients (60.5%), mortality was associated with an AE. CONCLUSION: This is the first comprehensive study analysing the characteristics and impact on the clinical course of AEs in chILD. AEs have a significant and deleterious effect on the clinical course and health-related quality of life in chILD.

Lung function from school age to adulthood in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

The controversy of drug hypersensitivity in patients with cystic fibrosis and review of the literature.

BACKGROUND: Cystic fibrosis (CF) is reported to be a risk factor for drug hypersensitivity. However, there are conflicting data about true prevalence of drug hypersensitivity in children with CF. METHODS: The suspicious drug hypersensitivity reactions (DHRs) of children with CF were enquired by the European Network for Drug Allergy (ENDA) questionnaire, and skin tests and/or drug provocation tests were performed according to the established guidelines. RESULTS: Two hundred and nineteen children (48.9% boys; median [IQR] age, 8.4 years [4.8-12.4 years]) with cystic fibrosis were included in the study, among which 22 patients with 24 suspected DHRs were evaluated. Most of the suspected DHRs were of non-immediate (n = 16, 66.6%) type, and the offending drugs were amoxicillin-clavulanic acid (n = 7), macrolides (n = 4), trimethoprim-sulfamethoxazole (TMP/SMX) (n = 2), piperacillin-tazobactam (n = 1), pancrelipase (n = 1), and ursodeoxycholic acid (n = 1). Eight (33.3%) of the DHRs were classified as immediate (ceftriaxone [n = 2], ceftazidime [n = 2], meropenem [n = 1], AmBisome [n = 2], and vancomycin [n = 1]). The main clinical presentations were maculopapular eruption (41.6%) and urticaria (37.5%), accompanied by angioedema (8.3%), flushing (12.5%), and vomiting (8.3%). Nine skin tests (with beta-lactam protocol in 6 patients) and 24 DPTs were performed, and none of the skin tests revealed a positive result; however, 2 DPTs with TMP/SMX were positive. CONCLUSION: Actual drug hypersensitivity was demonstrated in 2 of 219 patients (0.9%) with non-beta-lactam antibiotics. These results conflict with previous researches that showed higher drug hypersensitivity rates but are consistent with some recent studies. Allergological diagnostic workup is mandatory in patients with cystic fibrosis in case of a suspicious DHR.

Obstructive sleep apnea in children with Down syndrome: is it possible to predict severe apnea?

The objectives are to explore the demographic and polysomnographic features of children with Down syndrome and to determine the predictive factors associated with severe sleep apnea. A total of 81 children with Down syndrome referred for full-night polysomnography were analyzed. In addition, parental interviews were performed for each child. Data were available for 81 children, with a mean age of 4.8 years. Severe obstructive sleep apnea was determined in 53.1%. Age, sex, exposure to second-hand smoke, clinical findings, anthropometric features, and the presence of comorbidities were not predictors of severe obstructive sleep apnea. Children who were exposed to second-hand smoke had more sleep-related symptoms. Even in children without symptoms, the prevalence of severe obstructive sleep apnea was 40%. Moreover, 86% of parents had no previous information regarding possible sleep breathing disorders in their children. Clinically significant central apnea was present in 10 patients (12.3%).Conclusion: Our results demonstrate that severe obstructive sleep apnea is common in children with Down syndrome, even in children without a history of symptoms of sleep apnea. It is not possible to predict patients with severe apnea; thus, screening of children with Down syndrome beginning from young ages is very important. Central apneas could be a part of the spectrum of sleep abnormalities in Down syndrome.

Human bocavirus and human metapneumovirus in children with lower respiratory tract infections: Effects on clinical, microbiological features and disease severity .

BACKGROUND: We aimed to compare the clinical findings of human bocavirus (HBoV) and human metapneumovirus (HMPV) infections, and to analyze the effects of coinfections on clinical features and disease severity in children with HBoV and HMPV infections. METHODS: Data were collected from 125 children with lower respiratory tract infections due to HBoV or HMPV, detected from nasal swap by real-time polymerase chain reaction (PCR) during the period from January, 2013 to December, 2017. In total, there were 101 HBoV (group 1) and 23 HMPV (group 2) infections in our data. The patients were further divided into four subgroups according to the coinfection status: HoBV only (subgroup 1, n = 41), HMPV only (subgroup 2, n = 19), HBoV and coinfection with other respiratory viruses (subgroup 3, n = 60), and HMPV and coinfection with other respiratory viruses (subgroup 4, n = 4). RESULTS: The majority (88.8%) of the patients were aged 5 years or younger. Coinfections with other respiratory viruses were significantly more common in group 1 (P = 0.001). Among patients who had nosocomial pneumonia, patients with HBoV infections had significantly longer mean length of hospital stay (LOS) than those with HMPV infections (P = 0.032). The hospitalization and antibiotic requirements were significantly higher in subgroup 1 than subgroup 3 (P = 0.005, 0.039, resp.) According to the logistic regression analyses, the LOS increased by 21.7 times with HBoV infections (P = 0.006). CONCLUSIONS: Human bocavirus and HMPV infections are serious pathogens mostly seen in children and usually requiring hospitalization regardless of co-infection status. The HBoV infections caused longer LOS than the HMPV infections in patients with nosocomial infections.

The effect of Pseudomonas aeruginosa eradication regimens on chronic colonization and clinical outcomes in pediatric patients with cystic fibrosis.

BACKGROUND: Chronic Pseudomonas aeruginosa colonization (Pa-CC) affects cystic fibrosis (CF) progression, including pulmonary exacerbations and pulmonary function tests. There are few studies of the effects of eradication protocols on colonization time. Here, we aimed to evaluate the effect of eradication regimens on chronic colonization and assess the impact of Pa-CC on body mass index, lung functions, and pulmonary exacerbations. METHODS: A retrospective review was conducted of medical records, over a period of 11 years, of children aged under 18 years with CF who had Pa-CC in our tertiary care pediatric hospital. RESULTS: Pseudomonas aeruginosa was detected in 215 of our patients with CF during the study period. Forty-four patients with Pa-CC were recruited for the study. The eradication treatment for the initial acquisition of P. aeruginosa was inhaled antibiotics in 27 (61.4%) patients; the remainder were given intravenous antibiotics. It was observed that eradication treatment with either IV or inhaled antibiotics did not affect the time between the P. aeruginosa and the time of Pa-CC(P = 0.791). There was a non-significant decrease in the body mass index z-score from the Pa-IA to the last visit(P = 0.27), a significant decline in forced expiratory volume in 1 s (FEV1%) (P = 0.01) over time, and the annual number of exacerbations after colonization was significantly higher than before colonization (P = 0.03). CONCLUSIONS: There was no difference between eradication regimens in delaying the age at Pa-CC. Pseudomonas aeruginosa colonization in patients with CF was also associated with poorer lung functions, lower body mass index, and more pulmonary exacerbation regardless of mucoid type. Consequently, to slow the progression of lung disease, we must prevent Pa-CC, which we can achieve with early eradication. Despite conventional eradication protocols, future studies need to evaluate those who fail to clear P. aeruginosa.

Physical fitness and activities of daily living in primary ciliary dyskinesia: A retrospective study.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare, hereditary, autosomal recessive disorder characterized by recurrent upper and lower respiratory tract infections. This study aimed to compare pulmonary function, respiratory muscle strength, exercise capacity, physical fitness, and activities of daily living (ADLs) retrospectively between patients with PCD and healthy controls. METHODS: Data from 20 patients with PCD and 20 matched, healthy counterparts recorded between July 2015 and January 2017 were analyzed. The data evaluated and recorded included pulmonary function using a portable spirometer, respiratory muscle strength (using a mouth pressure device, exercise capacity using the incremental shuttle walk test,), physical fitness (using the Munich Fitness Test), and ADLs (using the Glittre ADL test). RESULTS: Pulmonary function, respiratory muscle strength, incremental shuttle walk test scores (all parameters), and total Munich Fitness Test scores were lower in the PCD group relative to controls (P < 0.05). The duration to complete the Glittre ADL test was higher in PCD patients than in healthy subjects (P < 0.05). CONCLUSIONS: Pulmonary function, respiratory muscle strength, exercise capacity, physical fitness, and ADL were affected by PCD. Thus, pulmonary rehabilitation regimens should be tailored according to these impacts.

Clinical findings of patients with cystic fibrosis according to newborn screening results.

BACKGROUND: Cystic fibrosis (CF) is a lethal recessive genetic disease caused by loss of function associated with mutations in the CF trans-membrane conductance regulator. It is highly prevalent (approximately 1 in 3,500) in Caucasians. The aim of this study was to compare demographic and clinical features, diagnostic tests, treatments, and complications of patients with CF whose newborn screening (NBS) with twice-repeated immune reactive trypsinogen testing was positive, normal, and not performed. METHODS: In this study, 359 of all 1,488 CF patients recorded in the CF Registry of Turkey in 2018, who had been born through the process of NBS, were evaluated. Demographic and clinical features were compared in patients diagnosed with positive NBS (Group 1), normal (Group 2), or without NBS (Group 3). RESULTS: In Group 1, there were 299 patients, in Group 2, there were 40 patients, and in Group 3, there were 20 patients. Among all patients, the median age at diagnosis was 0.17 years. The median age at diagnosis was higher in Groups 2 and 3 than in Group 1 (P = 0.001). Fecal elastase results were higher in Group 2 (P = 0.033). The weight z-score was lower and chronic Staphylococcus aureus infection was more common in Group 3 (P = 0.017, P = 0.004, respectively). CONCLUSIONS: Frequency of growth retardation and chronic S. aureus infection can be reduced with an early diagnosis using NBS. In the presence of clinical suspicion in patients with normal NBS, further analyses such as genetic testing should be performed, especially to prevent missing patients with severe mutations.

FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs!

Aminoacyl-tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non-canonical) functions outside of translation. Bi-allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi-allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl-tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient-derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non-canonical function in FARS1-associated recessive disease.

Evaluation of sleep-disordered breathing and its relationship with respiratory parameters in children with mucopolysaccharidosis Type IVA and VI.

The aims of the study were to evaluate the prevalence of sleep-disordered breathing (SDB) by using polysomnography (PSG) in children with MPS IVA and MPS VI who underwent enzyme replacement therapy (ERT) and to analyze the effect on SDB of having upper airway surgery, pulmonary functions, and exercise capacity. A retrospective cross-sectional study was conducted on patients with MPS IVA (n:17) and MPS VI (n:11) aged under 19 years who underwent polysomnography. Descriptive and nonparametric analyses were performed for demographic, PSG, pulmonary function and exercise capacity variables. The frequency of sleep apnea in the study sample was 85.7% (24/28). Four patients (14.3%) had no sleep apnea, 15 (53.6%) had mild, and nine (32.1%) had moderate-to-severe sleep apnea. Two patients (7.1%) had central sleep apnea and 22 had obstructive sleep apnea (OSA) (78.6%). Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were negatively correlated to apnea-hypopnea index (AHI) (r = -0.594, p = .009; r = -0.636, p = .005, respectively). Despite ERT and previous upper airway surgery, the prevalence of OSA was high in patients with MPS IVA-MPS IV, emphasizing the importance of PSG screening for sleep disorders. Pulmonary function tests may be useful for predicting sleep apnea in patients with MPS IVA and MPS VI.

Does cystic fibrosis make susceptible to celiac disease?

Patients with cystic fibrosis (CF) have a higher incidence of celiac disease (CD) than the healthy population; however, the actual incidence of coexisting CF and CD is unclear. In this report, we aimed to evaluate the frequency of CD and CF coexistence and to assess the clinical findings of affected patients during follow-up. We conducted a retrospective review of patients with CF to reveal the frequency of CD and also investigated the clinical characteristics and clinical response to gluten-free diet in patients with CD. The incidence of CD in 515 patients with CF was 1.4%. The median age at the time of CF diagnosis was 2 months (1-6 months). CD was diagnosed in six patients with poor weight gain, fatty stools, and low z score for BMI and one patient with poor weight gain despite a high protein and calorie diet and pancreatic enzyme replacement. The median age of CD diagnosis was 8 years (2-12 years). Except for one patient who was recently diagnosed, the other six patients gained weight and their accompanying symptoms resolved after starting a gluten-free diet.Conclusion: CD should be investigated in patients with CF in the presence of inadequate weight and/or height gain or poor control of malabsorption symptoms despite appropriate and adequate nutritional and enzyme replacement treatment. What is Known: • CFTR dysfunction may be a risk factor for CD, due to increased intestinal permeability and intestinal inflammation, pancreatic exocrine insufficiency that results in higher antigen load and increased antibodies against to nutritional antigens such as anti-gliadin IgA antibodies. • Although coexistence of CF and CD are rare in the same patient; there is still no consensus on when children with CF should be screened for CD. What is New: • Physicians should consider the investigation of CD in patients with CF, in the presence of inadequate weight and/or height gain or poor control of malabsorption symptoms despite appropriate and adequate nutritional and enzyme replacement treatment. • CFTR dysfunction has been emphasized to develop susceptibility to CD, and patients with CF who have persistent gastrointestinal symptoms despite appropriate and adequate nutritional and enzyme replacement treatment should be screened for CD.

Evaluation of blood and tooth element status in asthma cases: a preliminary case-control study.

BACKGROUND: Asthma is a common respiratory disorder; some data were present on the correlation between increased levels of trace elements and the risk of asthma development. It was aimed to evaluate the levels of 13 selected blood and tooth elements (magnesium, phosphorus, calcium, chromium, manganese, iron, copper, zinc, strontium, molybdenum, cadmium, lead, mercury) in a well-controlled asthma group and the control group. METHODS: During the study period, 17 asthma patients and 26 age and gender-matched healthy children donated shed deciduous teeth having neither decay nor filling and enrolled for the study. The element levels in blood and teeth matrixes were analyzed with inductively coupled plasma mass spectrometry. Differences in blood and tooth elements in groups were evaluated with generalized linear models after adjusting confounding factors. RESULTS: After adjusting the child's "z scores of body mass index for age", history of iron deficiency anemia, and status of parental smoking, the generalized linear model revealed significantly lower tooth magnesium levels, lower blood zinc levels, and lower blood zinc/copper ratio in the asthma group than the control group (p = 0.042, p = 0.034, p = 0.002, respectively). Other studied elements for tooth and blood matrixes were similar in groups. CONCLUSION: Our study revealed some differences in tooth and blood element levels in the asthma group. Further studies on zinc and magnesium levels of severe asthma cases are necessary for the interpretation of the results.

The frequency and related factors of non-tuberculosis mycobacteria infections among patients with cystic fibrosis.

BACKGROUND: Non-tuberculous mycobacteria (NTM) can cause chronic lung infection particularly in patients who have structural lung disease such as cystic fibrosis (CF). We evaluated the incidence and management of NTM infections in patients with CF in our center. METHODS: A retrospective cohort study was carried out on CF patients having at least one positive NTM isolate between 2012 and 2020. RESULTS: Ten patients (2.1%) had at least one positive NTM culture from respiratory samples. All of them were vaccinated with Bacille Calmette-Guérin (BCG) vaccine, which is in the national vaccination program in our country. Eight patients had the Mycobacterium abscessus complex, one had Mycobacterium avium, and one had Mycobacterium szulgai growth in their respiratory samples. Three patients had transient NTM infection, two had persistent, and five had active NTM infection (NTM pulmonary disease). Patients with NTM pulmonary disease received antibiogram-directed antimycobacterial therapy. In patients with NTM pulmonary disease, the median ppFEV1 and BMI decreased by 17% and 1%, respectively, at the time of the first NTM isolation when compared with the values one year before the first NTM isolation. Culture conversion was not seen in any patient infected with Mycobacteriunm abscessus complex. CONCLUSIONS: The NTM infection incidence is lower in our country than in those countries where the BCG vaccine is not routinely applied. The BCG vaccine may be a protective factor for NTM infection. Further studies are needed about the prevalence of NTM infections, facilitating and protective factors, and appropriate management of NTM infections in patients with CF.