Clinical Manifestations Of Cystic Fibrosis Research Articles

Clinical manifestations of cystic fibrosis

Cystic fibrosis is a severe genetic disease that is inherited in an autosomal recessive manner, affecting the short arm of chromosome 7 of the CFTR gene, causing alterations in the transmembrane conductance regulator protein (CFTR), This causes dysfunctional transport of chloride, sodium and bicarbonate leading to the generation of thick and viscous secretions in the lungs, pancreas, liver, intestine and reproductive tract while in the sweat glands there will be increased salt content. The clinical manifestations depend on the degree of mutation present in the gene, and may appear within a few months of birth or may even take decades. Life expectancy in patients with cystic fibrosis in Ecuador is 9.5 years and is mainly related to the quality of treatment and especially with early diagnosis since lung damage begins at birth. A retrospective study was made with various databases and keywords related to Cystic Fibrosis and it was found that the main system affected is the respiratory system, its main clinical manifestations, persistent productive cough, hyperinflation of lung fields and airway obstruction, as the disease progresses and exposure to infections, there will be a progressive deterioration of the lung that will manifest itself in acute exacerbations of cough, tachypnea, dyspnea and increased sputum production. With respect to the digestive system, two thirds of CF patients have pancreatic insufficiency and most have signs of poor or deficient fat absorption, including symptoms and signs such as steatorrhea, growth retardation or weight gain, and in infants edema, hypoproteinemia, electrolyte loss and anemia may occur.

The Effect of Complex Alleles of the CFTR Gene on the Clinical Manifestations of Cystic Fibrosis and the Effectiveness of Targeted Therapy.

The authors of this article analyzed the available literature with the results of studying the prevalence of complex alleles of the CFTR gene among patients with cystic fibrosis, and their pathogenicity and influence on targeted therapy with CFTR modulators. Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of the CFTR protein, and more than 2000 genetic variants are known. Clinically significant variants are divided into seven classes. Information about the frequency of complex alleles appears in a number of registers, along with the traditional presentation of data on genetic variants. Complex alleles (those with the presence of more than two nucleotide variants on one allele) can complicate the diagnosis of the disease, and change the clinical manifestations of cystic fibrosis and the response to treatment, since each variant in the complex allele can contribute to the functional activity of the CFTR protein, changing it both in terms of increasing and decreasing function. The role of complex alleles is often underestimated, and their frequency has not been studied. At the moment, characteristic frequently encountered complex alleles have been found for several populations of patients with cystic fibrosis, but the prevalence and pathogenicity of newly detected complex alleles require additional research. In this review, more than 35 complex alleles of the CFTR gene from existing research studies were analyzed, and an analysis of their influence on the manifestations of the disease and the effectiveness of CFTR modulators was also described.

Cystic Fibrosis: Back to the Basics

Cystic fibrosis (CF) is the most common genetic disorder in Caucasian individuals, with an incidence of 1/2,500-3,500 live births. When CF was first described in 1938, most children died in infancy. Currently, the average lifespan is 28-47.7 years. Although new breakthroughs have occurred, CF is still incurable. Both early diagnosis and treatment by multidisciplinary teams are essential to optimize short- and long-term outcomes. It is imperative for neonatal clinicians to keep up to date on the most current research, treatment, and management of CF to provide the best outcomes. This article offers clinicians an updated review of the pathophysiology and clinical manifestations of CF, as well as current evidence-based diagnostics and treatment regimens.

PECULIARITIES OF CYSTIC FIBROSIS IN NEWBORN ON THE EXAMPLE OF A CLINICAL CASE

Cystic fibrosis is a severe genetic disease, which is inherited in an autosomal recessive manner and is characterized by a polyorganic clinical presentation with predominantly exocrine, respiratory and digestive gland involvement. Every year more than 45 000 children are born worldwide with this genetic disease. According to official statistics, 674 children with cystic fibrosis are registered in Ukraine, 25 of them in the Vinnytsia region. The disease is caused by a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The F508del mutation is most common in the paediatric population (19-34%). The most common clinical manifestations of cystic fibrosis in newborns are disorders of the gastrointestinal tract, pancreas, hepatobiliary system and respiratory system. In 20% of newborns, one of the earliest manifestations of cystic fibrosis is meconial ileus, which may pose a risk of complications such as meconium peritonitis, sputum, gangrene or intestinal necrosis. Early diagnosis with neonatal screening, improved care for the neonatal manifestations of meconial ileus and adequate medical follow-up by a multidisciplinary team of specialists, and improved lifelong replacement fermentation therapy have a significant impact on the life expectancy of patients with cystic fibrosis.This article presents a clinical case of early diagnosis of cystic fibrosis in a newborn. When meconial ileus is present and cysticfibrosis is suspected in a newborn, early genetic diagnosis is mandatory, in addition to timely and correctly performed neonatal screening. Comprehensive and timely treatment leads to improvement in cystic fibrosis patients and slows down the development of pathological changes in the bronchopulmonary and hepatobiliary systems.Conclusions. Prevention of a severe course of cystic fibrosis is in early detection of the disease during neonatal screening, indiagnosis at the first signs of the disease and early start of pathogenetic treatment, which improves the quality of life of patients.

Potential opportunities and challenges for infection prevention and control for cystic fibrosis in the modern era.

We describe recent changes in care for people with cystic fibrosis (PwCF) that could impact infection prevention and control (IP&C) practices. Current IP&C guidelines primarily aim to prevent acquisition and transmission of pathogens in PwCF utilizing evidence-based recommendations for healthcare settings. Currently, highly effective modulator therapy (HEMT) is dramatically improving the clinical manifestations of cystic fibrosis and reducing pulmonary exacerbations and hospitalizations. Thus, it is feasible that long-term, sustained improvements in pulmonary manifestations of cystic fibrosis could favorably alter cystic fibrosis microbiology. The COVID-19 pandemic increased the use of virtual care, enabling PwCF to spend less time in healthcare settings and potentially reduce the risk of acquiring cystic fibrosis pathogens. The increasing use of whole genome sequencing (WGS) shows great promise in elucidating sources of cystic fibrosis pathogens, shared strains, and epidemic strains and ultimately could allow the cystic fibrosis community to monitor the safety of changed IP&C practices, if deemed appropriate. Finally, given the nonhealthcare environmental reservoirs for cystic fibrosis pathogens, practical guidance can inform PwCF and their families about potential risks and mitigation strategies. New developments in the treatment of PwCF, a shift toward virtual care delivery of care, and use of WGS could change future IP&C practices.

Leveraging Open Electronic Health Record Data and Environmental Exposures Data to Derive Insights Into Rare Pulmonary Disease.

Research on rare diseases has received increasing attention, in part due to the realized profitability of orphan drugs. Biomedical informatics holds promise in accelerating translational research on rare disease, yet challenges remain, including the lack of diagnostic codes for rare diseases and privacy concerns that prevent research access to electronic health records when few patients exist. The Integrated Clinical and Environmental Exposures Service (ICEES) provides regulatory-compliant open access to electronic health record data that have been integrated with environmental exposures data, as well as analytic tools to explore the integrated data. We describe a proof-of-concept application of ICEES to examine demographics, clinical characteristics, environmental exposures, and health outcomes among a cohort of patients enriched for phenotypes associated with cystic fibrosis (CF), idiopathic bronchiectasis (IB), and primary ciliary dyskinesia (PCD). We then focus on a subset of patients with CF, leveraging the availability of a diagnostic code for CF and serving as a benchmark for our development work. We use ICEES to examine select demographics, co-diagnoses, and environmental exposures that may contribute to poor health outcomes among patients with CF, defined as emergency department or inpatient visits for respiratory issues. We replicate current understanding of the pathogenesis and clinical manifestations of CF by identifying co-diagnoses of asthma, chronic nasal congestion, cough, middle ear disease, and pneumonia as factors that differentiate patients with poor health outcomes from those with better health outcomes. We conclude by discussing our preliminary findings in relation to other published work, the strengths and limitations of our approach, and our future directions.

Исследование функциональной активности CFTR-канала у пациента с муковисцидозом и генотипом E92K/4428insGA

Clinical manifestations of cystic fibrosis depend on the patient’s genotype since there are more than 2,000 variants of the CFTR gene. Main complications of the disease are expressed in a reduction or loss of pancreatic function and bacterial lung infection, leading to respiratory failure. The E92K (p.(Glu92Lys) and 4428insGA (p.(Ser1435Glyfs*14) mutations in the CFTR gene are accompanied by a high frequency of preserved pancreatic function. In a 3-year-old patient with recurrent pancreatitis and E92K/4428insGA genotype, the functional activity of the CFTR channel was studied using the intestinal current measurement method on rectal biopsy specimens and the forskolin-induced swelling assay in intestinal organoids. The personalized assessment of the action of CFTR modulators was also performed on organoid cultures obtained from the patient’s intestinal biopsies. In a 3-year-old child with cystic fibrosis and recurrent pancreatitis with frequent exacerbations, a high preservation of residual CFTR channel function was revealed. All the investigated targeted drugs were effective in increasing the functional activity of the CFTR chloride channel. Key words: cystic fibrosis, CFTR gene, targeted therapy, pancreatitis, intestinal organoids, intestinal current measurement, E92K, 4428insGA

Генетически детерминированная сочетанная патология поджелудочной железы: муковисцидоз, панкреатит, диабет

In this article, we report a case of cystic fibrosis (CF) with untypical manifestations, including obstructive pancreatitis with relative pancreatic insufficiency, complicated by pancreatolithiasis and type 1 diabetes mellitus (DM1). Interestingly, the patient had almost none clinical manifestations of CF in the lower respiratory tract. The first manifestation was abdominal pain associated with chronic obstructive pancreatitis. The patient had only laboratory manifestations of DM1 without any clinical signs. DM1 treatment led to an increase in the child's body weight and increased external respiration, which allowed an operation for pancreatitis. We removed calculi and performed longitudinal pancreaticojejunostomy. The surgery alleviated pain and increased the external secretion of the pancreas. Thus, this case demonstrates difficulties associated with CF diagnosis, as well as effectiveness and feasibility of surgical treatment for obstructive pancreatitis, even in cases when it is believed to be an inherited and incurable disease. Key words: cystic fibrosis, pancreatitis, pancreatic insufficiency, pancreatolithiasis, type 1 diabetes mellitus

Clinical and genetic characteristics of rare pathogenic variants of the CFTR gene in Russian patients with cystic fibrosis

The variety of clinical manifestations of cystic fibrosis is driven by the diversity of the CFTR gene nucleotide sequence. Descriptions of the clinical manifestations in patients with the newly identified genetic variants are of particular interest.The aim of this study was to describe clinical manifestations of the disease with the newly identified genetic variants.Methods. Data from Registry of patients with cystic fibrosis in the Russian Federation (2018) were used. The data review included three steps — the search for frequent mutations, Sanger sequencing, and the search for extensive rearrangements by MLPA. 38 pathogenic variants were identified that were not previously described in the international CFTR2 database. We selected and analyzed full case histories of 15 patients with 10 of those 38 pathogenic variants: p.Tyr84*, G1047S, 3321delG, c.583delC, CFTRdele13,14del18, CFTRdele19-22, c.2619+1G>A, c.743+2T>A, p.Glu1433Gly, and CFTRdel4-8del10-11.Results. A nonsense variant p.Tyr84* was found in 5 patients (0.08 %). Two missense variants c.3139G>A were found in 2 siblings (0.03 %). The c.4298A>G was found in 1 patient. Other variants were detected in a single patient (0.02 %) each. They included two variants of a deletion with a shift of the reading frame 3321delG and c.583delC, two splicing disorders c.2619+1G>A and c.743+2T>A, three extended rearrangements CFTRdele19-22, CFTRdele13,14del18, and CFTRdel4-8del10-11. The last two variants include 2 rearrangements on one allele, which cause the severe course in two young children. 8 of the 10 variants are accompanied by pancreatic insufficiency (PI). Among patients with p.Tyr84*, one had ABPA, one had liver transplantation, and all had Pseudomonas aeruginosa infection. Nasal polyps were diagnosed in 2 patients with p.Tyr84*, 1 with G1047S, 1 with CFTRdel4-8del10-11, and 1 patient with 3321delG, who also had osteoporosis and cystic fibrosis-related diabetes (CFRD). 2 patients with PI with 3321delG and CFTRdel4-8del10-11 genetic variants, and 1 with PI with p.Glu1433Gly genetic variant had severe protein-energy malnutrition (PEM).Conclusion. Clinical manifestations of previously undescribed CFTR genetic variants were described. 5/10 genetic variants should be attributed to class I, 3/10 – to class 7 of the function classification of pathogenic CFTR gene variants associated with transcription and translation disruptions. Class of the identified missense variants c.3139G>A and c.4298A>G has not been established and requires further functional, cultural, and molecular genetic studies.

The first report on CFTR mutations of meconium ileus in cystic fibrosis population in Saudi Arabia: A single center review.

IntroductionMeconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is suspected if a baby fails to pass meconium shortly after birth and develops symptoms of bowel obstruction, such as distention of the abdomen or vomiting. MI can lead to bowel perforation, a twisting of the bowel, or inflammation and infection of the abdominal cavity.ObjectivesTo find the incidence and prevalence of meconium ileus in cystic fibrosis patients and to report on the most common gene mutation of MI in CF patients.MethodologyRetrospective review of the medical documentations of all MI patients during the period of 1989–2018.ResultsA total of 40 CF confirmed patients were presented with MI. Twenty-nine patients (71%) are alive and 11 patients (29%) died or lost to follow-up. The following CFTR mutations were found: Eight patients (20%) with c.2988+1G>A; Intron 18. Seven patients (17.5%) with c.1418delG; Exon 11. Five patients (12.5%) with c.579+1G>T; Intron 5. Four patients (10%) with c.1911delG; Exon 14. Four patients (10%) with c.1521_1523delCTT; Exon 11. Four patients (10%) with c.416A>T; Exon 13. Three patients (7.5%) with c.2421A>G; Exon 14. Two patients (5%) with c.3908A>C; Exon 21. One patient (2.5%) with c.3889dupT; Exon 24. One patient (2.5%) with c.1657C>T; Exon 12. One patient (2.5%) with c.2547C>A; Exon 14a. Eighteen patients (45%) were presented with vomiting, 38 patients (95%) had postnatal radiological findings, 7 patients (17.5%) had electrolytes imbalance. Five patients (12.5%) had cholestasis and 4 patients (10%) developed chronic liver disease. Thirty-five patients (79.5%) underwent surgical repair and 9 patients (20.5%) were treated medically. Mean age of operation was 2.25 (2) days. Of 9 patients, 6 (66.6%) were treated with gastrograffin enema, 2 patients (22.2%) with oral N-acetylcysteine and 1 patient (11.1%) with saline rectal wash. Thirteen patients (31.5%) required TPN. Five patients had recurrent operation.ConclusionCF and meconium ileus are commonly present in CF patients in Saudi Arabia. Prognosis is similar to other CFs without MI, if treated early. Thirty percent of our CF/MI patients have intronic mutations.

Identification of a Mutation in the Novel Compound Heterozygous CFTR in a Chinese Family with Cystic Fibrosis.

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders among Caucasians of Northern European descent but is uncommon in the Chinese population. Objectives. To elucidate the mutation in the novel compound heterozygous CFTR causing CF in Chinese family. Materials and Methods. Clinical samples were obtained from a Chinese family, the brother and sister with recurrent airway infections, hypoxemia and obstructive ventilatory impairment, sinusitis, clubbed fingers, salty sweat, and nasal polyposis. We performed whole-exome sequencing on the family and validated all potential variants by Sanger sequencing. Results. Next-generation sequencing showed a novel compound heterozygous CFTR mutation (c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162∗) which resulted in CF in the family. Conclusions. As this mutation is consistent with the observed clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that their CF phenotypes are caused by the compound heterozygous mutation, c.400 A > G p.Arg134Gly and c.3484 C > T p.Arg1162∗. As c.400 A > G is not currently listed in the Cystic Fibrosis Mutation Database, this information, regarding the CF-causing mutations in two Chinese patients, is of interest.

TAS2R38 is a novel modifier gene in patients with cystic fibrosis

The clinical manifestation of cystic fibrosis (CF) is heterogeneous also in patients with the same cystic fibrosis transmembrane regulator (CFTR) genotype and in affected sibling pairs. Other genes, inherited independently of CFTR, may modulate the clinical manifestation and complications of patients with CF, including the severity of chronic sinonasal disease and the occurrence of chronic Pseudomonas aeruginosa colonization. The T2R38 gene encodes a taste receptor and recently its functionality was related to the occurrence of sinonasal diseases and upper respiratory infections. We assessed the T2R38 genotype in 210 patients with CF and in 95 controls, relating the genotype to the severity of sinonasal disease and to the occurrence of P. aeruginosa pulmonary colonization. The frequency of the PAV allele i.e., the allele associated with the high functionality of the T2R38 protein, was significantly lower in i) CF patients with nasal polyposis requiring surgery, especially in patients who developed the complication before 14 years of age; and ii) in CF patients with chronic pulmonary colonization by P. aeruginosa, especially in patients who were colonized before 14 years of age, than in control subjects. These data suggest a role for T2R38 as a novel modifier gene of sinonasal disease severity and of pulmonary P. aeruginosa colonization in patients with CF.

Magnesium Rescues Cystic Fibrosis- and Age-Related Bone Diseases Through an ATF4-Dependent Wnt/β-Catenin Signaling

Bone fragility has emerged as a key clinical manifestation of cystic fibrosis, a genetic disease caused by CFTR mutation, which is not well understood and currently lacks effective therapeutic options. Here we report that CFTR is downregulated in aged wild-type mouse bones; CFTR-deficient mice show early activation of bone cell senescence, abnormal bone micro-architecture, altered osteogenic genes expression and impaired bone fracture healing, mimicking age-related bone disease. We also observed that magnesium ion enters bone cells, activates a transcription factor, ATF4, and promotes Wnt/β-catenin signaling. Magnesium implant improves bone fracture healing in CFTR-mutant mice, which is blocked by Wnt/β-catenin inhibition or ATF4 knockdown. Importantly, oral magnesium or local administration of VX809, a drug that restores CFTR function, improves bone quality in aged wild-type rats/mice. Together, these results collectively show that CFTR-deficiency mimics aging to cause bone defects , while suggesting magnesium supplementation as a possible therapy for CFTR deficiency-associated bone diseases.

Клинико-генетическая характеристика больных муковисцидозом с впервые описанным патогенным вариантом CFTR c.1083G> A (p.Trp361*) и функциональной оценкой работы хлорного канала

В статье впервые представляется клинико-генетическая характеристика мутации c.1083G>A (p.Trp361*) в гене CFTR. Патогенный генетический вариант c.1083G>A (p.Trp361*) гена CFTR относится к нонсенс-мутациям (I класс) и впервые был внесён в базу данных CFTR1 (http://www.genet.sickkids.on.ca) в середине 2019 г. без описания клинической картины муковисцидоза. Методы. Проведен анализ амбулаторных карт и историй болезни двух пациентов из неродственных семей с редким генетическим вариантом c.1083G>A (p.Trp361*). Для определения разности кишечных потенциалов (ОРКП) и проведения форсколинового теста на кишечных органоидах использовали биопсийный материал слизистой прямой кишки пациентов. ДНК для секвенирования выделяли из лейкоцитов венозной крови пациентов. Результаты. Анализ клинических проявлений заболевания у детей 6 и 9 лет показал наличие хронической панкреатической недостаточности, более выраженной у одного ребенка с синдромом дистальной интестинальной обструкции кишечника в анамнезе. Клиническая картина второго пациента характеризовалась развитием в раннем возрасте транзиторной гипербилирубинемии, синдрома псевдо-Барттера, а в дальнейшем - повторными эпизодами бронхиальной обструкции и развитием полипозного риносинусита. ОРКП и форсколиновый тест на кишечных органоидах показали, что генетический вариант c.1083G>A (p.Trp361*) относится к вариантам гена CFTR с отсутствием функции хлорного канала. Выводы. Впервые представлены описание клинической картины муковисцидоза у двух пациентов из неродственных семей с патогенным вариантом c.1083G>A (p.Trp361*) в компаунде с вариантом c.1521_1523delCTT (p.Phe508del) (ранее называемом F508del) и результаты оценки функции белка CFTR методом ОРКП и форсколиновым тестом на кишечных органоидах. In this article we continue to describe the pathogenic variants of the CFTR gene identified among Russian cystic fibrosis (CF) patients. For the first time the clinical and genetic characteristics of the mutation c.1083G> A (p.Trp361 *) are presented. The pathogenic genetic variant c.1083G> A (p.Trp361 *) of the CFTR gene belongs to the nonsense mutations (class I) and was listed for the first time in the CFTR1 database (http://www.genet.sickkids.on.ca) by Professor Milan Macek et al. in mid-2019 without any description of clinical manifestations of cystic fibrosis. Methods. The data of the National Register of Patients with Cystic Fibrosis of the Russian Federation 2017 were analyzed. Outpatient records and case histories of two patients from unrelated families carrying a rare genetic variant c.1083G> A (p.Trp361 *) were analyzed. To determine the Intestinal current measurement (ICM) and Forskolin-induced swelling (FIS) in intestinal organoids, rectal biopsy material of CF patients was used. DNA for sequencing was isolated from leukocytes of venous blood of the patients. Results. Variant c.1083G> A (p.Trp361 *) was found in two patients from unrelated families from different regions of the Russian Federation, according to the Register of Cystic Fibrosis Patients in the Russian Federation 2017. Analysis of clinical manifestations of the disease in children 6 and 9 years old showed the presence of chronic pancreatic insufficiency, more expressed in one child with a history of distal intestinal obstruction syndrome. The clinical manifestation of the second patient was characterized by the development of transient hyperbilirubinemia, Pseudo-Bartter’s syndrome at an early age, and subsequently repeated episodes of bronchial obstruction and the development of polypoid rhinosinusitis. The ICM method and the FIS in intestinal organoids showed that the genetic variant c.1083G> A (p.Trp361 *) refers to the variants of the CFTR gene with the absence of chlorine channel function. Conclusion. The clinical picture of cystic fibrosis in two patients from unrelated families with the pathogenic variant c.1083G> A (p.Trp361 *) in the compound with variant c.1521_1523delCTT (p.Phe508del) (variant legacy name F508del) and results of the evaluation of the CFTR protein functions, obtained by the method of ICM and using the FIS assay in intestinal organoids, are presented for the first time. Patients continue to be under the control in Russian CF centers.

THE ROLE OF CONNECTIVE TISSUE DYSPLASIA IN CHILDREN’S CYSTIC FIBROSIS. CLINICAL AND GENETIC ASPECTS

The article considers the issue of cystic fibrosis – a monogenic autosomal recessive disease. It describes the history of the CFTR gene discovery, the further search for modifier genes to explain the variability of the clinical manifestations of cystic fibrosis. The review discusses problems of connective tissue dysplasia and somatic pathology, which is formed due to the connective tissue dysmorphogenesis in patients with cystic fibrosis; and also the article contains justification for the connection between the formation of severe fibrosis of the lungs and liver and the presence of clinical and genetic markers of connective tissue dysplasia. The author assumes that the clinical and genetic polymorphisms of connective tissue influence the course of cystic fibrosis, formation of bronchiectasis, interstitial pneumofibrosis, cystic fibrosis dysplasia, liver fibrosis and cirrhosis.

GENOTYPE-PHENOTYPE CORRELATIONS OF THE COURSE OF CYSTIC FIBROSIS IN RUSSIAN CHILDREN. THE FIRST DESCRIPTION OF ELEVEN NEW MUTATIONS

Background. Cystic fibrosis is a hereditary disease that occurs as a result of mutations in the regulator gene of chloride ion transmembrane transport (CFTR). Finding mutations in the CFTR gene is necessary for identification of the clinical features of cystic fibrosis. Objective. Our aim was to identify genotype-phenotype correlations between mutations of the first class of pathogenicity and clinical manifestations of cystic fibrosis based on studying the prevalence and structure of CFTR gene mutations. Methods. The study included children under 18 years with cystic fibrosis admitted to hospital between 2013 and 2017. Biallelic mutations in the CFTR gene were the noninclusion criterion. The CFTR gene variants were analyzed by next-generation sequencing method. Results. In 125 patients with cystic fibrosis, 59 different variants of the CFTR gene were detected, 11 of them not previously described. The most common was the deletion c.1521_1523del found in 98 (39.2%) of the 250 analyzed CFTR gene alleles and the deletion c.1545_1546del found in 22/250 (8.8%) alleles. It has been shown that the mutation c.1545_1546del, p.Y515* was more often found in children of the Chechen nation — odds ratio (OR) 139 (95% confidence interval 15–1,257). It has been established that meconium ileus, pancreatic deficiency and cirrhosis are more common in patients with mutations of the first category of pathogenicity: OR 3.9 (95% CI 1.0–15.0), 4.4 (95% CI 1.8–11.1), and 351 (95% CI 17.5–7,046), respectively. The association of CFTR gene mutations with the development of bronchiectases and polypous pancinusitis has not been found. Conclusion . Correlations between the genotype and clinical manifestations of cystic fibrosis in Russian children with CFTR gene mutations of the first class of pathogenicity have been established.

Particle-Tracking Microrheology Using Micro-Optical Coherence Tomography

Clinical manifestations of cystic fibrosis (CF) result from an increase in the viscosity of the mucus secreted by epithelial cells that line the airways. Particle-tracking microrheology (PTM) is a widely accepted means of determining the viscoelastic properties of CF mucus, providing an improved understanding of this disease as well as an avenue to assess the efficacies of pharmacologic therapies aimed at decreasing mucus viscosity. Among its advantages, PTM allows the measurement of small volumes, which was recently utilized for an in situ study of CF mucus formed by airway cell cultures. Typically, particle tracks are obtained from fluorescence microscopy video images, although this limits one’s ability to distinguish particles by depth in a heterogeneous environment. Here, by performing PTM with high-resolution micro-optical coherence tomography (μOCT), we were able to characterize the viscoelastic properties of mucus, which enables simultaneous measurement of rheology with mucociliary transport parameters that we previously determined using μOCT. We obtained an accurate characterization of dextran solutions and observed a statistically significant difference in the viscosities of mucus secreted by normal and CF human airway cell cultures. We further characterized the effects of noise and imaging parameters on the sensitivity of μOCT-PTM by performing theoretical and numerical analyses, which show that our system can accurately quantify viscosities over the range that is characteristic of CF mucus. As a sensitive rheometry technique that requires very small fluid quantities, μOCT-PTM could also be generally applied to interrogate the viscosity of biological media such as blood or the vitreous humor of the eye in situ.

A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis

Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians but is rarer in the Chinese population, because mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To elucidate the causative role of a novel compound heterozygous mutation of CF. In this study, clinical samples were obtained from two siblings with recurrent airway infections, clubbed fingers, salt-sweat and failure to gain weight in a non-consanguineous Chinese family. Next-generation sequencing was performed on the 27 coding exons of CFTR in both children, with confirmation by Sanger sequencing. Next-generation sequencing showed the same compound heterozygous CFTR mutation (c.865A>T p.Arg289X and c.3651_3652insAAAT p.Tyr1219X) in both children. As this mutation is consistent with the clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that the CF phenotype is caused by compound heterozygosity for c.865A>T and c.3651_3652insAAAT. As c865A>T is not currently listed in the "Cystic Fibrosis Mutation Database", this information about CF in a Chinese population is of interest.

Standardization of Research-Quality Anthropometric Measurement of Infants and Implementation in a Multicenter Study.

Malnutrition is one of the earliest clinical manifestations of cystic fibrosis (CF) and is associated with poorer pulmonary and cognitive outcomes and survival later in life. Infant growth can be a responsive measure for clinical research in this age group if obtained and characterized accurately. We report here the methods to standardize and implement research-quality anthropometric measurement of infants with cystic fibrosis in the Baby Observational Nutrition Study multicenter trial.

The Cystic Fibrosis Intestine

The clinical manifestations of cystic fibrosis (CF) result from dysfunction of the cystic fibrosis transmembrane regulator protein (CFTR). The majority of people with CF have a limited life span as a consequence of CFTR dysfunction in the respiratory tract. However, CFTR dysfunction in the gastrointestinal (GI) tract occurs earlier in ontogeny and is present in all patients, regardless of genotype. The same pathophysiologic triad of obstruction, infection, and inflammation that causes disease in the airways also causes disease in the intestines. This article describes the effects of CFTR dysfunction on the intestinal tissues and the intraluminal environment. Mouse models of CF have greatly advanced our understanding of the GI manifestations of CF, which can be directly applied to understanding CF disease in humans.