复旦大学：《医学遗传学 Medical Genetics》课程教学资源（学习报告）Francesca_Liu_08301016039Literature_Review_on_Fibrosis_Otorhinolaryngologic_Manifestations.doc_大学文库

Literature Review on Fibrosis otorhinolaryngologic Manifestations Introduction The cystic fibrosis is a severe exocrinopathy that affects mainly Caucasian patients. It is the most lethal recessive autosomal disease that affects this population, and occurs in the frequency of 1 per each 2.000 to 2.500 bom alive in Europe. In the United States, approximately 30.000 people are affected, with the frequency of one gene per each 20 to 25 people. It's less frequent in African and Asian patients, and occurs in 1 per 15.300 and 1 per 32. 100, respectively Mutation The Cystic Fibrosis mutation was located in a gene found in chromosome 7(7q 31) that decodes the Cystic Fibrosis Transmembrane conductance Regulator(CF TR). This protein is the pump of chlorine depending on cyclic Adenosine-Mono Phosphate(AMPc), whose mutation leads to a failure on the thal ion transport There are more than 1.000 mutations identified, and the most common is the deletion of three pairs of bases that decodes the phenylalanine in position 508, kno wn as delta F508 or AF508 The CF TR mutation may be divided into five categories: First is the absence of CF TR production. Second is the production of CFTR, but failure in the intracellular processing and transport. Third is the normal intracellular transport, but deregulation in the cellular membrane. Fourth is the normal expression of the cellular membrane, but change in the chlorine conductance and the last is the diminished synthesis. The first 3 categories are associated with a more severe disease Clinical Manifestations Cystic Fibrosis can also be called mucoviscidosis, it is characterized by an abnomal mechanism of systemic ionic transport, which generates a diminished permeability to the chlorine, and causes recurrent pulmonary infections; chronic pulmonary obstructive disease; rhinosinusitis; nasosinusal polyposis: bad gastrointestinal absorption resulting from pancreatic dysfunction; spastic ileus of the newbom; retal prolapse and infertility for obstruction of the vas deferens In the respiratory epithelium, there is a failure in the chlorine secretion, which causes an excessive absorption of sodium, results in a higher water inflow to the cells and therefore increases the mucus viscosity The mucus becomes thicker than the normal by four-fold to six-fold It does not affect the mucociliary beating directly, but it becomes inefficient in the clearance of such a viscous substance and generates stasis, that allows the ostia obstruction and increase of bacterial colonization, resulting to a recurring infection in the respiratory lining. On the other hand, in the sweat glands epithelium, it leads to low absorption of chlorine and sodium of the glandular lumen, which results in sweating with a strong concentration of these The most frequent otorhinolaryngological manifestations are chronic rhinosinusitis and nasosinusal polyposis It is 100% present among Cystic Fibrosis patients in the paranasal sinuses. The symptoms include nasal obstruction, rhinorrhea, cough, headache, and facial pain. Although with repetition infection of the pulmonary disease is the 1st Cystic Fibrosis manifestation in 40% of the patients Diagnosis The Cystic Fibrosis diagnosis is made in the presence of one or more of the aforesaid clinical manifestations associated with the presence of two gene mutations of the cystic Fibrosis or two positive results in the sweat test, (up to 30 mmol/L it's nomal, from 30 to 60 mmol/L it's dubious and above 60 it's altered), or change in the nasal potential difference According to the level of the mutation found in the patients there are several phenotypes of the disease. The classical one includes pancreatic and sweating glands dysfunction(exocrine dysfunction), respiratory tract disease and vas deferens malformation(males). These patients normally have their diagnosis in the first six

Literature Review on Fibrosis Otorhinolaryngologic Manifestations Introduction The cystic fibrosis is a severe exocrinopathy that affects mainly Caucasian patients. It is the most lethal recessive autosomal disease that affects this population, and occurs in the frequency of 1 per each 2.000 to 2.500 born alive in Europe. In the United States, approximately 30.000 people are affected, with the frequency of one gene per each 20 to 25 people. It's less frequent in African and Asian patients, and occurs in 1 per 15.300 and 1 per 32.100, respectively. Mutation The Cystic Fibrosis mutation was located in a gene found in chromosome 7 (7q31) that decodes the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). This protein is the pump of chlorine depending on cyclic Adenosine-MonoPhosphate (AMPc), whose mutation leads to a failure on the thal ion transport. There are more than 1.000 mutations identified, and the most common is the deletion of three pairs of bases that decodes the phenylalanine in position 508, known as delta F508 or ΔF508. The CFTR mutation may be divided into five categories: First is the absence of CFTR production. Second is the production of CFTR, but failure in the intracellular processing and transport. Third is the normal intracellular transport, but deregulation in the cellular membrane. Fourth is the normal expression of the cellular membrane, but change in the chlorine conductance and the last is the diminished synthesis. The first 3 categories are associated with a more severe disease. Clinical Manifestations Cystic Fibrosis can also be called mucoviscidosis, it is characterized by an abnormal mechanism of systemic ionic transport, which generates a diminished permeability to the chlorine, and causes recurrent pulmonary infections; chronic pulmonary obstructive disease; rhinosinusitis; nasosinusal polyposis; bad gastrointestinal absorption resulting from pancreatic dysfunction; spastic ileus of the newborn; retal prolapse and infertility for obstruction of the vas deferens. In the respiratory epithelium, there is a failure in the chlorine secretion, which causes an excessive absorption of sodium, results in a higher water inflow to the cells and therefore increases the mucus viscosity. The mucus becomes thicker than the normal by four-fold to six-fold. It does not affect the mucociliary beating directly, but it becomes inefficient in the clearance of such a viscous substance and generates stasis, that allows the ostia obstruction and increase of bacterial colonization, resulting to a recurring infection in the respiratory lining. On the other hand, in the sweat glands epithelium, it leads to low absorption of chlorine and sodium of the glandular lumen, which results in sweating with a strong concentration of these. The most frequent otorhinolaryngological manifestations are chronic rhinosinusitis and nasosinusal polyposis. It is 100% present among Cystic Fibrosis patients in the paranasal sinuses. The symptoms include nasal obstruction, rhinorrhea, cough, headache, and facial pain. Although with repetition infection of the pulmonary disease is the 1st Cystic Fibrosis manifestation in 40% of the patients. Diagnosis The Cystic Fibrosis diagnosis is made in the presence of one or more of the aforesaid clinical manifestations, associated with the presence of two gene mutations of the Cystic Fibrosis or two positive results in the sweat test, (up to 30 mmol/L it's normal, from 30 to 60 mmol/L it's dubious and above 60 it's altered), or change in the nasal potential difference. According to the level of the mutation found in the patients there are several phenotypes of the disease. The classical one includes pancreatic and sweating glands dysfunction (exocrine dysfunction), respiratory tract disease and vas deferens malformation (males). These patients normally have their diagnosis in the first six

months of life and some of the diagnosis criteria, are as follows: the sweat test, may fail in certain patients which makes their identification difficult and may be taken for granted in the childhood There is also the presence of patient s cariers of Cystic Fibrosis Transmembrane conductance gene mutation, who present with a higher proneness to the chronic sinusitis, recurrent pancreatitis or vas deferens obstruction without other features of the disease, which may conf use the diagnosis. However, it cannot fully determine how severe patients Cystic Fibrosis will be in the future Treatment The objective of the treatment is to reduce the patient s symptoms through the re-establishing of nasosinusal ventilation and draining to control infections, eliminate the pulmonary infection reservoir and improve the patients nutritional state. Despite the use of medications or even surgery, the patients with Cystic Fibrosis are not cured. Basically treating patients with Cystic Fibrosis means to improve the quality of life, not suffering from recurring infections. Hence, various treatments and therapy are done cautiously to the people suffering with Cystic Fibrosis, such are the nasal treatment consists of washing with saline solution, intranasal corticosteroids antimicrobial therapy and Functional Endoscopic Sinus Surgery(FESS). Another treatment is the saline olution is aimed at liquidifying the secretion and providing nasal hygiene. It may be used in isotonic or hypertonic imigations with the advantage of decongesting the nose The antibiotics are the most important medications in the Cystic Fibrosis treatment. They must cover quinolone antibiotics, despite these are not released for children by the FDA. other antibiotics used ap and Pseudomonas, Staphylococcus, as well as the anaerobe germs. The mostly used are the aminosidine piperacillin, ceftazidime and imipenem. Moreover, there are a lot of risks on undertaking the surgery since the patients situation isn't stable because of their advanced pulmonary disorder, extensive sinusal disease, anatomic changes caused by prior surgeries, coagulopathy for vitamin K deficiency, pancreatic and hepatic diseases, as well as nutritional deficiency. In spite of rigorous treatment, the recurrence is a rule and the average of free time from symptoms ranges from 1 to 4 years Final Consideration Despite otorhinolaryngological manifestations arent the main cause of death in the Cystic Fibrosis patients however, it does bring a significant morbidity. With the extensive research going on for decades, the life expectancy of Cystic Fibrosis patients has increased dramatically especially when the antibiotic therapy and improvement of surgical techniques was administered to the patients. As per today there is no exact cure for Cystic Fibrosis

months of life and some of the diagnosis criteria, are as follows: the sweat test, may fail in certain patients, which makes their identification difficult and may be taken for granted in the childhood. There is also the presence of patient’s carriers of Cystic Fibrosis Transmembrane conductance gene mutation, who present with a higher proneness to the chronic sinusitis, recurrent pancreatitis or vas deferens obstruction without other features of the disease, which may confuse the diagnosis. However, it cannot fully determine how severe patients Cystic Fibrosis will be in the future. Treatment The objective of the treatment is to reduce the patient's symptoms through the re-establishing of nasosinusal ventilation and draining, to control infections, eliminate the pulmonary infection reservoir and improve the patient's nutritional state. Despite the use of medications or even surgery, the patients with Cystic Fibrosis are not cured. Basically treating patients with Cystic Fibrosis means to improve the quality of life, not suffering from recurring infections. Hence, various treatments and therapy are done cautiously to the people suffering with Cystic Fibrosis, such are the nasal treatment consists of washing with saline solution, intranasal corticosteroids, antimicrobial therapy and Functional Endoscopic Sinus Surgery (FESS). Another treatment is the saline solution is aimed at liquidifying the secretion and providing nasal hygiene. It may be used in isotonic or hypertonic irrigations with the advantage of decongesting the nose. The antibiotics are the most important medications in the Cystic Fibrosis treatment. They must cover Pseudomonas, Staphylococcus, as well as the anaerobe germs. The mostly used are the aminosidine and quinolone antibiotics, despite these are not released for children by the FDA. Other antibiotics used are piperacillin, ceftazidime and imipenem. Moreover, there are a lot of risks on undertaking the surgery since the patients situation isn’t stable because of their advanced pulmonary disorder, extensive sinusal disease, anatomic changes caused by prior surgeries, coagulopathy for vitamin K deficiency, pancreatic and hepatic diseases, as well as nutritional deficiency. In spite of rigorous treatment, the recurrence is a rule and the average of free time from symptoms ranges from 1 to 4 years. Final Considerations Despite otorhinolaryngological manifestations aren’t the main cause of death in the Cystic Fibrosis patients, however, it does bring a significant morbidity. With the extensive research going on for decades, the life expectancy of Cystic Fibrosis patients has increased dramatically especially when the antibiotic therapy and improvement of surgical techniques was administered to the patients. As per today, there is no exact cure for Cystic Fibrosis