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  1. Congenital lung defects BIO361.001 Group 9 Evan Kinney Charlee Pittman Mina Yegani

  2. Cystic Fibrosis Charlee Pittman

  3. Cystic Fibrosis • Cystic fibrosis is an inherited chronic disease of the mucus glands which can affect various body systems • Lungs and sinuses • Gastrointestinal tract • Liver • Pancreas • Endocrine system • Reproductive system • One of the most widespread and life-shortening genetic diseases

  4. The Genetics • Cystic fibrosis has been linked to a mutation in a single gene and its associative protein: Cystic Fibrosis Transmembrane Conductance Regulator, or CFTR • Involves a mutation on chromosome 7 of the CFTR gene • Inherited in an autosomal recessive pattern.

  5. The Genetics • A three base pair deletion known as ΔF508 is the most common mutation that causes cystic fibrosis. • It results in the deletion of a single amino acid (phenylalanine) at position 508.

  6. Five Types of CFTR Mutations Defective protein production Defective protein processing Defective protein regulation Defective protein conductance Reduced amounts of functioning CFTR protein

  7. The CFTR Gene • Provides the instructions necessary for making an active ion channel that transports negative chloride ions in and out of the cells • The flow of these ions helps to control the movement of water in various tissues which helps to produce thin and free-flowing mucus

  8. The CFTR Gene • Various mutations in the CFTR gene interrupt the functioning of the chloride channels, preventing them from regulating the chloride ion and water flow across cell membranes

  9. Mucus • Unregulated flow results in a multitude of cells lining the different passageways of the pancreas, lungs, and other organs • Contributes to the production of thick and sticky mucus

  10. Mucus • Causes chronic coughing, wheezing, and inflammation • Over an extended period of time, mucus buildup causes damage to the lungs and other organs • Formation of scar tissue (fibrosis) • Growth of cysts

  11. Symptoms • More frequent, greasy, and/or smelly bowel movements • Fleshy growths inside the nose (nasal polyps) • Enlarged or clubbed fingertips/toes • Fatigue • Salty tasting skin • Dehydration • Constant or nagging cough • May have blood streaking • Thick/viscous mucus in the lungs • Repeated infections (e.g. bronchitis, pneumonia, sinusitis) • Difficulty gaining weight • Abdominal pain • Flatulence • Asthma

  12. Diagnosis • Observation of symptoms • Genetic testing (defective chromosome 7) • Amniocentesis • Chorionic villus biopsy • Newborns can be tested with a simple blood test (trypsinogen) • Sweat test ([NaCl])

  13. Treatment • Currently no cure for cystic fibrosis • Treatment goals include: • Preventing and controlling infections in the lungs • Preventing intestinal blockages • Loosening and removal of mucus from the lungs • Providing adequate nutrition

  14. Treatment [Antibiotics] • Primary treatment • Helps to treat infections of the airways in the lungs • Antibiotic used will depend on • Different strains of bacteria present • Overall severity of the condition • Previous antibiotic use

  15. Treatment [Chest Therapy] • Also known as postural drainage • Chest and back are pounded continuously in order to dislodge the mucus from the lungs so that it can be coughed up • Typically done three to four times per day while sitting or laying prone with the head down

  16. Treatment [Chest Therapy] Demonstration of technique used to loosen mucus.

  17. Treatment [Exercise] • Helps to loosen the mucus in the lungs by inducing coughing • Improves overall physical health

  18. Treatment [Oxygen Supplementation]

  19. Treatment [Lung Transplantation] • Only performed in the most severe cases.

  20. Congenital Cystic Adenomatoid Malformation Evan Kinney

  21. Overview • Congenital disorder • Results in abnormal formation of lung tissue • Typically presents as complete lobe replacement • Cause currently unknown • Detection methods are mostly non-invasive • Outcomes typically good • Rarely requires surgery

  22. Origin and Diagnosis • Over-expression of localized fibroblast growth factors (e.g. FGF10) • Lung mesenchymal cells • 35-55 days gestation • Diagnosed through somnography or MRI • Maximum lesion size ~25-28 weeks gestation

  23. Classification • Stocker system • Type I • Most common • Multiple cysts > 2cm in diameter • Single large cyst surrounded by smaller cysts • Type II • 40% of cases • Multiple cysts < 1cm in diameter • Type III • 5% of cases • Multiple microcysts • Appears as solid mass

  24. Fig. 1 Stocker type I congenital adenomatoidmalformation.

  25. Fig. 2 Stocker type II congenital adenomatoidmalformation.

  26. Fig. 3 Stocker type III congenital adenomatoidmalformation.

  27. Treatment • Usually not necessary • Resolves in utero for most cases • Surgical intervention indicated for • Cardiomyopathies induced by cyst growth • Presence of hydrops • Radiography indicated post-natal even if lesion resolves itself • Can increase chance of developing comorbidities if left untreated

  28. Research [Origins] • 2008 study • Induced over-expression of FGF10 during both developmental stages of lung tissue in rats • Relationship between cyst formation and time/location of expression • Supports theory of FGF10 as inducer of CCAM in human models

  29. Fig. 4 FGF10 mesenchymal overexpression coincides with location of cystic malformations. Lungs from injected fetuses at E15.5 and E18.5 were analyzed by whole mount in situ hybridization (wISH) for fgf10, 24 hours after injection (E16.5, f–j, and E19.5, k–o, respectively). The macroscopic view (a, f, k) and fluorescence stereomicroscopy images for GFP (b, g, l) are depicted alongside the wISH images for comparison. FGF10 is overexpressed in the mesenchyme of the cystic area (h–j; m–o).

  30. Fig. 5 Quantitative PCR for FGF10 in lung. FGF10 expression of injected lungs at E15.5 was analyzed at E16.5, E18.5, and E21.5. Quantitative PCR was performed in PBS control, AdGFP-FGF10 injected, and contralateral lungs. Fgf10 mRNA levels were significantly higher at E16.5 in AdGFP-FGF10 ipsilateral lungs versus PBS and contra- lateral lungs. However, at E18.5 and E21.5 FGF10 expression was not significantly different among groups. Scale bars correspond to 50 mm for methacrylate sections of hybridized lungs.

  31. Research [Retrospective Analysis] • 1993 study • Vast majority of cases involved only one lobe • More common in males than females • Usually diagnosed before six month mark • Two abnormal cases • Abnormal radiological presentation; not discovered until third birthday • Stillborn infant; only probable case of bilateral CCAM • Patients not requiring surgical intervention had no significant clinical events (average 12 year followup)

  32. Fig. 6 Summary of reported cases of congenital cystic adenomatoidmalformation.

  33. References • Cystic Fibrosis Foundation [homepage on the Internet]. Bethesda (MD): Schaner & Lubitz, PLLC; 2010. [cited 2010 Nov. 12]. Available from: • Genetics Home Reference [homepage on the Internet]. Bethesda (MD): United States National Library of Medicine National Institutes of Health; 1993 Jan. 1. [cited 2010 Nov. 12]. Available from: • Koboldt D. The Genetics of Cystic Fibrosis [homepage on the Internet]. 2010. [cited 2010 Nov. 10]. Available from: • Cystic Fibrosis [homepage on the Internet]. Mayo Foundation for Medical Education and Research; 2010. [cited 2010 Nov. 13]. Available from: • [homepage on the Internet]. Ashland (OR): Web Ring Incorporated; 2007. [cited 2010 Nov. 13]. Available from: • Cloutier, M. M., D. A. Schaeffer, et al. (1993). "Congenital cystic adenomatoid malformation." Chest 103(3): 761-764. • Gonzaga, S., T. Henriques-Coelho, et al. (2008). "Cystic adenomatoid malformations are induced by localized FGF10 overexpression in fetal rat lung." American Journal of Respiratory Cell and Molecular Biology 39(3): 346-355. • Mathai, A., H. Kini, et al. (2010). "Congenital cystic adenomatoid malformation of lung type 1." Journal of Pediatric Surgery 45(2): E25-28. • Moore, L. and R. Handy (2009). "Congenital Cystic Adenomatoid Malformation : A Brief Review With Images." Journal of Diagnostic Medical Sonography 25(168): 168-172.

  34. Questions