Inherited respiratory disease

Question 1

Cystic fibrosis

Answer 1

Description:

• autosomal recessive disease
• caused by defective variants in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a complex chloride channel and regulatory protein found in all exocrine tissues
• Deranged transport of chloride and/or other CFTR-affected ions, such as sodium and bicarbonate –> leads to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract, and to increased salt content in sweat gland secretions

Clinical features:

Multiple organ system involvement (pancreas, upper and lower respiratory tract, and male reproductive tract)

• Respiratory manifestations: persistent pulmonary infection, productive cough, hyperinflation of the lung fields on chest radiograph, and pulmonary function tests that are consistent with obstructive airway disease inc chronic bronchitis and bronchiectasis. Finger clubbing present.
• sinus disease: Nasal polyposis is seen in 10-32 % of patients, chronic nasal congestion, headaches, cough caused by chronic postnasal drip, and sleep disturbance
• pancreatic disease: pancreatic insufficiency (present in 2/3 of CF patients) leading to fat (and ADEK vitamins) malabsorption (steatorrhoea) and protein malabsorption (failure to thrive). Risk of recurrent pancreatitis (seen in 10% of CF patients).
• CF-related diabetes: due to exocrine pancreas insufficiency, glucose intolerance
• infertility: >95% males with CF are infertile. This is commonly due to blockage or absence of the sperm canal, known as congenital bilateral absence of the vas deferens (CBAVD). This congenital defect results in the absence of the anatomic ducts through which spermatozoa pass from the testes to the urethra. No spermatozoa are found in the semen, a condition referred to as obstructive azoospermia. This occurs esp when two CFTR gene variants are present). Spermatogenesis is not affected.
• Bowel obstruction (distal intestinal obstructive syndrome or DIOS)
• Focal biliary cirrhosis caused by thickened bile is present in many patients. Lead to hepatomegaly, high ALP, cholelithiasis
• reduced bone mineral content and increased rates of fractures and kyphoscoliosis. Due to malabsorption of vitamin D, poor nutritional status, physical activity, glucocorticoid therapy, and delayed pubertal maturation or hypogonadism.
• Nephrolithiasis and nephrocalcinosis are common in patients with CF
• Aquagenic wrinkling of the palms (wrinkling and nodules that develop after several minutes of immersion in water
• recurrent venous thrombosis, probably in part due to the frequent need for a central venous catheter (CVC)

Acute exaccerbation:

• cough, tachypnea, dyspnea, increased sputum production, malaise, anorexia, and weight loss.
• Transient airway infection with pathogenic bacteria inc Staphylococcus aureus, gram-negative bacteria, H. influenzae, pseudomonas aeruginosa. Other microbes inc Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia complex, nontuberculous mycobacteria (especially Mycobacterium avium complex and Mycobacterium abscessus), and the filamentous fungus Aspergillus fumigatus

Diagnosis:

BOTH of the following criteria must be met to diagnose cystic fibrosis (CF)

●Clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or genetic testing for siblings of patients with CF

AND

●Evidence of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction (any of the following):

• Elevated sweat chloride ≥60 mmol/L
• Presence of two disease-causing variants in CFTR, one from each parental allele
• Abnormal nasal potential difference

Other features:

• anaemic, iron deficient, vit D deficient

Management:

• Microsurgical epididymal sperm aspiration and intracytoplasmic sperm injection can permit affected men to become biologic fathers
• Careful genetic counseling is essential for prospective parents with CF since all offspring of such individuals will be carriers of CF variants and the risk of children affected with CF is high.