Cystic fibrosis (CF) is the commonest recessive genetic disorder in white populations of European origin. It causes a molecular defect in a cellular membrane chloride channel which leads to the production of excessively thick mucus in many body systems. The sweat is considerably saltier than normal (>60 mmol/L). There is no cure, but effective treatment can greatly improve the quality and length of life.

Genetics

CF is caused by a gene defect in the CF transmembrane regulator (CFTR) gene on chromosome 7. Over 1000 different mutations have been identified but 75% are due to a mutation known as ΔF508. The inheritance is autosomal recessive (see Chapter 8). To be affected by CF, children must inherit an abnormal CFTR gene from each parent. These may be two copies of the same mutation (homozygous) or two different CF-causing mutations (compound heterozygous). Carriers are unaffected. Some mutations may result in an atypical presentation and progression of the disease.

The abnormal CFTR channel in the cell membrane leads to production of excessively viscid secretions in the body. This leads to obstruction of the small and large airways and recurrent infection. Abnormal sweat gland function leads to excessive sodium and chloride in sweat, which can be measured to confirm the diagnosis. There is usually pancreatic exocrine failure and in males absence of the vas deferens leading to infertility.

Presentation

Children with CF may be diagnosed by screening soon after birth, or antenatally in affected families. 1 in 10 present with meconium ileus (obstruction due to viscid meconium in the newborn bowel). Others will have failure to thrive and malabsorption from infancy or may present with recurrent chest infections. Atypical cases may present much later.

Common problems and their management

Chest infections

Thick viscid mucus causes obstruction and predisposes to lung infection. Children may develop chronic respiratory infection, especially when colonized with Pseudomonas aeruginosa or Burkholderia cepacia. Infection with these bacteria can lead to a rapid deterioration in lung function, and cross-infection to other people with CF must be avoided (e.g. by avoiding mixing individuals with CF in the same clinic). Treatment may involve regular bronchodilators, antibiotics (oral, nebulized or intravenously, which can be delivered at home via an indwelling central line). Steroid therapy may be needed to suppress lung inflammation. Nebulized DNAse enzymes can help break down mucus in the lung.

Preventive physiotherapy includes regular airway clearance by a variety of techniques including exercise, autogenic drainage, positive expiratory pressure, inhalation therapy and postural awareness. Prophylactic immunization against influenza and pneumococcus is recommended.

Malabsorption

Pancreatic failure means that fatty food cannot be broken down easily and causes steatorrhoea. This can lead to malnutrition and deficiency of fat-soluble vitamins (A, D, E, K). Taking pancreatic enzyme capsules with food can help with fat absorption and should be started even in babies. High-calorie diets may be required as children with CF have high metabolic demands. Fat-soluble vitamin supplements and advice from a specialist dietician are recommended.

Diabetes melitus

25% will develop impaired glucose tolerance. Optimization of blood glucose is associated with an improvement in lung function.

Salt loss

Salt supplementation may be required to replace sweat losses. This must be carefully monitored, especially in infancy where excessive salt intake can be dangerous.

Liver disease

Sluggish bile flow may cause biliary disease and rarely cirrhosis. Ursodeoxycholic acid can help. Children with CF may develop ‘pseudo-obstruction’ of the bowel which can easily be mistaken for appendicitis but usually responds to adjustment of pancreatic enzyme replacement or osmotic laxatives and does not require surgery.

Subfertility

Most men with cystic fibrosis have absence of the vas deferens leading to infertility. Assisted conception techniques can help. Women may be subfertile but most women with CF can achieve conception. Carrier testing of partners should be considered. Antenatal diagnosis of CF is possible via chorionic villus biopsy or amniocentesis.

Diagnosis

• Newborns: may be diagnosed by newborn bloodspot screening (see Chapter 8). Immunoreactive trypsin levels are elevated in affected babies. There is a better prognosis if CF can be diagnosed before it causes symptoms.
  
• Gene testing: Children presenting with a typical history or detected by screening should be diagnosed by mutation analysis of the CFTR gene. A panel of mutations are assessed but these routinely include only 30 of over 1000 mutations. Non-white families may have unusual variants which can be missed.
  
• Sweat test: This is the diagnostic test for CF and requires measuring sodium and chloride concentration in sweat, collected by passing a small electric current across the skin.

Prognosis

There is presently no cure for CF. The prognosis has improved enormously in the last 25 years with aggressive nutritional and respiratory support, and more than half of affected children live beyond the age of 38 years. Lung function tests (e.g. FEV₁) are the best measure of disease progression. Lung or heart–lung transplantation is offered to those with end-stage respiratory disease. Some individuals have survived 15 years following transplantation.