Cystic fibrosis

Cystic fibrosis (CF) is an inherited condition that typically presents in early childhood and worsens over time, with increasing damage to the lungs and digestive system. Milder forms of the condition may not present until later in childhood or even into adulthood. Although life expectancy is reduced, with around half of individuals currently living beyond the age of 40, affected individuals who are being born now are likely to live longer than this.

Clinical features of CF include:

• Respiratory symptoms:
  • persistent productive cough with thick mucus;
  • wheeze;
  • recurrent lung infections leading to bronchiectasis;
  • haemoptysis;
  • sinusitis;
  • nasal polyps; and
  • reduced exercise tolerance.
• Gastrointestinal symptoms:
  • meconium ileus in neonates (presenting as bowel obstruction);
  • echogenic bowel observed in the prenatal period;
  • foul-smelling, greasy stools;
  • diarrhoea and/or constipation;
  • difficulty in gaining weight and poor growth;
  • diabetes;
  • liver disease;
  • intestinal obstruction; and
  • rectal prolapse.
• Reproductive symptoms:
  • missing or blocked vas deferens causes infertility for most men; and
  • women may have reduced fertility, while pregnancy can worsen disease progression.

CF is caused by pathogenic variants in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There are many different pathogenic variants in the CFTR gene: some are common (such as delta F508), some are rare, some result in severe disease and some result in a milder presentation.

In the UK, most new diagnoses of CF are made through the newborn blood spot test (previously called the heel prick test) which includes the analysis of immunoreactive trypsinogen (IRT). If IRT levels are above a set cut-off point, genomic testing for up to 100 known common variants in the CFTR gene is conducted.

Though this testing approach is generally effective, occasionally cases are missed. Milder presentations involving rare variants are more likely to be missed; errors at clinical, laboratory or administrative levels are also possible. It is important to consider the diagnosis of CF in children born outside the UK in countries where newborn screening is not offered.

For information about testing, see Presentation: Clinical suspicion of cystic fibrosis.

This condition may be identified before any symptoms appear – for example, through the Generation Study. Confirmation of the diagnosis will require referral to clinical genetics services. Please refer to your regional pathway.

CF is an autosomal recessive condition.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected.
  • 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

The parents of most affected individuals are carriers for the condition and therefore have a 25% (one-in-four) chance of having an affected child in each subsequent pregnancy.

Unaffected siblings and other close relatives have a high chance of being carriers. As around 1 in 25 people with European ancestry are carriers of a CF variant (it is lower in other ethnic groups, but still present), there is a small but significant chance that the partner of a carrier may also be a carrier themselves. Siblings and close relatives should therefore be offered the opportunity to have genomic counselling and testing at an appropriate age to inform their own reproductive choices.

Where both partners are known to be carriers for cystic fibrosis, options may include preimplantation genetic testing and non-invasive prenatal diagnosis.

For more information about carrier testing and reproductive options for known carriers, see:

• Presentation: Pregnancy at risk of cystic fibrosis
• Presentation: Patient in early pregnancy with a family history of cystic fibrosis

Management of children with CF is complex and should be delivered via a multidisciplinary team. NICE guidelines are available.

Although there is, to date, no definitive cure for CF, there are many approved treatments and a wealth of research and clinical trials. A comprehensive overview of clinical trials in CFTR modulator therapies is available.

This condition may be identified before any symptoms appear, for example through the Generation Study. Therefore, management of these individuals may differ from those presenting symptomatically.

The Cystic Fibrosis Foundation provides useful documents for health professionals, including clinical guidelines, research pipelines and details of clinical trials. For more resources, see below.

For clinicians

• Cystic Fibrosis Foundation: For medical professionals
• National Organization for Rare Disorders: Cystic fibrosis
• NICE: Guidelines for the diagnosis and management of cystic fibrosis
• UpToDate: Cystic fibrosis: Genetics and pathogenesis
• NHS England: National Genomic Test Directory
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• ClinicalTrials.gov

For patients

• British Lung Foundation: Cystic fibrosis
• Cystic Fibrosis Foundation
• Cystic Fibrosis Trust