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Genetic aspects of cystic fibrosis

Cystic fibrosis (or cystic fibrosis of the pancreas) is an autosomic recessive hereditary genetic disease : only those subjects who have inherited two mutations – one from the father, the other from the mother – are affected.

The gene responsible for the disease, called the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene was identified in 1989 ; it is located on the long arm of chromosome 7 (7q31) and codes for the CFTR protein intervening in the regulation of chloride ions in the cell membrane. More than 2000 mutations have been identified to date, among which the most frequent (found in approximately 80% of cystic fibrosis patients in France) is the F508del mutation.

Screening for cystic fibrosis

Symptoms and sweat test

Before setting up systematic neonatal screening, the diagnosis was most often made after a more or less lengthy period of diagnostic meandering, with clinical signs (meconium ileus, fatty diarrhea, recurrent congestion and/or infections of the respiratory tract) and confirmed by a positive sweat test revealing a high rate of chloride ions in the sweat. This was completed by the molecular analysis of the CFTR gene and the search for the mutations involved.

Systematic neonatal screening

Since 2002, systematic neonatal screening has been extended to all of metropolitan France as well as the overseas territories. The Health Ministry has given the responsibility of screening to the French Association for Screening and Prevention of Childhood Disabilities (Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant, AFDPHE). The screening algorithm calls for a blood test for immunoreactive trypsin (IRT) and the search for the most frequent CFTR mutations (30 then 29 since 01/01/2015). IRT is a protein whose presence is more abundant in cases of pancreatic abnormalities during fetal life and the first months of life. Testing for IRT identifies up to 95% of newborns with cystic fibrosis; however, the insufficient specificity of the IRT test (which also selects children who do not have cystic fibrosis) explains the need for combining this test with molecular analysis.

After a search for the main CFTR mutations, three specific cases can arise :

  • two mutations are identified. The newborn and his or her parents are called into a cystic fibrosis resource and skills center (CRCM) for confirmation of the diagnosis based on the clinical assessment and a positive sweat test, and also to set up treatment and follow-up.
  • a single mutation is identified (the risk of a second mutation not being identified is approximately 10%). The sweat test should be done in a specialized center. If the test is positive, the child is managed in the same way as the above-mentioned group. If the test turns out to be negative, information on the newborn’s heterozygosis will be given to the parents during a genetic counseling consultation.
  • no mutation is found and the ITR is very high, the ITR will be rechecked toward 21 days of life with a dried blood spot test on filter paper. Persistence of high ITR at D21 will lead to a consultation in a specialized center for complementary assessment (sweat test). A sweat test whose result is suspect (intermediary) should be repeated.

If the genetic study is not done (absence of parental consent on the back of a Guthrie filter paper) and if the IRT is above the threshold value, the IRT will be rechecked toward 21 days of life with a dried blood spot on filter paper blotter if high IRT persists, which will lead to a consultation in a specialized center for complementary assessment (sweat test).

Disease manifestations and cystic fibrosis treatments

Cystic fibrosis manifests in a variety of ways

The CFTR protein dysfunction is mainly expressed in the respiratory tract, the digestive tube, liver, sweat glands, and the genital tract. From one patient to another, great diversity of clinical expression is observed, in terms of age at onset of the first symptoms as for the severity of disease progression. The severity of the respiratory involvement conditions the vital prognosis in the majority of cases.

Treat the symptoms... and one day the causes of cystic fibrosis

The symptomatic treatments – highly burdensome – are essentially based on respiratory treatment (physical therapy, inhaled treatments, antibiotic therapy, oxygen therapy), and digestive and nutritional treatment (pancreatic extracts and diet). Lung transplantation is the last resort treatment in a serious respiratory failure situation. Over the past several years, “new therapies” targeting the dysfunctions related to certain CFTR mutations (modulator or corrector treatments) aim for the disease’s causal mechanism. Patient education is an integral part of the multidisciplinary management.

Source: French CF Patient Registry

In practice

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Filière MUCO-CFTR - Hôpital Femme – Mère – Enfant - 59 Boulevard Pinel

69677 Bron Cedex - FRANCE - Tél : 04 27 85 62 57