Newborn screening programmes for cystic fibrosis

doi:10.1016/S1526-0542(03)00093-9

Paediatric Respiratory Reviews

Volume 4, Issue 4, December 2003, Pages 299-305

https://doi.org/10.1016/S1526-0542(03)00093-9 Get rights and content

Abstract

We review the current situation with respect to newborn cystic fibrosis screening (NCFS) across the world. The challenges of establishing an NCFS programme are reflected in the diversity of those programmes identified. All employ an initial immunoreactive trypsinogen (IRT) measurement during the first week of life. If this is positive, a second IRT analysis at 4 weeks of age improves the specificity of the test; most programmes have, however, moved to DNA analysis at this point, which improves their sensitivity. Incorporating DNA analysis results in the identification of carriers, which may have implications for families but is generally considered positive. Some programmes have incorporated a second IRT test as well as DNA analysis, either to increase the sensitivity of the test in an area with a low ΔF508 frequency or to reduce the number of infants requiring a sweat test. Whichever algorithm is selected, the implementation of a successful programme relies on clear pathways and good information for parents.

Section snippets

NEWBORN SCREENING FOR CYSTIC FIBROSIS: LESSONS FROM AROUND THE WORLD

Newborn screening tests have been available for cystic fibrosis (CF) for over three decades but few national programmes exist, most being based at a regional or local level. Reasons for this include uncertainty over the long-term benefits of implementing newborn CF screening (NCFS) and the lack of a definitive test.¹ Evidence of long-term benefit is now stronger and developments in DNA analysis have meant that a screening test with sufficient sensitivity and specificity is available when this

INTERNATIONAL EXPERIENCE

To the best of our knowledge, the following section reflects the current state of NCFS around the world. We would value any further information on local screening programmes or discrepancies compared with the information provided.

IMPLICATIONS FOR NEWBORN SCREENING

The varied state of NCFS across the world reflects the challenge of establishing such programmes. At the heart of most established schemes lies an enthusiastic team (or occasionally an individual) that has driven forward the programme, often from a CF perspective rather than a public health background. More so than other newborn screening programmes, CF screening results in the involvement of families in second-phase tests or sweat tests to exclude CF. In addition, protocols that involve DNA

PRACTICAL ISSUES FOR IMPLEMENTATION

In contrast to programmes for other newborn conditions, such as phenylketonuria, screening for CF requires the concerted efforts of a number of laboratory and clinical specialities. For a NCFS programme to be successful, it needs not only to recognise CF infants at an asymptomatic stage but also do no harm and to cause minimal distress to families. The nature of both the condition and the screening tests available means there is plenty of scope for causing distress. To reduce this, the

Acknowledgements

The authors thank all those who have provided information on the state of neonatal CF screening in their countries.

References (56)

B Wilcken et al.
Reduced morbidity in patients with cystic fibrosis detected by neonatal screening
Lancet
(1985)
R.J Massie et al.
Pancreatic function and extended mutation analysis in DF508 heterozygote infants with elevated immunoreactive trypsinogen but normal sweat electrolyte levels
J. Pediatr.
(2000)
B Wilcken et al.
Neonatal screening for cystic fibrosis: a comparison of two strategies for case detection in 1.2 million babies
J. Pediatr.
(1995)
J.L Dhondt et al.
Results of pilot screening in the French neonatal screening programme; cystic fibrosis, congenital adrenal hyperplasia and sickle cell disease
Screening
(1993)
V Scotet et al.
Neonatal screening for cystic fibrosis in Brittany, France: assessment of 10 years’ experience and impact on prenatal diagnosis
Lancet
(2000)
D Siret et al.
Does neonatal screening of cystic fibrosis affect outcome? Comparative study of two cohorts in Brittany and Loire-Atlantique with follow-up after ten years
Arch. Pediatr.
(2000)
G Mastella et al.
Neonatal screening for cystic fibrosis: long-term clinical balance
Pancreatology
(2001)
J.R Crossley et al.
Neonatal screening for cystic fibrosis using immunoreactive trypsin in dried blood spots
Clin. Chim. Acta
(1981)
J.J Telleria Orriols et al.
Neonatal screening for cystic fibrosis
An Esp. Pediatr.
(2002)
J Murray et al.
Screening for cystic fibrosis
Health Technol. Assess.
(1999)

P.M Farrell et al.

Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Wisconsin Cystic Fibrosis Neonatal Screening Study Group

Pediatrics

(2001)

Wilcken B. Neonatal screening for cystic fibrosis – current issues. In: Travert G, Wursteisen B (eds) Neonatal...

E Ranieri et al.

Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years’ experience

BMJ

(1994)

F Bowling et al.

Neonatal screening for cystic fibrosis

Arch. Dis. Child

(1988)

R.J Massie et al.

Newborn screening for cystic fibrosis in Victoria: 10 years’ experience (1989–1998)

Med. J. Austr.

(2000)

D.L Waters et al.

Arch. Dis. Child

(1999)

J Massie et al.

Sweat testing following newborn screening for cystic fibrosis

Pediatr. Pulmonol.

(2000)

J Larsen et al.

Cystic fibrosis screening in neonates measurement of immunoreactive trypsin and direct genotype analysis for DF508 mutation

Eur. J. Pediatr.

(1994)

O.A Bodamer

Neonatal screening in Austria. Current situation, new developments and future perspectives

Pädiatr. Prax.

(2002)

Eyskens F, Coles B. Neonatal screening for cystic fibrosis (CF): the experience in the province of Antwerp, Belgium....

B Norgaard-Pedersen et al.

Screening of newborn infants for cystic fibrosis. A combined analysis of immunoreactive trypsin and delta F508 mutation; a screening without false positive results [in Danish]

Ugeskr. Laeger

(1994)

Norgaard-Pedersen B. Neonatal or carrier screening for cystic fibrosis in Denmark. In: Travert G, Wursteisen B (eds)...

T Klaassen et al.

Neonatal screening for the cystic fibrosis main mutation delta F508 in Estonia

J. Med. Screen

(1998)

C Ferec et al.

Neonatal screening for cystic fibrosis – results of a pilot study using both immunoreactive trypsin and cystic-fibrosis gene mutation analysis

Hum. Genet.

(1995)

U Stephan et al.

Cystic fibrosis detected by means of a test strip

Pediatrics

(1975)

P Wunderlich et al.

Mucoviscidosis screening of newborn infants in the Dresden district. Results from 1 June 1996 to 31 March 2000 [in German]

Dtsch. Med. Wochenschr.

(2000)

B.M Assael et al.

Epidemiology and survival analysis of cystic fibrosis in an area of intense neonatal screening over 30 years

Am. J. Epidemiol.

(2002)

C Castellani et al.

Newborn screening strategy for cystic fibrosis: a field study in an area with high allelic heterogeneity

Acta Paediatr.

(1997)

Cited by (22)

Cystic fibrosis
2021, The Lancet
Citation Excerpt :
Sweat testing,30 done in an accredited clinical laboratory, remains the gold standard test of CFTR function: chloride concentrations of more than 60 mmol/L are diagnostic; concentrations between 30–59 mmol/L are in the intermediate range; and concentrations less than 30 mmol/L are considered normal. Several newborn screening strategies are in use, most of which use an initial biochemical screen (commonly immunoreactive trypsinogen measurement from dried blood spot) followed by genetic testing or sweat chloride testing, or both.31 The selection of CFTR mutations included in newborn screening panels is based on local population prevalence, in general, seeking to detect as many patients with cystic fibrosis as possible while trying to minimise false positives.
Cystic fibrosis is a monogenic disease considered to affect at least 100 000 people worldwide. Mutations in CFTR, the gene encoding the epithelial ion channel that normally transports chloride and bicarbonate, lead to impaired mucus hydration and clearance. Classical cystic fibrosis is thus characterised by chronic pulmonary infection and inflammation, pancreatic exocrine insufficiency, male infertility, and might include several comorbidities such as cystic fibrosis-related diabetes or cystic fibrosis liver disease. This autosomal recessive disease is diagnosed in many regions following newborn screening, whereas in other regions, diagnosis is based on a group of recognised multiorgan clinical manifestations, raised sweat chloride concentrations, or CFTR mutations. Disease that is less easily diagnosed, and in some cases affecting only one organ, can be seen in the context of gene variants leading to residual protein function. Management strategies, including augmenting mucociliary clearance and aggressively treating infections, have gradually improved life expectancy for people with cystic fibrosis. However, restoration of CFTR function via new small molecule modulator drugs is transforming the disease for many patients. Clinical trial pipelines are actively exploring many other approaches, which will be increasingly needed as survival improves and as the population of adults with cystic fibrosis increases. Here, we present the current understanding of CFTR mutations, protein function, and disease pathophysiology, consider strengths and limitations of current management strategies, and look to the future of multidisciplinary care for those with cystic fibrosis.
Infertility Management in Men with Cystic Fibrosis
2009, Journal of Reproduction and Contraception
Cystic fibrosis (CF) is a multisystem autosomal recessive disorder. CF has a reported incidence of 1 in 2 500 and a carrier frequency of 1 in 25. It is caused by mutations in a gene located on the long arm of chromosome 7. With almost 50% of patients with CF now in the adult population, and a very high interest in future parenting (78% of men wanting children), there is an increasing need to be proactive in terms of advice about reproductive health. Discussion on reproduction should start in early adolescence and be regularly updated by medical staff. The recent advances in reproductive techniques have allowed the development of sperm aspiration coupled with intra-cytoplasmic sperm injection (ICSI). Spermatozoa can be retrieved from either the epididymis or the testes. Genetic counselling is strongly recommended for both partners when congenital bilateral aplasia of vas deferens (CBAVD) is diagnosed as there is the inevitability of transmitting a mutated CFTR gene, and an increased risk of producing an affected child with serious long-term implications. Most treatment centres, with the introduction of ICSI, routinely screen all males with azoospermia caused by obstruction (other than that caused by vasectomy) or germ cell failure. Protocols usually involve screening for 28 relatively common CFTR mutations. Further advanced testing may be necessary up to a final detection level of approximately 98.5%. Before considering any assisted reproduction treatment, it is pertinent that CF patients receive medical and psychological counselling.
Neonatal screening of cystic fibrosis in France and in the world. Organization, advantages and difficulties. 2007 Update
2007, Journal de Pediatrie et de Puericulture
Cela fait plus de 40 ans que le dépistage de la mucoviscidose en période néonatale a débuté. Après la possibilité d'un test de dépistage par dosage de l'albumine méconiale, le dosage de la trypsine immunoréactive sanguine sur papier buvard couplé à la recherche des principales mutations du gène CFTR est utilisé de façon courante avec une bonne sensibilité et spécificité du test. Ce dépistage a longtemps fait l'objet de controverses, mais ses avantages au moins à moyen terme et notamment sur le plan nutritionnel, sont bien démontrés. L'intérêt d'un tel dépistage est rappelé au vu des expériences françaises et étrangères. Ces résultats sont étroitement liés avec la qualité du suivi de l'enfant dépisté dans des centres spécialisés. Dès lors, ce dépistage néonatal n'a de sens que s'il est assorti de ce type de suivi. C'est la raison pour laquelle la généralisation du dépistage néonatal sur l'ensemble de la France en 2002 s'est accompagnée de recommandations de suivi de l'enfant dépisté dans des centres de soins que les autorités de santé ont officialisé et dénommé centres de ressources et de compétences de la mucoviscidose. La France est ainsi devenue le premier pays au monde à effectuer ce dépistage sur l'ensemble de son territoire, dont l'organisation a été confiée à l'Association française de dépistage et de prévention des handicaps de l'enfant. Depuis le début du programme, 621 nouveau-nés ont été ainsi repérés, soit une incidence de 1/4376, avec de fortes variabilités régionales. Le problème actuel, qui se produit dans 14 % des cas, est celui de la révélation de formes cliniques ou paucisymptomatiques avec des tests de la sueur intermédiaires ou normaux et au moins une mutation dite modérée et dont on ignore le pronostic. Néanmoins, en évaluant les bénéfices et les risques d'un tel dépistage, le CDC estime maintenant que ce dépistage est justifié.
Newborn screening (NBS) for cystic fibrosis (CF) began more than 40 years ago. After using a screening test with meconium albumin, a twin test (rate of blood immunoreactive trypsin on blotting paper and search for main mutations of CFTR gene) is now performed routinely with good sensibility and specificity. This screening has been debatable for a long time, but it benefits, at least in the medium-term, particularly on nutritional status, are now well proved. The interest of this screening is reminded through the French and foreign experiences. Its results depend on the quality of children follow-up by specialized centres. From then on, this neonatal screening makes sense only when backed up with this kind of follow-up. That is why the spread of CF neonatal screening for the whole France in 2002 has been accompanied by recommendations for screened children to be follow-up in specialized centres: “centres de resources et de compétences de la mucoviscidose” (CRCM: resources and competences centres for CF). Two million seven hundred seventeen thousand nine hundred (and) ninety-two screened neonates (2002-Dec 31, 2005): 621 CF patients were diagnosed; the incidence of CF diagnosed through NBS was lower than expected 1/4376 with important regional variations. Fourteen percentage of the NBS CF patients resulted from dilemma cases either with a borderline sweat test plus 1 or 0 mutation or a borderline/normal sweat test with 2 mutations. A longer follow-up is needed to establish the clinical long-term outcome of these non-classical CF. Evaluating benefits and risks of this newborn screening for CF, the CDC believe that is now justified.
Prevalence of diseases: Estimation and relevance
2005, Medicina Clinica
Newborn screening for cystic fibrosis: An opportunity to improve care and outcomes
2005, Journal of Pediatrics
Citation Excerpt :
Subsequent to this task force, 2 randomized clinical trials15,16 and a number of observational studies17-22 have examined the long-term benefits of CF NBS. These studies have been the subject of several thoughtful reviews, with generally positive conclusions about recommendations for CF NBS.23-28 New data, not available to previous reviewers, are included in this supplement and strengthen the argument for CF NBS.
Risk calculations for cystic fibrosis in neonatal screening by immunoreactive trypsinogen and CFTR mutation tests
2005, Genetics in Medicine
Although neonatal screening (or newborn screening) for cystic fibrosis (CF) is commonly practiced, systematic methods for accurate risk calculations are currently lacking.
Methods and Results: We evaluated characteristics of the immunoreactive trypsinogen (IRT) test using the published data. The probability that a neonate has a positive IRT test, if the neonate is affected, a carrier, or a noncarrier, is ≈ 1, 0.041, or 0.011, respectively. We provide methods to calculate genetic risks for a variety of commonly encountered scenarios in which neonates are positive by the IRT test.
Our Bayesian methods permit CF disease probabilities to be calculated accurately, taking into account all relevant information.

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MINI-SYMPOSIUM: SCREENING IN CYSTIC FIBROSISNewborn screening programmes for cystic fibrosis

Abstract

Section snippets

NEWBORN SCREENING FOR CYSTIC FIBROSIS: LESSONS FROM AROUND THE WORLD

INTERNATIONAL EXPERIENCE

IMPLICATIONS FOR NEWBORN SCREENING

PRACTICAL ISSUES FOR IMPLEMENTATION

Acknowledgements

Lancet

J. Pediatr.

J. Pediatr.

Screening

Lancet

Arch. Pediatr.

Pancreatology

Clin. Chim. Acta

An Esp. Pediatr.

Screening for cystic fibrosis

Health Technol. Assess.

Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Wisconsin Cystic Fibrosis Neonatal Screening Study Group

Pediatrics

Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years’ experience

BMJ

Neonatal screening for cystic fibrosis

Arch. Dis. Child

Newborn screening for cystic fibrosis in Victoria: 10 years’ experience (1989–1998)

Med. J. Austr.

Arch. Dis. Child

Sweat testing following newborn screening for cystic fibrosis

Pediatr. Pulmonol.

Cystic fibrosis screening in neonates measurement of immunoreactive trypsin and direct genotype analysis for DF508 mutation

Eur. J. Pediatr.

Neonatal screening in Austria. Current situation, new developments and future perspectives

Pädiatr. Prax.

Screening of newborn infants for cystic fibrosis. A combined analysis of immunoreactive trypsin and delta F508 mutation; a screening without false positive results [in Danish]

Ugeskr. Laeger

Neonatal screening for the cystic fibrosis main mutation delta F508 in Estonia

J. Med. Screen

Neonatal screening for cystic fibrosis – results of a pilot study using both immunoreactive trypsin and cystic-fibrosis gene mutation analysis

Hum. Genet.

Cystic fibrosis detected by means of a test strip

Pediatrics

Mucoviscidosis screening of newborn infants in the Dresden district. Results from 1 June 1996 to 31 March 2000 [in German]

Dtsch. Med. Wochenschr.

Epidemiology and survival analysis of cystic fibrosis in an area of intense neonatal screening over 30 years

Am. J. Epidemiol.

Newborn screening strategy for cystic fibrosis: a field study in an area with high allelic heterogeneity

Acta Paediatr.

MINI-SYMPOSIUM: SCREENING IN CYSTIC FIBROSIS
Newborn screening programmes for cystic fibrosis