John A. Dodge

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice

It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.

Cystic fibrosis: terminology and diagnostic algorithms

There is great heterogeneity in the clinical manifestations of cystic fibrosis (CF). Some patients may have all the classical manifestations of CF from infancy and have a relatively poor prognosis, while others have much milder or even atypical disease manifestations and still carry mutations on each of the CFTR genes. It is important to distinguish between these categories of patients. The European Diagnostic Working Group proposes the following terminology. Patients are diagnosed with classic or typical CF if they have one or more phenotypic characteristics and a sweat chloride concentration of >60 mmol/l. The vast majority of CF patients fall into this category. Usually one established mutation causing CF can be identified on each CFTR gene. Patients with classic CF can have exocrine pancreatic insufficiency or pancreatic sufficiency. The disease can have a severe course with rapid progression of symptoms or a milder course with very little deterioration over time. Patients with non-classic or atypical CF have a CF phenotype in at least one organ system and a normal (<30 mmol/l) or borderline (30–60 mmol/l) sweat chloride level. In these patients confirmation of the diagnosis of CF requires detection of one disease causing mutation on each CFTR gene or direct quantification of CFTR dysfunction by nasal potential difference measurement. Non-classic CF includes patients with multiorgan or single organ involvement. Most of these patients have exocrine pancreatic sufficiency and milder lung disease. Algorithms for a structured diagnostic process are proposed.

Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome

Shwachman‐Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic exocrine insufficiency and bone marrow failure, often associated with neurodevelopmental and skeletal abnormalities. Mutations in the SBDS gene have been shown to cause SDS. The purpose of this document is to provide draft guidelines for diagnosis, evaluation of organ and system abnormalities, and treatment of hematologic, pancreatic, dietary, dental, skeletal, and neurodevelopmental complications. New recommendations regarding diagnosis and management are presented, reflecting advances in understanding the genetic basis and clinical manifestations of the disease based on the consensus of experienced clinicians from Canada, Europe, and the United States. Whenever possible, evidence‐based conclusions are made, but as with other rare diseases, the data on SDS are often anecdotal. The authors welcome comments from readers.

An international/multicentre report on patients with cystic fibrosis (CF) over the age of 40 years.

BACKGROUND The lifespan of patients with cystic fibrosis (CF) is increasing significantly. The objective of this international pilot study was to study the characteristics of these long-term survivors. METHODS Four centres with large CF clinics from London (UK), Minneapolis (USA), Toronto (Canada) and Verona (Italy) identified 366 patients who had survived 40 years and longer. RESULTS At all centres males survived longer than females. There were more pancreatic sufficient patients in Verona (60%) and Toronto (40%) than in London (16%) and Minneapolis (21%). The percentage of DeltaF508 homozygous patients varied between 47% in London and 45% in Minneapolis to only 26% in Toronto and 9% in Verona. Average FEV(1) and BMI values of the surviving population appeared to stabilise after 40 years of age. FEV(1) was on average 12% higher in patients who were pancreatic sufficient (p > 0.0001). There was no difference in survival between the centres. The overall median survival after the age of 40 was 13 years. The estimated annual death rate was approximately 3.4% from the age of 40-60 years. CONCLUSIONS Significant numbers of patients are now surviving to 40 years or more, and it is hoped that an in-depth study of these patients may identify the factors contributing to longer survival.

The importance of rare diseases: from the gene to society

What exactly do we mean by a rare disease (RD), and why are they important for paediatricians? The definition used for public health purposes in Europe is that an RD is one which affects fewer than one citizen in 2000; in the USA it is fewer than one in 1250.1 There are estimated to be between 6000 and 8000 known RDs in the world, many of which are predominantly paediatric disorders. About 75% of the diseases meeting the criteria for RD affect children, and about 30% of all patients with RDs die before their fifth birthday.2 Approximately 80% of RDs have a defined genetic basis.2 The true incidence and prevalence of individual RDs are often unclear. When the condition is fatal in childhood or early adult life, the prevalence in the population (table 1) will be well below the birth incidence, and will not reflect the gene frequency. Thus, to take the familiar example of cystic fibrosis, the birth incidence in the UK is about one in 2500 live births, but the population prevalence is given as about one in 8000. View this table: Table 1 Some examples of estimated European population prevalence given on the Orphanet website (http://www.orpha.net)5 Although individually rare, the cumulative burden of RDs is significant. RDs may affect as many as 30 million Europeans, with at least 3 million in the UK and 4 million in Germany, and this statistic has not been lost on the European Union (EU). A Committee of experts on rare diseases (EUCERD) was set up in November 2009 to assist and advise the European Commission, including, inter alia, drawing …

Cystic fibrosis is no longer an important cause of childhood death in the UK

Edited by Mark Selikowitz. Oxford: Oxford University Press, 2004, pp 235 £11.99. ISBN 0 19 852628 8 ![Graphic][1] This book opens badly, with two long histories that, for some reason, are presented in tiny font size. Already irritated I was then dismayed to find the cases described maintaining the tired stereotypes of the dreamy inattentive girl and the hyperactive, impulsive boy . The boy is, disappointingly, also violent and aggressive. There are girls who are hyperactive and impulsive, and hyperactive, impulsive children of both sexes who are neither violent nor aggressive. Unfortunately the media stereotype, reinforced here, is not a helpful one for most children with ADHD trying to make sense of themselves. The relation between real and administrative prevalence, or the political and social factors which can influence both, are not discussed. ADHD is, at the severe end of the scale, a disabling disorder with clear neurobiological deficits. However it … [1]: /embed/graphic-1.gif

Pancreatic enzyme therapy in cystic fibrosis.

When cystic fibrosis (CF) of the pancreas was first described by the Swiss pediatrician Guido Fanconi in 1936 [1] and the American Dorothy Andersen in 1938 [2], it was the pancreatic failure and its corresponding pathology that were the dominant features of the reports. Affected children failed to thrive and usually died from pneumonia (often staphylococcal) in the first year of life, before chronic pulmonary disease and bronchiectasis had time to develop. Now, 70 years later, when the mean life-span of CF patients approaches 40 years [3] and the majority are now being managed by adult pulmonologists, in our preoccupation with control of chronic pulmonary infection, we can easily underestimate the importance of pancreatic insufficiency.

Pancreatic enzymes and Fibrosing Colonopathy

This is an old issue which should have been laid to rest many years ago, but I feel bound to respond to the letter by Drs Peckham and Whitaker replying to Professor Taylor (July 2014) on the subject of Fibrosing Colonopathy (FC). It remains important because younger clinicians may still believe that enzymes which do not contain Eudragit are safer than those which do. The studies which made this claim were carried out by an industry-funded pathologist described by Prof Taylor as “discredited”. That is an understatement. An official enquiry in 2001, which did not take into account his FC history, found him guilty of, inter alia, “falsifying records, statistics and work output; falsifying research applications; falsifying post mortem reports; falsely representing that diagnoses and research papers were supported by histological examination, when no histology had been carried out; lying to parents; encouraging staff to falsify records and statistics; practising deceit upon (the sponsors of his post), the University and (the hospital); and taking with him, after his dismissal, complete medical records”. As chairman of the UK enquiry into FC, I would add that he removed or destroyed all the histological material on which the conclusions of our enquiry were based. He fraudulently added the names of two senior pathologists to a report he sent to the Medicines Control Agency, although they had not seen the report or most of the material. He had refused to examine the slides together. He

O-191 European And International Initiatives Addressing Rare Diseases And Chronic And Disabling Health Conditions In Children: Eap Working Parties Research Engagements

Background and aims In response to a WHO discussion paper, in December 2013 the European Academy of Paediatrics Working Parties on Ethics and Rare Diseases created a position paper on the early identification, diagnostic confirmation, and longitudinal management of disease in early childhood. The presentation examines the EAP’s research engagement in developing infrastructure in primary and specialist care as well as at national and European levels. Methods The EU Rare Disease programmes and actions, have encouraged the EAP to engage in research on the pooling and structuring of data on child health that can improve global chronic disease prevention and management in paediatric practice. The EAP supports the development of a repository of existing rare disease guidelines. Rare diseases are usually chronic, and in 75% affect children and/or present in childhood. An EU model will be developed that includes both preventive child health care and rare disease management. For cross-border collaboration is needed to compile patient registries, the development of a shared platform for European patients within the framework of the developing EU eHealth policy is essential: as part of an Open Access Paediatric Healthcare Resource as a child health reference for rare, chronic, and/or disabling diseases. Results An overview of the current European and international frameworks for rare, chronic, and/or disabling diseases within eHealth is presented. Conclusions Improved access to knowledge about early diagnosis and disease management for primary and specialist paediatric health care professionals, can bring the EAP experience and expertise to bear on current European and international research.