Hypoelectrolytemia and metabolic alkalosis in infants with cystic fibrosis.

The records of all children in the Tucson area diagnosed as having cystic fibrosis (CF) before the age of 12 months were reviewed to ascertain the prevalence of metabolic alkalosis as a major presenting manifestation of CF. Five of eleven infants (46%) in whom CF had been diagnosed between 1 and 12 months of age initially were seen with hypokalemia, hypochloremia, and metabolic alkalosis unassociated with marked dehydration, hyperpyrexia, or major pulmonary and/or gastrointestinal symptoms. Two infants had repeated episodes of metabolic alkalosis; for one of these infants, both episodes of metabolic alkalosis occurred before the diagnosis of CF. It is postulated that chronic loss of sweat electrolytes together with mild gastrointestinal or respiratory illness may predispose the infant with cystic fibrosis to a severe electrolyte and acid-base disturbance. The lack of shock and hyperpyrexia together with the apparent chronicity of electrolyte losses differentiates metabolic alkalosis from the heat prostration syndrome, a more acute complication of cystic fibrosis. Quantitative sweat testing should be part of the evaluation of any infant with unexplained metabolic alkalosis. Serum electrolytes should be assessed regularly in infants with cystic fibrosis during hot weather months.     

Protein–energy malnutrition as the first manifestation of cystic fibrosis in infancy

Background:  The protein–energy malnutrition (PEM) that is characterized by hypoproteinemia, edema, and anemia has been reported in 5–13% of infants with cystic fibrosis (CF). Due to the surprising higher incidence of PEM as the first presenting manifestation of CF in Macedonia, the aim of the present study was to evaluate the possible risk factors in its development.
Methods:  Clinical and laboratory profiles (hemoglobin, red blood cell count, total serum protein, serum albumin and liver enzyme levels) and genotype data were analyzed in 115 newly diagnosed infants with CF, during the period 1990–2006.
Results:  PEM manifested in 39 CF infants (33%), usually within the first 5 months of life and in breast-fed infants. Mean hemoglobin, red blood cell count, total serum protein and serum albumin values in the PEM subgroup were, respectively, 76.0 g/L, 2.4 × 10¹²/L, 38.0 g/L and 16.6 g/L. Clinically significant liver involvement was found in 22 patients (56.4%) with PEM. Concerning the molecular basis of CF in these patients, PEM was always associated with ▵F508 , G542X , N1303K and other severe mutations.
Conclusion:  PEM is a common manifestation of CF in infancy. Early infant age, breast-feeding, impaired liver function and the presence of severe cystic fibrosis transmembrane conductance regulator mutations are predisposing factors for the development of PEM.     

Delayed diagnosis of cystic fibrosis in children with a rare genotype (ΔF508/R117H)

Objectives: In neonatal screening for cystic fibrosis (CF), infants recognised as ΔF508 heterozygotes require a sweat test to confirm the diagnosis. However, compound heterozygotes with ΔF508 and the R117H mutation are known to have non-diagnostic sweat chlorides (<60 mmol/L) at an early age. As genotyping for rare mutations is not readily available in Australia, there is a need to determine whether quantitative pancreatic stimulation tests could facilitate the diagnosis of CF in three infants with the ΔF508/R117H mutation.
Methodology Formal sweat testing, genotyping and pancreatic stimulation tests were performed in three subjects heterozygous for ΔF508 who initially had non-diagnostic sweat chloride results (40-60 mmol/L) but presented later with persisting chest symptoms and/or signs consistent with CF.
Results All three patients were shown to have the ΔF508/R117H genotype with initial sweat chloride results ranging from 40 to 58 mmol/L. Pancreatic stimulation tests demonstrated reduced enzyme secretion in two and decreased fluid, bicarbonate and chloride secretion in all three patients.
Conclusions In infants recognized as ΔF508 heterozygotes by the newborn screening programme, the presence of an equivocal sweat chloride does not exclude the diagnosis of CF. If such patients with an initially equivocal sweat chloride subsequently develop symptoms suggestive of CF and have a persisting non-diagnostic sweat chloride then the diagnosis of CF can be confirmed by more extensive genotyping if available or by pancreatic stimulation testing.     

Turkish infant with hypoelectrolytemia and metabolic alkalosis as the sole manifestations of a mild form of cystic fibrosis (mutation D110H)

We report the history of an infant who presented with hypotonic dehydration and metabolic alkalosis, in whom the diagnosis of cystic fibrosis was made on the basis of investigations for rare cystic fibrosis mutations. Since no other signs and symptoms of the CF disease were present, the finding of the rare mutation D110H on exon 4 of the CFTR-gene was paramount in the delineation of his underlying illness. He is now thriving well with a daily oral substitution of 1-2 grams of sodium chloride. A mild variant of cystic fibrosis has to be considered in infants presenting with unexplained hypoelectrolytemia and metabolic alkalosis. Like in our child, typical signs and symptoms of cystic fibrosis like maldigestion may not be present. The search has to be extended into "mild" mutations of the disease like D110H which was found in our case.     

Role of <Emphasis Type="Italic">CFTR</Emphasis> mutation analysis in the diagnostic algorithm for cystic fibrosis

Background:The cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation identification is being used with increased frequency to aid in the diagnosis of cystic fibrosis (CF) in those suspected with CF.Aim of this study was to identify diagnostic outcomes when CFTR mutational analysis was used in CF diagnosis.CFTR mutational analysis results were also compared with sweat chloride results.Methods:This study was done on all patients at our institution who had CFTR mutation analysis over a sevenyear period since August 2006.Results:A total of 315 patients underwent CFTR mutational analysis.Fifty-one (16.2％) patients had two mutations identified.Among them 32 had positive sweat chloride levels (≥60 mmol/L),while seven had borderline sweat chloride levels (40-59 mmol/L).An additional 70 patients (22.3％) had only one mutation identified.Among them eight had positive sweat chloride levels,and 17 had borderline sweat chloride levels.Fifty-five patients (17.5％) without CFTR mutations had either borderline (n=45) or positive (n=10) sweat chloride results.Three patients with a CF phenotype had negative CFTR analysis but elevated sweat chloride levels.In eighty-three patients (26.4％) CFTR mutational analysis was done without corresponding sweat chloride testing.Conclusions:Although CFTR mutation analysis has improved the diagnostic capability for CF,its use either as the first step or the only test to diagnose CFTR dysfunction should be discouraged and CF diagnostic guidelines need to be followed.     

Chloride deficiency as a presentation or complication of cystic fibrosis

Thirteen children with cystic fibrosis (CF), aged 1.5 months–15 years, had 18 episodes of hypochloraemia and metabolic alkalosis over the period 1983–1991. Five patients were not known to have CF prior to developing these electrolyte disturbances. There were two distinct clinical presentations: 5 patients had an acute isolated picture of heat exhaustion while 8 patients (all infants) had a more chronic course associated with failure to thrive. Many episodes were not associated with particularly high environmental temperatures, although most occurred during the summer and early autumn months. Serum electrolytes should be assessed regularly in children with CF, and this diagnosis should be considered in any infant presenting with unexplained hypochloraemic metabolic alkalosis.     

Experience with neonatal screening for cystic fibrosis in New Zealand using measurement of immunoreactive trypsinogen

Abstract Neonatal cystic fibrosis (CF) screening has been performed in New Zealand for a total of 7 years. This study reports the experience with this procedure in New Zealand over a 4 year period and compares it with 2 years when diagnoses of CF were suggested by clinical features only. A total of 72 infants were confirmed as having CF during 4 years of screening. Twenty-eight infants were found to have CF during 2 years in which screening was not performed. There were 29 false positive diagnoses during the screening years and six false negative diagnoses. Three of the false negative diagnoses occurred because of laboratory error, but three occurred because either the first or second measurement of immunoreactive trypsinogen (IRT) was normal. Faecal chymotrypsin was measured in samples from 434 infants at the time of the second IRT and assisted with the diagnosis for one infant which might otherwise have been missed. Only 42.5% of infants were asymptomatic at the time of the confirmatory sweat test. Significant morbidity and mortality was associated with meconium ileus which occurred in 24% of infants with CF. Improved ascertainment of cases of CF has occurred since screening began. Further follow-up is required to determine other benefits of newborn screening.     

Cystic fibrosis presenting with recurrent vomiting and metabolic alkalosis

Between January 1980 and December 1987, ten Saudi Arabian children at Saudi Arabian Oil Co. (Saudi Aramco) health care facilities in the Eastern Province of Saudi Arabia had cystic fibrosis (CF). The incidence of CF in Saudi Arab children 14 years was 1 in 4243. Five of the ten children had hypoelectrolytaemia and metabolic alkalosis on initial presentation. Two of the five had recurrent vomiting, hypoelectrolytaemia and metabolic alkalosis alone and initially no chest symptoms. Early exclusion of CF should be part of the workup in any child, especially in an infant with hypoelectrolytaemia and metabolic alkalosis.     

儿童囊性纤维化并发变应性支气管肺曲霉菌病1例报告并文献复习

目的 分析囊性纤维化(CF)并发变应性支气管肺曲霉菌病(ABPA)的临床特征.方法 回顾分析1例确诊为CF并发ABPA患儿的临床资料,分析近10年PubMed、中国知网、万方数据库中报道CF并发ABPA的资料.结果 11岁患儿,男,曾诊断哮喘,因持续咳嗽、喘息入院,初步确诊ABPA.基因检测显示患儿CFTR基因变异,汗...     

Negative sweat test in hypertrypsinaemic infants with cystic fibrosis carrying rare <Emphasis Type="Italic">CFTR</Emphasis> mutations

Persistent hypertrypsinaemia in newborn screening for cystic fibrosis (CF) recognises subjects at high risk to be affected. Diagnosis is confirmed by a positive sweat test and/or by the presence of two mutations in the cystic fibrosis transmembrane regulator gene. The aim of the present study was to evaluate the occurrence of a negative sweat test (chloride < 60 mmol/l) during the first months of life, in hypertrypsinaemic infants, which would lead to a delayed diagnosis. We reviewed clinical charts of CF patients born between January 1993 and September 1998, when the neonatal screening programme consisted of an immunoreactive trypsinogen (IRT)/DNA (F508del) + IRT strategy. Laboratory and clinical data were collected for patients diagnosed after 12 months of life. Out of 446,492 newborns, 104 CF patients were diagnosed giving an overall incidence of 1:4293. Of these, six had a blood IRT level above the cut off value (99th percentile) and a negative sweat test in the first trimester of life. At a mean age of 3.5years, the patients were again referred to our CF Centre for re-evaluation in order to confirm or exclude the disorder. Molecular analysis identified the following genotypes: F508del/A309D, F508del/3849 + 10kbC-->T, F508del/R117H (in two patients), R117H/ L997F, and F508del/R117L. CONCLUSION: Infants with cystic fibrosis bearing a spectrum of mild cystic fibrosis transmembrane regulator gene mutations may present as hypertrypsinaemic newborns with a sweat chloride within the normal range. Reference values for normal sweat test during the first months of life should be revised. A wide molecular genetic analysis is recommended for newborns presenting persistent hypertrypsinaemia and a sweat test result > 30 mmol/l in order to diagnose atypical forms of the disease.     

Buccal cell DNA mutation analysis for diagnosis of cystic fibrosis in newborns and infants inaccessible to sweat chloride measurement

OBJECTIVES: To assess the application of DNA-based cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis as a primary cystic fibrosis (CF) diagnostic test in preterm and term newborns and infants for whom the quantitative pilocarpine iontophoresis test (QPIT) cannot be used. DESIGN: Retrospective survey. SETTING: DNA Diagnostic Laboratory, Children's Hospital, Boston, Massachusetts. Buccal cell DNA samples were received from inpatients, outpatients, and three neonatal intensive care units. OUTCOME MEASURE: Detection of at least 1 of 12 CFTR mutations. PATIENTS: Between November 1, 1992, and April 30, 1994, 28 newborns and infants under 12 months of age at risk for CF had CFTR DNA mutation analysis performed because a sweat chloride (SC) value could not be obtained. QPIT was either not performed (infant weight <2 kg, QPIT not available at site of hospitalization, or infant not accessible to QPIT laboratory) or was inconclusive (sweat volume <75 mg or indeterminate SC [>/=40, <60 mEq/L]). The postnatal age at time of testing ranged from 1 day to 11 months, and gestational age at birth from 25 to 40 weeks. RESULTS: Six (21%) of 28 infants with unobtainable or indeterminate QPIT had 1 or 2 CFTR mutations detected. Immediate CF diagnosis by direct detection of 2 CFTR mutations was made in 5 of these 6 patients. Definitive CF diagnosis in the infant with 1 CFTR mutation was delayed until an elevation in SC could be documented. The patients with no CFTR mutations detected had a low likelihood of CF. CONCLUSIONS: For infants in whom CF is suspected but QPIT cannot be obtained, buccal cell DNA-based CFTR mutation analysis can be used as a rapid, noninvasive primary diagnostic test. This simple mode of DNA collection may aid in the diagnosis of other inherited disorders in newborns.     

Cystic fibrosis screening in neonates — measurement of immunoreactive trypsin and direct genotype analysis for ΔF508 mutation

This study investigated the clinical usefulness of screening for cystic fibrosis (CF) in 19992 newborns, over 39 months, in an Austrian population. Immunoreactive serum trypsin (IRT) determination was followed by sweat chloride analysis (sweat test) to establish diagnosis. In a retrospective analysis covering 6 months of the study period, individuals who were considered to be at risk after IRT estimation (n = 22) were analysed for F508 mutation, using a new method of DNA extraction from the initial dried blood specimens. A total of 119 infants (0.6%) had values greater than 750mg trypsin/ml whole blood. In 88 babies sweat tests were performed, leading to the diagnosis of CF in 11 cases. One patient was not initially identified by screening but was later discovered due to his clinical status. Three infants were noted to carry the F508 mutation (1 homozygous, 2 heterozygous). Two of these babies already had CF. The second heterozygote was a carrier. A highly efficient three tier screening strategy is presented in which IRT estimation, determination of F508 status and sweat chloride testing could lead to a high sensitivity analysis of this population.     

Clinical features and treatment approaches in cystic fibrosis with pseudo-Bartter syndrome

INTRODUCTION: Infants with cystic fibrosis (CF) are prone to develop episodes of hyponatraemic, hypochloraemic dehydration with metabolic alkalosis, which are biochemical hallmarks of the pseudo-Bartter syndrome (PB). METHOD: We reviewed the clinical and laboratory features and treatment approaches of 29 children with CF and PB who were under follow-up in our institution from May 1992 to November 2003. RESULTS: Of 241 patients with CF, PB was detected in 29 (12%) with a median age of 4 months at the time of the first attack. Most patients experienced vomiting, loss of appetite and dehydration during episodes of PB. All patients were managed with intravenous fluids and sodium chloride solutions. During follow-up, 12/29 cases required hospital admission for recurrent PB attacks. The oldest age at the time of the last attack was 48 months. CONCLUSIONS: CF should be considered in the differential diagnosis of metabolic alkalosis in young children. Vomiting and loss of appetite are important warning signs of possible PB in CF patients, particularly before 4 years of age. To prevent serious complications, it is crucial that parents and physicians recognise PB as early as possible.     

Parental attitudes to the identification of their infants as carriers of cystic fibrosis by newborn screening

AIM: To investigate parental attitudes to cystic fibrosis (CF) carrier detection of their infant by newborn screening (NBS). METHODS: Data were collected from a postal questionnaire sent to parents of infants identified as CF carriers by NBS in 1996-1997 (inclusive) and 2001 in Victoria, Australia (n = 66). RESULTS: Almost all parents remembered their child being identified as a CF carrier (97%: 1996/1997; 100%: 2001); yet the majority were unaware at the time that NBS could detect carriers (70%: 1996/1997; 49%: 2001). More parents in the later cohort reported having carrier testing compared with the earlier cohort (85% and 53% respectively) but recall was more uncertain in the earlier cohort when validated against health records. Cascade testing was not utilised frequently by other family members in either cohort. Residual risk of being a carrier if testing was negative was not well understood by parents. Some parents (28%: 1996/1997; 18%: 2001) had residual anxiety about the current health of their carrier child and their future reproductive decision making. Most parents were satisfied with the information provided to them at the time of the sweat test. Few differences were seen between the cohorts. CONCLUSION: Although the NBS process for CF in Victoria is working efficiently for the majority of families whose infant is identified as a carrier there are areas that can be improved. We recommend that greater attention should be given to informing parents that a consequence of NBS is CF carrier detection and strategies to improve utilisation of cascade testing should be developed.     

Failure to thrive: the earliest feature of cystic fibrosis in infants diagnosed by neonatal screening

The benefits of early treatment of nutritional and respiratory problems in the CF infant and of genetic counselling for the parents are widely recognized. However, clinical diagnosis of CF is often delayed despite early onset of symptoms and the usefulness of neonatal population screening as a preventive measure is still under debate. This study analyses the clinical history of CF patients diagnosed exclusively on the basis of positive neonatal screening tests with the aim of identifying the earliest markers of the disease. We studied 103 CF infants bom in north-east Italy, diagnosed following neonatal screening: assay of immunoreactive trypsin (IRT) from a heel-prick blood sample followed by a measurement of meconium lactase in cases with raised IRT. Diagnosis was confirmed by sweat test at an average age of 39 days. Eighty-one patients (79%) had symptoms strongly suggestive of CF at diagnosis, and signs and/or symptoms of pancreatic insufficiency were present in 16 of the remaining 22 cases. The most frequent symptom was growth failure (69% of infants) and of these. 44% weighed the same as at birth or less. Pancreatic insufficiency was confirmed by the low level of faecal chymotrypsin found in 85% of cases. IRT was elevated in all cases. CF had not been suspected in any symptomatic infant, although most of the infants had been monitored by a paediatrician. In conclusion, most infants with CF diagnosed by neonatal screening are already symptomatic in the first six weeks of life and the most frequent symptom is failure to thrive; pancreatic insufficiency was already present in most cases. In areas without CF neonatal screening programs, the disease should be excluded by differential diagnosis in all cases with growth failure notwithstanding adequate caloric intake in the first months of life. The high sensitivity, low cost and simple execution of IRT and fecal chymotrypsin tests make them an ideal first step in suspect cases before proceeding to the sweat test, often performed late because of limited availability.     

Myocardial fibrosis — a rare complication in patients with cystic fibrosis

We report a 10-month-old male infant who was admitted to our hospital with a history of failure to thrive and bulky stools. On examination, he was dystrophic and had a protruding abdomen, but he was well oxygenated and his lungs were clear on auscultation. A tachycardia of 145 beats per min and radiological evidence of cardiomegaly indicated involvement of the heart, but an ECG failed to show signs of myocarditis or cardiac hypertrophy. An elevated sweat chloride concentration of 141 mEq/l confirmed the diagnosis of cystic fibrosis (CF). Molecular analysis revealed heterozygosity for the common mutation delta F₅₀₈. He died unexpectedly of a sudden cardiac arrest 2 days later. Autopsy revealed scattered myocardial necrosis and fibrosis. Some 50 documented cases of myocardial fibrosis in infants with CF have been reported. Suggested causes such as malnourishment and hypovitaminosis remain speculative as systematic studies have yet to be done.     

Physiological Measurements Confirming the Diagnosis of Cystic Fibrosis: the Sweat Test and Measurements of Transepithelial Potential Difference

Post-natal screening allied with genetic mutation testing has altered our perception of cystic fibrosis (CF) as a clinical entity. Increasingly, infants identified through screening programmes have few or no symptoms or present with atypical forms of the disease. We review how the sweat test has evolved to be the gold standard for confirming the diagnosis of CF and examine its limitations. Other physiological measurements, including nasal potential difference and intestinal current measurement, which might aid in establishing the diagnosis, particularly in patients exhibiting a mild phenotype, are also considered.     

False negative results on newborn screening for cystic fibrosis

Over a 5 year period in Newcastle, 18 new cases of cystic fibrosis (CF) were diagnosed in children who had been screened in the newborn period. In six of these children, the screening programme failed. Four of these children had a normal screen and an additional two had elevated immunoreactive trypsin (IRT), but there were problems with the notification procedure. Three of the children missed by the screening process had a significantly delayed diagnosis; in all three cases the diagnosis of CF was suspected clinically, but a sweat test was delayed because of false reassurance from the fact that the child had been screened for CF. In a fourth case, multiple elevated sweat electrolyte levels were obtained, but the diagnosis of CF was considered to be in doubt because of the normal IRT assay. A sweat test should be performed on any child in whom there is clinical suspicion of CF.     

Malnutrition: A Cause of Elevated Sweat Chloride Concentration

ABSTRACT. In order to document the frequency and causes of elevated sweat chlorides we reviewed all sweat chloride determinations performed over a 2-year period. Seven hundred and thirty-five quantitative tests were performed. Three hundred and three positive or borderline results were obtained from 133 patients. Thirty-three of these patients did not have clinical evidence of CF. Fourteen of them (42%) suffered from malnutrition or growth stunting when tested. The remaining patients who were normally nourished, represented a very heterogeneous group with no unifying diagnosis. Initial sweat chlorides in 11/14 malnourished children were in the abnormal range (>60 mmol/1). These tended to revert to normal coincident with improvement in nutritional status. Less remarkable elevations in sweat chloride levels were noted in the normally nourished patients, since almost 50% (9/19) were in the intermediate range (50-60 mmol/1). We conclude that malnutrition can be the cause of elevated sweat chlorides, which may lead to an erroneous diagnosis of cystic fibrosis. Clinicians should be aware of this association and adhere to strict criteria for the diagnosis of cystic fibrosis. Also, repeated sweat chloride determinations should be obtained, preferably following re-nutrition.     

Cystic fibrosis-an Indian perspective on recent advances in diagnosis and management

Cystic fibrosis (CF) is a common inherited disorder in caucasians. The estimated incidence of CF in Asians varies from 1∶10,000 to 1∶12,000. Indian data is restricted to faw case reports. The gene for CF is located on the long arm of chromosome 7 at position 7q13. There are more than 300 identified mutations in CF. The basic defect in CF is a mutational change in the gene for chloride conductance channel. Failure of chloride conductance by epithelial cells leads to dehydration of secretions that are too viscid and difficult to clear. The disease is characterized by abnormal secretions in the respiratory, gastrointestinal and reproductive tract and sweat glands. The common clinical manifestations include meconium ileus in neonatal period, recurrent lower respiratory tract infections (pseudomonas pneumonia, bronchiectasis), steatorrhoea, azoospermia, and in late stages hepatobiliary and endocrine pancreatic dysfunctions. The diagnosis of disease is established by clinical criteria and sweat chloride concentration more than 60 mEq/L. Facilities for DNA diagnosis of common CF mutations are now available in India. The treatment of CF includes early diagnosis, daily clearance of respiratory passages, appropriate antibiotic therapy, aerosolised recombinant human DNase and antibiotics, and nutritional supplementation. The latter include changes in diet composition, pancreatic enzyme supplementation and vitamins and trace mineral supplementation. Gene therapy for the pulmonary manifestations is being tried in a number of centres abroad. Other considerations include heart lung transplantation and ameloride inhalation therapy.