Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening

OBJECTIVES: To characterize the time course and physiologic significance of decline in serum immunoreactive trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability. STUDY DESIGN: We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies. RESULTS: Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable. CONCLUSIONS: IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.     

Isolated liver transplantation in children with cystic fibrosis – An Australian experience

Nightingale S, O’Loughlin EV, Dorney SFA, Shun A, Verran DJ, Strasser SI, McCaughan GW, Jermyn V, Van Asperen P, Gaskin KJ, Stormon MO. Isolated liver transplantation in children with cystic fibrosis – An Australian experience.
Pediatr Transplantation 2010: 14:779–785. © 2010 John Wiley & Sons A/S. Abstract: CF liver disease is an uncommon indication for pediatric LT. Determining optimal timing and type (isolated liver versus multi‐organ) of transplantation for those with severe liver disease can be challenging and involves consideration of the extent of liver disease (PHT, synthetic dysfunction) and extrahepatic factors such as pulmonary function. We present the experience of isolated LT for CF at our center. Eight children received one allograft each (3.9% of all grafts). One‐ and four‐yr survivals are both 75%. The two deaths occurred within the first two months after LT, and in both cases, invasive fungal infections were implicated, one following treatment for acute severe rejection. All had significant PHT, and six had synthetic dysfunction. All had roux‐en Y biliary anastomoses and none developed long‐term biliary complications. Seven had pulmonary colonization with Pseudomonas aeruginosa and six with fungus at time of transplantation. Mean pre‐LT FEV1 was 80% (range 59–116%) predicted, and lung function post‐LT was stable. Isolated LT in children with CF is successful in those with relatively preserved pulmonary function, which does not appear to deteriorate as a consequence. Roux‐en Y biliary anastomosis and antifungal prophylaxis should be a part of management of these patients.     

Quality-of-life in children and adolescents with cystic fibrosis managed in both regional outreach and cystic fibrosis center settings in Queensland

OBJECTIVES: To assess the health-related quality-of-life (HRQOL) of children/adolescents with cystic fibrosis (CF) and compare HRQOL in children managed by cystic fibrosis outreach service (CFOS) with those treated in a cystic fibrosis center (CFC). To compare HRQOL of children with CF in Queensland with previously published HRQOL data from the United States and examine the relationship between HRQOL scores and pulmonary function. STUDY DESIGN: Participants were children/adolescents with CF and their parents managed by the Royal Children's Hospital Queensland at a CFC or CFOS. Two HRQOL surveys were used: PedsQL and Cystic Fibrosis Questionnaire (CFQ). RESULTS: There were 91 CFC and 71 CFOS participants with similar demographics. PedsQL total summary score was statistically higher in CFOS, P=.05. There was no significant difference in CFQ scores between groups. Queensland parents reported lower HRQOL for their children compared with US parents (P<.01) despite similar pulmonary function. Declining pulmonary function correlated with worse CFQ scores in adolescents, P<.05. CONCLUSIONS: Children living in regional Queensland reported as good as or slightly better HRQOL compared with children attending a CFC. Parent proxy HRQOL scores were generally low suggesting a reduced perception of HRQOL by parents for their children.     

Epidemiology of cystic fibrosis-related diabetes

OBJECTIVES: Cystic fibrosis-related diabetes (CFRD) has emerged as an important complication of CF. To better understand who is at risk of developing CFRD, to gain insight into the impact of CFRD on pulmonary and nutritional status, and to assess the association of CFRD with various practice patterns and comorbid conditions, we characterized the Epidemiologic Study of Cystic Fibrosis (ESCF) patient population. STUDY DESIGN: Analyses were performed on the 8247 adolescents and adults who were evaluated at one of 204 participating sites during 1998. CFRD was defined as the use of insulin or an oral hypoglycemic agent at any time during the year. RESULTS: Previously reported risk factors for CFRD including age, gender (female), and pancreatic insufficiency were confirmed in this study. Patients with CFRD had more severe pulmonary disease, more frequent pulmonary exacerbations, and poorer nutritional status as compared with those without diabetes. CFRD also was associated with liver disease. CONCLUSIONS: CFRD is a common complication in adolescents and adults that is associated with more severe disease.     

Liver disease as risk factor for cystic fibrosis-related diabetes development

AIM: To evaluate clinical and genetic factors, besides pancreatic insufficiency, associated with increased risk of cystic fibrosis-related diabetes. METHODS: Case-control (1:1) study on 138 cystic fibrosis patients. Data were collected on gender, age at diagnosis, reason for cystic fibrosis diagnosis, family history of type 1 or 2 diabetes mellitus, pre-existing severe liver disease, and class of cystic fibrosis transmembrane regulation mutation. Moreover, information was obtained on lung involvement and degree of exocrine pancreatic insufficiency evaluated 1 year before the diagnosis of cystic fibrosis-related diabetes in patients and age-matched controls. RESULTS: Compared to controls, patients with cystic fibrosis-related diabetes had a higher probability of having already been diagnosed with liver disease (16.7% versus 1.7%, OR = 11.6, 95% CI 1.43-93.0). Moreover, in the year before diabetes onset, cases had slightly worse pulmonary function compared to controls (FEV1 = 58.4 +/- 27% predicted versus 67.4 +/- 21% predicted; p = 0.05). No significant effects related to the other factors considered were found. CONCLUSION: Severe liver disease was found to significantly increase the risk of developing cystic fibrosis-related diabetes. Patients with liver disease should be scheduled for earlier diabetes screening in order to identify and possibly treat glucose intolerance.     

Ear disease is not a common complication in cystic fibrosis

Although upper respiratory tract involvement is a common finding in cystic fibrosis (CF), there is no agreement on whether hearing is affected in these patients. We studied 75 CF subjects and 50 healthy agematched children with the same audiological protocol. An original scoring system was used to quantify the degree of hearing involvement (normal, mild, moderate and severe) in each subject. Prevalence of ear involvement in children with CF was similar to that in agematched control subjects (25.4% and 18% respectively,P>0.05). Ear disease in CF was not related to pulmonary disease, radiological sinusitis, nasal polyposis, or use of parenteral aminoglycosides. These data showed that the risk of ear disease in CF was not increased even if patients with severe audiological involvement were described only in the CF group.     

The evolution of liver disease in cystic fibrosis.

OBJECTIVES: To describe prospectively the evolution of liver abnormalities in cystic fibrosis (CF), and to assess their impact on nutritional status. STUDY DESIGN: 124 children (61 boys) with CF (median age, 5.4 years; range, 0.1-13.9) were followed longitudinally for a median of four years. Annual clinical examination, biochemistry, and ultrasound assessment were performed. Chrispin-Norman score, anthropometry, and bacterial colonisation of airway secretions were measured at each assessment. RESULTS: At initial assessment, 45% of the patients had no liver abnormalities, 42% had biochemical abnormality, 35% ultrasound abnormality, and 6% had clinical abnormality of the liver. In this cross sectional analysis, abnormal biochemistry was present in 40% of children with ultrasound or clinical abnormalities, but when longitudinal follow up data were analysed, abnormal biochemistry preceded or coincided with abnormal ultrasound or clinical hepatosplenomegaly in three quarters of 53 children developing new abnormalities. Eighty four of 124 children (68%) showed ultrasound or clinical evidence of liver abnormality at some point during the four years of follow up. No association was found between liver disease and nutritional status. CONCLUSIONS: Hepatic abnormality was common in this group of children with CF, was often predicted by intermittent biochemical abnormalities, and was not associated with deterioration in nutritional status.     

Increased plasma homocysteine and S-adenosylhomocysteine and decreased methionine is associated with altered phosphatidylcholine and phosphatidylethanolamine in cystic fibrosis

OBJECTIVE: We used a novel approach based on the intersection of phospholipid and methionine metabolism at the S-adenosylmethionine (SAM)-dependent methylation of phosphatidylethanolamine (PE) to study potential alterations in phospholipid metabolism in children with cystic fibrosis (CF). Methyl groups from methionine via SAM are used for sequential methylation of PE to form phosphatidylcholine (PC) with the generation of S-adenosylhomocysteine (SAH) and homocysteine. STUDY DESIGN: Plasma phospholipids and methionine metabolites and plasma and red blood cell phospholipid fatty acids were determined in 53 children with CF and 18 control children. RESULTS: Plasma methionine and the PC/PE ratio was lower and homocysteine, SAH, and PE were higher in children with CF than in control children (P<.001). Plasma methionine was inversely (P<.05) and SAH and homocysteine were positively (P<.001) correlated with the plasma PE. Docosahexaenoic acid (22:6n-3) was significantly lower in plasma phospholipids and triglycerides and in red blood cell PC and PE of children with CF than in control children (P<.05). CONCLUSIONS: These studies demonstrate that methionine metabolism is altered and associated with alteration of the plasma PC/PE ratio in CF. Altered phospholipid and methionine metabolism may contribute to the clinical complications associated with CF.     

Variability of markers of inflammation and infection in induced sputum in children with cystic fibrosis

To determine reproducibility of inflammatory marker concentrations in induced sputum from subjects with cystic fibrosis (CF), 15 nonexpectorating children, 6 to 13 years of age with mild CF lung disease, underwent 3 weekly sputum inductions with 3% saline. Neutrophil elastase concentration and bacterial cultures were reproducible. This study provides useful information for investigators designing trials of anti-inflammatory therapies in CF involving sputum induction.     

Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease.

AIM: To determine whether serum hyaluronic acid (HA) concentrations are abnormal in patients with cystic fibrosis (CF) liver disease, and if so, whether the abnormality is associated with disease severity. METHODS: A total of 74 patients with CF were assessed for evidence of liver involvement as indicated by clinical, ultrasound, and biochemical findings. Serum hyaluronic acid concentrations were measured and compared with concentrations in 293 normal controls. Lung function in the CF patients was also recorded. RESULTS: Thirty four CF patients had no evidence of liver disease; in these, serum HA concentrations were similar to those in healthy controls (median (range): 16.1 (9.4-75.1) v 15 (1-77) microg/l). Nineteen CF patients had established liver disease detected by clinical and ultrasound examination, with significantly increased HA concentrations (56.1 (26-355) microg/l). Serum HA concentrations were also significantly increased, although to a lesser extent, in 21 CF patients with an abnormal liver ultrasound scan alone (22.4 (9.5-43.4) microg/l). There was no correlation between serum HA concentration and lung function. CONCLUSION: Serum HA concentrations were significantly increased in children with clinical or ultrasound evidence of liver disease, being higher in those with more advanced hepatic damage. Despite the inflammation and fibrosis present in CF lungs there was no correlation between HA concentration and lung function, suggesting that high concentrations were a failure of hepatic clearance rather than overproduction in the lung. Longitudinal measurement of HA concentrations may prove a useful marker for the development of significant liver damage in CF patients.     

Clinical and Genetic Features in Patients with Cystic Fibrosis in Southwestern Iran

Objective

Cystic fibrosis (CF) is a common autosomal recessive genetic disease caused by a mutation in the CF transmembrane conductance regulatory (CFTR) gene. This study attempted to identify the most common CFTR mutations and any correlations between certain mutations and the clinical presentation of the disease in CF patients in southwestern Iran.

Methods

Twenty nine common CFTR gene mutations were examined in 45 CF patients.

Findings

Chronic cough, intestinal obstruction, dehydration, heat exhaustion and steatorrhea were the most common early clinical symptoms among our patients. The most common mutation was ΔF508, with an allele frequency of 21%. The homozygous ΔF508 mutation was observed in eight patients (18%), and three patients (7%) were ΔF508 carriers. The 2183AA > G mutation was observed in four patients, one of whom was also a ΔF508 carrier. The R1162X mutation was detected in two patients. The G542X, R334W and N1303K mutations were detected each in one patient, the first of whom was also a ΔF508 carrier.

Conclusion

Out of 45 patients, 27 (60%) had none of the CFTR gene mutations we tested for. The most frequent mutations in southwestern Iranian patients with CF should be identified by sequencing the entire CFTR gene in order to optimize the design of a diagnostic kit for common regional mutations.     

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.     

Impact of underlying cause of bronchiectasis on clinical outcome: A comparative study on CF and Non-CF bronchiectasis in Egyptian children

Background

Bronchiectasis represents an important cause of chronic lung disease in children in developing countries and continues to be one of the leading causes of morbidity and mortality with worsening quality of life in these children.

Mild to moderate cystic fibrosis is not associated with increased fracture risk in children and adolescents

OBJECTIVES: To determine whether children and adolescents with cystic fibrosis (CF), pancreatic insufficiency (PI), and mild-to-moderate lung disease have an increased risk of fracture compared with concurrent healthy control subjects. STUDY DESIGN: A lifetime fracture history questionnaire was administered to 186 subjects (ages 6 to 25 years) with CF, PI and mild-to-moderate lung disease and 427 healthy white control subjects (ages 4 to 25 years). RESULTS: A fracture was reported by 24% of subjects with CF and 23% of healthy control subjects. Average age of first fracture was similar between the groups (8.3 years for subjects and 8.8 years for controls). The radius/ulna was the most common fracture site in both groups. Risk of fracture, adjusted for sex and age, was not greater in the CF group compared with the control group (hazard ratio: 0.96, 95% CI: 0.68, 1.30, P = .82). CONCLUSION: Children and adolescents with CF, PI, and mild-to-moderate lung disease were not at an increased risk of fracture.     

Phenotypic and genetic characterization of patients with features of "nonclassic" forms of cystic fibrosis

OBJECTIVE: To determine which features of incomplete or "nonclassic" forms of cystic fibrosis (CF) are associated with deleterious CF transmembrane conductance regulator gene ( CFTR ) mutations, and to explore other etiologies for features not associated with deleterious CFTR mutations. STUDY DESIGN: Clinical features were compared between 57 patients with deleterious mutations in each CFTR and 63 with no deleterious mutations. The Shwachman Bodian Diamond syndrome gene ( SBDS ) was sequenced to search for mutations in patients with no deleterious CFTR mutations and steatorrhea to determine if any had unrecognized Shwachman-Diamond syndrome (SDS). RESULTS: The presence of a common CF-causing mutation, absence of the vas deferens, and Pseudomona aeruginosa in the sputum correlated with the presence of two deleterious CFTR mutations, whereas sweat chloride concentration, diagnostic criteria for CF, and steatorrhea did not. However, sweat chloride concentration correlated with CFTR mutation status in patients infected with P aeruginosa. One patient had disease-causing mutations in each SBDS . CONCLUSIONS: Presence of a common CF-causing mutation, absence of the vas deferens and/or P aeruginosa infection in a patient with features of nonclassic CF are predictive of deleterious mutations in each CFTR , whereas steatorrhea in the same context is likely to have etiologies other than CF transmembrane conductance regulator (CFTR) dysfunction.     

Potential impact of newborn screening for cystic fibrosis on child survival: a systematic review and analysis

OBJECTIVE: To estimate the population impact of child mortality as a result of cystic fibrosis (CF) potentially preventable by newborn screening. STUDY DESIGN: A systematic literature review of mortality in children with classic CF without meconium ileus (MI) in screened and unscreened cohorts was extended by contacting investigators for unpublished data. In addition, survival in US states with and without newborn screening (NBS) programs for CF was compared using data from the Cystic Fibrosis Foundation Patient Registry (CFFPR). RESULTS: Among non-US studies, CF-related mortality risk to approximately 10 years of age was lower by 5 to 10 per 100 in screened cohorts. Unpublished US data from a trial of NBS for CF indicate no CF-related deaths to 10 years of age in either cohort. CFFPR data suggest improved survival among children with CF born in US states with NBS, with a CF-related mortality difference to 10 years of age between the screened and unscreened groups between 1.5 and 2 per 100 children with CF without MI. CONCLUSION: In addition to improving nutritional outcomes, newborn screening for CF may result in improved child survival. The absolute differential in mortality risk, although modest in size, appears comparable to NBS for certain other genetic disorders.     

Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease

Aim: To determine whether serum hyaluronic acid (HA) concentrations are abnormal in patients with cystic fibrosis (CF) liver disease, and if so, whether the abnormality is associated with disease severity. Methods: A total of 74 patients with CF were assessed for evidence of liver involvement as indicated by clinical, ultrasound, and biochemical findings. Serum hyaluronic acid concentrations were measured and compared with concentrations in 293 normal controls. Lung function in the CF patients was also recorded. Results: Thirty four CF patients had no evidence of liver disease; in these, serum HA concentrations were similar to those in healthy controls (median (range): 16.1 (9.4–75.1) v 15 (1–77) µg/l). Nineteen CF patients had established liver disease detected by clinical and ultrasound examination, with significantly increased HA concentrations (56.1 (26–355) µg/l). Serum HA concentrations were also significantly increased, although to a lesser extent, in 21 CF patients with an abnormal liver ultrasound scan alone (22.4 (9.5–43.4) µg/l). There was no correlation between serum HA concentration and lung function. Conclusion: Serum HA concentrations were significantly increased in children with clinical or ultrasound evidence of liver disease, being higher in those with more advanced hepatic damage. Despite the inflammation and fibrosis present in CF lungs there was no correlation between HA concentration and lung function, suggesting that high concentrations were a failure of hepatic clearance rather than overproduction in the lung. Longitudinal measurement of HA concentrations may prove a useful marker for the development of significant liver damage in CF patients.     

Retinol binding protein status in relation to ocular surface changes in patients with cystic fibrosis treated with daily vitamin A supplements

Cystic fibrosis (CF) is an autosomal recessive disease characterised by increased viscosity of mucus secretions and high chloride concentration in exocrine secretions. Clinically, the patients suffer from chronic pulmonary changes, chronic pancreatic deficiency, and an obstruction of the gastrointestinal tract. The disease affects all secretory epithelia including the eye. The influence of nutritional status on long-term survival and quality of life of CF patients is well documented. Steatorrhea, a consequence of decreased fat digestion and absorption may be associated with vitamin deficiences, including vitamin A. The aim of this study was to document plasma retinol binding protein (RBP) status, a specific plasma transport protein for vitamin A, and ocular surface changes in children and adolescents with CF. The patients were recruited at the 3rd Department of Paediatric Diseases, Medical University of Bialystok, Poland. All patients were regularly seen by a CF specialist dietitian. A group of 15 patients had the following investigations: plasma RBP, visual acuity, physical examination, tear film break-up time, fluorescein staining and Schirmer tear test. A group of 15 age- and sex-matched controls without CF or ocular pathology were also recruited. Plasma RBP concentrations were significantly lower in patients with CF than in the control group. CF patients showed a statistically significant increase in the incidence of clinical blepharitis. Five of the CF patients had clinical evidence of dry eyes. Conclusion:Low plasma retinol binding protein levels frequently occur in clinically stable and retinol supplemented cystic fibrosis patients, of whom five had dry eyes. We recommend monitoring of plasma retinol binding protein levels and evaluation of ocular surface changes, especially those with dry eye symptoms in all cystic fibrosis patients.     

Effect of exocrine pancreatic function on resting energy expenditure in cystic fibrosis

AIM: To prove the hypothesis that exocrine pancreatic function determines resting energy expenditure (REE) in cystic fibrosis (CF). METHOD: Thirty-eight CF individuals, 9-34 (19.98 +/- 1.0) years, were divided into three groups: Six pancreatic sufficient patients (PS; group A), 21 pancreatic insufficient patients (PI), whose pulmonary function was comparable to that of group A (group B1) and 11 PI patients, whose pulmonary function was significantly worse than that of group A (group B2). REE was estimated by indirect calorimetry. Predicted REE was based on Schofield equations. Measured REE was expressed as % of the predicted. BMI, BMI z-scores, serum albumin, cholesterol and triglycerides levels were related to REE. Results were expressed as mean +/- standard error. RESULTS: Groups B1 and B2 had significantly higher REE% (111.7 +/- 2.75% and 119.94 +/- 3.8, respectively) as opposed to group A (98.9 +/- 3.81%; p = 0.022 and 0.035, respectively) whose REE% was similar to that predicted. REE% between group B1 and B2 was not statistically significant. In groups A, B1 and B, mean FEV1% was 86.33 +/- 10.1%, 90.24 +/- 4.39%, 44.54 +/- 3.47%, respectively, mean BMI was 25.6 +/- 2.06, 19.48 +/- 0.64 and 20.09 +/- 8.8, respectively, BMI z-scores were 0.75 +/- 0.51, -0.52 +/- 0.24 and -1.07 +/- 0.37, respectively. Significant correlation was demonstrated between REE%, BMI z-scores and cholesterol levels in group A. CONCLUSION: Clinically stable CF patients, who had comparable pulmonary function, exhibited increased REE% only in the presence of exocrine pancreatic insufficiency. REE% strongly correlated with BMI z-scores in pancreatic sufficiency. These findings support the hypothesis that pancreatic rather than pulmonary function may determine nutritional status as well as REE in CF.     

Structural airway abnormalities in infants and young children with cystic fibrosis

OBJECTIVES: To determine whether the airway structure of infants and young children with cystic fibrosis (CF) differs from that of normal children by using high-resolution computed tomography (HRCT) imaging. Study design Full-inflation, controlled ventilation HRCT images of the lungs were obtained at four anatomic levels in 34 infants with CF (age, 2.4+/-1.4 years) and 20 control infants (age, 1.8+/-1.4 years). Short axis diameters of all clearly identifiable, round airway/vessel pairs were measured to obtain airway wall thickness (AWT), airway lumen diameter (ALD), and vessel diameter (VD). RESULTS: In infants with CF, mean AWT (+/-SD) was 0.58+/-0.13 mm, ALD was 1.31+/-0.56 mm, and VD was 1.62+/-0.58 mm. In control infants, mean AWT was 0.49+/-0.13 mm, ALD was 1.07+/-0.42 mm, and VD was 1.86+/-0.64 mm. Mean AWT and ALD were greater in children with CF than in normal subjects (P<.001). ALD:VD ratios increased with age in patients with CF compared with control subjects (P=.026). CONCLUSIONS: The airways of infants and young children with CF have thicker walls and are more dilated than those of normal infants.