Clinical complications in children with false-negative results in cystic fibrosis newborn screening

Abstract Objective: To present signs and symptoms and clinical course in cystic fibrosis patients with false-negative newborn screening (CF NBS). Materials and methods: All children presented in this paper were covered by CF NBS. The group of 1.869.246 newborns was screened in the Institute of Mother and Child in Warsaw within a period of 01.01.1999 - 31.05.2019. Screening protocols evolved over time from IRT/IRTto IRT/DNA/EGA. Results: The authors identified 11 patients with false-negative NBS, in whom CF was diagnosed based on clinical symptoms or the examination of siblings with positive CF NBS. In the study group, the diagnosis was made significantly later in comparison to positive CF NBS patients ranging from 2 months to 15 years of age. CF NBS strategy does not significantly affect the sensitivity of the screening. Conclusion: In the presence of clinical symptoms, additional diagnostics must be implemented, in spite of the negative screening results. At first, the sweat test should be conducted, followed by a DNA analysis of the most common mutations in the given population. The diagnostic process requires searching for CFTR mutations not typically associated with a high chloride concentration in sweat. Repetition of sweat chloride concentration enables the diagnosis in children whose initial chloride values in sweat are borderline, and no CF-causing mutations are detected. In strong clinical indications, the extension of DNA analysis (EGA) is recommended in order to identify rare CF variants. In children with meconium ileus, genetic analysis is mandatory.

Clinical complications in children with false-negative results in cystic fibrosis newborn screening.

OBJECTIVE: To present signs and symptoms and clinical course in cystic fibrosis patients with false-negative newborn screening (CF NBS). MATERIALS AND METHODS: All children presented in this paper were covered by CF NBS. The group of 1.869.246 newborns was screened in the Institute of Mother and Child in Warsaw within a period of 01.01.1999 - 31.05.2019. Screening protocols evolved over time from IRT/IRT to IRT/DNA/EGA. RESULTS: The authors identified 11 patients with false-negative NBS, in whom CF was diagnosed based on clinical symptoms or the examination of siblings with positive CF NBS. In the study group, the diagnosis was made significantly later in comparison to positive CF NBS patients ranging from 2 months to 15 years of age. CF NBS strategy does not significantly affect the sensitivity of the screening. CONCLUSION: In the presence of clinical symptoms, additional diagnostics must be implemented, in spite of the negative screening results. At first, the sweat test should be conducted, followed by a DNA analysis of the most common mutations in the given population. The diagnostic process requires searching for CFTR mutations not typically associated with a high chloride concentration in sweat. Repetition of sweat chloride concentration enables the diagnosis in children whose initial chloride values in sweat are borderline, and no CF-causing mutations are detected. In strong clinical indications, the extension of DNA analysis (EGA) is recommended in order to identify rare CF variants. In children with meconium ileus, genetic analysis is mandatory.

Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020.

BACKGROUND: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). METHODS: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. RESULTS: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133). CONCLUSIONS: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination.

Clinical characteristics of rare CFTR mutations causing cystic fibrosis in Polish population.

INTRODUCTION: More than 2000 mutations have been identified since the discovery of the CFTR gene in 1989. However, only 346 mutations have been classified as cystic fibrosis (CF)-causing mutations. Due to the increasing number of mutations and poor correlation between the genotype and phenotype, there is an urgent need to determine the mutations that are pathogenic, nonpathogenic, or lead to variable symptoms. AIM: The aim of the study was to present the clinical characteristics of Polish patients with rare and novel CFTR mutations, with an attempt to determine the pathogenicity status of those variants. MATERIALS AND METHODS: The group included 13 patients born between September 2006 and May 2019, who underwent CF newborn screening and in whom two CFTR mutations, including at least one rare or a novel mutation, were identified. RESULTS: We identified 13 patients with mutations in both alleles of the CFTR gene, one of which was at least rare in Polish population (R289NfsX17, I618RfsX2, T682KfsX40, S1347PfsX13, W356X, E33X, dup.16,17A) or was a mutation of unknown clinical consequences (H199R, L468P, A1217E, Q359R, T1036I, W1282R). None of them were described in the CFTR2 database. In all examined patients, sweat tests were elevated. The diagnosed patients presented with a wide spectrum of clinical symptoms. Broad clinical characteristics and test results are presented. CONCLUSION: Pathogenic mutations are H199R, L468P, A1217E, Q359R, T1036I, W1282R, R289NfsX17, I618RfsX2, T682KfsX40, S1347PfsX13, W356X, E33X, dup.16,17A. Every patient with a mutation of unknown clinical consequences in one CFTR allele requires attentive follow-up.

Determining the enzymatic activities of iodothyronine 5'-deiodinases in renal medulla and cortex.

INTRODUCTION: Thyroid hormone disorders in patients with chronic kidney disease (CKD) are a result of impaired conversion of T4 to T3. The importance of kidneys in thyroid hormones conversion is not fully understood. The activities of different types of iodothyronine deiodinases in the kidney structures have not been determined yet. The aim of this study was to determine the activity of deiodinase type 1 (D1) and type 2 (D2) in renal cortex and medulla in renal cancer patients. MATERIAL AND METHODS: Samples of renal cortex and medulla (ten patients) or renal cortex alone (13 patients) were taken from kidneys resected because of malignant cancer, from a site opposite to the cancer. Resections were performed in the 23 patients (seven female and 16 male) who were 52-82 years old. The material was stored at -72 oC. RESULTS: Activity of D1 in renal cortex was 3.785 ± 2.041 fmol 125I/mg protein/minute and activity of D2 was 0.236 ± 0.125 fmol 125I/mg protein/minute. There was a strong positive correlation between D1 and D2 activities in renal cortex (r = 0.890, p 〈 0.001). Activity of D1 in renal medulla was 2.157 ± 2.176 fmol 125I/mg protein/minute, and activity of D2 was 0.168 ± 0.095 fmol 125I/mg protein/minute. A positive correlation between D1 and D2 in renal medulla (r = 0.661, p = 0.038) was observed as well. Activities of D1 in cortex and medulla were strongly and positively associated (r = 0.794, p = 0.006), whereas there was no correlation between the activities of D2 in cortex and medulla (r = 0.224, p = 0.553). CONCLUSIONS: Results presented in this study suggest that both cortical and medullary D1 and D2 may be involved in thyroid hormone metabolism. This finding could be of clinical relevance in patients with impaired renal function.

Renal amyloidosis in Whipple disease: a case report.

INTRODUCTION: Whipple disease is a rare systemic infection caused by Tropheryma whippelii that usually manifests with joint pain, weight loss, diarrhoea and abdominal pain. However, in some cases the infection may involve other organs and tissues. CASE PRESENTATION: We report on a 44-year-old man with Whipple disease which led to renal amyloidosis and end-stage renal failure. In this case, the patient was diagnosed with Whipple disease and commenced on a 12-month trimetoprime-sulfametoxasole therapy with good result. Six months after cessation of therapy the patient was readmitted to hospital due to signs of renal failure. An urgent kidney biopsy was performed which revealed secondary amyloidosis. Despite intensive immunosuppressive treatment, renal parameters gradually deteriorated and haemodialysis was started eventually. Three months later the patient's general condition dramatically worsened with bloody diarrhoea, bilious vomiting and progressive malnutrition. The repeated endoscopic examination confirmed severe recurrence of Whipple disease. Ceftriaxone and total parenteral nutrition was started what greatly improved patient's state. CONCLUSIONS: To our knowledge based on systematic review, this is the first case report on Whipple disease complicated by secondary amyloidosis and kidney failure maintained on permanent renal replacement therapy. It is strongly suspected that the use of immunosuppressive treatment in such cases may exacerbate the course of Whipple disease and cause life-threatening complications.