Every CFTR variant counts - Target-capture based next-generation-sequencing for molecular diagnosis in the German CF Registry.

BACKGROUND: In times of genotype guided therapy options, a total of 3.2 % of people with CF (pwCF) in the German CF Registry[1] only have one or no CFTR-variant detected after genetic analysis. Additionally, genetic data in the Registry can be documented as free text and can therefore be prone to error. In order to allow the greatest possible amount of pwCF access to modern therapies, we conducted a re-evaluation of free text entries and established a custom-whole-CFTR-locus NGS-approach for all pwCF who remained without genetic confirmation afterwards. METHODS: To this end, we assembled 731 free text variants of 655 pwCF in the German CF Registry. All variants were evaluated using ClinVar, HGMD and CFTR1/2, corrected in the Registries' database and uploaded to ClinVar. PwCF whose diagnosis remained uncertain as well as additional pwCF or pwCFTR-RD that were assembled through a nationwide call for testing of unclear cases were offered genetic analysis. Samples were analysed using a target-capture based NGS-custom-design-panel covering the entire CFTR-locus. RESULTS: Evaluation of free text variants led to the discovery of 43 variants not formerly reported in the context of CF. The Registries' dropdown list was extended by 497 variants and over 500 pwCF were provided with their most up-to-date genotype. Samples of 47 pwCF/pwCFTR-RD were sequenced via NGS with an overall success rate of 61.7 %, resulting in implementation of entire CFTR-genotyping into routine diagnostics. CONCLUSION: Entire CFTR-genotyping can greatly increase the genetic diagnostic rate of pwCF/pwCFTR-RD and should be considered after inconspicuous CFTR screening panels in CFTR-diagnostics.

Comparative meta-analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia.

BACKGROUND AND OBJECTIVE: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta-analysis. METHODS: Data of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics. RESULTS: Seven new patients were identified with seven different pathogenic variants in KDM6A (n = 4) or KMT2D (n = 3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta-analysis, 24 KS patients with HH had a significantly higher frequency of variants in KDM6A compared to 373 KS patients without HH (50% vs 11.5%, P < .001), and KDM6A-KS was more likely to be associated with HH than KMT2D-KS (21.8% vs. 3.5%, P < .001). Sex distribution and other phenotypic features did not differ between KS with and without HH. CONCLUSION: The higher incidence of HH in KDM6A-KS compared to KMT2D-KS indicates that KDM6A loss of function variants predispose more specifically to beta cell dysfunction compared to KMT2D variants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.

Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis.

Cystic fibrosis (CF) is characterised by chronic airway infection with bacteria and fungi. Infections caused by Scedosporium/Lomentospora species can occur and are difficult to treat. Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. Our aim was to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF.

Relationship of Serum Fetuin A with Metabolic and Clinical Parameters in German Children and Adolescents with Type 1 Diabetes.

BACKGROUND AND AIM: The hepatokine fetuin A is upregulated in the metabolic syndrome and in type 2 diabetes (T2D), while its role in adolescent type 1 diabetes (T1D) is unclear. We assessed the relationship between circulating fetuin A levels and metabolic control, comorbidities, and complications in adolescent T1D patients. METHODS: We studied the relationship between serum fetuin A and clinical diabetes-related data from the DPV registry (Diabetes-Pa-tienten-Verlaufsdokumentation) in 172 adolescent T1D patients with early-onset (<5 years) long-standing (>10 years) T1D. Fetuin A levels were further compared between adolescent T1D and T2D patients. RESULTS: Serum fetuin A levels in T1D patients (mean 0.267 ± 0.043 g/L) did not correlate with age, diabetes duration, gender, body mass index (BMI), glycated hemoglobin, serum lipid levels, blood pressure, celiac or thyroid disease, nephropathy, or retinopathy. An association of fetuin A levels with insulin requirements was only evident within the subgroup of overweight T1D patients (rs = 0.439, p = 0.028, n = 25, BMI >90th percentile), disappearing after adjustment for multiple testing. Adolescent T1D patients showed distinctly lower fetuin A levels than patients with T2D (p ≤ 0.001). CONCLUSION: Overall, we did not observe a clinically relevant association of fetuin A levels with surrogate parameters for insulin sensitivity in our juvenile T1D cohort. A correlation with insulin requirements was detectable in overweight patients only. We hypothesize that multiple factors, such as obesity, puberty, inadequate metabolic control, and hepatic steatosis, have to add up before a clinically relevant effect of fetuin A on insulin sensitivity becomes evident.

Vascular risk factors in children, adolescents, and young adults with type 1 diabetes complicated by celiac disease: results from the DPV initiative.

OBJECTIVE: Celiac disease (CD) is a common comorbidity of type 1 diabetes (T1D). Long-term consequences of CD are not completely understood, and adhering to a gluten-free diet is a burden for many patients. We investigated the effect of CD on vascular risk factors in a large cohort of T1D patients aged <20 yr. RESEARCH DESIGN AND METHODS: Within the longitudinal Diabetes Patienten Verlaufsdokumentation (DPV)-diabetes registry, data were analyzed from 59,909 < 20-yr-old T1D patients treated at 392 centers in Germany and Austria. A total of 974 patients with biopsy-proven celiac disease (BPCD) were compared with 28,398 patients without CD with respect to blood pressure (BP), lipids, glycohemoglobin (HbA1c ), body mass index (BMI), and reported smoking behavior. RESULTS: Patients with T1D and BPCD showed significantly lower high-density lipoprotein (HDL) cholesterol levels [median (interquartile range): 53.0 (43.0-62.6) mg/dL] than patients without CD [55.0 (45.0-66.0) mg/dL; p < 0.01; p < 0.001 after adjustment for confounding variables]. Systolic BP was lower in patients with CD [105.5 (100.0-112.5) mmHg] than in patients without CD [110.0 (102.0-117.0) mmHg; p < 0.0001; p < 0.001 after adjustment]. There were no significant differences regarding smoking behavior, BMI, or HbA1c . In a subgroup of 335 patients with BPCD, HDL cholesterol was measured 1 yr after diagnosis of CD:HDL increased by 8% (p < 0.01). CONCLUSION: Young people with T1D and CD have lower HDL cholesterol values than patients without CD. As low HDL cholesterol is associated with vascular risk, our findings support screening for CD and monitoring of HDL cholesterol in young people with T1D.

Comorbidity of type 1 diabetes and juvenile idiopathic arthritis.

OBJECTIVE: To analyze the prevalence of juvenile idiopathic arthritis (JIA) and diabetes end points in pediatric patients with type 1 diabetes. STUDY DESIGN: Patients with type 1 diabetes, recorded from 1995 up to September 2013 in the Diabetes Patienten Verlaufsdokumentation database (n = 54,911, <16 years of age, 47% girls), were analyzed. The patients' height, weight, and body mass index SDS, glycosylated hemoglobin A1c (HbA1c); insulin dose; hypertension and dyslipidemia prevalence; rate of hypoglycemic events; and ketoacidosis were compared between patients with and without JIA. To adjust for age, sex, diabetes duration, and migration background, data were analyzed in hierarchic multivariable regression models. RESULTS: The prevalence of JIA in type 1 diabetes was 106 of 54,911 patients; 66% were girls. Diabetes onset was earlier in children with JIA (7.2 years vs 8.3 years, P = .04). Children with JIA were smaller (SDS: -0.22 vs 0.09, P = .004). Correspondingly, weight SDS was lower in patients with JIA (-0.02 vs 0.22, P = .01). Body mass index SDS did not differ. HbA1c was marginally lower in children with JIA (63 mmol/mol [8.0%] vs 67 mmol/mol [8.3%], P = .06). Insulin requirement was greater in patients with JIA (1.03 vs 0.93 insulin units/weight/day, P = .003). Hypertension and dyslipidemia were comparable in both groups. CONCLUSIONS: The JIA-prevalence in patients with type 1 diabetes (0.19%) was considerably greater than in the general population (0.05%). Growth is influenced negatively by JIA. Surprisingly, HbA1c was somewhat lower in children with JIA, possibly because of a more intensive treatment or a latent hemolysis caused by the inflammation.