Exome sequencing (ES) of a pediatric cohort with chronic endocrine diseases: a single-center study (within the framework of the TRANSLATE-NAMSE project).

BACKGROUND: Endocrine disorders are heterogeneous and include a significant number of rare monogenic diseases. METHODS: We performed exome sequencing (ES) in 106 children recruited from a single center within the TRANSLATE­NAMSE project. They were categorized into subgroups: proportionate short stature (PSS), disproportionate short stature (DSS), hypopituitarism (H), differences in sexual development (DSD), syndromic diseases (SD) and others. RESULTS: The overall diagnostic yield was 34.9% (n = 37/106), including 5 patients with variants in candidate genes, which have contributed to collaborations to identify gene-disease associations. The diagnostic yield varied significantly between subgroups: PSS: 16.6% (1/6); DSS: 18.8% (3/16); H: 17.1% (6/35); DSD: 37.5% (3/8); SD: 66.6% (22/33); others: 25% (2/8). Confirmed diagnoses included 75% ultrarare diseases. Three patients harbored more than one disease-causing variant, resulting in dual diagnoses. CONCLUSIONS: ES is an effective tool for genetic diagnosis in pediatric patients with complex endocrine diseases. An accurate phenotypic description, including comprehensive endocrine diagnostics, as well as the evaluation of variants in multidisciplinary case conferences involving geneticists, are necessary for personalized diagnostic care. Here, we illustrate the broad spectrum of genetic endocrinopathies that have led to the initiation of specific treatment, surveillance, and family counseling.

Arginine-stimulated copeptin based diagnosis of central diabetes insipidus in children and adolescents.

INTRODUCTION: Diagnosis of central diabetes insipidus (CDI) remains challenging. Water deprivation testing and hypertonic saline infusion, as established diagnostic tests, are mentally and physically demanding for patients. Arginine-stimulated copeptin has been shown as a putative parameter for the differential diagnosis of CDI in adults. METHODS: In this single-centre retrospective study, we identified paediatric patients with suspected pituitary disorders who underwent standard arginine-testing. Patients with CDI, matched controls and primary polydipsia (PP) were identified. Diagnoses were confirmed retrospectively using comprehensive clinical and diagnostic characteristics. Serum copeptin concentrations were measured using a commercially available automated immunofluorescence assay (B.R.A.H.M.S Copeptin-proAVP KRYPTOR®) in samples stored for a median of 4.6 years (1.3-10.84) and collected before and 60 minutes after arginine-infusion. Cut-off analyses were performed using ROC curves. RESULTS: Serum samples from 32 patients with CDI, 32 matched controls and 5 patients with PP (n=69; 51 males, 18 females) were available for analysis. Median copeptin concentrations increased from 4.47 pmol/l (IQR: 3.47-8.36) to 6.96 pmol/l (IQR: 4.51-12.89; p<0.001) in controls, from 1.46 pmol/l (IQR: 1.21-2.12) to 1.44 (IQR: 1.10-1.87; p=0.645, ns) in CDI and from 4.40 pmol/l (3.95-6.33) to 9.58 pmol/l (8.19-11.42; p<0.001) in PP. The published cut-off value of 3.8 pmol/l revealed a sensitivity of 100 % and a specificity of 86.5 % in confirming CDI. CONCLUSION: Our results suggest that arginine-stimulated serum copeptin concentrations are a sensitive and specific diagnostic tool for CDI in paediatric patients, which may replace and simplify the conventional diagnostic pathway of water deprivation testing and hypertonic saline infusion.