Extensive clinical, hormonal and genetic screening in a large consecutive series of 46, XY neonates and infants with atypical sexual development

Background: One in 4500 children is born with ambiguous genitalia, milder phenotypes occur in one in 300 newborns. Conventional time-consuming hormonal and genetic work-up provides a genetic diagnosis in around 20-40% of 46, XY cases with ambiguous genitalia. All others remain without a definitive diagnosis. The investigation of milder cases, as suggested by recent reports remains controversial. Methods: Integrated clinical, hormonal and genetic screening was performed in a sequential series of 46, XY children, sex-assigned male, who were referred to our pediatric endocrine service for atypical genitalia (2007-2013). Results: A consecutive cohort of undervirilized 46, XY children with external masculinization score (EMS) 2-12, was extensively investigated. In four patients, a clinical diagnosis of Kallmann syndrome or Mowat-Wilson syndrome was made and genetically supported in 2/3 and 1/1 cases respectively. Hormonal data were suggestive of a (dihydro) testosterone biosynthesis disorder in four cases, however no HSD17B3 or SRD5A2 mutations were found. Array-CGH revealed a causal structural variation in 2/6 syndromic patients. In addition, three novel NR5A1 mutations were found in non-syndromic patients. Interestingly, one mutation was present in a fertile male, underlining the inter-and intrafamilial phenotypic variability of NR5A1-associated phenotypes. No AR, SRY or WT1 mutations were identified. Conclusion: Overall, a genetic diagnosis could be established in 19% of non-syndromic and 33% of syndromic cases. There is no difference in diagnostic yield between patients with more or less pronounced phenotypes, as expressed by the external masculinisation score (EMS). The clinical utility of array-CGH is high in syndromic cases. Finally, a sequential gene-by-gene approach is time-consuming, expensive and inefficient. Given the low yield and high expense of Sanger sequencing, we anticipate that massively parallel sequencing of gene panels and whole exome sequencing hold promise for genetic diagnosis of 46, XY DSD boys with an undervirilized phenotype

Energy and protein requirements for children with CKD stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce

Dietary management in pediatric chronic kidney disease (CKD) is an area fraught with uncertainties and wide variations in practice. Even in tertiary pediatric nephrology centers, expert dietetic input is often lacking. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, was established to develop clinical practice recommendations (CPRs) to address these challenges and to serve as a resource for nutritional care. We present CPRs for energy and protein requirements for children with CKD stages 2-5 and those on dialysis (CKD2-5D). We address energy requirements in the context of poor growth, obesity, and different levels of physical activity, together with the additional protein needs to compensate for dialysate losses. We describe how to achieve the dietary prescription for energy and protein using breastmilk, formulas, food, and dietary supplements, which can be incorporated into everyday practice. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgment. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.Peer reviewe

Nutritional management of the infant with chronic kidney disease stages 2-5 and on dialysis

The nutritional management of children with chronic kidney disease (CKD) is of prime importance in meeting the challenge of maintaining normal growth and development in this population. The objective of this review is to integrate the Pediatric Renal Nutrition Taskforce clinical practice recommendations for children with CKD stages 2-5 and on dialysis, as they relate to the infant from full term birth up to 1 year of age, for healthcare professionals, including dietitians, physicians, and nurses. It addresses nutritional assessment, energy and protein requirements, delivery of the nutritional prescription, and necessary dietary modifications in the case of abnormal serum levels of calcium, phosphate, and potassium. We focus on the particular nutritional needs of infants with CKD for whom dietary recommendations for energy and protein, based on body weight, are higher compared with children over 1 year of age in order to support both linear and brain growth, which are normally maximal in the first 6 months of life. Attention to nutrition during infancy is important given that growth is predominantly nutrition dependent in the infantile phase and the growth of infants is acutely impaired by disruption to their nutritional intake, particularly during the first 6 months. Inadequate nutritional intake can result in the failure to achieve full adult height potential and an increased risk for abnormal neurodevelopment. We strongly suggest that physicians work closely with pediatric renal dietitians to ensure that the infant with CKD receives the best possible nutritional management to optimize their growth and development.Peer reviewe

The dietary management of calcium and phosphate in children with CKD stages 2-5 and on dialysis-clinical practice recommendation from the Pediatric Renal Nutrition Taskforce

In children with chronic kidney disease (CKD), optimal control of bone and mineral homeostasis is essential, not only for the prevention of debilitating skeletal complications and achieving adequate growth but also for preventing vascular calcification and cardiovascular disease. Complications of mineral bone disease (MBD) are common and contribute to the high morbidity and mortality seen in children with CKD. Although several studies describe the prevalence of abnormal calcium, phosphate, parathyroid hormone, and vitamin D levels as well as associated clinical and radiological complications and their medical management, little is known about the dietary requirements and management of calcium (Ca) and phosphate (P) in children with CKD. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists, who develop clinical practice recommendations (CPRs) for the nutritional management of various aspects of renal disease management in children. We present CPRs for the dietary intake of Ca and P in children with CKD stages 2-5 and on dialysis (CKD2-5D), describing the common Ca- and P-containing foods, the assessment of dietary Ca and P intake, requirements for Ca and P in healthy children and necessary modifications for children with CKD2-5D, and dietary management of hypo- and hypercalcemia and hyperphosphatemia. The statements have been graded, and statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. These CPRs will be regularly audited and updated by the PRNT.Peer reviewe

Assessment of nutritional status in children with kidney diseases-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce

In children with kidney diseases, an assessment of the child's growth and nutritional status is important to guide the dietary prescription. No single metric can comprehensively describe the nutrition status; therefore, a series of indices and tools are required for evaluation. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists who develop clinical practice recommendations (CPRs) for the nutritional management of children with kidney diseases. Herein, we present CPRs for nutritional assessment, including measurement of anthropometric and biochemical parameters and evaluation of dietary intake. The statements have been graded using the American Academy of Pediatrics grading matrix. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. Audit and research recommendations are provided. The CPRs will be periodically audited and updated by the PRNT.Peer reviewe

Assessment and management of obesity and metabolic syndrome in children with CKD stages 2-5 on dialysis and after kidney transplantation-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce

Obesity and metabolic syndrome (O&MS) due to the worldwide obesity epidemic affects children at all stages of chronic kidney disease (CKD) including dialysis and after kidney transplantation. The presence of O&MS in the pediatric CKD population may augment the already increased cardiovascular risk and contribute to the loss of kidney function. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists who develop clinical practice recommendations (CPRs) for the nutritional management of children with kidney diseases. We present CPRs for the assessment and management of O&MS in children with CKD stages 2-5, on dialysis and after kidney transplantation. We address the risk factors and diagnostic criteria for O&MS and discuss their management focusing on non-pharmacological treatment management, including diet, physical activity, and behavior modification in the context of age and CKD stage. The statements have been graded using the American Academy of Pediatrics grading matrix. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. Research recommendations are provided. The CPRs will be periodically audited and updated by the PRNT.Peer reviewe

Vestibular Infant Screening (VIS)–Flanders : results after 1.5 years of vestibular screening in hearing-impaired children

Due to the close anatomical relationship between the auditory and vestibular end organs, hearing-impaired children have a higher risk for vestibular dysfunction, which can affect their (motor) development. Unfortunately, vestibular dysfunction often goes unnoticed, as vestibular assessment in these children is not standard of care nowadays. To timely detect vestibular dysfunction, the Vestibular Infant Screening–Flanders (VIS–Flanders) project has implemented a basic vestibular screening test for hearing-impaired infants in Flanders (Belgium) with a participation rate of 86.7% during the first year and a half. The cervical Vestibular Evoked Myogenic Potentials (cVEMP) test was applied as vestibular screening tool to map the occurrence of vestibular (mainly saccular) dysfunction in this population. At the age of 6 months, 184 infants were screened. No refers on vestibular screening were observed in infants with permanent conductive hearing loss. In infants with permanent sensorineural hearing loss, a cVEMP refer rate of 9.5% was observed. Failure was significantly more common in infants with severe-profound compared to those with mild-moderate sensorineural hearing loss (risk ratio = 9.8). Since this is the first regional study with a large sample size and successful participation rate, the VIS–Flanders project aims to set an example for other regions worldwide

The External Genitalia Score (EGS): A European Multicenter Validation Study

CONTEXT: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. OBJECTIVES: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). DESIGN, SETTING: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. PATIENTS AND METHODS: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia. RESULTS: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia. CONCLUSIONS: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research