Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

CONTEXT: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. OBJECTIVE: We investigated genetic causes of PAI in children and young people over a 25 year period. DESIGN SETTING AND PARTICIPANTS: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. INTERVENTION AND OUTCOME MEASUREMENTS: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). RESULTS: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. CONCLUSIONS: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved.

Generating longitudinal growth charts from preterm infants fed to current recommendations.

OBJECTIVE: To use repeated measurements of weight, length and head circumference to generate growth centile charts reflecting real-world growth of a population of very preterm infants with a well-described nutritional intake close to current recommendations. DESIGN: Infants born before 30 weeks gestational age (GA) were recruited. Infants received nutrition according to an integrated care pathway, with nutrient intake recorded daily, weight recorded twice-weekly and length and head circumference weekly. The LMS method was used to construct growth centile charts between 24 and 36 weeks corrected GA for each parameter. SETTING: A single tertiary neonatal unit in England. PATIENTS: 212 infants (124 male) (median GA at birth: 27.3 weeks, median birth weight: 900 g). RESULTS: Median daily energy, protein, carbohydrate and fat intake were within 3% of published recommendations. The total number of measurements recorded was 5944 (3431 for weight, 1227 for length and 1286 for head circumference). Centile charts were formed for each parameter. Data for male and female infants demonstrated similar patterns of growth and were pooled for LMS analysis. A web application was created and published (bit.ly/sotongrowth) to allow infants to be plotted on these charts with changes in SD score of measurements reported and graphically illustrated. CONCLUSIONS: These charts reflect growth in a real-world cohort of preterm infants whose nutrient intakes are close to current recommendations. This work demonstrates the feasibility of forming growth charts from serial measurements of growing preterm infants fed according to current recommendations which will aid clinicians in setting a benchmark for achievable early growth.

Handheld 3D scanning as a minimally invasive measuring technique for neonatal anthropometry.

BACKGROUND: Measurement of length and head circumference (HC) in addition to weight is vital in assessing the nutritional status of preterm infants. Current anthropometry represents an interruption to preterm infants, and may not be possible in unstable infants. Handheld 3D scanning has the potential to perform bedside anthropometry (length and HC) in a less invasive manner. We aimed to evaluate the feasibility and performance of 3D scanning as a 'non-touch' measuring technique for routine anthropometry. METHODS: Preterm infants born before 30 weeks gestation were recruited from a single neonatal unit. HC and length were measured both manually and by a handheld 3D scanner at recruitment and weekly until discharge. The two methods were compared using the Bland-Altman method and linear regression. RESULTS: Seventeen infants had manual and 3D-scan measurements (67 HC, 87 length). The mean difference (95%CI) between manual and 3D-scan measures, as a percentage of the manual value, was 2.87% (2.27-3.47%) for HC and 3.10% (2.65-3.54%) for length. Correlation between manual and 3D measures was high; HC r = 0.957 and length 0.963. Bland-Altman plots showed reasonable agreement between the two methods, and there was a high correlation between scanner and manual measurements. CONCLUSIONS: These data show a high correlation between measurements gathered from 3D scan images and standard anthropometry. However, 3D measures are not yet precise enough for routine clinical use. Refinement of technique/technology may translate into practical monitoring the growth of preterm infants with minimal handling and without interruption to developmental care.

Measuring body composition in the preterm infant: Evidence base and practicalities.

Preterm birth and body composition have demonstrable effects on growth and later health outcomes. Preterm infants reach term equivalent age with a lower proportion of lean mass and higher body fat percentage than their term equivalent counterparts. Weight and length do not give an accurate assessment of body composition. Tracking body composition rather than just weight is a fundamental part of improving nutritional outcomes. This is important given the ongoing controversies regarding the nutritional needs of preterm infants, as well as establishing suitable targets for their growth. In this review we describe current methodologies used in the measurement of body composition of the preterm infant and the review the recent published evidence for their accuracy and utility. Current measurement techniques employed include air displacement plethysmography, bioelectrical impedance analysis, isotope dilution techniques, MRI and a combination of manual measurements including skinfold thickness, body mass index and mid upper arm/mid-thigh circumference. These measures allow for the estimation of fat mass, fat-free mass and regional assessment of adiposity. Some methods, such as dual-energy X-ray absorptiometry and air displacement plethysmography do allow for comparison of change in body composition over time in cohorts of preterm infants that may be studied over a longer period of time and into adult life. However, none of the currently described methods give an accurate and practically achievable method of obtaining body composition measures in preterm infants in day to day routine clinical practise, although this remains a key priority when decisions are being made about how best to feed.

Embedding electronic growth charts into clinical practice at a children's hospital.

Embedding electronic growth charts (EGCs) into clinical practice in a children's hospital. We employed initial implementation in the outpatient setting and subsequently extended this across inpatients with the growth chart following the child's records through both settings and significantly increasing growth data documentation.