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Background Sapropterin has been approved as a treatment option for individuals with Phenylketonuria in the United Kingdom. Individuals are assessed as responsive to Sapropterin by a ≥30% reduction in Phenylalanine (Phe) concentrations using dried blood spot (DBS) specimens. DBS quality is critical for accurate and precise measurement of Phe. Currently, UK national guidelines for DBS specimen acceptance do not exist for patient-collected DBS specimens. We adopted evidence-based guidelines for specimen acceptance criteria and retrospectively assessed the impact of introducing these guidelines on specimen rejection rates. Methods: Laboratories were invited to audit the quality of DBS specimens routinely received for Phe monitoring using: (1) existing acceptance/rejection criteria and (2) proposed national guidelines. Results Ten laboratories audited 2111 specimens from 1094 individuals. Using existing local guidelines, the median rejection rate was 4.0% (IQR 1.5–7.2%). This increased to 21.9% (IQR 10.0–33.0%) using the proposed guidelines. Where reason(s) for rejection were provided ( n = 299); 211/299 (70.6%) of DBS specimens were too small or multi-spotted. 380 individuals had more than one sample evaluated; 231/380 (60.8%) provided specimens of acceptable quality, 37/380 (9.7%) consistently provided poor-quality DBS specimens. Conclusions There is significant variability in the quality of patient-collected DBS specimens. If unacceptable specimens are not rejected, imprecise/inaccurate results will be used in clinical decision making. Using annual workload data for England, this equates to 12,410 incorrect results. Individuals and parents/carers should receive ongoing training in blood collection technique to ensure use of evidence-based acceptability criteria does not cause undue distress from increased sample rejection rates.

Background Severe hyperammonaemia is associated with significant morbidity and mortality. Rapid analysis and reporting of ammonia results is essential to prevent patient harm. The aim was to investigate the laboratory sample acceptance criteria, ammonia analysis and the reporting of ammonia results. Methods A questionnaire was distributed to clinical biochemistry laboratories in the United Kingdom. The results were collated and compared to updated best practice guidelines on hyperammonaemia issued by the Metabolic Biochemistry Network ( MetBio.net ). Results Seventy-six laboratories responded to the audit questionnaire. Although 83% laboratories are aware of the updated MetBio.net hyperammonaemia guidelines, most laboratories continue to reject samples for ammonia that are ‘too old’ for analysis (64%), haemolysed (72%) or not sent on ice (24%). Rapid ammonia analysis is available in 96% laboratories and all laboratories offer ammonia analysis on a 24/7 basis. Nearly all laboratories had implemented critical phoning limits for ammonia. Conclusions Laboratories are rejecting samples for ammonia analysis that have not been collected/transported in an optimal manner. Laboratories should review their sample acceptance criteria for ammonia and accept all samples in order to avoid delaying the diagnosis and management of hyperammonaemia.

Context Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important. Objective We aimed to better understand the presentation and prevalence of pediatric DSD. Methods A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood. Conclusion DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care.

Background Total serum 25-hydroxyvitamin D [25(OH)D] is considered the best marker of vitamin D status and used routinely in clinical practice. However, 25(OH)D is predominantly bound to vitamin D-binding protein (VDBP), and it has been reported that the free-25(OH)D and 25(OH)D loosely bound to albumin fraction correlates better with clinical outcomes. Methods We assessed total-25(OH)D, measured free-25(OH)D, and calculated free-25(OH)D and their relationship with VDBP and biomarkers of mineral metabolism in 61 children (22 CKD 2–3, 18 dialysis, and 21 post-transplant). Results Total-25(OH)D concentrations were comparable across the three groups (p = 0.09), but free- and bioavailable-25(OH)D (free- and albumin-25(OH)D) were significantly lower in the transplant group (both: p = 0.01). Compared to CKD and dialysis patients, the transplant group had significantly higher VDBP concentrations (p = 0.03). In all three groups, total-25(OH)D concentrations were positively associated with measured free-, calculated free-, and bioavailable-25(OH)D. Multivariable regression analysis showed that total-25(OH)D was the only predictor of measured free-25(OH)D concentrations in the dialysis group (β = 0.9; R2 = 90%). In the transplant group, measured free-25(OH)D concentrations were predicted by both total-25(OH)D and VDBP concentrations (β = 0.6, − 0.6, respectively; R2 = 80%). Correlations between parathyroid hormone with total-25(OH)D and measured and calculated free-25(OH)D were only observed in the transplant group (all: p Conclusions In transplanted patients, VDBP concentrations were significantly higher compared to CKD and dialysis patients, and consequently, free-25(OH)D concentrations were lower, despite a comparable total-25(OH)D concentration. We suggest that free-25(OH)D measures may be required in children with CKD, dialysis, and transplant, with further research required to understand its association with markers of mineral metabolism.

Funder: National Institute for Health Research (NIHR), INTRODUCTION: There has been an increase in the birth prevalence of congenital hypothyroidism (CH) since the introduction of newborn screening, both globally and in the UK. This increase can be accounted for by an increase in CH with gland in situ (CH-GIS). It is not known why CH-GIS is becoming more common, nor how it affects the health, development and learning of children over the long term. Our study will use linked administrative health, education and clinical data to determine risk factors for CH-GIS and describe long-term health and education outcomes for affected children. METHODS AND ANALYSIS: We will construct a birth cohort study based on linked, administrative data to determine what factors have contributed to the increase in the birth prevalence of CH-GIS in the UK. We will also set up a follow-up study of cases and controls to determine the health and education outcomes of children with and without CH-GIS. We will use logistic/multinomial regression models to establish risk factors for CH-GIS. Changes in the prevalence of risk factors over time will help to explain the increase in birth prevalence of CH-GIS. Multivariable generalised linear models or Cox proportional hazards regression models will be used to assess the association between type of CH and school performance or health outcomes. ETHICS AND DISSEMINATION: This study has been approved by the London Queen Square Research Ethics Committee and the Health Research Authority's Confidentiality Advisory Group CAG. Approvals are also being sought from each data provider. Obtaining approvals from CAG, data providers and information governance bodies have caused considerable delays to the project. Our methods and findings will be published in peer-reviewed journals and presented at academic conferences.

Summary Background and objectives Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease. The hypothesis was that nutritional vitamin D (ergocalciferol) supplementation in children with CKD stages 2–4 delays the onset of secondary hyperparathyroidism. Design, setting, participants, & measurements A randomized, double-blinded, placebo-controlled study in children with CKD2–4 who had 25-hydroxyvitamin D [25(OH)D] deficiency was conducted. Ergocalciferol (or a matched placebo) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines. The primary endpoint was the time to development of hyperparathyroidism. Results Seventy-two children were screened. Forty-seven children were 25(OH)D-deficient and randomly assigned to receive ergocalciferol or placebo. Twenty children in each arm completed the study; median followup was 12 months. Groups were well matched for age, race, estimated GFR, and season when recruited. Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95% confidence interval, 1.02–21.00). The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95% confidence interval, 0.09–0.93, P=0.05). With ergocalciferol treatment, normal 25(OH)D levels were achieved in all 8 children with CKD2, 8 of 11 childrenwithCKD3,butnotinthesinglepatientwithCKD4.Therewerenoergocalciferol-relatedadverseevents. 25(OH)D levels .100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D. Conclusions Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2–3. Clin J Am Soc Nephrol 7: 216–223, 2012. doi: 10.2215/CJN.04760511

To assess the profile of thiopurine transmethyltransferase (TPMT) enzyme activities in children and discuss the utility of measuring TPMT levels before commencing azathioprine therapy.Retrospective study in a single pediatric center of all patients who had TPMT enzyme assay measured during a 3-year period before the start of azathioprine therapy. Patients' TPMT enzyme activities were classified as normal (26-50 pmol/h/mgHb), intermediate (10-25 pmol/h/mgHb), and deficient (10 pmol/h/mgHb). Medical and electronic prescribing records were studied, with records of patients' demographic data, diagnoses, dosages, and adverse drug reactions monitored.A total of 228 (45% female) patients ages 1-18 years (median 10 years) were tested for TPMT activity. They were all subsequently commenced on azathioprine. Erythrocyte TPMT activities were 14-76 (median 33.7) pmol/h/mgHb with 88% and 12% of patient having normal and intermediate activity respectively (none were deficient). The initial prescribed dosage of azathioprine was 0.7-3.5 (median 2.0) mg/kg/day. Only 2 patients developed mild neutropenia and required reduction of azathioprine dosage.This large cohort study demonstrates that the majority of pediatric patients had normal TMPT activities. We would recommend close monitoring of full blood counts after instituting azathioprine therapy but would question the cost-effectiveness of pretreatment TPMT activity in pediatric practice.

Randomized trials in adults have shown reduced all-cause and cardiovascular mortality on hemodiafiltration (HDF) compared to high-flux hemodialysis (HD), but the mechanisms leading to improved outcomes are not clear. We studied biomarkers of inflammation, oxidative stress, anti-oxidant capacity and endothelial dysfunction in 22 children (13 female, age 8-15 years). All children received HD for at least 3 months, and were then switched to HDF, keeping all dialysis related parameters and dialysis time constant. All the biomarkers of inflammation (ß2-microglobulin, IL-6, IL-10, high sensitive C-reactive protein [hsCRP]), oxidative stress (nitrotyrosine, advanced glycation end-products [AGEs], oxidized low density lipoprotein [ox-LDL] and anti-oxidant capacity) and endothelial dysfunction (asymmetric dimethyl arginine [ADMA], symmetric dimethyl arginine [SDMA]), were comparable between incident and prevalent patients on HD, suggesting that even a short dialysis vintage of 3 months on HD increases inflammation and endothelial stress. After 3 months of HDF therapy there was a significant reduction in ß2-microglobulin (pTrial registrationClinicalTrials.gov: NCT02063776.

Total plasma antioxidant status (TPAS), lipid peroxide concentration (LPX) and cardiac troponin T (cTnT) were measured in 24 patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Samples were obtained preoperatively and at 1.5 h, 6 h, 24 h and 72 h after CPB. The absolute TPAS values were significantly lower at 1.5 h, 6 h, 24 h and 72 h after CPB than were preoperative values ( P < 0.05). The LPX concentration was significantly elevated at 1.5 h after CPB ( P < 0.05). Cardiac troponin T concentrations were significantly elevated at all time points postoperatively ( P < 0.05). Preoperative TPAS values were significantly correlated with the magnitude of fall in TPAS at 1.5 h ( P < 0.05). The greater the fall in TPAS between 0 and 1.5 h, the less LPX was formed between 0 and 1.5 h. The LPX at 1.5 h displayed a significant correlation with cTnT release from myocardial myocytes ( P < 0.05). These data provide evidence for the first time that the consumption of antioxidants during CABG surgery with CPB protects against the production of reactive oxygen species and subsequent myocyte necrosis. Furthermore, the availability of protective antioxidants is dependent upon preoperative TPAS.

Background There are a number of inborn errors of dopamine biosynthesis for which prolactin measurement may be a useful screening tool. However, the interpretation of prolactin results is difficult as age-related paediatric reference intervals are scant especially in infancy. Methods Serum prolactin reference intervals were calculated from the existing laboratory data using an indirect method, based on patients (n = 2369) attending a tertiary care hospital over a 10-year period. The data were log transformed and partitioned by age and sex. Results The prolactin results for all age and sex stratifications show non-Gaussian distributions (P < 0.0001). There are apparent age-related differences for prolactin during the first year of life with prolactin declining sharply during the first year of life and continuing to decline until five years of age when the concentrations stabilize. The sex differences are small until 13-17 years of age when prolactin is higher in girls than in boys. Conclusions This is the first published study to report age-related prolactin reference intervals spanning all paediatric age groups where the data are age partitioned in infants under one year of age using an ‘indirect’ approach. It is envisaged that these reference intervals will be used to aid in the selection of patients presenting with features of central dopamine deficiency for lumbar puncture. Also, these reference intervals have the potential for treatment monitoring of patients with diagnoses of inborn errors of dopamine biosynthesis.

Aim Azathioprine is an effective immunosuppressive agent for the management of a wide spectrum of diseases, including systemic lupus erythematosus, vasculitis and in renal transplantation. Myelosuppression is a known major side-effect so some authors advocate that erythrocyte thiopurine transmethyltransferase (TPMT) activity is required to identify those patients at increased risk. In such cases, the azathioprine dosage can be adjusted prior to prescribing. However, there is a lack of data to support routine TPMT monitoring in paediatric patients. Methods Retrospective study in a single paediatric centre of all patients who had TPMT enzyme assay measured over a three year period prior to the commencement of azathioprine therapy. Patients with TPMT enzyme activities of 26-50, 10-25 and Results 363 (51% female) patients aged 1-19 (median 10.2) years were tested for TPMT activity of whom 228 patients were subsequently commenced on azathioprine. Erythrocyte TPMT activities were 14-76 (median 33.7) pmol/h/mgHb with 88% and 12% of patient having normal and intermediate activity respectively (none were deficient). The initial prescribed dosage of azathioprine was 0.7-3.5 (median 2.0) mg/kg/day. Only two patients required reduction of azathioprine dosage due to mild neutropenia in this cohort. Conclusion This is the first large paediatric cohort study which demonstrates that the majority of paediatric patients had normal TMPT activities and no patients developed severe neutropenia as a result of azathioprine treatment. We estimate the cost for testing this patient cohort was £16,000 without clinical benefit. We would recommend close monitoring of full blood counts after instituting azathioprine therapy but would question the value of pre-treatment TPMT activity in paediatric practice.