Congenital hyperinsulinism: management and outcome, a single tertiary centre experience.

Hyperinsulinemic hypoglycaemia (HH) is the most frequent cause of persistent hypoglycaemia in neonates and infants. The most severe forms of HH are inherited and referred to as congenital hyperinsulinism (CHI). Diazoxide is the mainstay of treatment, with surgery being an option in appropriate cases. To describe the management and outcome of patients with CHI within our service. Children referred to or attending HH clinic between 2009 and 2017 were identified. Clinical course, genetics and interventions were documented. A total of 39 children were identified, and seven patients with secondary and syndromic HH were excluded. Most were born with an appropriate weight for gestational age (62.5%). Diazoxide was started in all patients; however, 7 did not respond and required octreotide/continuous feeding, with 6/7 requiring surgery. Genetic mutations were detected in 12/32 (37.5%). Hyperinsulinism resolved in conservatively treated patients within 12 months in 11/32 (34.3%) compared to 14/32 (43.7%) requiring more than 12 months of medication. A total of 7 patients underwent pancreatectomy.Conclusion: Although LGA and SGA are risk factors, most babies in our cohort are born AGA. A genetic mutation does not exclude medical remission; long-term conservative treatment of CHI is feasible as surgery does not guarantee complete remission.What is Known:•Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disorder that is the most common cause of permanent hypoglycaemia in infants and children.•Identification of genetic mutations and the use of 18F-DOPA PET scan when feasible lead to better outcomes.What is New:•The study describes clinical criteria, management and outcome of large number of patients with CHI in single tertiary centre.•Conservative treatment is feasible without the need for surgery, with HH resolving in over 30% within 12 months, irrespective of genetic mutation.

Childhood-onset growth hormone deficiency and the transition to adulthood: current perspective.

Childhood-onset growth hormone deficiency (CO-GHD) is an endocrine condition associated with a broad range of health issues from childhood through to adulthood, which requires particular attention during the transition period from adolescence to young adulthood. There is uncertainty in the clinical practice of the management of CO-GHD during transition regarding the clinical assessment and management of individual patients during and after transition to obtain optimal follow-up and improved health outcomes. Despite the availability of clinical guidelines providing the framework for transition of young adults with CO-GHD, there remains substantial variation in approaching transitional care among pediatric and adult services. A well-structured and coordinated transitional plan with clear communication and direct collaboration between pediatric and adult health care to ensure optimal management of adolescents with CO-GHD during transition is needed.

Fludrocortisone-a treatment for tubulopathy post-paediatric renal transplantation: A national paediatric nephrology unit experience.

Calcineurin inhibitors post-renal transplantation are recognized to cause tubulopathies in the form of hyponatremia, hyperkalemia, and acidosis. Sodium supplementation may be required, increasing medication burden and potentially resulting in poor compliance. Fludrocortisone has been beneficial in addressing tubulopathies in adult studies, with limited paediatric data available. A retrospective review of data from an electronic renal database from December 2014 to January 2016 was carried out. Forty-seven post-transplant patients were reviewed with 23 (49%) patients on sodium chloride or bicarbonate. Nine patients, aged 8.3 years (range 4.9-16.4), commenced fludrocortisone 22 months (range 1-80) after transplant and were followed up for 9 months (range 2-20). All patients stopped sodium bicarbonate; all had a reduction or no increase in total daily doses of sodium chloride. Potassium levels were significantly lower on fludrocortisone, 5.2 vs 4.5 mmol/L, P = .04. No difference was noted in renal function (eGFR 77.8 vs 81.7 mL/min/1.73 m2 , P = .45) and no significant increase in systolic blood pressure (z-scores 0.99 vs 0.85, P = .92). No side effects secondary to treatment with fludrocortisone were reported. A significant proportion of renal transplant patients were on sodium supplementation and fludrocortisone reduced sodium supplementation without significant effects on renal function or blood pressure. Fludrocortisone appears to be safe and effective for tubulopathies in children post-transplantation.

Mechanisms of obesity in Prader-Willi syndrome.

Obesity is the most common cause of metabolic complications and poor quality of life in Prader-Willi syndrome (PWS). Hyperphagia and obesity develop after an initial phase of poor feeding and failure to thrive. Several mechanisms for the aetiology of obesity in PWS are proposed, which include disruption in hypothalamic pathways of satiety control resulting in hyperphagia, aberration in hormones regulating food intake, reduced energy expenditure because of hypotonia and altered behaviour with features of autism spectrum disorder. Profound muscular hypotonia prevents PWS patients from becoming physically active, causing reduced muscle movements and hence reduced energy expenditure. In a quest for the aetiology of obesity, recent evidence has focused on several appetite-regulating hormones, growth hormone, thyroid hormones and plasma adipocytokines. However, despite advancement in understanding of the genetic basis of PWS, there are contradictory data on the role of satiety hormones in hyperphagia and data regarding dietary intake are limited. Mechanistic studies on the aetiology of obesity and its relationship with disease pathogenesis in PWS are required. . In this review, we focused on the available evidence regarding mechanisms of obesity and potential new areas that could be explored to help unravel obesity pathogenesis in PWS.

Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement.

Until quite recently, the management of children with growth hormone deficiency (GHD) had focussed on the use of recombinant human GH (rhGH) therapy to normalise final adult height. However, research over the past two decades that has demonstrated deficits in bone health and cardiac function, as well as impaired quality of life in adults with childhood-onset GHD (CO-GHD), has questioned this practice. Some of these studies suggested that there may be short-term benefits of rhGH in certain group of adolescents with GHD during transition, although the impact of GHD and replacement during the transition period has not been adequately investigated and its long-term benefits remain unclear. GH therapy remains expensive and well-designed long-term studies are needed to determine the cost effectiveness and clinical benefit of ongoing rhGH during transition and further into adulthood. In the absence of compelling data to justify widespread continuation of rhGH into adult life, there are several questions related to its use that remain unanswered. This paper reviews the effects of growth hormone deficiency on bone health, cardiovascular function, metabolic profile and quality of life during transition and young adulthood.

An audit of the management of childhood-onset growth hormone deficiency during young adulthood in Scotland.

BACKGROUND: Adolescents with childhood onset growth hormone deficiency (CO-GHD) require re-evaluation of their growth hormone (GH) axis on attainment of final height to determine eligibility for adult GH therapy (rhGH). AIM: Retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition. PATIENTS: Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005 and 2013 were reviewed. Median (range) age at initial diagnosis of CO-GHD was 10.7 years (0.1-16.4) with a stimulated GH peak of 2.3 µg/l (0.1-6.5). Median age at initiation of rhGH was 10.8 years (0.4-17.0). RESULTS: Of the 130 CO-GHD adolescents, 74/130(57 %) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74 (82 %) remained GHD with 51/74 (69 %) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Of the remaining 56/130 (43 %) patients who were not re-tested, 34/56 (61 %) were transferred to adult services on rhGH without biochemical retesting and 32/34 of these had MPHD. The proportion of adults who were offered rhGH without biochemical re-testing in the four centres ranged between 10 and 50 % of their total cohort. CONCLUSIONS: A substantial proportion of adults with CO-GHD remain GHD, particularly those with MPHD and most opt for treatment with rhGH. Despite clinical guidelines, there is significant variation in the management of CO-GHD in young adulthood across Scotland.

Frequency and aetiology of hypercalcaemia.

BACKGROUND: Hypercalcaemia is rare in children and may present with characteristic signs/symptoms or coincidentally following investigations for a variety of non-specific conditions. The aetiologies of childhood hypercalcaemia are diverse. Untreated sustained hypercalcaemia has serious clinical consequences. However there is limited data regarding the true frequency and aetiologies of childhood hypercalcaemia. AIM: To determine the frequency of severe childhood hypercalcaemia in routine clinical practice. METHODS: The laboratory database was searched for all children (0-17 years) with severe hypercalcaemia defined as non-adjusted ≥2.90 mmol/L from 2007-2012. Hypercalcaemia was categorised as either transient (1 day) or sustained (≥2 consecutive days). Retrospective analysis of all cases of sustained severe hypercalcaemia was performed to identify the underlying aetiology. RESULTS: Over the 5 year period, 206 children were identified as severely hypercalcaemic ≥2.90 mmol/L (0.3% all 61,380 calcium requests). Of these 131 (63.3%) children were classified as having sustained hypercalcaemia. The frequency of severe hypercalcaemia was highest in neonates (42% of sustained cases) and was inversely related to age. Sepsis was the most common aetiology (24%), particularly in neonates where it accounted for 41% of all causes of neonatal hypercalcaemia. Endocrine aetiologies included congenital adrenal hyperplasia (2 cases), fat necrosis (1), Addison's disease (2). A genetic cause was identified in 3 children (2 familial hypocalciuria hypercalcaemia, 1 Williams syndrome). CONCLUSIONS: Sustained hypercalcaemia affects 1 in 500 children in a general hospital setting. The frequency was highest in neonates and underlying aetiology differed markedly with age. All children with sustained hypercalcaemia require thorough investigation to determine the underlying aetiology to ensure appropriate management.

Vitamin D and its effects on glucose homeostasis, cardiovascular function and immune function.

In recent years there has been increasing interest in the non-skeletal effects of vitamin D. It has been suggested that vitamin D deficiency may influence the development of diabetes, cardiovascular dysfunction and autoimmune diseases. This review focuses on the current knowledge of the effects of vitamin D and its deficiency on cardiovascular function, glucose homeostasis and immune function, with a particular focus on children. Although, there is good evidence to show that there is an association between vitamin D deficiency and an abnormality of the above systems, there is little evidence to show that vitamin D supplementation leads to an improvement in function, especially in childhood.

MRI-based abnormalities in young adults at risk of adverse bone health due to childhood-onset metabolic & endocrine conditions.

OBJECTIVE: Traditional methods of bone densitometry may not provide a comprehensive assessment of bone health. We aimed to assess bone micro-architecture and bone marrow adiposity (BMA) by MRI in adults with osteogenesis imperfecta (OI) and endocrinopathy including GH deficiency and/or hypogonadism. MEASUREMENTS: High-resolution micro-MRI images were acquired at the tibia using 3T MRI to calculate parameters of bone micro-architecture in seven adults with OI and 10 adults with endocrinopathies. MR Spectroscopy was performed in participants to calculate vertebral BMA, which was expressed as percentage fat fraction (%FF). Lumbar spine DXA was performed to assess bone mineral density. The MRI data were compared with a group of 22 healthy adults who were divided into two age-matched control groups. RESULTS: Intra-operator repeatability was high, with an average CoV of 1% for micro-MRI and 2·5% for MRS. The ratio of apparent bone volume to total volume (appBV/TV) in the endocrinopathy and OI groups was lower than in age-matched control groups (P = 0·003 and P = 0·008 respectively). A weak association between DXA BMD and appBV/TV was also observed (r = 0·5, P = 0·045). %FF was higher in the endocrinopathy group than in the age-matched control group (P = 0·005), but no difference in %FF was observed between the OI group and their age-matched control group (P = 0·26). CONCLUSIONS: MRI provides valuable detailed information on the micro-architecture and adiposity of bones and is capable of showing clear differences in bone parameters in a range of clinical conditions associated with abnormal bone health.

Recent trends and clinical features of childhood vitamin D deficiency presenting to a children's hospital in Glasgow.

BACKGROUND: The incidence of vitamin D deficiency is unclear in the context of continuing demographic changes and the introduction of new public health measures. METHODS: All cases in which vitamin D deficiency was suspected as the primary cause of the clinical presentation were studied. RESULTS: Between 2002 and 2008, 160 cases of symptomatic vitamin D deficiency were identified with twice as many cases in 2008 (n, 42) as in the previous years. The median age of the cohort was 24 months (range 2 weeks-14 years).Three cases were recorded in children of European background, whereas the rest were in children of South Asian, Middle Eastern or sub-Saharan ethnic background. Presenting features included bowed legs in 64 (40%) and a fit in 19 (12%). In one infant, concerns were raised following a presentation with cardiac failure and hypocalcaemia. SUMMARY: Symptomatic vitamin D deficiency remains prevalent in the West of Scotland. There is a need for effective public health education, action and surveillance.

Skewed X inactivation is associated with phenotype in a female with adrenal hypoplasia congenita.

Adrenal hypoplasia congenita (AHC) can occur due to deletions or mutations in the DAX 1 (NR0B1) gene on the X chromosome (OMIM 300200). This form of AHC is therefore predominantly seen in boys. Deletion of the DAX 1 gene can also be part of a larger contiguous deletion including the centromeric dystrophin and glycerol kinase (GK) genes. We report a girl with a de novo deletion at Xp21.2 on the maternal chromosome, including DAX1, the GK gene and 3' end of the dystrophin gene, who presented with salt losing adrenal insufficiency and moderate developmental delay, but relatively mild features of muscular dystrophy. Investigation using the androgen receptor as a marker gene identified skewed inactivation of the X chromosome. In the patient's leucocytes, the paternal X chromosome was completely inactive, but in muscle 20% of the active chromosomes were of paternal origin. Thus skewed X inactivation (deletion on the active maternal X chromosome with an inactive paternal X chromosome) is associated with AHC in a female. Variability in X inactivation between tissues may account for the pronounced salt loss and adrenal insufficiency but mild muscular dystrophy.

Body fat estimation using bioelectrical impedance.

BACKGROUND/AIMS: Although childhood obesity is a major problem, routine assessment methods do not reflect fat mass. Body mass index, which is most commonly used, gives an indication of weight for height and not a degree of adiposity. METHODS: Bioelectrical impedance and dual-energy X-ray absorptiometry (DEXA) were used in a group of obese children to assess body fat. RESULTS: Comparison between DEXA and commercial bioelectrical impedance scales in 46 children showed a highly significant correlation (R = 0.944, p < 0.001) in fat mass. Fat mass measured using bioelectrical impedance was 2.4 kg lower compared to measurement using DEXA. CONCLUSION: These bioelectrical scales may prove useful in the management of childhood obesity as they are able to provide important clinical information regarding fat mass and adiposity.

Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia.

OBJECTIVES: Mutations in the genes encoding the transcription factors PROP1 and POUF-1 (Pit-1) have been reported as common causes of combined pituitary hormone deficiency (CPHD), and HESX1 mutations have been identified in children with septo-optic dysplasia (SOD). There are few data on UK children. We have performed mutation analysis in a large cohort of affected children within the West Midlands region to assess the feasibility of a screening strategy for molecular diagnosis in CPHD and SOD. DESIGN AND PATIENTS: The three coding exons of PROP1, and six exons of POUF-1 in 27 children from 26 families with CPHD, and three exons of HESX1 in 23 children from 22 families with SOD were directly sequenced from a well-characterized regional cohort. RESULTS: We identified a C to T transition in exon 6 of POUF-1, resulting in a known missense mutation (R271W) in a mother and daughter from one family with CPHD. We also found a novel homozygous T to C transition in exon 6 of POUF-1, resulting in a missense mutation (F233L) in a twin with CPHD. This mutation was excluded in 100 ethnically matched control alleles. We did not identify any mutations in the PROP1 gene or HESX1. The median maternal age at delivery for the CPHD children was 27 years, compared to 21 years for the mothers of SOD children (P = 0.04). CONCLUSIONS: Mutations in POUF-1, PROP1 and HESX1 are rare causes of CPHD and SOD, respectively, in children from the West Midlands. In particular, we did not confirm the reported 'hotspot' in PROP1. A screening strategy that targets familial cases is highly likely to increase the mutation yield. The young maternal age at conception of children with SOD and potential teratogen exposure indicate the predominance of environmental factors in this condition compared with CPHD.

Thyroxine unmasks Addison's disease.

UNLABELLED: Patients with primary hypothyroidism may also have other underlying associated endocrinopathies, which are important to exclude. A 15-y-old girl presented with clinical biochemical evidence of hypothyroidism. CONCLUSION: Thyroxine replacement unmasked Addison's disease and precipitated an acute adrenal crisis. On physiological steroid replacement therapy, her "hypothyroidism" resolved.

Transient neonatal hypothyroidism due to a maternal vegan diet.

Iodine is an important constituent of thyroid hormones and deficiency can lead to a range of problems depending on the degree and at what stage of life the deficiency occurs. We report a 10 day-old infant with a goitre, who presented with raised TSH on dried blood spot screening. It was observed that her mother also had a goitre. The mother was a vegan and, on dietary assessment, her iodine intake was extremely low. Both mother and infant had abnormal thyroid function tests. Mother was given Lugol's iodine and her thyroid function tests normalised. Her baby was initially prescribed thyroxine on the basis of the raised screening TSH. This was subsequently withdrawn at the age of 2 weeks, following a normal plasma TSH. Thyroid function tests remained normal and the goitre disappeared by the age of 2 months. Iodine deficiency is uncommon in the Western World. However the incidence may be rising in otherwise iodine replete areas, particularly in those who adhere to restrictive and unusual diets. In the case of pregnant mothers their unborn child's health is in danger. This report demonstrates the need to ascertain maternal diets early in antenatal care, and supplement if necessary to avoid risk to their own health and that of their offspring.

Chronic cyclosporin A (CsA) nephrotoxicity in the rat: the effect of calcium blockade with verapamil.

Renal structure and function were assessed in groups of male Sprague-Dawley rats, either surgically intact (SI) or nephrectomized (N), treated with either CsA alone (20 mg/kg, p.o.) or in combination with verapamil (VER; 10 mg/kg/day, i.p.) daily for up to 28 days. Compared to vehicle treated controls, reduced creatinine clearance rates (CCR, mean +/- s.e.m.) were noted following CsA treatment in Sl animals on days 21 and 28 (279 +/- 4 vs 196 +/- 20 and 296 +/- 13 vs 122 +/- 13 ml/h/kg, respectively, both P < 0.05). However, CCR was around 60% of pretreatment values in all N animals from day 7 onwards. A two to three-fold elevation in urinary N-acetyl-beta-D-glucosaminidase activity was noted from day 7 to 28 in all CsA treated animals. In addition, a similar severity of both renal tubular basophilia and corticomedullary microcalcification (but not proximal tubular vacuolation), was noted at all time points in animals receiving CsA alone. Co-treatment with VER reduced the severity of microcalcification in CsA groups, particularly N animals, increased CCR on day 14 in the Sl (196 +/- 23 vs 391 +/- 64) and days 21 and 28 in N (141 +/- 14 vs 357 +/- 32 and 152 +/- 28 vs 261 +/- 20) groups, respectively but had no effect on the magnitude of enzymuria, despite significantly increased trough whole blood CsA levels (20-30%) in both Sl and N groups. These results indicate that calcium blockade reduces both structural and functional features of chronic CsA nephrotoxicity.