Medical, statistical, ethical and human rights considerations in the assessment of age in children and young people subject to immigration control.

BACKGROUND: Unprecedented changes in both the scale and the complexity of international migration have led to international concern and controversy over the assessment of age in children and young people subject to immigration control or seeking asylum who say they are children yet have no documents to prove their stated age. SOURCES OF DATA: The article reviews the existing evidence on the reliability of medical and non-medical techniques for the assessment of chronological age. AREAS OF AGREEMENT: There is evidence that radiography (X-rays) of bones and teeth, which is increasingly relied upon by immigration authorities, is imprecise, unethical and potentially unlawful, and should not be used for age assessment. AREAS OF CONTROVERSY: Medical techniques including X-rays continue to be relied upon in the absence of an alternative approach resulting in legal challenges and uncertainty for children and young people. AREAS TIMELY FOR DEVELOPING RESEARCH: Further work is needed to establish a process for age assessment based on a 'holistic' multi-disciplinary approach which focuses not on chronological age exclusively but rather on the needs of children and young people subject to immigration control.

Hyperinsulinaemic hypoglycaemia in infancy and childhood--resolving the enigma.

Children with severe hypoglycaemia due to persistent hyperinsulinism in infancy (HI) generate some of the most formidable problems of management in contemporary paediatric endocrinology. Until recently its pathophysiology was an enigma, although it was thought to be due to an anatomical abnormality in the islets of Langerhans (so called 'nesidioblastosis'). During the last 6 years there has been an explosion of knowledge providing fundamental insights into the pathological mechanisms underpinning the abnormal insulin secretion. This knowledge has been facilitated by ENRHI, a programme of research funded by the European Union, which brings together clinicians and basic scientists from 14 different countries. This collaboration encompasses clinical paediatric endocrinology, intracellular biochemistry, membrane physiology and molecular biology. This collaboration has resulted in numerous publications generating new insights into the pathophysiology of HI and represents a paradigm for collaboration in paediatric endocrinology. This review article is based on a plenary lecture delivered at the European Society for Paediatric Endocrinology meeting in Montreal on behalf of the European Network for Research into Hyperinsulinism of Infancy (ENRHI).

Severe transient neonatal hyperinsulinism associated with hyperlactataemia in non-asphyxiated infants.

Transient hyperinsulinism (HI) occurs in infants born to diabetic mothers, in infants experiencing perinatal asphyxia and in infants with intrauterine growth retardation. The precise mechanism of transient HI in these different aetiologies is not fully understood. Lactic acidosis is commonly seen in neonates as a secondary phenomenon due to hypoxia, hypovolaemia, anaemia and infection. The combination of transient HI and lactic acidosis is rare. We present the clinical and biochemical features of five infants presenting with transient HI associated with hyperlactataemia in the absence of markers of perinatal stress. This combination lasted for 3-4 weeks with complete resolution except in one patient in whom the hyperinsulinism lasted until 6 months before resolution. The precise mechanism of this association is not clear but may be related either to immaturity of the pyruvate dehydrogenase complex or to the accumulation of abnormal intramitochondrial intermediary metabolites. Infants presenting with HI should have a free flowing blood sample drawn for the measurement of plasma lactate levels.

Circulating aldosterone levels are unexpectedly low in children with acute meningococcal disease.

The incidence of meningococcal disease in childhood has risen over the past decade. Mortality remains high for those who develop septic shock and purpura fulminans. Poor perfusion, hypotension, and loss of intravascular circulating volume may be expected to influence both mineralocorticoid and glucocorticoid secretion. The aim of the study was to define adrenocortical hormone status at presentation. Sixty children admitted to the pediatric intensive care unit were studied. Children were divided into two groups: group A (n = 31), with meningococcal sepsis, mean age 4.4 yr (range 0.5-14.4), predicted risk of mortality mean 32.3% (range 0.5-99.3%); and group B (n = 29), with other diagnoses (post major surgery and with severe respiratory infections), mean age 4.1 yr (range 0.3-16.3), predicted risk of mortality mean 9.4% (range 0.2-83%). The groups were not significantly different for age. Plasma levels of aldosterone and cortisol were determined by RIA. The mean plasma aldosterone concentration on admission in group A was 427.5 +/- 88.1 pg/ml, with 96.7% of values within the normal range for age for healthy children and were significantly lower than group B mean, 1489.2 +/- 244.2 pg/ml (P < 0.0001), with 59.3% of values above the normal range. In group A there was no correlation with plasma concentrations of sodium, potassium, or volume of colloid infused in the previous 8 h. In group A mean serum cortisol mean values were 799.5 +/- 75.9 nmol/liter and in group B cortisol levels were 703.4 +/- 78.6 nmol/liter (P = n.s.). We conclude that children with meningococcal disease present with lower plasma aldosterone concentrations than other patients in the pediatric intensive care unit, for which there is no clear explanation. Further work is needed to elucidate the mechanisms underlying this finding and to examine its clinical implications.

Hypoketotic hypofattyacidaemic hypoinsulinaemic hypoglycaemia in a child with hemihypertrophy? A new syndrome.

BACKGROUND: Recurrent and persistent hypoketotic, hypofattyacidaemic hypoglycaemia in infancy and childhood is most frequently due to hyperinsulinism of infancy. This biochemical profile can also be due to non-islet cell tumour hypoglycaemia or circulating insulin-receptor autoantibodies. Hyperinsulinaemic hypoglycaemia is also seen in children with the Beckwith-Wiedemann syndrome, where it is usually transient. METHODS/RESULTS: We report a novel case of child with hemihypertrophy and severe persistent hypoketotic, hypofattyacidaemic hypoinsulinaemic hypoglycaemia. No 'big' pro-IGF2 forms or circulating insulin-receptor antibodies were found. Glucose and protein isotope turnover studies showed marked suppression of hepatic glucose production during fasting. There was no evidence for constitutive autophosphorylation of the insulin or IGF-1 receptor, and no evidence for up-regulation of IGF-1 receptor. CONCLUSION: The precise pathophysiology of this novel case is still unclear.

Hyperinsulinaemic hypoglycaemia in preterm neonates.

Hyperinsulinism in infancy (HI) is an important cause of severe and recurrent hypoglycaemia in newborn infants. It usually appears in infants born at term, and only one case of its occurrence in a prematurely born infant has been reported as an incidental finding. This is a report of seven infants born at 31-36 weeks gestation who experienced severe persistent hyperinsulinism. Two infants were large for dates. All infants were difficult to manage, suggesting that the occurrence of HI with prematurity may be associated with a particularly aggressive illness. HI should be considered in the differential diagnosis of severe hypoglycaemia in preterm infants.

Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses.

Serum cortisol plays an important role in counterregulation to hypoglycemia. It antagonizes the peripheral effects of insulin and also directly influences glucose metabolism. Classically serum cortisol concentrations rise in response to hypoglycemia, but the response in neonates with hyperinsulinemic hypoglycemia is unclear. To investigate the serum cortisol responses in neonates with hyperinsulinemic hypoglycemia, 13 neonates (34-40 wk gestation; male/female ratio, 7/6) with hyperinsulinemic hypoglycemia underwent diagnostic fasts. The serum cortisol concentration was measured before the commencement of the fast and at the time of hyperinsulinemic hypoglycemia. The hypoglycemia was then treated with iv glucose (1 ml/kg bolus of 10% dextrose), and serum cortisol concentrations were measured at 10-min intervals for a total of 50 min. Six of the 13 neonates had plasma ACTH concentrations measured at the time of hypoglycemia and then received a 62.5- microg i.v. bolus injection of Synacthen. The mean (+/-SEM) serum cortisol concentration 15 min before the hypoglycemic episode was 156 +/- 24 nmol/liter, and that at the time of hypoglycemia was 182 +/- 28 nmol/liter. Mean cortisol concentrations at 10, 20, 30, 40, and 50 min for the first seven neonates who were not given Synacthen at the time of hypoglycemia were 213 +/- 44, 223 +/- 48, 209 +/- 49, 228 +/- 46, and 252 +/- 30 nmol/liter, respectively. The six neonates who received an i.v. bolus dose of Synacthen had significantly greater (P < 0.01) serum cortisol concentrations at the same time points, 208 +/- 39, 219 +/- 46, 378 +/- 139, 664 +/- 57, 905 +/- 121, 1048 +/- 247, and 1192 +/- 105 nmol/liter, respectively. Plasma ACTH levels were inappropriately low in all six neonates at the time of hypoglycemia (mean plasma ACTH concentration, 13.2 pg/ml). Neonates with hyperinsulinemic hypoglycemia fail to generate an adequate serum cortisol counterregulatory hormonal response. This appears to be related to the lack of drive from the hypothalamic-pituitary axis, with inappropriately low plasma ACTH concentrations at the time of hypoglycemia. The normal serum cortisol response to an i.v. bolus injection of Synacthen suggests that this is a centrally mediated phenomenon and does not imply that these patients have adrenal insufficiency.

Spontaneous hypoglycemia in childhood is accompanied by paradoxically low serum growth hormone and appropriate cortisol counterregulatory hormonal responses.

Hypoglycemia is a potent stimulus for GH and cortisol secretion. The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol responses from the hypothalamic-pituitary-adrenal axis. The serum GH and cortisol responses to spontaneous hypoglycemia in 22 children were compared with those of 16 children undergoing an ITT for diagnostic purposes. The mean serum GH and cortisol concentrations 1 h before spontaneous hypoglycemia were 6.9 +/- 1.1 mU/liter and 424 +/- 51 nmol/liter, respectively, and at the time of spontaneous hypoglycemia they were 6.7 +/- 1.3 mU/liter and 601 +/- 66 nmol/liter, respectively. The mean serum GH and cortisol values at +10, +20, +30, +40, and +50 min from the time of hypoglycemia were 5.4 +/- 1.0, 4.7 +/- 0.7, 4.6 +/- 1.0, 5.4 +/- 1.4, and 5.5 +/- 1.3 mU/liter and 633 +/- 69, 645 +/- 71, 668 +/- 70, 680 +/- 72, and 662 +/- 77 nmol/liter, respectively. There was no significant difference between any of these means for GH secretion. In contrast, in the ITT the mean serum GH concentration before hypoglycemia was 5.1 +/- 1.3 mU/liter, and at the time of hypoglycemia it was 29.2 +/- 7.30 mU/liter. The difference between these means was highly significant (P < 0.01, by t test). There was no significant difference between the cortisol response to spontaneous hypoglycemia and that to the ITT. Physiological changes in the serum nonesterified fatty acid concentration had no significant effect on serum GH secretion. In conclusion, the mechanism(s) of the serum GH response to spontaneous hypoglycemia is different from that due to the ITT. A low GH level detected at the time of spontaneous hypoglycemia does not necessarily imply GH deficiency or GH as a cause of the hypoglycemia.

Growth hormone enhances proinflammatory cytokine production by monocytes in whole blood.

Growth hormone (GH) has been used as anabolic therapy to treat catabolic patients. In a recent study, however, administration of high doses of GH to critically ill adults was associated with an increase in morbidity and mortality. Preponderance of septic shock and uncontrolled infections as causes of death in these patients suggests an immuno-modulatory effect of GH. Our hypothesis was that GH treatment may modulate the production of proinflammatory cytokines, which are implicated in sepsis. In our study, human monocytes in whole blood were activated with lipopolysaccaharide (LPS) (1-100 ng/ml) purified from a clinical isolate of group B Neisseria meningitidis in the presence of a high dose of GH (100 ng/ml). The subsequent proinflammatory cytokine response was analysed by intracellular cytokine staining and flow cytometry. Our results show that GH enhances IL1-alpha, IL-6 and TNF-alpha production by LPS activated monocytes in whole blood. The modulation of cytokines by GH may be responsible for the adverse consequences of GH in critically ill patients.

Hyperinsulinism in infancy: understanding the pathophysiology.

Hyperinsulinism in infancy (HI) is the commonest cause of persistent and recurrent hypoglycaemia in the infancy and childhood period. HI is a heterogeneous disorder with respect to clinical presentation, histology, molecular biology and genetics. Recent advances have provided unique insights into the pathophysiology of this intriguing disease as well as providing an understanding of the normal physiological and biochemical mechanisms regulating insulin secretion from pancreatic beta-cells. The histological differentiation of focal and diffuse forms of HI has radically changed the surgical management to this disease. So far mutations in five different genes have been described which lead to dysregulated insulin secretion from beta-cells. Despite these advances the genetic defect is still unknown in about 60% of cases.

Uncontrolled insulin secretion from a childhood pancreatic beta-cell adenoma is not due to the functional loss of ATP-sensitive potassium channels.

We report the case of an 8-year-old child who presented with severe hyperinsulinaemic hypoglycaemia due to a pancreatic islet cell adenoma. In vivo, there was no beneficial response to the hyperglycaemia-inducing agent diazoxide and as a consequence the child underwent a subtotal pancreatectomy. In vitro studies of adenomatous beta-cells revealed no operational defects in ATP-sensitive potassium channel activity and appropriate responses to diazoxide. In comparison with patients with focal adenomatous hyperplasia, genetic analysis of the isolated adenoma showed no loss of heterozygosity for chromosome 11p15 and expression of the cyclin-dependent kinase inhibitor p57(kip2). This case illustrates that the excess insulin secretion from an infantile adenoma has an aetiology different from that observed in hyperinsulinism in infancy.

p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy.

Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.

Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion.

A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.

Congenital adrenal hyperplasia: management during critical illness.

BACKGROUND: Little is known of the optimal dose and administration schedule of hydrocortisone in critically ill patients with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency. AIM: To determine plasma cortisol concentrations after intravenous administration of hydrocortisone in children with CAH and to relate these to plasma cortisol concentrations achieved by endogenous secretion in the stress of critical illness in previously healthy children. METHODS: Plasma cortisol concentrations were measured in 20 patients with classical CAH (median age 11.2 years, range 6.1-16.4) following intravenous administration of hydrocortisone 15 mg/m(2); and in 60 critically ill mechanically ventilated children (median age 2.5 years, range 0.25-16.3) on admission to the paediatric intensive care unit and for 24 hours thereafter. RESULTS: In the CAH patients, plasma cortisol reached a mean peak of 1648.3 nmol/l (SD 511.9) within 10 minutes of the intravenous bolus, and fell rapidly thereafter; levels remained greater than 450 nmol/l for 2.5 hours only. In critically ill children, mean plasma cortisol on admission to the intensive care unit was 727 nmol/l (SD 426.1). Cortisol concentrations remained raised during the first 24 hours. CONCLUSIONS: Critically ill patients with classical CAH may be best managed with a single intravenous hydrocortisone bolus followed by a constant rate infusion of hydrocortisone.

Hyperinsulinism of infancy: the regulated release of insulin by KATP channel-independent pathways.

Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic beta-cells. Here we describe stimulus-secretion coupling mechanisms in beta-cells and intact islets of Langerhans isolated from three patients with a novel SUR1 gene defect. 2154+3 A to G SUR1 (GenBank accession number L78207) is the first report of familial HI among nonconsanguineous Caucasians identified in the U.K. Using patch-clamp methodologies, we have shown that this mutation is associated with both a decrease in the number of operational ATP-sensitive K+ channels (KATP channels) in beta-cells and impaired ADP-dependent regulation. There were no apparent defects in the regulation of Ca2+- and voltage-gated K+ channels or delayed rectifier K+ channels. Intact HI beta-cells were spontaneously electrically active and generating Ca2+ action currents that were largely insensitive to diazoxide and somatostatin. As a consequence, when intact HI islets were challenged with glucose and tolbutamide, there was no rise in intracellular free calcium ion concentration ([Ca2+]i) over basal values. Capacitance measurements used to monitor exocytosis in control and HI beta-cells revealed that there were no defects in Ca2+-dependent exocytotic events. Finally, insulin release studies documented that whereas tolbutamide failed to cause insulin secretion as a consequence of impaired [Ca2+]i signaling, glucose readily promoted insulin release. Glucose was also found to augment the actions of protein kinase C- and protein kinase A-dependent agonists in the absence of extracellular Ca2+. These findings document the relationship between SUR1 gene defects and insulin secretion in vivo and in vitro and describe for the first time KATP channel-independent pathways of regulated insulin secretion in diseased human beta-cells.

Management of hyperinsulinism in infancy and childhood.

Hyperinsulinism (HI) in infancy presents a formidable challenge for the paediatrician as it is one of the most difficult problems to manage in contemporary paediatric endocrinology. Although there have been major advances in understanding the condition over the last five years, the neurological outcome remains poor choice, and the choice of treatments continue to be unsatisfactory. This review article updates the management of HI derived from a Consensus Workshop held by the European Network for Research into Hyperinsulinism (ENRHI) in 1999.

A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene.

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.