Fetal Growth Trajectories and Their Association with Maternal, Cord Blood, and 5-year Child Adipokines.

BACKGROUND: The growth of the fetus is a complex process influenced by multiple factors. Studies have highlighted the important role of biochemical growth markers such as leptin and adiponectin on fetal growth. OBJECTIVE: To compare fetal growth trajectories with biochemical growth markers from maternal blood samples at 28 weeks' gestation, cord blood samples at birth, and in child blood samples at 5 years of age from mother-infant pairs who were part of the longitudinal ROLO study. METHODS: 781 mother-infant pairs from the ROLO and ROLO Kids study were included. Ultrasound measurements and birth weight were used to develop fetal growth trajectory groups for estimated abdominal circumference and estimated weight. Blood serum levels of leptin, adiponectin, insulin, TNF-alpha, and IL-6 from maternal, cord, and 5-year child samples were recorded. ANOVA and chi-square tests were applied to test the associations between fetal growth trajectory membership and maternal and child biochemical growth indicators. The influence of child sex was also investigated. RESULTS: Male sex was associated with a faster weight trajectory compared to females (p=0.001). At 28 weeks' gestation, maternal leptin levels were significantly higher in mothers with a fetus on a slower estimated abdominal circumference trajectory compared to fast (25616 [IQR: 11656.0 to 35341.0] vs. 14753.8 [IQR: 8565.4 to 24308.1], p < 0.001) and maternal adiponectin levels were lower in fetuses on a slower estimated abdominal circumference trajectory compared to a fast trajectory (22.4 [IQR: 13.6 to 35.9] vs. 27.6 [IQR: 17.6 to 46.3], p=0.027). No associations were noted with inflammatory markers. No associations were identified between fetal growth trajectories and growth markers at 5 years of age. CONCLUSIONS: This study shows that male sex is associated with an accelerated estimated weight trajectory. Furthermore, high leptin and low adiponectin in maternal serum in late gestation are associated with a slower fetal growth trajectory. No associations were identified with blood growth markers after pregnancy.

The evolving course of HNF4A hyperinsulinaemic hypoglycaemia--a case series.

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4A) gene mutations have a well-recognized role in maturity-onset diabetes of the young and have recently been described in congenital hyperinsulinism. A biphasic phenotype has been postulated, with macrosomia and congenital hyperinsulinism in infancy, and diabetes in young adulthood. In this case series, we report three children with HNF4A mutations (two de novo) and diazoxide-responsive congenital hyperinsulinism, highlighting the potential for ongoing diazoxide requirement and the importance of screening for these mutations even in the absence of family history. CASE REPORTS: All patients presented with macrosomia (mean birthweight 4.26 kg) and hyperinsulinaemic hypoglycaemia soon after birth (median age 1 day). All three (age range 7 months to 11 years 10 months) remain on diazoxide therapy, with dose requirements increasing in one patient. There was no prior family history of diabetes, neonatal hypoglycaemia or macrosomia. Parents were screened for HNF4A mutations post-diagnosis and one father was subsequently found to have maturity-onset diabetes of the young. CONCLUSIONS: This case series follows the evolving course of three patients with confirmed HNF4A-mediated congenital hyperinsulinism, highlighting (1) the variable natural history of these mutations, (2) the potential for prolonged diazoxide requirement, even into adolescence, and (3) the need for screening, regardless of family history.

Twice-daily variable insulin regimens: proportions of insulin types have little impact on glycaemic control in primary school-aged children.

AIM: To ascertain the relationship between glycaemic outcome and proportions and timing of insulin admixture in a cohort of primary school-aged children who were receiving insulin in a twice-daily regimen. METHODS: Children aged 4-10 years with Type 1 diabetes of > 2 years duration and on twice-daily variable insulin regimens were eligible for inclusion in this study, which took place over a 12-month period. Characteristics of insulin regimen [total daily dose (TDD), proportion of total daily dose given in the morning and proportion of the TDD given as intermediate-acting insulin] were compared with parameters of glycaemia including glycated haemoglobin (HbA(1c)) and continuous glucose monitoring measures (mean glucose, per cent time in various glycaemic ranges, and intra- and inter-day glycaemic variation). RESULTS: Forty-nine children completed the study. Participants were all prepubertal at the start of the study and representative of the local diabetes population aged 4-10 years (mean age 8.2 years, mean duration of diabetes 3.5 years, mean HbA(1c) 8.1%). The mean TDD was 0.9 units/kg/day (range 0.6-1.3). The TDD, percentage of TDD given as intermediate-acting insulin and the percentage of TDD given as the morning dose were not associated with HbA(1c), mean continuous glucose monitoring system glucose, per cent time in various glycaemic ranges or intra- and inter-day glycaemic variation. CONCLUSIONS: Insulin proportions in twice-daily, variable insulin regimens are not associated with any short- or medium-term glycaemic outcomes.

Social consumption of alcohol in adolescents with Type 1 diabetes is associated with increased glucose lability, but not hypoglycaemia.

AIM: To determine the effects of social consumption of alcohol by diabetic adolescents on glycaemic control. METHODS: Fourteen (five male) patients aged > 16 years were recruited from the diabetes clinic at the Royal Children's Hospital. The continuous glucose monitoring system (CGMS) was attached at a weekend when alcohol consumption was planned for one night only. For each patient, the 12-h period from 18.00 h to 06.00 h for the night with alcohol consumption (study period) was compared with the same period with non-alcohol consumption (control period) either 24 h before or after the alcohol study night. Thus, each subject was his/her own control. Glycaemic outcomes calculated from continuous glucose monitoring included mean blood glucose (MBG), percentage of time spent at low glucose levels (CGMS < 4.0 mmol/l), normal glucose levels (CGMS 4.0-10.0 mmol/l) and high glucose levels (> 10.0 mmol/l) and continuous overall net glycaemic action (CONGA). RESULTS: The mean number of standard alcohol drinks consumed during the study period was 9.0 for males and 6.3 for females. There was no difference in percentage of time at high and normal glucose levels in the study and control periods. During the control period, there was a higher percentage of time with low glucose levels compared with the study period (P < 0.05). There was an increased level of glycaemic variation during the study time when compared with the control period. CONCLUSIONS: In an uncontrolled, social context, moderately heavy alcohol consumption by adolescents with Type 1 diabetes appears to be associated with increased glycaemic variation, but not with low glucose levels.

A novel approach to continuous glucose analysis utilizing glycemic variation.

BACKGROUND: Various methodologies have been proposed for analysis of continuous glucose measurements. These methods have mainly focused on the proportion of low or high glucose readings and have not attempted to analyze other dimensions of the data obtained. This study proposes an algorithm for analysis of continuous glucose data including a novel method of assessing glycemic variability. METHODS: Mean blood glucose and mean of daily differences (MODD) assessed the degree that the Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA) trace was representative of the 3-month glycemic pattern. Percentages of times in low, normal, and high glucose ranges were used to assess marked glycemic excursion. Continuous overall net glycemic action (CONGA), a novel method developed by the authors, assessed intra-day glycemic variability. These methods were applied to 10 CGMS traces chosen randomly from those completed by children with type 1 diabetes from the Royal Children's Hospital, Melbourne, Victoria, Australia and 10 traces recorded by healthy volunteer controls. RESULTS: The healthy controls had lower values for mean blood glucose, MODD, and CONGA. Patients with diabetes had higher percentages of time spent in high and low glucose ranges. There was no overlap between the CONGA values for patients with diabetes and for controls, and the difference between controls and patients with diabetes increased markedly as the CONGA time period increased. CONCLUSIONS: We advocate an approach to the analysis of CGMS data based upon a hierarchy of relevant clinical questions alluding to the representative nature of the data, the amount of time spent in glycemic excursions, and the degree of glycemic variation. Integrated use of these algorithms distinguishes between various patterns of glycemic control in those with and without diabetes.

Primary adrenal insufficiency in childhood and adolescence: advances in diagnosis and management.

OBJECTIVES: Primary adrenal insufficiency occurring in childhood and adolescence is due to abnormalities of gland development, gland responsiveness, and steroid biosynthesis or target organ response. Causes include autoimmune Addison's disease, tuberculosis, HIV, adrenoleukodystrophy, adrenal hypoplasia congenita and syndromes including triple A and IMAGe. We aimed to define the causes of adrenal insufficiency for a cohort of children in Melbourne. METHODS: We reviewed the frequency and variety of presentation of primary adrenal insufficiency to the Royal Children's Hospital over the past 10 years through an audit of patient records, collating demographic information, presentation and investigations. RESULTS: Sixteen cases (13 male, 3 female) of primary adrenal insufficiency were diagnosed at this hospital between January 1993 and July 2003. Median age at presentation was 7.7 years (range: birth to 14.8 years). Symptoms at presentation included weakness, increased pigmentation, abdominal pain, nausea, developmental delay or a reduction in school performance. Four patients presented with adrenal crisis. Median adrenocorticotrophic hormone (ACTH) at diagnosis was 246 pmol/L (range 30-969 pmol/L). Autoantibodies were positive in five patients. Five patients had elevation of very long chain fatty acids. Five patients were diagnosed with autoimmune adrenal insufficiency, five with adrenal hypoplasia congenita, five with adrenoleukodystrophy and one with IMAGe syndrome. CONCLUSIONS: A high index of suspicion results in earlier detection and possible prevention of adrenal crisis with a reduction in associated morbidities. Definitive diagnosis is now possible for almost all cases of primary adrenal insufficiency using technologies for screening autoimmunity, adrenoleukodystrophy (ALD) and genetic screening.

Adrenal cortical tumours: 25 years' experience at the Royal Children's Hospital, Melbourne.

AIMS: Adrenal cortical tumours remain a rare entity with inconsistent consensus about treatment and follow up. This article reviews 25 years of experience in the Royal Children's Hospital, Melbourne, Australia. METHODS: All records with the diagnosis of adrenal adenoma or carcinoma between 1976 and 2001 were reviewed, excluding tumours of the adrenal medulla. Details were recorded for age, gender, family history, presentation, biochemistry, imaging, histology, diagnosis, treatment and outcome. RESULTS: Twelve children (six boys, six girls) were diagnosed with adrenal cortical tumours in this period. Median age at diagnosis was 2.5 years (range 0.5-15.6 years). Six of the 12 children presented with virilization. The remaining six identified by ultrasound performed for hemi-hypertrophy (2), hypertension (2), and fever with abdominal pain (2). Five children had a family history of tumour and two of these five had a p53 mutation demonstrated on molecular genetic analysis. Tumours in five of the 12 children were defined as malignant on histology. Surgery was deemed curative in nine cases. Only one case required further surgery and two required chemotherapy. Time since diagnosis ranged from 1 to 25.8 years. Two children died from complications of the tumour. One other child died following development of a second tumour. CONCLUSION: Adrenal cortical tumours should always be considered in the differential for adrenal hormone excess. New information provided by mutational analysis may predict ongoing risks. Lifelong regular follow up is required.