Fergus J. Cameron

Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study

CONTEXT AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN This study was an international, multicenter, retrospective case collection/database analysis. SETTING The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Central Nervous System Function in Youth With Type 1 Diabetes 12 Years After Disease Onset

OBJECTIVE—In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis. RESEARCH DESIGN AND METHODS—We studied type 1 diabetic (n = 106) and control subjects (n = 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis. RESULTS—Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P < 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P < 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P < 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P < 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia. CONCLUSIONS—This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity.

Continuing Stability of Center Differences in Pediatric Diabetes Care: do advances in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood Diabetes

OBJECTIVE—To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis. RESEARCH DESIGN AND METHODS—This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11–18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005. RESULTS—Mean A1C was 8.2 ± 1.4%, with substantial variation between centers (mean A1C range 7.4–9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 ± 2.0% vs. 8.2 ± 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C. CONCLUSIONS—Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.

Psychiatric morbidity and health outcome in Type 1 diabetes--perspectives from a prospective longitudinal study.

Aims  To describe psychiatric status and relationship to metabolic control in adolescents with Type 1 diabetes studied prospectively from diagnosis.

The Child Health Questionnaire in children with diabetes: cross-sectional survey of parent and adolescent-reported functional health status

SUMMARY

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes

Aims  To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries.

Reduced bone density in children on long-term warfarin.

Vitamin K is essential for development of normal bone density and achieving adequate peak bone mass in childhood and is thought to be important in preventing the development of osteoporosis in later life. Warfarin, a vitamin K antagonist, is being used with greater frequency in children. The long-term effect of warfarin on bone density of children is not known. We performed a case control study survey of bone density in children on long-term warfarin (n = 17, average duration of warfarin treatment 8.2 y) compared with randomly selected controls (n = 321). There was a marked reduction in bone mineral apparent density of lumbar spine between patients and controls [patients 0.10 g/cm3; 95% confidence interval (CI), 0.93–0.11 g/cm3, controls 0.12 g/cm3; 95% CI, 0.11–0.12 g/cm3, p < 0.001). The lumbar spine areal bone mineral density Z-score of patients was reduced compared with controls [patients, −1.96 (95% CI, −2.52 to −1.40). This difference persisted after adjustment for age and body size. The etiology for the reduced bone density is likely to be multifactorial, however, screening of children on long-term warfarin for reduced bone density should be considered.

Routine Psychological Screening in Youth With Type 1 Diabetes and Their Parents: A notion whose time has come?

In the post-DCCT (Diabetes Control and Complications Trial) (1) and -EDIC (Epidemiology of Diabetes Interventions and Complications) (2) eras, considerable effort has been expended on early detection and treatment of diabetes-related microvascular complications in youth using screening programs. Numerous consensus statements have been generated relating to the timing, frequency, and content of such programs (3–7). Although each recommends a slightly different approach to screening, the same basic principles apply—achieve and maintain excellent glycemic control; reduce known and modifiable risk factors, such as smoking, obesity, hyperlipidemia, and hypertension; and screen for nephropathy and retinopathy on a regular basis following the inset of puberty. To be considered successful, any screening program must satisfy several criteria (8): Certainly, given what we know about microvascular complications and their progression and treatment, universal diabetes complication screening programs satisfy most of these prerequisites. Ten years after the DCCT, average levels of metabolic control have improved in most clinical reports of children and adolescents with type 1 diabetes, although population-based data remain scanty and perhaps less optimistic (9–14). Contemporary clinic-based reports of microvascular complication rates in adolescence have shown a concomitant improvement (15–18). On the other hand, reports relating to health-related quality of life (HRQOL) and psychological outcomes have been distressingly suboptimal (19–24). Although not all studies report significant associations (25–27), there are a number of reports showing that psychosocial dysfunction and family conflict are close correlates of poor health …

Therapy Insight: the impact of type 1 diabetes on brain development and function

The CNS is one of the main organ systems that is affected in type 1 diabetes, as both cerebral glucose and insulin levels are frequently abnormal, even when the diabetes is well-controlled. Literature is emerging that documents pathophysiological CNS changes and neurocognitive deficits in both adults and children with type 1 diabetes, but empirical findings to date have often been inconsistent and difficult to interpret. This article provides a comprehensive review of current knowledge about the impact of type 1 diabetes on brain development and function, focusing particularly on the evidence for specific illness-related risk factors for CNS sequelae. We argue that clinical management of young patients with type 1 diabetes should take into account current knowledge of the relative risks of hypoglycemia and hyperglycemia to the developing brain.

Diabetes in adolescence

Leicester Royal Infirmary Children’s Hospital, Leicester, UKCorresponding author:John M Court, MD,Albert Road Clinic31 Albert RoadMelbourne, Victoria 3004Australia.Tel: 161 3 92793560;fax: 161 3 92793599;e-mail: johncourt@iprimus.com.auAcknowledgement: Barbara Anderson.Editors of the ISPAD Clinical Practice Consensus Guidelines2006–2007: Kim Donaghue, Ragnar Hanas, GeorgeannaKlingensmith, and Peter Swift.