Somatic gain-of-function mutations of GNAS cause a spectrum of clinical phenotypes, ranging from McCune-Albright syndrome (MAS) to isolated disease of bone, endocrine glands, and more rarely, other organs. In MAS, a syndrome classically characterized by polyostotic fibrous dysplasia (FD), café-au-lait (CAL) skin spots, and precocious puberty, the heterogenity of organ involvement, age of onset, and clinical severity of the disease are thought to reflect the variable size and the random distribution of the mutated cell clone arising from the postzygotic mutation. We report a case of neonatal MAS with hypercortisolism and cholestatic hepatobiliary dysfunction in which bone changes indirectly emanating from the disease genotype, and distinct from FD, led to a fatal outcome. Pulmonary embolism of marrow and bone fragments secondary to rib fractures was the immediate cause of death. Ribs, and all other skeletal segments, were free of changes of typical FD and fractures appeared to be the result of a mild-to-moderate degree of osteopenia. The mutated allele was abundant in the adrenal glands and liver, but not in skin, muscle, and fractured ribs, where it could only be demonstrated using a much more sensitive PNA hybridization probe-based FRET (Förster resonance energy transfer) technique. Histologically, bilateral adrenal hyperplasia and cholestatic disease matched the abundant disease genotype in the adrenals and liver. Based on this case and other sporadic reports, it appears that gain-of-function mutations of GNAS underlie a unique syndromic profile in neonates characterized by CAL skin spots, hypercortisolism, hyperthyroidism, hepatic and cardiac dysfunction, and an absence (or latency) of FD, often with a lethal outcome. Taken together, our and previous cases highlight the phenotypic severity and the diagnostic and therapeutic challenges of MAS in neonates. Furthermore, our case specifically points out how secondary bone changes, unrelated to the direct impact of the mutation, may contribute to the unfavorable outcome of very early-onset MAS.

The study examined how transition readiness skills develop from relationship processes with parents, friends, and healthcare providers. During their senior year of high school and one year later, participants (n=217) with type 1 diabetes completed measures of transition readiness skills (Self-Management; Self-Advocacy), adherence, HbA1c, and relationships with providers (patient-centered communication), parents (monitoring/knowledge), and friends (knowledge/helpfulness) surrounding diabetes. Self-Management skills increased across time. Higher friend knowledge/helpfulness during emerging adulthood was associated with increased Self-Management skills. Adherence improved when relationships with providers and friends matched transition readiness skills, indicating that these relationships may facilitate transition skills in early emerging adulthood.

The study examined in adolescents with type 1 diabetes whether higher intelligence was predictive of better subsequent metabolic control through better self-control. Two-hundred fifty two adolescents with type 1 diabetes completed an intelligence test and a measure of self-control at baseline. HbA1c was gathered from medical records at baseline and six months later. A path model revealed that adolescent intelligence at Time 1 was associated with changes in HbA1c from Time 1 to Time 2 through adolescents' higher self-control. Higher intelligence may be a resource for the application of self-regulatory skills during adolescence that facilitate metabolic control.

Purpose: To predict trajectories of metabolic control across adolescence from parental involvement and adolescent psychosocial maturity, and to link metabolic control trajectories to health care utilization.Methods: Two hundred fifty-two adolescents (M age at study initiation = 12.5 years, SD = 1.5, range = 10-14 years) with type 1 diabetes (54.4% female, 92.8% Caucasian, length of diagnosis M = 4.7 years, SD = 3.0, range = 1-12 years) participated in a 2-year longitudinal study. Metabolic control was gathered from medical records every 3 months. Adolescents completed measures of self-reliance (functional autonomy and extreme peer orientation), self-control (self-control and externalizing behavior), and parental involvement in diabetes care (acceptance, monitoring, and frequency of help). At the end of the study, mothers reported health care utilization (diabetes-related emergency room visits and hospitalizations) over the past 6 months.Results: Latent class growth analyses indicated two distinct trajectories of metabolic control across adolescence: moderate control with slight deterioration (92% of the sample; average HbA1c = 8.18%) and poor control with rapid deterioration (8% of the sample; average HbA1c of 12.09%). Adolescents with poor and rapidly deteriorating metabolic control reported lower paternal monitoring and frequency of help with diabetes management, lower functional autonomy, and lower self-control than others. Those with poor and rapidly deteriorating metabolic control were 6.4 times more likely to report diabetes-related emergency room visits, and 9.3 times more likely to report diabetes-related hospitalizations near the end of the study.Conclusions: Parental involvement and adolescents' psychosocial maturity predict patterns of deteriorating metabolic control across adolescence and could be targeted for intervention. (C) 2012 Society for Adolescent Health and Medicine. All rights reserved.

Objective To examine whether adolescents’ and parents’ perceptions of patient-centered communication (PCC) with the physician may be associated with aspects of patient empowerment (e.g., perceptions of competence) and diabetes management (i.e., adherence and HbA1c). Methods One hundred and ninety adolescents with type 1 diabetes and their parents rated perceptions of PCC following a clinic visit and completed measures of competence, illness perceptions, self-efficacy, and adherence in the weeks following their clinic visit, and again 6 months later. Metabolic control was indexed from medical records. Results Higher levels of PCC with physicians were associated cross-sectionally and longitudinally with greater perceptions of control and competence for both adolescents and parents. Mediation analyses indicated that PCC was indirectly related to subsequent adherence and metabolic control through perceptions of the adolescent’s competence in diabetes management. Conclusions Perceptions of PCC with healthcare providers may empower adolescents and parents in their diabetes management.

OBJECTIVES To examine pump duration associations with adolescents' metabolic control and whether parental involvement moderated this association. METHODS This study used a cross-sectional sample of 10- to 14-year-olds with diabetes (N = 252, 53.6% female) and parents' reported parental involvement; HbA1c was obtained from medical records. Half (50.8%) were on an insulin pump (continuous subcutaneous insulin infusion, CSII), with the remainder prescribed multiple daily injections (MDI). RESULTS Adolescents on CSII displayed better HbA1c than those on MDI. A curvilinear association revealed that participants on CSII for <2 years showed a positive pump duration-HbA1c association, while those on CSII longer showed no association. Parental involvement interacted with pump duration to predict HbA1c. Pump duration was associated with poorer HbA1c only when parents were relatively uninvolved. CONCLUSIONS Within the limitations of a cross-sectional design, data suggest that adolescents on CSII have better HbA1c than those on MDI, but may experience a period of deterioration that can be offset by parental involvement.

ObjectivesTo examine how perceptions of parental responsibility for diabetes management are associated with age, pubertal status, adolescents self-efficacy, and parental perceptions of adolescents efficacy, and if parental responsibility is associated with better metabolic control as a function of adolescents self-efficacy and parental perceptions of adolescents efficacy.MethodsQuestionnaires assessing parental responsibility, pubertal status, adolescents self-efficacy, and parental perceptions of adolescents efficacy were given to 185 adolescents with type 1 diabetes, 185 mothers, and 145 fathers.ResultsGreater parental responsibility was negatively associated with age, perceptions of pubertal status, and efficacy for all reporters. Interactions between parental responsibility and parental perceptions of adolescents efficacy indicated that parental responsibility was associated with better metabolic control when adolescents were perceived to have lower efficacy.ConclusionsAdolescents and parents perceptions of parental responsibility are related to multiple factors. Metabolic control is best when high parental responsibility is maintained among adolescents with lower efficacy.

OBJECTIVE - This study examined 1) whether the benefits of mothers' and fathers' acceptIng relationships with their adolescents regarding diabetes control were due to parental monitoring and 2) how parents together may provide sufficient acceptance and monitoring for diabetes management.RESEARCH DESIGN AND METHODS - Adolescents aged 10 -14 years with type 1 diabetes (n = 185) and their mothers (n = 185) and fathers (n = 145) completed assessments of parental acceptance and monitoring of diabetes tasks. Adolescents completed a modified version of the Self-Care Inventory (1) to measure adherence. A1C scores were used as a marker of glycemic control.RESULTS - Mediational analyses revealed that the benefits of adolescents' reports of fathers' acceptance on A1C and mothers' and fathers' acceptance on better adherence were partially mediated by monitoring. Both mothers' and fathers' monitoring and fathers' acceptance had independent effects in predicting adherence. However, only fathers' monitoring had an independent effect on A1C. The effect of fathers' monitoring on A1C occurred as fathers were monitoring at a lower level than mothers. Mothers' and fathers' reports of their own acceptance and monitoring were not associated with A1C or adherence.CONCLUSIONS - Results reveal the importance of fathers' acceptance and monitoring in diabetes management, a role that should be encouraged, despite the little attention it has received.

OBJECTIVE - The purpose of this study was to examine whether perceptions of physician recommendations about maternal involvement in adolescent diabetes management are associated with children's reports of mothers' involvement during the subsequent week.RESEARCH DESIGN AND METHODS - Youth with type I diabetes (aged 10-15 years) and mothers completed scales measuring perceptions of physician recommendations about maternal involvement. At their appointment, and again I week later, children reported mothers' involvement in diabetes over the preceding week.RESULTS - A total of 53 dyads provided usable data at both time points. Perceived recommendations to increase involvement were associated with children's reports of increased maternal collaboration during the subsequent week (B = 0.81, P < 0.05), an effect that was stronger among boys (13 = - 1.21, P < 0.005). Increased maternal collaboration correlated with better AIC (r = -0.39, P < 0.005).CONCLUSIONS- Physicians may facilitate adaptive forms ofmaternal involvement during adolescence by conveying messages about involvement to patients and families.

OBJECTIVETo examine how children's and mother's appraisals of each other's involvement in coping with diabetes events are associated with emotional adjustment.METHODSOne hundred and twenty-seven children (ages 10-15 years) with type 1 diabetes and their mothers reported on their own emotional adjustment and how each other was involved in coping strategies surrounding diabetes stressful events.RESULTSAppraisals that mothers and children were uninvolved with each other's stressors were associated with greater depressive symptoms and less positive mood; children's appraisals of mother's supportive involvement with children's less depressive symptoms, and appraisals of collaborative involvement with less depressive symptoms and more positive mood for both mothers and children. Appraised control was most detrimental for children for older females and for mothers of younger children.CONCLUSIONSCollaborative involvement in coping efforts may be an important resource for addressing negative emotions that both children and mothers experience surrounding type 1 diabetes, especially across adolescence.

Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3 gamma 1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 9.6% of response at study entry in drug-treated patients vs. 53 +/- 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA(1c), and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8(+) T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3 gamma 1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.

OBJECTIVE:To estimate the degree of familial aggregation of juvenile idiopathic arthritis (JIA), determine whether the aggregation of JIA and the aggregation of type 1 diabetes mellitus (type 1 DM) overlap, and identify multiplex JIA pedigrees.METHODS:Records of individuals with JIA or type 1 DM were probabilistically linked with records in the Utah Population Database (UPDB), a large computerized family history database. For each case of JIA or type 1 DM, 10 matched controls or 5 matched controls, respectively, were selected. All familial relationships among cases of JIA or type 1 DM were established. A familial risk score was calculated for each subject. For various levels of familial exposure to JIA or type 1 DM, one's risk (odds ratio [OR]) of developing JIA or type 1 DM was established (cases compared with controls). Recurrence risks for JIA were computed for relatives of JIA cases compared with relatives of controls. Extended JIA families were identified from a list of common ancestors.RESULTS:Records of a total of 443 patients were linked with the UPDB. Of these, 381 (86.0%) met criteria for JIA. An increased risk for JIA was observed among relatives of probands with JIA. The prevalence of type 1 DM among JIA cases was higher than the US prevalence of type 1 DM (P < 0.003). The recurrence risk for JIA was significantly elevated among first-degree relatives of cases with JIA (OR 30.4). The overall prevalence of JIA was 28/100,000. Four extended JIA pedigrees were identified.CONCLUSION:There is familial aggregation of JIA in the Intermountain West region of the US. We have demonstrated that multiplex JIA pedigrees can be identified using a genealogic database.

Type 1 diabetes, a chronic autoimmune disease, causes destruction of insulin-producing beta-cells over a period of years. Although many markers of the autoimmune process have been described, none can convincingly predict the rate of disease progression. Moreover, there is relatively little information about changes in insulin secretion in individuals with type 1 diabetes over time. Previous studies document C-peptide at a limited number of time points, often after a nonphysiologic stimulus, and under non-steady-state conditions. Such methods do not provide qualitative information and may not reflect physiologic responses. We have studied qualitative and quantitative insulin secretion to a 4-h mixed meal in 41 patients with newly diagnosed type 1 diabetes and followed the course of this response for 24 months in 20 patients. Newly diagnosed diabetic patients had an average total insulin secretion in response to a mixed meal that was 52% of that in nondiabetic control subjects, considerably higher than has been described previously. In diabetic patients there was a decline of beta-cell function at an average rate of 756 +/- 132 pmol/month to a final value of 28 +/- 8.4% of initial levels after 2 years. There was a significant correlation between the total insulin secretory response and control of glucose, measured by HbA(1c) (P = 0.003). Two persistent patterns of insulin response were seen depending on the peak insulin response following the oral meal. Patients with an early insulin response (i.e., within the first 45 min after ingestion) to a mixed meal, which was also seen in 37 of 38 nondiabetic control subjects, had a significantly accelerated loss of insulin secretion, as compared with those in whom the insulin response occurred after this time (P < 0.05), and significantly greater insulin secretory responses at 18 and 24 months (P < 0.02). These results, which are the first qualitative studies of insulin secretion in type 1 diabetes, indicate that the physiologic metabolic response is greater at diagnosis than has previously been appreciated, and that the qualitative insulin secretory response is an important determinant of the rate of metabolic decompensation from autoimmune destruction.

BACKGROUND:Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease.METHODS:We studied the effects of a nonactivating humanized monoclonal antibody against CD3--hOKT3gamma1(Ala-Ala)--on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease.RESULTS:Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment.CONCLUSIONS:Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.