Bruce A. Boston

Targeted disruption of the melanocortin-4 receptor results in obesity in mice

The melanocortin-4 receptor (MC4-R) is a G protein-coupled, seven-transmembrane receptor expressed in the brain. Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome, which results from ectopic expression of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R.

The Role of Melanocortins in Adipocyte Function

ABSTRACT: It has been demonstrated that adipocytes express high affinity ACTH and α‐MSH binding sites, and that ACTH, α‐MSH, and β‐LPH are potent lipolytic Hormones. Considerable species variability exists in the lipolytic response to melanocortins, however. Recently, MC2 and MC5 receptor‐MRNA was found in both murine adipocytes and in the 3T3‐L1 murine embryonic fibroblast cell line, but only after the 3T3‐L1 cells had differentiated into adipocytes. The 3T3‐L1 cell line was used to characterize the pharmacological properties of both MC2 and MC5 receptors in situ. Both murine MC2 and MC5 receptors are functional in the adipocyte, although the MC5 receptor required high doses of α‐MSH to activate cylase. ACTH potently stimulates cyclase with EC50 values that are consistent with the hypothesis that the murine MC2 receptor, not the MC5 receptor, mediates stress‐induced lipolysis via release of ACTH from the pituitary.

Congenital Hypothyroidism Caused by Excess Prenatal Maternal Iodine Ingestion

We report the cases of 3 infants with congenital hypothyroidism detected with the use of our newborn screening program, with evidence supporting excess maternal iodine ingestion (12.5 mg/d) as the etiology. Levels of whole blood iodine extracted from their newborn screening specimens were 10 times above mean control levels. Excess iodine ingestion from nutritional supplements is often unrecognized.

Prevalence and Trends of Metabolic Syndrome Among Korean Adolescents: From the Korean NHANES Survey, 1998-2005

OBJECTIVES To evaluate the prevalence and trend of metabolic syndrome (MetS) among Korean adolescents. STUDY DESIGN Data from 1998, 2001, and 2005 Korean National Health and Nutrition Examination Surveys were analyzed (N = 4164; age, 10 to 19 years) for MetS prevalence using the modified International Diabetes Federation criteria. RESULTS The combined prevalence of MetS in Korean adolescents was 2.2% in 1998, 3.6% in 2001, and 1.8% in 2005. MetS in Korean boys increased from 1.4% in 1998 to 5.3% in 2001 but decreased to 2.0% in 2005. The prevalence of MetS in girls decreased over the study periods (3.0% in 1998, 1.9% in 2001, and 1.6% in 2005). MetS prevalence declined from 1998 to 2005 despite an increase in overweight or obese individuals among both sexes (1998: boys, 15.1%; girls, 17.8%; 2005: boys, 26.8%; girls, 21.7%). Among individual MetS components, hyperglycemia decreased dramatically in 2005 in both sexes and accounted for the majority of the decline in the prevalence of the MetS in Korean adolescents. CONCLUSIONS The prevalence of MetS has declined despite an increase in obesity in Korean youth. Recent changes in physical activity in addition to national health care initiatives in Korea may have had a positive impact on the prevalence of MetS.

Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia

Imatinib mesylate, a tyrosine kinase inhibitor, is used in the treatment of chronic myelogeneous leukemia (CML). Given its ease of administration and manageable side effects in adults, imatinib mesylate was introduced as therapy for pediatric CML. Recently published case reports describe growth deceleration in children treated with imatinib. This study details the growth phenotype of seven pediatric patients maintained in remission on imatnib mesylate over an extended period of time.

Thyroxine-binding globulin deficiencydetected by newborn screening

We examined the results of the Northwest Regional Screening Program from May 1975 to June 1991 to determine the prevalence of inherited thyroxine-binding globulin (TBG) deficiency and its effect on thyroid hormone concentrations in infants. Serum thyroxine (T4), triiodothyronine resin uptake (T3RU), and thyrotropin values were requested of physicians caring for all infants with a single filter paper T4 level < 38.6 nmol/L (3 micrograms/dl) or a T4 level < 3rd percentile on two filter paper tests (at birth and 2 to 6 weeks of age). From 1,367,724 infants screened in five states, TBG deficiency, an X-linked disorder, was identified in 317 infants (285 boys). For the entire screening program the calculated frequency of TBG deficiency was 1:4315 infants (1:2400 for boys). In Oregon, where 95% of infants have two screening tests performed, the calculated frequency was somewhat higher (1:3080 infants; 1712 boys) and is probably more accurate. The mean serum T4 concentration for TBG-deficient boys was 41.9 nmol/L (3.26 micrograms/dl); 31% had values < 25.7 nmol/L (2.0 micrograms/dl). The mean serum T4 concentration for TBG-deficient girls was 60.2 nmol/L (4.68 micrograms/dl), with none < 2.0 micrograms/dl. The mean T3RU value was 0.472 in TBG-deficient boys, and 0.412 in TBG-deficient girls; the T3RU value was > 0.55 in 24% of TBG-deficient boys but was > 0.55 in only one girl. Free serum T4 levels were normal in all 56 TBG-deficient infants studied, and TBG levels were low in all 20 infants studied. Inherited TBG deficiency is common in boys in the Northwest, with a frequency of 1:1700 and a male/female ratio of 8.9:1. Boys with TBG deficiency have mild, moderate, or severe alterations in total T4 and T3RU values, but severe deficiency is rare in girls.

Reversible cardiomyopathy in an infant with unrecognized congenital adrenal hyperplasia.

We describe an infant who had a dilated cardiomyopathy and who was later found to have congenital adrenal hyperplasia. The cardiomyopathy resolved after replacement of glucocorticoid and mineralocorticoid. We believe that glucocorticoid deficiency may have played a direct role in the evolution of this cardiomyopathy.

Natural history of idiopathic diabetes insipidus

OBJECTIVE To determine what percentage of diabetes insipidus (DI) in childhood is idiopathic and to assess the natural history of idiopathic DI. STUDY DESIGN We conducted a retrospective chart review of 105 patients with DI who were born or had DI diagnosed between 1980-1989 at 3 medical centers. A second cohort of 30 patients from 6 medical centers in whom idiopathic DI was diagnosed after 1990 was evaluated retrospectively for subsequent etiologic diagnoses and additional hypothalamic/pituitary deficiencies and prospectively for quality of life. RESULTS In the first cohort, 11% of patients had idiopathic DI. In the second cohort, additional hypothalamic/pituitary hormone deficiencies developed in 33%, and 37% received an etiologic diagnosis for DI. Health-related quality of life for all the patients with idiopathic DI was comparable with the healthy reference population. CONCLUSIONS Only a small percentage of patients with DI will remain idiopathic after first examination. Other hormone deficiencies will develop later in one-third of those patients, and slightly more than one-third of those patients will have an etiology for the DI diagnosed. Long-term surveillance is important because tumors have been diagnosed as long as 21 years after the onset of DI. Quality of life for these patients is as good as the reference population.

A novel presentation of familial glucocorticoid deficiency (FGD) and current literature review.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder, which manifests as isolated glucocorticoid deficiency with normal mineralocorticoid function. The disease is secondary to ACTH unresponsiveness, with low serum cortisol concentrations in the presence of markedly elevated ACTH levels. Approximately 40% of patients with FGD have an identifiable mutation in the ACTH receptor gene. The typical presentation of FGD includes recurrent hypoglycemia, failure to thrive, and hyperpigmentation prior to 5 years of age. Patients with point mutations in the ACTH receptor gene are noted to be of tall stature. We report a patient with an atypical initial presentation of this condition. Our patient differed from the typical presentation by having late age of onset, short stature, and few symptoms of FGD. Sequence analysis of the ACTH receptor gene showed compound heterozygosity, with two previously reported mutations: S74I and T159K. Her unique presentation further illustrates the phenotypic heterogeneity of this disorder in light of reported mutations.

Predictors of First-Year Growth Response to a Fixed-dose Growth Hormone Treatment in Children Born Small for Gestational Age: Results of an Open-Label, Multicenter Trial in the United States

BACKGROUND Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.