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1.  The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene 
Hormone research in paediatrics  2013;80(4):10.1159/000355384.
GNAS is a complex imprinted locus leading to several different gene products that show exclusive monoallelic expression. GNAS also encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitously expressed signaling protein that is essential for the actions of many hormones and other endogenous molecules. Gsα is expressed biallelically in most tissues but its expression is silenced from the paternal allele in a small number of tissues. The tissue-specific paternal silencing of Gsα results in different parent-of-origin specific phenotypes in patients who carry inactivating GNAS mutations. In this paper, we review the GNAS complex locus and discuss how disruption of Gsα expression and the expression of other GNAS products shape the phenotypes of human disorders caused by mutations in this gene.
PMCID: PMC3874326  PMID: 24107509
GNAS; pseudohypoparathyroidism; Gsα; alpha-subunit of the stimulatory G protein
2.  Internet informs parents about growth hormone 
Parent knowledge influences decisions regarding medical care for their children.
Parents of pediatric primary care patients aged 9-14 years, irrespective of height, participated in open focus groups (OFG). Moderators asked, “How do people find out about growth hormone (GH)?” Because many parents cited the Internet, the top 10 results from the Google searches, growth hormone children and parents of children who take growth hormone, were examined as representative. Three investigators independently performed content analysis, then reached consensus. Results were tabulated via summary statistics.
Eighteen websites were reviewed, most with the purpose of education (56%) and many funded by commercial sources (44%). GH treatment information varied, with 33% of sites containing content only about U.S Food and Drug Administration-approved indications. Fifty-six percent of sites included information about psychosocial benefits from treatment, 44% acknowledging them as controversial. Although important to OFG participants, risks and costs were each omitted from 39% of websites.
Parents often turn to the Internet for GH-related information for their children, though its content may be incomplete and/or biased. Clinicians may want to provide parents with tools for critically evaluating Internet-based information, a list of pre-reviewed websites, or their own educational materials.
PMCID: PMC4114729  PMID: 23942255
Growth Hormone; Internet; Risk; Benefit; Parents
3.  Maternal Leptin Predicts Adiposity of the Neonate 
Increased adiposity at birth may identify infants at high risk of developing obesity. Maternal obesity and hyperglycemia in pregnancy are associated with increased neonatal adiposity; however, features of maternal obesity that contribute to increased neonatal adiposity need further study.
To measure adiposity in neonates of obese and normal-weight women without gestational diabetes to test the hypothesis that obese women have neonates with increased adiposity compared to neonates of normal-weight women.
Sixty-one pregnant women, with a normal or obese BMI, and their neonates participated in this cross-sectional study at an academic medical center. Neonatal adiposity, expressed as percent body fat (fat mass/body mass), was measured by air displacement plethysmography and cord blood was assayed for biomarkers.
Adiposity in neonates of obese and normal-weight mothers did not differ. Stratifying mothers by leptin level showed that neo nates born to mothers with higher leptin had significantly higher adiposity (13.2 vs. 11.1%, p = 0.035). In the entire cohort, adiposity positively correlated with cord blood leptin (r = 0.48, p < 0.001) and adiponectin (r = 0.27, p = 0.04) levels.
Obesity in normoglycemic pregnant women was not associated with increased neonatal adiposity. High maternal leptin levels identified neonates with increased adiposity.
PMCID: PMC4123455  PMID: 24334975
4.  Dominant Form of Congenital Hyperinsulinism Maps to HK1 Region on 10q 
Hormone research in paediatrics  2013;80(1):10.1159/000351943.
In a family with congenital hyperinsulinism (HI), first described in the 1950s by MacQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI.
We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing.
Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21–22, a region containing 48 genes. Three novel non-coding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2.
Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21–22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
PMCID: PMC3876732  PMID: 23859901
beta-cell; hypoglycemia; genetics; hyperinsulinism; insulin secretion
5.  Isolated Central Hypothyroidism in Young Siblings as a Manifestation of PROP1 Deficiency: Clinical Impact of Whole Exome Sequencing 
Hormone research in paediatrics  2013;79(6):379-386.
Central hypothyroidism (CH) in children is rare and may be due to a variety of genetic defects. Most of these defects, but not all, are associated with additional pituitary hormone deficits. In a young child presenting with CH, it is important to determine whether additional pituitary hormone deficiencies are present, but this may be difficult to establish clinically.
We describe the clinical characteristics of two young siblings, ages 6 months and 2 years, presenting with isolated CH. Whole exome sequencing was performed to determine the genetic basis of isolated CH.
A homozygous frameshift mutation of PROP1 (296delGA) was identified in both probands. Defects in PROP1 cause progressive deficiency of multiple pituitary hormones. Based on this genetic diagnosis, further clinical testing was performed that demonstrated growth hormone deficiency in one sibling.
PROP1 deficiency may present as isolated central hypothyroidism at a very young age. In disorders with multiple potential causative genes, whole exome sequencing may facilitate rapid genetic diagnosis and lead to important changes in clinical management.
PMCID: PMC3788832  PMID: 23652424
central hypothyroidism; PROP-1; whole exome sequencing; gene diagnostics; genetics of endocrinopathies
6.  Response to Vitamin D3 Supplementation in Obese and Non-obese Caucasian Adolescents 
Hormone research in paediatrics  2012;78(4):226-231.
Vitamin D deficiency is highly prevalent in obese children. Obese children tend to respond poorly to vitamin D supplementation. The objective of the study was to compare the response to vitamin D3 supplementation (2000 IU once daily for 12 weeks) between obese and non- obese Caucasian adolescents.
The study design was open label non-randomized. It was carried out at a single center. Eighteen obese adolescents (age 12-18 years) and the same number of age, gender and season matched non-obese adolescents received Vitamin D3 (2000 IU/day) orally for 12 weeks. Total serum 25(OH) D, PTH, calcium and phosphorus were measured at baseline and at the end of the 12 week period.
The mean baseline 25 (OH)D level was higher in the non-obese subjects compared to the obese subjects (mean, 28.9 vs. 25.2 ng/mL, p=0.029). The increment in 25(OH) D levels following vitamin D supplementation was significantly lower in the obese adolescents (mean change, 5.8 vs. 9.8 ng/mL, p=0.019).
Higher doses of vitamin D are required to treat vitamin D deficiency in obese adolescents than in their non-obese peers.
PMCID: PMC3557792  PMID: 23128469
7.  Diabetes Mellitus in Neonates and Infants: Genetic Heterogeneity, Clinical Approach to Diagnosis, and Therapeutic Options 
Hormone Research in Pædiatrics  2013;80(3):137-146.
Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas.
PMCID: PMC3884170  PMID: 24051999
Neonatal diabetes; Monogenic diabetes of infancy ; Permanent neonatal diabetes; Transient neonatal diabetes ; Type 1 diabetes

8.  Absence of Functional LIN28B Mutations in a Large Cohort of Patients with Idiopathic Central Precocious Puberty 
Hormone research in paediatrics  2012;78(3):144-150.
To investigate LIN28B gene variants in children with idiopathic central precocious puberty (CPP).
Patients and Methods
We studied 178 Brazilian children with CPP (171 girls,16.8% familial cases). A large multiethnic group (1599 subjects; MEC cohort) was used as control. DNA analysis and biochemical in vitro studies were performed.
A heterozygous LIN28B variant, p.H199R, was identified in a girl who developed CPP at 5.2 yrs. This variant was absent in 310 Brazilian control individuals, but it was found in the same allele frequency in women from the MEC cohort, independently of the age of menarche. Functional studies revealed that when ectopically expressed in cells the mutant protein was capable of binding pre-let-7 miRNA and inhibiting let-7 expression to the same extent as wild-type Lin28B protein. Other rare LIN28B variants (p.P173P, c.198+32_33delCT, g.9575731A>C and c.-11C>T) were identified in CPP patients and controls. Therefore, no functional mutation was identified.
In vitro studies revealed that the rare LIN28B p.H199R variant identified in a girl with CPP does not affect the Lin28B function in the regulation of let-7 expression. Although LIN28B SNPs were associated with normal pubertal timing, rare variations in this gene do not seem to be commonly involved in the molecular pathogenesis of CPP.
PMCID: PMC3526815  PMID: 22964795
LIN28B; central precocious puberty; let-7; microRNA; early and late menarche
9.  Consequences of stopping and restarting leptin in an adolescent with lipodystrophy 
Hormone research in paediatrics  2012;78(5-6):320-325.
Lipodystrophy encompasses a group of rare disorders characterized by deficiency of adipose tissue resulting in hypoleptinemia, and metabolic abnormalities including insulin resistance, diabetes, dyslipidemia, and non-alcoholic steatohepatitis. Leptin replacement effectively ameliorates these metabolic derangements. We report effects of leptin discontinuation and resumption in a child with acquired generalized lipodystrophy.
Intermittent treatment with leptin with follow-up over 5y.
Pre-treatment metabolic abnormalities included insulin resistance, hypertriglyceridemia and steatohepatitis. Leptin was started at age 10y. After 2y, the family requested discontinuation of leptin due to lack of visible physical changes. Nine months later, worsened metabolic abnormalities and arrest of pubertal development were observed. Leptin was restarted, followed by improvements in metabolic parameters. Laboratory changes (before vs. 6 months after restarting leptin) were: Fasting glucose: 232 to 85 mg/dl. Insulin: 232 to 38.9 mcU/ml. HbA1c: 7.5 to 4.8%. Triglycerides: 622 to 96 mg/dl. ALT: 229 to 61 U/L. AST: 91 to 18 U/L. Urine protein/creatinine ratio: 5.4 to 0.3. Progression of puberty was observed 1y after restarting leptin.
Initial leptin therapy likely prevented progression of metabolic abnormalities. Treatment discontinuation led to rapid metabolic decomposition and pubertal arrest. Reintroduction of leptin reversed metabolic abnormalities and allowed normal pubertal progression.
PMCID: PMC3590018  PMID: 22965160
Lipodystrophy; Leptin; Non-alcoholic steatohepatitis (NASH); Diabetes; Adipose Tissue; Adolescent
Disorders of Sex Development (DSD) are congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. Optimal management is patient- and family-centered and delivered by interdisciplinary teams. The present pilot study elicits concerns held by important stakeholders on issues affecting young patients with DSD and their families.
Content from focus groups with expert clinicians (pediatric urologists [n=7], pediatric endocrinologists [n=10], mental health professionals [n=4]), DSD patient advocates (n=4), and interviews with parents of DSD-affected children (newborn to 6 yrs; n=11) was coded and content-analyzed to identify health-related quality of life issues.
Key stressors varied across stakeholder groups. In general, family-centered issues were noted more than child-centered. In the child-centered domain, providers worried more about physical functioning; family and advocates emphasized gender concerns and body image. In the family-centered domain, parental concerns about medication management outweighed those of providers. Advocates reported more stressors regarding communication/information than other stakeholders.
Variability exists across stakeholder groups in the key concerns affecting young children/families with DSD. Interdisciplinary DSD healthcare team development should account for varying perspectives when counseling families and planning treatment.
PMCID: PMC3478759  PMID: 22832323
11.  A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency 
Recessive mutations in the LHX3 ho-meodomain transcription factor gene are associated with developmental disorders affecting the pituitary and nervous system. We describe pediatric patients with combined pituitary hormone deficiency (CPHD) who harbor a novel mutation in LHX3.
Two female siblings from related parents were examined. Both patients had neonatal complications. The index patient had CPHD featuring deficiencies of GH, LH, FSH, PRL, and TSH, with later onset of ACTH deficiency. She also had a hypoplastic anterior pituitary, respiratory distress, hearing impairment, and limited neck rotation. The LHX3 gene was sequenced and the biochemical properties of the predicted altered proteins were characterized.
A novel homozygous mutation predicted to change amino acid 194 from threonine to arginine (T194R) was detected in both patients. This amino acid is conserved in the DNA-binding homeodomain. Computer modeling predicted that the T194R change would alter the homeodomain structure. The T194R protein did not bind tested LHX3 DNA recognition sites and did not activate the α-glycoprotein and PRL target genes.
The T194R mutation affects a critical residue in the LHX3 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene.
PMCID: PMC3355643  PMID: 22286346
Growth; Transcription; LIM; Development; Pediatric patients
12.  Cross-Sectional Association between Blood Pressure, in vivo Insulin Sensitivity and Adiponectin in Overweight Adolescents 
Hormone Research in Pædiatrics  2011;76(6):379-385.
To examine the cross-sectional relationship between blood pressure (BP) and (1) in vivo insulin sensitivity (IS) and (2) circulating adiponectin levels in overweight adolescents, and to determine if these relationships are driven by adiposity.
Sixty-five white pubertal overweight adolescents underwent a hyperinsulinemic-euglycemic clamp to measure IS. Body composition and abdominal adiposity were determined by dual energy X-ray absorptiometry and computed tomography scan. BP was measured by an automated sphygmomanometer every 10 min over 1 h, between 06:00 and 07:00 a.m.
In vivo IS was not associated with BP after adjustment for adiposity measurements (body mass index, percentage body fat or abdominal adiposity). However, adiponectin was inversely related to systolic BP independent of adiposity.
Our findings demonstrate that in overweight adolescents the relationship between in vivo IS and systolic BP is mediated through adiposity. However, the association between adiponectin and BP is independent of adiposity suggestive of a potential modulatory role of adiponectin in BP regulation.
PMCID: PMC3696355  PMID: 21968570
Blood pressure; Insulin sensitivity; Adiponectin; Obesity; Adolescents; Adipose tissue
13.  Factors Associated with Insulin Resistance among Children and Adolescents Perinatally Infected with HIV-1 in the Pediatric HIV/AIDS Cohort Study 
Hormone Research in Pædiatrics  2011;76(6):386-391.
Because of prior inconsistent findings, we studied a large cohort of HIV-infected children to determine: (1) prevalence of insulin resistance (IR); (2) anthropometric and clinical correlates of IR, and (3) concomitant abnormalities of glucose tolerance.
The study population consisted of 451 children from the Pediatric HIV/AIDS Cohort Study. The outcome of interest was HOMA-IR. Covariates included demographic, metabolic, growth, body composition, HIV laboratory tests, and treatment characteristics. Children meeting triggers for IR underwent oral glucose tolerance tests and hemoglobin A1c (HbA1c) measurements.
Among 402 children with glucose and insulin measurements, 15.2% had IR of whom 79% were pubertal. IR was associated with higher alanine aminotransferase, body mass index, and nadir CD4%, Tanner stage 5, and ever having received amprenavir. Of those with IR, three had impaired fasting glucose (IFG), three impaired glucose tolerance (IGT), one IFG and IGT, none diabetic glucose tolerance, and three HbA1c between 6.1 and 6.5%.
In our cohort of HIV-infected adolescents, we observed a 15.2% prevalence of IR more closely linked to obesity than any other variable. This finding mirrors the high prevalence of obesity-mediated IR in American youth. However, associations with CD4 count and use of protease inhibitors may indicate some effect of HIV and/or its treatment.
PMCID: PMC3697231  PMID: 22042056
Insulin resistance; HIV; Highly active antiretroviral therapy; Homeostatic model assessment of insulin resistance
14.  Endothelial Function as Measured by Peripheral Arterial Tonometry Increases during Pubertal Advancement 
Hormone Research in Pædiatrics  2011;76(4):226-233.
Background/Aims:Sex steroids, such as estrogens, are known to influence endothelial function by their vasodilator action. The aim of this study was to study the relation of puberty and sex steroids with endothelial function using peripheral arterial tonometry (PAT). Methods: In 89 healthy school boys and girls, we determined height, weight, waist circumference, percent body fat, BMI, BMI z-score, blood pressure (BP), BP percentiles, lipid profile, insulin, and glucose levels after overnight fast. Estrone (E1), estradiol (E2), DHEAS and E1-sulfate were measured using ultrasensitive assays. Participants were divided into 3 pubertal groups on the basis of their estrogen levels: group 1 (Tanner stage I), group 2 (Tanner stages II–III), and group 3 (Tanner stages IV–V). Endothelial function was measured by Endo-PAT 2000® and expressed as PAT index. A higher PAT index represents a higher reactive hyperemia response. Results: The PAT index was lowest at 1.42 ± 0.44 (mean ± SD) in group 1 and significantly increased in group 2 at 1.71 ± 0.35 (p = 0.02) and group 3 at 1.92 ± 0.38 (p < 0.001). The PAT index correlated positively with E2, DHEAS and age. Conclusion: Enhancement of the PAT index was associated with an increment in Tanner stages. The changes in E2 and DHEAS levels may contribute to increasing endothelial response to shear stress or arterial blood flow.
PMCID: PMC3224510  PMID: 21778688
Peripheral arterial tonometry; Puberty; Endothelial function; Estradiol; DHEAS; Nitric oxide
15.  Relationship between Cardiovascular Risk Factors and Adipokines in Adolescents 
Hormone Research in Pædiatrics  2011;76(2):123-129.
This study evaluated the associations of adipokines with cardiovascular risk factors.
60 normal weight (BMI ≤75th percentile) and 60 overweight (BMI ≥95th percentile) adolescents aged 10–14 years. Resting systolic and diastolic blood pressures (SBP, DBP) and waist circumference were obtained in duplicate. Circulating adiponectin, resistin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), total cholesterol (TC), high-density lipoprotein (HDL), and triglycerides (TG) were measured from fasting plasma samples.
Simple correlations showed that SBP was significantly related (p < 0.05) to adiponectin (r = –0.185), resistin (r = 0.207), and IL-6 (r = 0.238); HDL was significantly related to adiponectin (r = 0.398) and TNF-α (r = –0.227). TG was only related to adiponectin (r = –0.292, p < 0.05). Multiple regression models controlling for puberty and ethnicity indicated that adiponectin (R2 = 0.152, p < 0.05), resistin (R2 = 0.152, p < 0.05), and IL-6 (R2 = 0.170, p < 0.05) were associated with SBP. The association between adiponectin and HDL was stronger in normal weight versus overweight adolescents (R2 = 0.336, p < 0.05). None of the other models showed differences in the associations by weight status.
In adolescents, SBP but not DBP was associated with most adipokines. HDL, but not TC, was also associated with some adipokines. TG were only associated with adiponectin. Associations were mostly related to adiposity.
PMCID: PMC3182039  PMID: 21701142
Blood pressure; Cytokines; Lipids; Obesity; Adolescents
16.  Treatment Approaches for Diabetes and Dyslipidemia 
Hormone Research in Pædiatrics  2011;76(Suppl 1):76-80.
Dyslipidemia is an important risk factor for cardiovascular complications in persons with diabetes. Low-density lipoprotein-cholesterol (LDL-C) is the ‘cornerstone’ for assessment of lipoprotein-associated risk. However, LDL-C levels do not reflect the classic ‘diabetic dyslipidemia’ of hypertriglyceridemia and low high-density lipoprotein-cholesterol (HDL-C). Measurements of plasma apolipoprotein B100 concentrations and non-HDL-C may improve the definition of dyslipidemia. Statins, nicotinic acid and fibrates have roles in treating dyslipidemia in diabetes. Residual risk (i.e. risk that persists after correction of ‘conventional’ plasma lipoprotein abnormalities) is a new concept in the role of dyslipidemia in the pathogenesis of diabetic vascular complications. For example, regardless of plasma levels, lipoprotein extravasation through a leaking retinal blood barrier and subsequent modification may be crucial in the development of diabetic retinopathy. The current approach to the management of dyslipidemia in diabetes is briefly summarized, followed by a discussion of new concepts of residual risk and emerging lipoprotein-related mechanisms for vascular disease in diabetes.
Effective treatments must correct adverse quantitative plasma lipoprotein levels and a spectrum of qualitative abnormalities in plasma and tissue, as well as the processes by which lipoproteins and cells interact at the sites of disease.
PMCID: PMC3202950  PMID: 21778754
Diabetes; Dyslipidemia; Nuclear magnetic resonance spectroscopy; Residual risk
17.  Coexistent Autoimmunity in Familial Type 1 Diabetes: Increased Susceptibility in Sib-Pairs? 
Hormone Research in Pædiatrics  2011;75(4):284-290.
Type 1 diabetes (T1D) patients are at risk for additional autoimmune diseases (AID).
To compare the characteristics of associated autoimmunity among familial (parent-offspring and sib-pair) subgroups and sporadic T1D patients.
Patients and Methods
Data regarding AID in T1D patients and their nuclear family members were extracted from medical files of 121 multiplex T1D families (58 parent-offspring, 63 sib-pairs) and 226 sporadic controls followed between 1979 and 2008.
The prevalence of associated autoimmunity was similar in familial and sporadic cases (33.6 vs. 32.7%). The frequency of additional AID and percentage of patients with two or more coexistent AID were significantly higher among sib-pairs than parent-offspring (p = 0.05 and p = 0.04, respectively). The median time elapsed between diagnosis of T1D and occurrence of additional autoimmunity tended to be shorter in the sib-pairs. Only in familial cases did a positive autoimmune family background predict the development of coexistent autoimmunity (OR = 2.11, CI [1.0, 4.49] p = 0.05).
Among sib-pairs with T1D, the higher prevalence of additional AID, the increased number of diseases per person, and the relatively earlier appearance of associated AID suggest an increased susceptibility for coexistent autoimmunity in this subgroup. Positive family history for autoimmunity in multiplex T1D families increased their risk for co-occurrence of AID.
PMCID: PMC3078238  PMID: 21242668
Type 1 diabetes; Familial type 1 diabetes; Coexistent autoimmunity
18.  Effects of Prenatal Ethanol Exposure on Postnatal Growth and the Insulin-Like Growth Factor Axis 
Hormone Research in Pædiatrics  2010;75(3):166-173.
To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation.
We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≥48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age.
IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects.
Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.
PMCID: PMC3068754  PMID: 20847545
Fetal alcohol syndrome; Pregnancy; Alcohol abuse; Insulin-like growth factor I; Insulin-like growth factor II
19.  Comparison of Multiple Steroid Concentrations in Serum and Dried Blood Spots throughout the Day of Patients with Congenital Adrenal Hyperplasia 
Periodic measurement of plasma concentrations of cortisol precursors on a clinic visit may be of limited value in patients with congenital adrenal hyperplasia because it does not reflect a patient's circadian patterns of adrenal steroid secretion. Steroid profiling in dried blood spots (DBS) may allow for more frequent and sensitive monitoring.
We compared the agreement between 17α-hydroxyprogesterone (17-OHP) and androstenedione (D4A) levels determined from DBS samples and concurrently collected serum samples. Blood was drawn from 9 congenital adrenal hyperplasia patients every 4 h over a 24-hour period. Serum and DBS steroid levels were measured by liquid chromatography tandem mass spectrometry.
DBS determinations of 17-OHP overestimated corresponding serum levels (mean difference 1.67 ng/ml), and underestimated D4A serum levels (mean difference 0.84 ng/ml). However, the DBS assay yielded excellent agreement (97%) with serum 17-OHP, but did considerably poorer for D4A (31%).
Our results indicate an excellent agreement between DBS and serum 17-OHP measurements to identify the peaks and troughs associated with an individual's circadian pattern. Larger-scale studies are required to evaluate the utility of DBS for home monitoring and to determine if more frequent monitoring leads to improved clinical outcomes.
PMCID: PMC3202930  PMID: 20798478
Congenital adrenal hyperplasia; 17α-hydroxyprogesterone; Tandem mass spectrometry; Circadian rhythms of hormones; Glucocorticoid therapy
20.  Associations of Progesterone Receptor Polymorphisms with Age at Menarche and Menstrual Cycle Length 
Hormone Research in Pædiatrics  2010;74(6):421-427.
Age at menarche and menstrual cycle characteristics are indicators of endocrine function and may be risk factors for diseases such as reproductive cancers. The progesterone receptor gene (PGR) has been identified as a candidate gene for age at menarche and menstrual function.
Women office workers ages 19–41 self-reported age at menarche and participated in a prospective study of menstrual function and fertility. First-morning urine was used as the DNA source. 444 women were genotyped for a functional variant in PGR, rs1042838 (Val660Leu), and 264 women were also genotyped for 29 other SNPs across the extended gene region.
Genetic variation across PGR was associated with age at menarche using a global score statistic (p = 0.03 among non-Hispanic whites). Women carrying two copies of the Val660Leu variant experienced menarche 1 year later than women carrying one or no copies of the variant (13.6 ± 0.5 vs. 12.6 ± 0.1; p = 0.03). The Val660Leu variant was also associated with decreased odds of short menstrual cycles (17–24 days) (OR, 95% CI: 0.54 [0.36, 0.80]; p = 0.002).
Genetic variation in PGR was associated with age at menarche and menstrual cycle length in this population. Further investigation of these associations in a replication dataset is warranted.
PMCID: PMC3021500  PMID: 20814185
Age at menarche; Menstrual cycles; Polymorphism; Progesterone receptor; Reproductive cancers
21.  Growth Hormone Treatment Does Not Affect Incidences of Middle Ear Disease or Hearing Loss in Infants and Toddlers with Turner Syndrome 
No randomized, controlled, prospective study has evaluated the effect of growth hormone (GH) on the rates of middle ear (ME) disease and hearing loss in girls with Turner syndrome (TS).
A 2-year, prospective, randomized, controlled, open-label, multicenter, clinical trial (‘Toddler Turner Study’; August 1999 to August 2003) was carried out.
The study was conducted at 11 US pediatric endocrine centers.
Eighty-eight girls with TS, aged 9 months to 4 years, were enrolled.
The interventions comprised recombinant GH (50 μg/kg/day, n = 45) or no treatment (n = 43) for 2 years.
Main Outcome Measures
The outcome measures included occurrence rates of ear-related problems, otitis media (OM) and associated antibiotic treatments, tympanometric assessment of ME function and hearing assessment by audiology.
At baseline, 57% of the girls (mean age = 1.98 ± 1.00 years) had a history of recurrent OM, 33% had undergone tympanostomy tube (t-tube) insertion and 27% had abnormal hearing. There was no significant difference between the treatment groups for annual incidence of OM episodes (untreated control: 1.9 ± 1.4; GH-treated: 1.5 ± 1.6, p = 0.17). A quarter of the subjects underwent ear surgeries (mainly t-tube insertions) during the study. Recurrent or persistent abnormality of ME function on tympanometry was present in 28–45% of the girls without t-tubes at the 6 postbaseline visits. Hearing deficits were found in 19–32% of the girls at the annual postbaseline visits. Most of these were conductive deficits, however, 2 girls had findings consistent with sensorineural hearing loss, which was evident before 3 years of age.
Ear and hearing problems are common in infants and toddlers with TS and are not significantly influenced by GH treatment. Girls with TS need early, regular and thorough ME monitoring by their primary care provider and/or otolaryngologist, and at least annual hearing evaluations by a pediatric audiologist.
PMCID: PMC2914351  PMID: 20424424
Turner syndrome; Somatropin; Conductive hearing loss; Sensorineural hearing loss; Tympanostomy tube; Otitis media, child; Preschool
22.  Preeclampsia and Adiponectin in Cord Blood 
To compare cord blood concentrations of total adiponectin in the offspring of pregnancies with and without preeclampsia.
Using a Luminex analyzer, cord blood adiponectin was measured in 182 singleton pregnancies with preeclampsia and compared to adiponectin measured in 511 singleton pregnancies without preeclampsia.
Adiponectin levels in cord blood increased with increasing gestational age, but overall, crude levels were similar in pregnancies with and without preeclampsia. However, in pregnancies with early delivery (weeks 32–36), and in pregnancies with delivery after spontaneous contractions, adiponectin levels were higher in the preeclampsia group.
In preterm pregnancies and in pregnancies with spontaneous contractions, adiponectin levels in cord blood were higher in the preeclampsia group than in pregnancies without preeclampsia, maybe reflecting the need to optimize energy in preeclampsia.
PMCID: PMC2919428  PMID: 20395665
Preeclampsia; Cord blood; Adiponectin; Infant development
23.  New Insights into Endocrine Pancreatic Development: The Role of Environmental Factors 
The pancreas is a mixed gland that contains endocrine and exocrine components. Within the pancreatic islets, β cells produce insulin and control the glycemia. Their deficiency leads to diabetes and several potential complications. In the last decade, numerous studies have focused on pancreas development. The objective was to characterize the cellular and molecular factors that control the differentiation of endocrine and exocrine cell types. Investigation of the role of transcription factors by using genetic approaches led to the discovery of key molecules that are expressed both in rodents and humans. Some of them are ubiquitous, and some others are specifically involved in endocrine or exocrine specification. In addition to these intrinsic factors, recent studies have focused on the role of environmental factors. In the present review, we describe the roles of nutrients and oxygen in the embryonic pancreas. Interestingly, these extrinsic parameters can interfere with β-cell differentiation and function. Altogether, these data should help to generate β cells in vitro and define strategies for a cell-based therapy of type 1 diabetes.
PMCID: PMC3202916  PMID: 20551619
Pancreas; β-Cell; Development; Hypoxia; Hypoxia-inducible factor; Nutrients; Transcription factors
24.  Central Precocious Puberty due to Hypothalamic Hamartomas Correlates with Anatomic Features but Not with Expression of GnRH, TGFα, or KISS1 
Hormone Research in Pædiatrics  2010;73(5):312-319.
Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor α (TGFα), and GRM1A, which encodes the type 1 metabotropic glutamate receptor α isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release.
Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFα, KISS1, GPR54, and GRM1A.
Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFα, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP.
Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.
PMCID: PMC2868525  PMID: 20389100
Kisspeptin; KISS1R; GPR54; Reproduction; LHRH; Hypothalamic hamartoma
25.  Acid-Labile Subunit Deficiency and Growth Failure: Description of Two Novel Cases 
Hormone Research in Pædiatrics  2010;73(5):328-334.
Mutations in the acid-labile subunit (ALS) gene (IGFALS) have been associated with circulating insulin-like growth factor I (IGF-I) deficiency and short stature. Whether severe pubertal delay is also part of the phenotype remains controversial due to the small number of cases reported. We report 2 children with a history of growth failure due to novel IGFALS mutations.
The growth hormone receptor gene (GHR) and IGFALS were analyzed by direct sequencing. Ternary complex formation was studied by size exclusion chromatography.
Two boys of 13.3 and 10.6 years, with pubertal stages 2 and 1, had mild short stature (−3.2 and −2.8 SDS, respectively) and a biochemical profile suggestive of growth hormone resistance. No defects were identified in the GHR. Patient 1 was homozygous for the IGFALS missense mutation P73L. Patient 2 was a compound heterozygote for the missense mutation L134Q and a novel GGC to AG substitution at position 546–548 (546–548delGGCinsAG). The latter causes a frameshift and the appearance of a premature stop codon. Size exclusion chromatography showed no peaks corresponding to ternary and binary complexes in either patient.
Screening of the IGFALS is important in children with short stature associated with low serum IGF-I, IGFBP-3 and ALS.
PMCID: PMC2868526  PMID: 20389102
Acid-labile subunit; Short stature; Insulin-like growth factor I deficiency; Mutations, acid-labile subunit; Linear growth

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