Longitudinal changes in acylated versus unacylated ghrelin levels may be involved in the underlying mechanisms of the switch in nutritional phases in Prader-Willi syndrome.

INTRODUCTION: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls. METHODS: Longitudinal study in 134 children with PWS and 157 healthy controls, from The Netherlands, France and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored. RESULTS: The AG/UAG ratio was in the first years of life lower in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p=0.114), while the UAG levels decreased from 290 pg/ml in phase 1a to 137 pg/ml in phase 2b (p<0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p= 0.012). CONCLUSIONS: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia.

Efficacy and safety of a 4-year combination therapy of growth hormone and gonadotropin-releasing hormone analogue in pubertal girls with short predicted adult height.

Objectives: To improve adult height in pubertal girls with a poor height prediction, treatment with growth hormone (GH) can be used in combination with a gonadotropin releasing hormone agonist (GnRHa), to delay closure of the growth plates. However, there are few studies to support this practice, and they show conflicting results. The objective of this trial is to assess the safety and efficacy of this combination treatment in early pubertal girls with a short predicted height, in comparison with matched controls. Design patients and methods: We designed an open-label, multicenter, interventional case-control study. Early pubertal girls with predicted adult height (PAH) below -2.5 SDS, were recruited in tertiary care centers in Belgium. They were treated for four years with GH and GnRHa. The girls were followed until adult height (AH) was reached. AH vs PAH, AH vs Height at start, and AH vs Target Height (TH) were evaluated, as well as safety parameters. Control data were assembled from historical patient files or from patients who preferred not to participate in the study. Results: Sixteen girls with mean age ( ± SD) at start of 11.0 years (± 1.3) completed the study protocol and follow-up. Their mean height ( ± SD) increased from 131.3 ± 4.1 cm (-2.3 ± 0.7 SDS) at start of treatment to 159.8 ± 4.7 cm (-1.1 ± 0.7 SDS) at AH. In matched controls, height increased from 132.3 ± 4.2 cm (-2.4 ± 0.5 SDS) to 153.2 ± 3.4 cm (-2.1 ± 0.6 SDS) (p<0.001). AH surpassed initial PAH by 12.0 ± 2.6 cm in treated girls; and by 4.2 ± 3.6 cm in the controls (p<0.001). Most treated girls reached normal adult height (>-2SD) (87.5%) and 68.7% reached or superseded the target height (TH), which was the case in only a minority of the controls (37.5% and 6.2%, respectively) (p= 0.003 and 0.001). A serious adverse event possibly related to the treatment, was a fracture of the metatarsals. Conclusion: A four-year GH/GnRHa treatment in early pubertal girls with a poor PAH seems safe and results in a clinically relevant and statistically significant increase in AH compared with matched historical controls. Clinical trial registration: ClinicalTrials.gov, identifier NCT00840944.

Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology.

Background: An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Summary: The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment, and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions, and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonization of diagnostics, treatment, and follow-up will optimize patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. Conclusions: This consensus guidelines update should be used to further optimize detection, diagnosis, treatment, and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition.

Criteria for First-Year Growth Response to Growth Hormone Treatment in Prepubertal Children With Growth Hormone Deficiency: Do They Predict Poor Adult Height Outcome?

Objective: Several criteria for first-year growth response (FYGR) to growth hormone (GH) treatment have been proposed. We explored which FYGR criteria predicted best the final height outcome after GH treatment in prepubertal children with GH deficiency (GHD). Design and methods: Height data of 129 GHD children (83 boys) who attained adult height and had been treated with GH for at least 4 consecutive years with at least 1 year before pubertal onset, were retrieved from the Belgian GH Registry. The FYGR parameters were: (1) increase in height (ΔHt) SDS, (2) height velocity (HV) SDS, (3) ΔHV (cm/year), (4) index of responsiveness (IoR) in KIGS prediction models, (5) first-year HV SDS based on the KIGS expected HV curve (HV KIGS SDS), (6) near final adult height (nFAH) prediction after first-year GH treatment. Poor final height outcome (PFHO) criteria were: (1) total ΔHt SDS <1.0, (2) nFAH SDS <-2.0, (3) nFAH minus midparental height SDS <-1.3. ROC curve analyses were performed to define the optimal cut-off for FYGR parameters to predict PFHO. Only ROC curves with an area under the curve (AUC) of more than 70% were further analyzed. Results: Twelve, 22 and 10% of the children had respectively a total ΔHt SDS <1, nFAH SDS <-2, and nFAH minus midparental height SDS <-1.3. The AUC's ranged between 73 and 85%. The highest AUC was found for first-year ΔHt SDS to predict total ΔHt SDS <1, and predicted nFAH SDS to predict nFAH SDS <-2. The currently used FYGR criteria had low specificities and sensitivities to detect PFHO. To obtain a 95% specificity, the cut-off value (and sensitivity) of FYGR parameters were: ΔHt SDS <0.35 (40%), HV SDS <-0.85 (43%), ΔHV <1.3 cm/year (36%), IoR <-1.57 (17%), HV KIGS SDS <-0.83 (40%) to predict total ΔHt SDS <1; predicted nFAH SDS (with GH peak) <-1.94 (25%), predicted nFAH SDS (without GH peak) <-2.02 (25%) to predict nFAH SDS <-2. At these cut-offs, the amount of correctly diagnosed poor final responders equals the amount of false positives. Conclusion: First-year growth response criteria perform poorly as predictors of poor final height outcome after long-term GH treatment in prepubertal GHD children.

Prader-Willi syndrome: A model for understanding the ghrelin system.

Subsequent to the discovery of ghrelin as the endogenous ligand of growth hormone secretagogue receptor 1a, this unique gut peptide has been found to exert numerous physiological effects, such as appetite stimulation and lipid accumulation via the central regulating mechanisms in the hypothalamus, stimulation of gastric motility, regulation of glucose metabolism and brown fat thermogenesis, and modulation of stress, anxiety, taste sensation, reward-seeking behaviour and the sleep/wake cycle. Prader-Willi syndrome (PWS) has been described as a unique pathological state characterised by severe obesity and high circulating levels of ghrelin. It was hypothesised that hyperghrelinaemia would explain at least a part of the feeding behaviour and body composition of PWS patients, who are characterised by hyperphagia, an obsession with food and food-seeking, and increased adiposity. Initially, the link between hyperghrelinaemia and growth hormone deficiency, which is observed in 90% of the children with PWS, was not fully understood. Over the years, however, the increasing knowledge on ghrelin, PWS features and the natural history of the disease has led to a more comprehensive description of the abnormal ghrelin system and its role in the pathophysiology of this rare and complex neurodevelopmental genetic disease. In the present study, we (a) present the current view of PWS; (b) explain its natural history, including recent data on the ghrelin system in PWS patients; and (c) discuss the therapeutic approach of modulating the ghrelin system in these patients and the first promising results.

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series.

Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.

Correlation Between the Responses to Growth Hormone (GH) Treatment During Childhood and Adulthood in a Monocentric Cohort of GH-Deficient Patients.

Our aim was to analyze a cohort of patients with childhood-onset growth hormone deficiency (GHD) to evaluate if there is some correlation between the response to GH treatment during childhood and adulthood, respectively. This was an observational retrospective monocentric cohort study of 47 patients treated with GH during childhood and adulthood. Changes in growth parameters during childhood were compared with the increase of IGF-I z-score and other indexes of GH response (body composition, lipid profile) after 1 year of treatment in adulthood. The only significant positive correlation was observed between final growth velocity during the last year of childhood GH treatment and increase in IGF-I z-score in GH-treated adults (r=0.592, p=< 0.01). No correlation was observed between growth-promoting effects of GH as child and metabolic changes induced by GH as adult. We also observed a negative correlation between weight at the end of childhood GH treatment and the IGF-I response during first year of treatment in adults (r=- 0.335, p <0.05). No significant positive correlation could be observed between the main parameters that evaluate response to GH treatment in children and adults. However, the final growth velocity, which may be considered as one of the main criteria of end of GH treatment in children, was identified as parameter that could predict future response to GH treatment in adulthood.

Blood versus urine ketone monitoring in a pediatric cohort of patients with type 1 diabetes: a crossover study.

BACKGROUND: The aim of our study was to determine the influence of routine ketone monitoring on hyperglycemic events (HE) and ketosis in youngsters with type 1 diabetes (T1D). METHODS: Our single-site, controlled and randomized study was conducted on children and adolescents with T1D outside of remission phase. During two crossover periods of 6 months, patients (n = 22) experiencing HE tested ketones alternatively with a blood ketone meter or urine ketone test strips and gave their opinion on screening methods after completion of clinical trial. Moreover, we evaluated levels of awareness of ketone production in a series of 58 patients and sometimes parents via a multiple-choice questionnaire. RESULTS: Based on self-monitoring data, patients experienced a mean of 4.8 HE/month (range 0-9.3). Patients performed accurate ketone tests more frequently during urine (46%) than during blood-testing (29%) periods (p < 0.05); while globally, 50% of ketone tests were inaccurate (i.e. without HE). Ketosis occurred significantly more often during urine (46.4%) than during blood (14.8%) monitoring (p = 0.01), although no episodes of diabetic ketoacidosis (DKA) were noticed. Duration of hyperglycemia was not different whether patients measured ketones or not, suggesting that ketone monitoring did not affect correction of glycemia. Patients evaluated blood monitoring more frequently as being practical, reliable, and useful compared with urine testing. Scores in the awareness questionnaire were globally low (36.8%) without difference between patients and their parents. CONCLUSIONS: Although our study shows differences in outcomes (e.g. accurate use, detection of ketosis) of urine versus blood ketone monitoring, these did not affect the occurrence of HE. Whereas ketone monitoring is part of standardized diabetes education, its implementation in daily routine remains difficult, partly because patient awareness about mechanisms of ketosis is lacking.

High unacylated ghrelin levels support the concept of anorexia in infants with prader-willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with different nutritional phases from suckling deficit with failure to thrive to early onset of obesity. Hyperghrelinemia has been described in PWS long before the development of obesity. Ghrelin is found in both acylated (AG) and unacylated (UAG) forms in the circulation. In contrast to AG, UAG has been shown to inhibit food intake and to be elevated in anorexia nervosa. The present project is aiming to determine the underlying mechanisms driving the different nutritional phases in PWS. METHODS: Measurement of at least 4 h-fasting plasma acylated and unacylated ghrelin in 37 infants with a genetic diagnosis of PWS aged from 1 month to 4 years and in 100 age-matched controls without endocrine disorder recruited prior to minor surgery. One blood sampling was analysed for each patient/control and clinical data were recorded. Eleven PWS infants underwent repetitive blood samples at 3 or 6-month intervals during routine visits. RESULTS: In infants with PWS, AG is not elevated (p = 0.45), UAG is significantly higher (p = 0.0044; confidence interval 1.06;1.33) resulting in a low AG/UAG ratio (p = 0.0056; confidence interval 0.76;0.95) compared to controls. CONCLUSION: Unlike children and adults with PWS that have high AG and AG/UAG ratio, infants with PWS have elevated UAG that supports the concept of anorexia in the early phases of the disease. The change in AG/UAG ratio possibly drives the switch from failure to thrive to obesity. CLINICAL TRIAL REGISTRATION: NCT02529085 .

GHRH excess and blockade in X-LAG syndrome.

X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.

Evaluation of the hypothalamic-pituitary-adrenal axis and its relationship with central respiratory dysfunction in children with Prader-Willi syndrome.

BACKGROUND: Children with Prader-Willi Syndrome (PWS) have been considered at risk for central adrenal insufficiency (CAI). Hypothalamic dysregulation has been proposed as a common mechanism underlying both stress-induced CAI and central respiratory dysfunction during sleep. OBJECTIVE: To evaluate CAI and sleep-related breathing disorders in PWS children. PATIENTS AND METHODS: Retrospective study of cortisol response following either insulin tolerance test (ITT) or glucagon test (GT) in 20 PWS children, and comparison with 33 non- Growth Hormone deficient (GHD) controls. Correlation between sleep related breathing disorders and cortisol response in 11 PWS children who received both investigations. RESULTS: In PWS children, the cortisol peak value showed a significant, inverse correlation with age (Kendall's τ = -0.411; p = 0.012). A similar though non-significant correlation was present between cortisol increase and age (τ = -0.232; p = 0.16). Similar correlations were found in controls. In only 1 of 20 PWS children (5 %), ITT was suggestive of CAI. Four patients had an elevated central apnea index but they all exhibited a normal cortisol response. No relationship was found between peak cortisol or cortisol increase and central apnea index (respectively p = 0.94 and p = 0.14) or the other studied polysomnography (PSG) parameters. CONCLUSIONS: CAI assessed by ITT/GT is rare in PWS children. Our data do not support a link between CAI and central respiratory dysregulation.

Characteristics and determinants of partial remission in children with type 1 diabetes using the insulin-dose-adjusted A1C definition.

To evaluate the characteristics and determinants of partial remission (PR) in Belgian children with type 1 diabetes (T1D), we analyzed records of 242 children from our center. Clinical and biological features were collected at diagnosis and during follow-up. PR was defined using the insulin-dose-adjusted A1C definition. PR occurred in 56.2% of patients and lasted 9.2 months (0.5 to 56.6). 25.6% of patients entered T1D with DKA, which correlated with lower PR incidence (17.6% versus 82.3% when no DKA). In our population, lower A1C levels at diagnosis were associated with higher PR incidence and in young children (0-4 years) initial A1C levels negatively correlated with longer PR. Early A1C levels were predictive of PR duration since 34% of patients had long PRs (>1 year) when A1C levels were ≤ 6% after 3 months whereas incidence of long PR decreased with higher A1Cs. C-peptide levels were higher in patients entering PR and remained higher until 3 years after diagnosis. Initial antibody titers did not influence PR except for anti-IA2 titers that correlated with A1C levels after 2 years. Presence of 2 versus 1 anti-islet antibodies correlated with shorter PR. PR duration did not influence occurrence of severe hypoglycemia or diabetes-related complications but was associated with lower A1C levels after 18 months. We show that, at diagnosis of T1D, parameters associated with ß-cell mass reserve (A1C, C-peptide, and DKA) correlate with the occurrence of PR, which affects post-PR A1C levels. Further research is needed to determine the long-term significance of PR.

A rare case of familial Cushing's syndrome with a common presentation of weight gain due to a mutation of the PRKAR1A gene causing isolated primary pigmented nodular adrenocortical disease.

BACKGROUND: Cushing's syndrome (CS) is uncommon in childhood and adolescence. Variable presentation with subtle symptoms and signs can make diagnosis difficult. CASE REPORT: We report the case of a 17-year-old girl referred for acne and progressive weight gain with an adrenocorticotropic hormone-independent CS. A computed tomography scan of the adrenals showed normal-sized adrenal glands with discrete bilateral shape irregularity. Bilateral adrenalectomy was performed and the histopathological findings were characteristic of primary pigmented nodular adrenocortical disease (PPNAD). Genetic analysis confirmed a germline mutation of the PRKAR1A gene. The same mutation was found in her sister, mother, and maternal grandfather. Endocrine tests showed that the sister of our patient also presented PPNAD requiring bilateral adrenalectomy and a similar histopathological pattern was observed. No other features of Carney complex was found among all affected members of the family. CONCLUSION: It is exceptional for PPNAD to be an isolated phenomenon as well as being revealed by progressive weight gain in adolescence.

Severe growth retardation, delayed bone age, and facial dysmorphism in two patients with microduplications in 2p16 → p22.

Interstitial duplications of the short arm of chromosome 2 have been rarely described. Here, we report on two unrelated patients with overlapping chromosome 2p16 → p22 de novo microduplications found by SNP-array analysis. The affected individuals were an 8-year-3-month-old boy with a direct duplication of approximately 14.6 Mb harboring 63 genes, and a 12-year-old girl with a direct duplication of around 9.6 Mb harboring 48 genes. Both patients have severe growth retardation, delayed bone age, prominent veins on trunk and extremities, total IGF1 level in the low range, mild developmental delay, and facial dysmorphism such as relative macrocephaly, a broad and prominent forehead, and a large anterior fontanelle. Comparison with patients previously reported in the literature and in the DECIPHER 5.1 and ECARUCA databases indicates a common region of interest of around 1.9 Mb responsible for most of the features. Two candidate genes (EPAS and RHOQ), may be particularly relevant for the marked growth retardation and developmental delay.

Characterization of insulin resistance in young adult survivors of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma.

INTRODUCTION: An increased prevalence of metabolic disorders and cardiovascular (CV) disease has been reported in childhood acute lymphoblastic leukaemia (ALL)/non-Hodgkin lymphoma (NHL) cancer survivors. OBJECTIVE: To characterize the determinants of insulin resistance (IR) observed in this population, according to the treatment received. METHODS: Ninety one patients (45 men, mean age: 24 ± 5 years; mean follow-up: 15 ± 5 years) previously treated for a childhood ALL (n = 76) or NHL (n = 15) were grouped according to their previous treatment: chemotherapy only (Group I; n = 43), chemotherapy + cranial irradiation (CI) (Group II; n = 32) and chemotherapy + bone marrow transplant (BMT)/total body irradiation (TBI) (Group III, n = 16). RESULTS: A high prevalence of IR (HOMA-S < 60%) was observed in the BMT/TBI group (88%) compared to groups I (9%) and II (16%). The IR patients from groups [I+II] (12% of these groups) showed higher BMI, fat mass (FM) and visceral fat when compared with the non-IR patients. In contrast, the IR patients from group III had mean BMI and total FM similar to those of non-IR patients but showed a reduction of lean body mass and an increase in the relative proportion of trunk FM similar to the IR patients from groups [I + II]. This was associated with an altered lipid profile, high TNF-α and IL-6 levels, and reduced adiponectin levels compared to IR patients from group [I + II] and non-IR patients. CONCLUSION: Childhood ALL/NHL survivors treated by BMT/TBI frequently develop severe insulin resistance associated with peripheral-to-central fat redistribution, rather than increased total FM, and low adiponectin levels which may contribute to their increased CV risk.

Long-term effects on bone mineral density of different therapeutic schemes for acute lymphoblastic leukemia or non-Hodgkin lymphoma during childhood.

BACKGROUND: Little is known regarding long-term bone deficit in relationship with the modalities of cancer therapy among survivors of childhood malignancy. METHODS: Bone mineral density (BMD) was evaluated at lumbar spine (LS), total hip and femoral neck in 89 patients (44 men) more than 5 years after remission of childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). The patients had received chemotherapy (group I; n = 41), chemotherapy and cranial irradiation (group II; n = 32), or bone marrow transplantation (BMT) with total body irradiation (TBI) (group III; n = 16). All patients had received methylprednisolone and 47 additional dexamethasone treatment. RESULTS: A reduced BMD at any site was observed in 44 of the 89 patients, more frequently in men (66%) than women (33%) (p < 0.001). In comparison with group I, mean BMD was significantly lower at all sites in group II and at the total hip and femoral neck in group III. A multivariate analysis showed independent significant influences of male gender at LS (p < 0.001) and of type of treatment and dexamethasone at the hip (p < 0.05). CONCLUSIONS: A low bone mass is frequently observed in adult survivors of childhood ALL and NHL, and is associated with male gender at the LS and with dexamethasone treatment, cranial irradiation and BMT/TBI at the hip.

Multiple neoplasia in a 15-year-old girl with familial adenomatous polyposis.

A 15-year-old girl with adenomatous polyposis coli gene (APC) mutation and brain tumor-polyposis syndrome developed an unusual succession of cervicocephalic tumors (medulloblastoma, meningeal low-grade myxoid tumor, and papillary thyroid carcinoma), at the age of 5, 9, and 15 years, respectively. We discuss the genetic profile of the thyroid tumor in which a large somatic deletion of APC gene was found and the physiopathology of thyroid carcinoma in patients with germline APC mutation. We also point out the uncommon phenotype in this young girl with early multiple neoplasias and the difficulties of management of such familial adenomatous polyposis patients with occurrence of extracolonic cancers that require the use of potential trigger agents as radiotherapy or chemotherapy.

Papillary thyroid carcinoma in a 9-year-old girl with ataxia-telangiectasia.

A 9-year-old female with ataxia-telangiectasia (AT) presenting with papillary thyroid carcinoma and lymph nodes involvement is reported. We discuss this novel association, the general risk of neoplasic complications in these patients, the natural history of thyroid carcinoma in the pediatric population and the potential link between thyroid carcinogenesis and ataxia-telangiectasia mutated gene (ATM) mutation. We also expose our therapeutic attitude, according to both clinical status and particular genetic background of our patient.

Determinants of early atherosclerosis in obese children and adolescents.

CONTEXT: Obesity in childhood is associated with an increased mortality due to cardiovascular (CV) diseases in adulthood, independent of adult weight. Recent studies in children indicate that the atherosclerosis process starts at an early age and is linked to obesity. OBJECTIVE: The aim of the study was to investigate determinants of increased carotid intima-media thickness (IMT), an early marker of atherosclerosis, in obese children. DESIGN: A total of 104 obese children [age, 12.7 +/- 0.2 yr; body mass index (BMI)-z-score, 2.8 +/- 0.7] underwent an oral glucose tolerance test. Fasting levels of glucose, insulin, C-reactive protein and adhesion molecules (sICAM, sVCAM, sE-selectin), lipid profile, adiponectin, and resistin were determined. IMT was measured by ultrasound. Insulin resistance was estimated by the homeostatic model assessment index. Baseline measurements of blood parameters were obtained from 93 nonobese children (age, 13.0 +/- 0.2 yr; BMI-z-score, -0.2 +/- 0.9), and IMT was measured in 23 other control children with similar characteristics. RESULTS: Univariate analysis showed a significant positive correlation between IMT and relative BMI, the degree of systolic hypertension, fasting insulin levels, homeostatic model assessment-R index, and resistin concentrations, whereas an inverse correlation with adiponectin levels was found. No correlation was obtained between IMT and classical CV risk factors such as positive familial history of type 2 diabetes or precocious CV disease, visceral obesity, or the lipid profile. C-reactive protein and adhesion molecule levels were not associated with IMT in our obese population. When controlled for sex, Tanner stage, and relative BMI, only adiponectin levels remained an independent determinant of IMT. CONCLUSION: Adiponectin more than conventional CV risk factors and inflammation status may be related to early atherosclerosis in obese children.