Forearm Fractures in Overweight-Obese Children and Adolescents: A Matter of Bone Density, Bone Geometry or Body Composition?

Forearm fractures in children and adolescents are associated with increased body mass index (BMI). This bone site is non-weight-bearing and therefore is appropriate to explore the effect of BMI on bone mineral density (BMD) and bone geometry, avoiding the confounding effect of increased weight-associated mechanical loading. The aim of this review was to summarize available evidence on bone indices and body composition assessed by peripheral quantitative computed tomography (pQCT) or dual X-ray absorptiometry (DXA) at the forearm level in overweight (Ow) or obese (Ob) subjects. We conducted a review of the literature according to the PICOS model. A total of 46 studies were identified following the literature search. A final number of 12 studies were included in this review. pQCT studies evidenced that Ow and Ob children typically have normal or increased volumetric BMD (vBMD), total bone area and cortical area, with normal or reduced cortical thickness at the forearm. Outcomes from DXA evaluations are less conclusive. In almost all the studies fat mass and lean mass area at the forearm are increased. A higher fat-to-lean mass ratio has been observed in few studies. Bone strength was reported as normal or increased compared to normal weight peers. In Ow or Ob children-adolescents, vBMD, bone size and bone strength are not reduced compared to normal weight peers. The local higher fat-to-lean mass ratio may give a mismatch between bone strength and the load experienced by the distal forearm during a fall, resulting in increased risk of forearm fractures.

A frequent oligogenic involvement in congenital hypothyroidism.

Congenital hypothyroidism (CH), the most frequent form of preventable mental retardation, is predicted to have a relevant genetic origin. However, CH is frequently reported to be sporadic and candidate gene variations were found in <10% of the investigated patients. Here, we characterize the involvement of 11 candidate genes through a systematic Next Generation Sequencing (NGS) analysis. The NGS was performed in 177 unrelated CH patients (94 gland-in-situ; 83 dysgenesis) and in 3,538 control subjects. Non-synonymous or splicing rare variants (MAF < 0.01) were accepted, and their functional impact was predicted by a comprehensive bioinformatic approach and co-segregation studies. The frequency of variations in cases and controls was extended to 18 CH-unrelated genes. At least one rare variant was accepted in 103/177 patients. Monogenic recessive forms of the disease were found in five cases, but oligogenic involvement was detected in 39 patients. The 167 variations were found to affect all genes independently of the CH phenotype. These findings were replicated in an independent cohort of additional 145 CH cases. When compared to 3,538 controls, the CH population was significantly enriched with disrupting variants in the candidate genes (P = 5.5 × 10-7), but not with rare variations in CH-unrelated genes. Co-segregation studies of the hypothyroid phenotype with multiple gene variants in several pedigrees confirmed the potential oligogenic origin of CH. The systematic NGS approach reveals the frequent combination of rare variations in morphogenetic or functional candidate genes in CH patients independently of phenotype. The oligogenic origin represents a suitable explanation for the frequent sporadic CH occurrence.

Indexes of adiposity and body composition in the prediction of metabolic syndrome in obese children and adolescents: Which is the best?

BACKGROUND AND AIM: There is no agreement about which index of adiposity and/or body composition is the most accurate in identifying the metabolic syndrome (METS). The aim of our study was to compare the accuracy of the different indexes in order to recognize the most reliable. METHODS AND RESULTS: We evaluated 1332 obese children and adolescents (778 females and 554 males), aged 14.4 ± 1.8 yrs, Body Mass Index (BMI) standard deviation scores (SDS) 2.99 ± 0.55, followed at the Istituto Auxologico Italiano, a tertiary center for childhood obesity. For each subject the following indexes were assessed: BMI, BMI SDS, Fat-Free Mass Index (FFMI), Fat Mass Index (FMI), Tri-Ponderal Mass Index (TMI), Waist-to-Height ratio (WtHR) and a new one, the Body Mass Fat Index (BMFI), which normalizes the BMI for percentage of body fat and the waist circumference. Thereafter we calculated for each index a threshold value for age and sex, in order to compare their accuracy, sensitivity and specificity in identifying the METS. There was a good correlation among indexes (p < 0.0001 for all). However, when the area under the curve (AUC) was compared, some of them, in particular the BMFI and the BMI, performed better than the other ones, although the differences were small. CONCLUSIONS: BMI, which neither considers body composition nor fat distribution, performs as good as other indexes, and should therefore be the preferred one, also because of the easiness of its calculation.

Bone Geometry, Quality, and Bone Markers in Children with Type 1 Diabetes Mellitus.

Adults with Type 1 diabetes mellitus show a high risk of bone fracture, probably as a consequence of a decreased bone mass and microarchitectural bone alterations. The aim of the study was to investigate the potential negative effects of type 1 diabetes on bone geometry, quality, and bone markers in a group of children and adolescents. 96 children, mean age 10.5 ± 3.1 years, agreed to participate to the study. Bone geometry was evaluated on digitalized X-rays at the level of the 2nd metacarpal bone. The following parameters were investigated and expressed as SDS: outer diameter (D), inner diameter (d), cortical area (CA), and medullary area (MA). Bone strength was evaluated as Bending Breaking Resistance Index (BBRI) from the geometric data. Bone turnover markers (PINP, CTX-I, and BAP), sclerostin, Dkk-1, PTH, and 25OH-Vitamin D were also assessed. A group of healthy 40 subjects of normal body weight and height served as controls for the bone markers. D (- 0.99 ± 0.98), d (- 0.41 ± 0.88), CA (- 0.85 ± 0.78), and MA (- 0.46 ± 0.78) were all significantly smaller than in controls (p < 0.01). BBRI was significantly lower (- 2.61 ± 2.18; p < 0.0001). PTH, PINP, and BAP were higher in the diabetic children. Multiple regression analysis showed that CA and D were influenced by insulin/Kg/day and by BMI, while d was influenced by PINP only. Type 1 diabetic children show smaller and weaker bones. The increased bone turnover could play a key role since it might amplify the deficit in bone strength associated with the inadequate osteoblastic activity caused by the disease itself.

A thicker intima-media carotid wall was found in a cohort of children with recent onset migraine.

AIM: Migraine affects approximately 10-20% of the general population, including children and adolescents, and an association between migraine and increased risks for cardiovascular disease and stroke have been reported in adult patients. This study aimed to address the lack of data on children with migraine. METHODS: This study comprised 30 children and adolescents (16 male) with migraine. We evaluated their biochemical profile, glucose homeostasis, vascular function by flow-mediated dilatation and arterial structure by carotid intima-media thickness (cIMT). A group of 32 age, sex and auxologically matched children (17 male) served as controls. RESULTS: The group of children with migraine had a normal biochemical profile and glucose homeostasis, but presented with significantly thicker cIMT than the control group (0.48 ± 0.07 mm versus 0.45 ± 0.04, p < 0.05). CONCLUSION: We observed a significantly thicker cIMT in children with migraine compared with the controls. The brief time interval between the onset of the disease and the time of the study makes it unlikely that repetitive migraine attacks could be responsible for the thickening of the cIMT. Thus, it may be speculated that primitive vascular function abnormalities were wholly or partly responsible for the development of migraine in this paediatric cohort.

Adults with Prader-Willi syndrome have weaker bones: effect of treatment with GH and sex steroids.

Obesity has been considered to have a protective effect against the risk of fractures in adults. However, a high frequency of fracture is described in obese adults with Prader-Willi syndrome. To evaluate bone geometry, density and strength in a group of adult obese patients with Prader-Willi syndrome (PWS) and to examine the modulating effect on bone of treatment with growth hormone (GH) and sex steroids. This was a cross-sectional study performed in 41 (17 males, 24 females) obese subjects with genetically confirmed PWS, aged 29.4 ± 8.6 years. Forty-six healthy subjects (22 males and 24 females) served as controls. Digitalized X-rays were evaluated at the level of the 2nd metacarpal bone to assess bone geometry, i.e. cross-sectional area (CSA), cortical area (CA), medullary area (MA), metacarpal index (MI) and bone strength evaluated as bending breaking resistance index (BBRI). DEXA was also used to evaluate body composition and bone mineral density (total body, lumbar spine and femoral neck). PWS subjects, after adjusting for height and bone size, had a reduced CSA, CA and BBRI, while bone density was not different. GH treatment had a positive effect and sex steroids a negative effect on bone size and strength. PWS subjects showed a reduced bone size at the metacarpus leading to a reduced strength, while bone density was appropriate for size. GH treatment improves bone geometry but not bone density. Bone strength was significantly reduced in PWS patients who did not receive GH and had been treated with sex steroids.

Higher circulating parathormone is associated with smaller and weaker bones in obese children.

Obese children have disadvantageous bone geometry, bone of low quality, and reduced strength at non-weight-bearing skeletal sites. The aim of our study was to investigate the role of parathormone (PTH) and the Wnt/ß-catenin signaling pathway and its inhibitors, sclerostin and Dickkopf-1 (DKK1), as negative modulators of fat mass on bone. This was a cross-sectional observational study performed in 44 (26 males and 18 females) obese subjects, aged 11.41 ± 2.61 years. Thirty-seven normal-weight, healthy children (22 males and 15 females) of the same chronological age served as controls for the biochemical parameters and bone markers, while the data on bone geometry were evaluated according to our normative data obtained previously in a group of 325 control children. Digitalized X-rays were evaluated at the level of the second metacarpal bone for the determination of bone geometry: total cross-sectional area (TCSA), cortical area (CA), medullary area (MA), and bone strength (bending breaking resistance index [BBRI]). Serum bone markers (intact procollagen-1N-terminal propeptide [P1NP] and serum carboxy-terminal telopeptide of collagen-1 [CTX]), sclerostin, DKK1, PTH, 25-hydroxyvitamin D and were also measured. Data for TCSA, CA, MA, and BBRI are expressed as a standard deviation score in order to normalize them for age and sex. TCSA (mean ± SD, -2.92 ± 2.71), CA (-0.60 ± 0.82), MA (-0.45 ± 1.14), and BBRI (-2.65 ± 2.31) were all significantly smaller than in controls (p < 0.01). Serum PTH (36.27 ± 23.89 vs. 19.33 ± 11.37 pg/mL) and CTX (1.55 ± 0.44 vs. 1.34 ± 0.46 ng/mL) were significantly increased (p < 0.05) in the obese children compared to controls, while sclerostin was significantly decreased (24.67 ± 10.06 vs. 30.42 ± 11.01 pmol/L, p < 0.05). P1NP was also significantly increased (p < 0.01). PTH was negatively correlated with TCSA, CA, and BBRI. Bone turnover is higher in obese children than in controls, and this is associated with smaller and apparently weaker bones. Higher PTH and lower sclerostin levels may be responsible for these findings.

Small metacarpal bones of low quality in obese children.

OBJECTIVE: It is still not known whether fat mass excess could exert a positive effect on bone. The aim of our study was to evaluate bone strength and quality in a group of overweight and obese children and adolescents by assessing bone geometry at metacarpal bones and ultrasound at phalangeal level. DESIGN AND PATIENTS: This is a cross sectional observational study performed in 123 subjects, aged 11.2 ± 2.9 years. MEASUREMENTS: Digitalized X-rays were evaluated at the level of the 2nd metacarpal bone for the determination of the outer (D) and inner (d) diameter, cortical area (CA), medullary endocortical area (EA), metacarpal index (MI) and bone strength (Bending Breaking Resistance Index; BBRI). A total of 98 subjects underwent amplitude dependent speed of sound (Ad-SOS) and bone transmission time (BTT) assessment by phalangeal ultrasonography. RESULTS: SDs for each measured parameter were as follows: Males: D = -0.71 ± 0.95, d = -0·29 ± 0.86, CA = -0.69 ± 0.69, EA = -0.32 ± 0.79, Ad-SOS = -1.14 ± 0.91, BTT = -1.17 ± 1.11 and BBRI (417 ± 151 vs 495 ± 174 mm(3) ) were all significantly lower than in controls (P < 0.05). Females: D = -1.03 ± 1.06, d = -0.38 ± 0.92, CA = -0.91 ± 0.72, EA = -0.46 ± 0.79, Ad-SOS = -1.08 ± 1.11, BTT = -0.97 ± 1.07 and BBRI (342 ± 117 vs 649 ± 318 mm(3) ) were all significantly lower than in controls (P < 0.05). CONCLUSIONS: Obese children show an unfavourable bone geometry and a bone of low quality and reduced strength compared to controls at a nonweight bearing skeletal site. This finding seems to support a detrimental effect of fat mass on bone and explain the frequent occurrence of wrist fractures in this group of children.

Premature Pubarche: Time to Revise the Diagnostic Approach?

Premature pubarche (PP) could represent the first manifestation of non-classic congenital adrenal hyperplasia caused by 21 hydroxylase deficiency (NC21OHD) (10-30% of cases). In the last 20 years, the necessity of performing an ACTH test to diagnose NC21OHD in all cases with PP has been questioned, with conflicting results. This study aims to retrospectively evaluate the predictive value of the basal androgens, 17-OHP levels, and auxological features in suggesting the presence of NC21OHD and, thus, the need for a standard ACTH test to confirm the diagnosis. In all, 111 consecutive patients (87 females) with PP and advanced bone age underwent an ACTH test. Of these, 6/111 cases (1 male) were diagnosed with NC21OHD. The mean baseline 17 hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), delta 4 androstenedione (Δ4A), and testosterone serum levels were higher in NC21OHD patients than in the others (p < 0.05). We found three predictive features for NC21OHD: basal 17 OHP of >200 ng/mL, bone age advance of >2 years, and DHEA-S levels of >228 ng/mL with sensitivity and specificity of 83.3% and 97.1%, 83.3% and 65.7%, and 83.3% and 96.2%, respectively. Our data confirm that the prevalence of NC21OHD is low among patients with PP. Serum 17-OHP of >200 ng/mL could be helpful to decide, in most cases, which patients should undergo the ACTH test. Bone age advance represented an inadequately specific predictive marker of NC21OHD.

The natural history of the normal/mild elevated TSH serum levels in children and adolescents with Hashimoto's thyroiditis and isolated hyperthyrotropinaemia: a 3-year follow-up.

OBJECTIVE: The natural history of Hashimoto's thyroiditis (HT) and isolated hyperthyrotropinaemia (IH) is not well defined. We therefore studied the natural course of patients with HT and IH and looked for possible prognostic factors. DESIGN: This is retrospective cross-sectional study. PATIENTS: Three hundred and twenty-three patients with HT (88 boys and 235 girls) and 59 with IH (30 boys and 29 girls), mean age 9·9 ± 3·8 years were included in the study. When first examined, 236 of the children with HT had a normal TSH (G0) and in 87, it was elevated but <100% of the upper limit (G1). All IH subjects had elevated TSH. Potential risk factors for thyroid failure were evaluated after 3 years and included the presence or familiarity for endocrine/autoimmune diseases, premature birth, signs and symptoms of hypothyroidism, TSH levels, antithyroid antibodies and thyroid volume. RESULTS: HT: Of those with HT, 170 G0 patients remained stable, 31 moved to G1 and 35 to G2 (hypothyroidism). Thirty-six G1 children moved to G0, 17 remained stable and 34 moved to G2. Of patients with IH: 23 normalized, 28 remained stable and eight became overtly hypothyroid. In patients with HT, the presence of coeliac disease, elevated TSH and thyroid peroxidase antibodies (TPOAb) increased the risk of developing hypothyroidism by 4·0-, 3·4- and 3·5-fold, respectively. The increase in TSH levels during follow-up was strongly predictive of the development of hypothyroidism. In patients with IH, no predictive factor could be identified. CONCLUSIONS: Coeliac disease, elevated TSH and TPOAb at presentation and a progressive increase in TSH are predictive factors for thyroid failure in HT patients.

Current clinical management of constitutional delay of growth and puberty.

BACKGROUND: Constitutional delay of growth and puberty (CDGP) is classified as the most frequent cause of delayed puberty (DP). Finding out the etiology of DP during first evaluation may be a challenge. In details, pediatricians often cannot differentiate CDGP from permanent hypogonadotropic hypogonadism (PHH), with definitive diagnosis of PHH awaiting lack of puberty by age 18 yr. Neverthless, the ability in providing a precise and tempestive diagnosis has important clinical consequences. MAIN TEXT: A growth failure in adolescents with CDGP may occur until the onset of puberty; after that the growth rate increases with rapidity. Bone age is typically delayed. CDGP is generally a diagnosis of exclusion. Nevertheless, other causes of DP must be evaluated. A family history including timing of puberty in the mother and in the father as well as physical examination may givee information on the cause of DP. Patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions, such as celiac disease, inflammatory bowel diseases, kidney insufficiency and anorexia nervosa, may experience a functional hypogonadotropic hypogonadism. PHH revealing testosterone or estradiol low serum values and reduced FSH and LH levels may be connected to abnormalities in the central nervous system. So, magnetic resonance imaging is required in order to exclude either morphological alterations or neoplasia. If the adolescent with CDGP meets psychological difficulties, treatment is recommended. CONCLUSION: Even if CDGP is considered a variant of normal growth rather than a disease, short stature and retarded sexual development may led to psychological problems, sometimes associated to a poor academic performance. A prompt and precise diagnosis has an important clinical outcome. Aim of this mini-review is throwing light on management of patients with CDGP, emphasizing the adolescent diagnosis and trying to answer all questions from paediatricians.

High Tg/HDL-Cholesterol Ratio Highlights a Higher Risk of Metabolic Syndrome in Children and Adolescents with Severe Obesity.

Few data are currently available on the reliability of the different anthropometric, instrumental and biochemical indexes in recognizing the presence of metabolic syndrome (MetS) in children and adolescents with severe obesity. Therefore, the objective of our study was to find out the simplest and most accurate predictive index of MetS in this population at-risk. In 1065 children and adolescents (563 f, 502 m), aged 14.6 ± 2.1 years (range 10-17), with severe obesity [BMI-SDS 3.50 ± 0.36 (range 3.00-5.17)], the following indexes were evaluated: BMI, BMI-SDS, Tri-Ponderal Mass Index, Waist-to-Height ratio, TG/HDL-Cholesterol ratio, Cardiometabolic Index (CMI), and Visceral Adiposity Index (VAI). For each subject, all the components of MetS, defined according to the IDF criteria, were determined. Overall, the presence of MetS was found in 324 patients (30.4%), 167 males (33.3%) and 157 females (27.9%). According to the ROC analysis, three indexes (VAI, CMI and TG/HDL-Cholesterol ratio), performed significantly better than the other ones in identifying MetS, with no difference among them. In conclusion, the TG/HDL ratio, which just needs the evaluation of two simple biochemical parameters, offers the same accuracy as other more sophisticated indexes in recognizing MetS in children and adolescents with severe obesity, thus making it the best predictor to be easily used.

Tissue sensitivity to thyroid hormones may change over time.

INTRODUCTION: Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment. METHODS: Nine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR. RESULTS: All patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively. CONCLUSIONS: We report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.

Seronegative phenotype in a pediatric population with Hashimoto's thyroiditis.

PURPOSE: The aim was to verify in a pediatric population with Hashimoto's thyroiditis whether there is a relationship between antithyroid antibodies and inflammatory status on thyroid ultrasound and thyroid function. SUBJECTS AND METHODS: A total of 154 children and adolescents, aged 4 to 18 years, diagnosed with Hashimoto's thyroiditis with normal body weight were followed up for 1 year. RESULTS: Patients with only antiperoxidase antibodies presented with higher TSH levels than subjects with only antithyroglobulin antibodies (p 0.027) but with similar FT4 levels and thyroid score. Prevalence of seronegative Hashimoto's thyroiditis in this cohort was 12.3% (19/154). At diagnosis, the seronegative group presented with lower prevalence of overt hypothyroidism, symptoms of hypothyroidism, and thyroid score, meaning less severe thyroid involvement. In contrast, similar TSH and FT4 values were found at diagnosis and during follow-up in both the seronegative and seropositive groups. A comparison between patients with seronegative Hashimoto's thyroiditis and an overweight/obese antibody-negative population, who presented superimposable altered parenchymal pattern on thyroid ultrasound without circulating antithyroid antibodies, presented similar clinical data. CONCLUSION: We report for the first time in the literature that seronegative Hashimoto's thyroiditis in the pediatric age group has a less severe pattern. The seronegative group presents similar characteristics to those of overweight/obese children and adolescents with ultrasound changes, but, according to the established knowledge, the latter condition is reversible and does not need follow-up examinations.

Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED.

Central hypothyroidism following chemotherapy for acute lymphoblastic leukemia.

BACKGROUND: It has been suggested that chemotherapy per se might impair the hypothalamus-pituitary-thyroid axis of childhood cancer survivors. OBJECTIVE: We examined six patients treated for acute lymphoblastic leukemia (ALL) with chemotherapy alone, with suspicious central hypothyroidism (CH). SUBJECTS AND METHODS: ALL was diagnosed at a mean age of 3.8 years (range 0.3-6 years), the mean follow-up is 6 years (range 6-13 years). Auxological data were recorded, and thyroid function, autoimmunity and ultrasonography (US) were evaluated. Three individuals underwent a thyrotropin-releasing hormone (TRH) test and a magnetic resonance imaging (MRI) scan of the hypothalamic-pituitary region. RESULTS: All study participants showed negative thyroid autoimmunity, normal thyroid ultrasound, and thyroid-stimulating hormone (TSH) above the normal range; free T4 (fT4) was abnormally low in two patients. After TRH infusion all patients showed TSH increase and slow TSH decline. CONCLUSIONS: Our study shows that CH could arise at any time after childhood leukemia following only chemotherapy treatment. Although overt hypothyroidism was detected in only two patients, a careful follow-up of thyroid function is also recommended for ALL survivors not treated by irradiation.

Growth hormone secretory pattern in non-obese children and adolescents with Prader-Willi syndrome.

The aetiology of impaired growth hormone (GH) secretion in Prader-Willi syndrome (PWS) remains controversial due to the common occurrence of obesity. To further clarify whether suboptimal GH secretion in PWS is an artefact of excess weight, we evaluated both GH immunological activity and GH bioactivity after arginine administration in 23 non-obese PWS patients [seven females, aged 6.9 +/- 0.9 years, body mass index (BMI) SDS 0.63 +/- 0.26], in comparison with a control group of 32 healthy subjects, matched for age, gender and BMI (10 females, aged 7.9 +/- 0.3 years, BMI SDS 0.21 +/- 0.20). Serum GH concentration was measured with a time-resolved immunofluorometric assay (IFMA), while GH bioactivity was evaluated by the Nb2 cell bioassay. Serum IGF-I concentrations were measured by double-antibody RIA. GH mean peak after pharmacological stimulation was significantly lower in PWS individuals compared with controls when measured either by IFMA (6.05 +/- 1.23 microg/L vs. 23.7 +/- 1.06 microg/L, p < 0.0001) or by Nb2 (6.87 +/- 0.55 microg/L vs. 12.88 +/- 0.19 microg/L, p < 0.0001). Analysis of integrated GH secretion (AUC) confirmed that the PWS group differed significantly from the control subjects (387.9 +/- 76.1 microg/L/h vs. 1498.1 +/- 56.2 microg/L/h, p < 0.0001); the same result was obtained when the GH rise after arginine administration was expressed as nAUC (278.2 +/- 53.3 microg/L/h vs. 1443.6 +/- 52.5 microg/L/h, p < 0.0001). PWS patients had an IGF-I SDS significantly lower than those found in control subjects (p < 0.0001). Subnormal IGF-I values were present in 19 PWS individuals (82.6%) and two healthy controls (6.2%). These findings are in agreement with the hypothesis that a complex derangement of hypothalamus-pituitary axis occurs in PWS.

The Role of Different Indexes of Adiposity and Body Composition for the Identification of Metabolic Syndrome in Women with Obesity.

The aim of this study was to compare the accuracy of different indexes of adiposity and/or body composition in identifying the metabolic syndrome (MetS) in a group of 1528 Caucasian women with obesity: (age ± standard deviation (SD): 50.8 ± 14 years (range 18-83); body mass index (BMI) 43.3 ± 5.9 kg/m2 (30.7-72.9 kg/m2)). The following indexes were assessed in each subject: BMI, fat-free mass index (FFMI), fat mass index (FMI), tri-ponderal mass index (TMI), waist-to-height ratio (WtHR), and the body mass fat index (BMFI). Thereafter, a threshold value adjusted for age, which could identify MetS, was calculated for each index. A significant correlation was found among all indexes (p < 0.0001 for all). However, when the area under the curve (AUC) was compared, WtHR performed significantly better in the whole group and in the different age groups, apart from a lack of statistical difference between WtHR and BMFI in the 45-55 years age group. In conclusion, WtHR seems to be a fair index useful for identifying MetS in women with obesity. The use of thresholds appropriate for age can help further improve its accuracy, thus reinforcing the clinical evaluation for MetS screening.

Parameters of Glucose Homeostasis in the Recognition of the Metabolic Syndrome in Young Adults with Prader-Willi Syndrome.

To verify the accuracy of different indices of glucose homeostasis in recognizing the metabolic syndrome in a group of adult patients with Prader-Willi syndrome (PWS), 102 PWS patients (53 females/49 males), age ±SD 26.9 ± 7.6 yrs, Body Mass Index (BMI) 35.7 ± 10.7, were studied. The following indices were assessed in each subject during an oral glucose tolerance test (OGTT): 1 h (>155 mg/dL) and 2 h (140-199 mg/dL) glucose levels, the oral disposition index (ODI), the insulinogenic index (IGI), the insulin resistance (HOMA-IR) were evaluated at baseline, 1 h and 2 h. Although minor differences among indices were found, according to the ROC analysis, no index performed better in recognizing MetS. Furthermore, the diagnostic threshold levels changed over the years and therefore the age-related thresholds were calculated. The easily calculated HOMA-IR at baseline may be used to accurately diagnose MetS, thus avoiding more complicated procedures.

Primary Adrenal Insufficiency in Childhood: Data From a Large Nationwide Cohort.

CONTEXT: Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children. OBJECTIVE: To describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI. PATIENTS AND METHODS: Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected. RESULTS: The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was -0.70 ± 1.20 standard deviation score. CONCLUSIONS: We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.