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Objectives Limited data on the evolution of thyroid disorders (TD) in Down syndrome (DS) are available. We characterized the timing, prevalence, and dynamics of TD in patients with DS during a long-term follow-up. Methods We retrospectively evaluated 91 children and adolescents with DS (12.5 ± 8.3; follow-up 7.5 ± 6.2). Children were monitored at birth, 6, and 12 months of age and twice a year thereafter. Thyroid status and autoimmunity were periodically investigated. Results TD were detected in 73.6% of patients, in particular congenital hypothyroidism (CH), autoimmune thyroid diseases (ATD) and subclinical hypothyroidism (SH) were recorded in 16.4, 31.8, and 25.3%, respectively. CH was diagnosed at newborn screening in 86.7% of cases and in the first 6 months of life in the remaining 13.3%; the condition was persistent in 61.5% of patients. In more than 30% of CH cases, glandular hypoplasia was also revealed. In the ATD group, 63.1% of patients with Hashimoto’s disease (HD, 82.6%) were treated with levothyroxine and subjects with Graves’ Disease (GD, 17.4%) started therapy with methimazole. DS with SH were treated in 42.1% of cases. A thyroid hypogenic echopattern, without autoantibody positivity was identified in 27.6% of SH patients. Conclusions The high prevalence and evolution of TD in SD requires frequent monitoring starting in the first months of life. CH can be misdiagnosed at screening. In DS subjects, there is a high prevalence of ATD and non-autoimmune diseases with early antibody-negative phases should not be excluded.

Patients with autoimmune thyroid disease (ATD) have a higher prevalence of autoimmune gastritis (AIG) compared with the general population. The association between ATD and AIG is poorly characterized in the pediatric age. We reviewed the prevalence of anti-gastric parietal cell antibodies (PCA) in young patients with ATD to evaluate its usefulness as a marker for AIG screening. We evaluated 220 children and adolescents (11.28 ± 6.37 years) with ATD (186 with autoimmune thyroiditis (AT) and 34 with Graves’ disease (GD). At ATD diagnosis and annually thereafter, blood counts and PCA levels were measured. In patients positive for PCA, plasma gastrin, chromogranin A, vitamin B12, iron and ferritin levels and H. pylori antigen were measured. PCA-positive patients > 18 years were invited to undergo a gastroscopic exam. PCA positivity was detected in ten (4.5%) subjects (5F/5M; 12.6 ± 3.4 years). The prevalence of PCA positivity was not significantly different in the comparison of GD and AT patients (p = 0.9). PCA positivity was detected after 2.7 ± 2.7 years of follow-up in AT and 4.4 ± 4.0 years in GD (p = 0.4). Autoantibody positivity was more prevalent in female patients, in both AT and GD (p = 0.02 and p = 0.03, respectively). At detection of PCA positivity, five out of ten PCA-positive patients had iron deficiency, four vitamin B12 deficiency, two anemia, three hypergastrinemia and two elevated chromogranin values. Two patients had H. pylori infection. Gastroscopy was performed in the five ATD patients and in all patients, AIG was confirmed. In the juvenile population, ATD and AIG may also be associated. PCA screening is useful to detect subjects at risk for this condition. Due to the longer life expectancy of the pediatric population and considering the relatively high risk of malignant transformation, early surveillance monitoring is mandatory for children and adolescents with ATD.

Background/Aim: The relationship between type 1 diabetes mellitus (T1DM) and autoimmune thyropathies is well known and has been described in the literature. Based on present knowledge, the relationship between thyropathies and other forms of diabetes, such as monogenic diabetes, has not been investigated. The aim of our study was to assess the prevalence of autoimmune thyroid diseases (ATD) in children and adolescents with maturity onset diabetes of the young type 2 (MODY2) in comparison with patients with T1DM and a control group. Patients and Methods: We examined 23 children and adolescents with MODY2 (11 F/12 M; 13.5 ± 5.3 years) and 166 patients with T1DM (80 F/86 M; 14.0 ± 4.7 years). The control group consisted of 62 age-matched healthy subjects (34 F/28 M). ATD diagnosis was based on the finding of one or more positive thyroid autoantibodies and characteristic thyroid ultrasound lacking homogeneity, with a hypogenic or mixed echo pattern. Results: ATD was diagnosed in 15 (10.5%; 9 F/6 M) patients with T1DM, in 4 with MODY2 (17.4%; 4 F), and in 1 (1.6%) control. A significantly higher ATD prevalence was detected in T1DM and MODY2 compared to the control subjects (p = 0.02), without differences between T1DM and MODY2 (p = 0.26). There were no gender differences noted in T1DM (p = 0.42); on the contrary, in MODY2 a higher prevalence was noted in females (p = 0.04). Celiac disease and a positive family history of ATD were not detected in subjects with MODY2. Conclusion: Our study showed an increased prevalence of ATD in patients with MODY2. Therefore, a careful follow-up of all children with MODY2 is recommended in order to assess the presence of thyroid disorders.

Background: The incidence of autoimmune thyroid diseases (ATD) may vary with the beginning of reproductive function, although few reports differentiate the incidence before and during the onset of puberty, examining gender bias. We analyzed onset of ATD in a pediatric population to assess gender differences in onset age, disease subtype, pubertal status, autoimmune co-morbidity, family history and treatment, focusing on the interaction between gender and pubertal stage.Patients and methods: We retrospectively recorded 382 children and adolescents with ATD. In each patient physical examination was considered. The presence of other associated autoimmune diseases (AAD) and familial predisposition was also recorded.Results: Predominant prevalence was noted in females compared to males (p < 0.001), both in Hashimoto's diseases (HD or HT) and Graves' disease (GD) (p < 0.001). Mean age at diagnosis showed no significant difference between sexes (p > 0.05). A higher prevalence in pubertal subjects was noted compared to prepubertal (p < 0.001, particularly HT in early and GD in late pubertal stage), without sexes difference intra-(prepubertal vs. pubertal) and inter-puberty groups (prepubertal vs. early pubertal vs. late pubertal). Both in HT and in GD, the prevalence of autoimmune associated diseases (AAD) was higher in males compared to females (p = 0.04), with similar distribution according to the pubertal maturation. The familial predisposition was similarly distributed in both genders (p > 0.05) and into pubertal stages (p > 0.05).Conclusions: Females are more prone to develop ATD during puberty, earlier in HT than in GD. The effect of puberty is not different between genders, suggesting the role of additional factors other than hormones. The screening for detection of ATD is recommended in all patients with positive family history and other autoimmune diseases, mostly in males. Considerations of gender in pediatrics could be important to define pathogenic mechanisms of ATD and to help in early diagnosis and clinical management.

Objectives The coexistence of celiac disease (CD) and obesity/overweight is not unusual. We investigate the prevalence and clinical presentation of CD, detected by screening, among children with excessive weight gain. Methods We enrolled 200 children referred for overweight/obesity to our outpatient clinic. Medical history during pregnancy and childhood and lifestyle variables were recorded. Patients were screened for CD with total immunoglobulin A (IgA), IgA anti-transglutaminase (tTG-IgA) and IgA anti-endomysial antibodies (EMA-IgA). In subjects with positive autoantibodies, esophagogastroduodenoscopy (EGDS) was performed and genetic testing for HLA DQ2 and/or DQ8 haplotypes was tested. Results CD positive antibodies (tTg-IgA and EMA-IgA) were detected in eight patients (4%); in all subjects CD diagnosis was confirmed by HLA-DQ2 and/or DQ8 compatibility and EGDS. No association between CD and medical history during pregnancy and childhood or lifestyle variables was noted; however, a dietary difference was identified with those testing positive for CD also reporting a lower weekly consumption of fruits and vegetables (p=0.04). Headache was reported more frequently in patients with than without CD (p=0.04). Familiar positivity for autoimmune diseases was revealed in CD patients (p=0.01). Conclusion CD should be considered in children with excessive weight gain. Familial predisposition to other autoimmune diseases may represent a risk factor for development of CD. Even though the relationship between headache and CD is not well defined, the patients with headache of unknown origin should be screened for CD.

Objectives Data on the predictive values of parameters included in the diagnostic work-up for precocious puberty (PP) remain limited. We detected the diagnostic value of basal sex hormone levels, pelvic ultrasound parameters and bone age assessment for activation of the hypothalamic-pituitary-gonadal axis in girls with PP, in order to help in the decision to perform GnRH testing. Patients and methods We retrospectively considered 177 girls with PP. According to puberty evolution, the girls were divided into two groups: rapid progressive central precocious puberty (RP-CPP) and non/slowly progressive/transient forms (SP-PP). In all patients we considered Tanner stage, basal luteinizing hormone (LH) and estradiol (E2) values, bone age, and pelvis examination. We assessed the diagnostic value of each variable and identified the number of pathological parameters that best identify patients with RP-CPP. Results Basal LH ≥ 0.2IU/L, E2 level ≥ 50 pmol/L, uterine longitudinal diameter ≥ 3.5 cm, transverse uterine diameter ≥ 1.5 cm, endometrial echo and ovarian volume ≥ 2 cm3 were significantly associated with RP-CPP (p ≤ 0.01). The ability to diagnose RP-CPP was enhanced with increasing number of pathological hormonal and instrumental parameters (p Conclusion Despite the availability of different tests, diagnosing RP-CPP remains difficult. A diagnosis model including at least three hormonal and/or ultrasound parameters may serve as a useful preliminary step in selecting patients who require GnRH testing for early detection of RC-PP.

Introduction: Allostatic load (AL) refers to the physiological response associated with the burden of chronic stress. Excessive weight is an important source of physiological stress that promotes a detrimental chronic low-inflammation state. In order to define a correlation between cumulative biological dysregulation and excess weight, we measured AL scores in a pediatric population.Patients and Methods: We enrolled 164 children and adolescents (11.89 ± 3.89). According to their body mass index (BMI) threshold, subjects were classified as normal in the BMI < 75th percentile, overweight in the BMI 75–95th percentile or obese in the BMI >95th percentile. Data based on 16 biomarkers were used to create the AL score. A dichotomous outcome for high AL was defined in those who had more than four dysregulated components.Results: High AL was noted in 88/164 subjects (53.65%), without significant differences between genders (p = 0.07) or pubertal status (p = 0.10). Subjects with a high AL, in addition to a higher BMI (p < 0.001), showed higher WC and WC/HtR (p < 0.001), triglycerides (p = 0.002), fasting blood glucose (p = 0.03), insulin resistance (p < 0.001), systolic (p < 0.001) and diastolic blood pressure (p = 0.001), GGT (p = 0.01), PCR (p = 0.01), and calprotectin (p < 0.01) as well as lower HDL cholesterol (p = 0.002) than subjects with a low AL. The rate of the cumulative biological dysregulation increased progressively with increases in BMI (p < 0.001).Conclusions: A high AL was associated with excess weight. AL may be considered a significant factor correlated with increased morbidity in children who are overweight/obese.

The triglyceride and glucose (TyG) index has been proposed as a simple surrogate of insulin resistance (IR) with high sensitivity as an IR index besides the well known homeostasis model assessment of IR (HOMA-IR). Limited data are reported in children. We investigated the sensitivity and specificity of TyG index in a pediatric Caucasian population, as a surrogate measure of IR and compared the results with HOMA-IR.We enrolled 541 children (11.7±2.71 yrs). According to body mass index (BMI) chart, the subjects were divided into three groups: normal weight BMI75th percentile, overweight BMI 75th–95th percentile, and obese95th percentile. TyG index was calculated as (ln[fasting triglycerides(mg/dl)×fasting plasma glucose(mg/dl)/2]) and considered pathological when exceeding 7.88. HOMA-IR was calculated as (insulin×glucose)/22.5 and defined pathological whenever exceeding 97.5th percentile for age and sex.In children with overweight/obesity TyG index was higher compared to normal weight subjects (p0.001). TyG index was correlated with BMI (p0.001); WHtR (p0.001), total and HDL cholesterol (p0.001); ALT (p0.001), blood pressure (p0.001). A correlation between TyG index and HOMAIR (p0.001) as well as high TyG index and pathological HOMA-IR (p0.001) were noted. The optimal cut-off for IR was considered 7.98 (sensitivity 60%; specificity 78%; AUC 0.69).TyG index is a useful and cost-effective index of IR among children and adolescents. The cutoff 7.98 may be used for IR risk screening in childhood obesity, but we recommend caution when used in other populations.

Background We depicted gender-differences in metabolic syndrome (MS) clustering before and after puberty in pediatrics, in order to develop gender specific preventive strategies for childhood obesity. Methods We considered 1079 children and adolescents (529 females and 550 males; mean age 11.5 ± 2.8 year). According to body mass index (BMI) percentiles the subjects were classified as normal weight BMI 95th. MS was diagnosed when three of the following criteria for age and sex percentiles were met: BMI >95th, triglycerides (TGs) level >95th, high-density lipoprotein-cholesterol (HDL-c) level 95th percentile, fasting blood glucose (FBG) >100 mg/dL and/or homeostatic model assessment- insulin resistance (HOMA-IR) >97.5th percentile. Results The prevalence of dismetabolic factors was similar in both genders, except for pathological BP, which was higher in males (p = 0.02). MS was detected only in patients with obesity, with a higher prevalence in pubertal than late/post-pubertal subjects (p Conclusions We confirm that MS is an important consequence related to obesity, particularly in the post-puberty stage. Some gender-based differences should be considered early in order to identify specific preventive and treatment strategies.

Background/Aims: Patients with type 1 diabetes mellitus (T1DM), autoimmune thyroiditis (ATD), and celiac disease (CD) are at increased risk for developing other autoimmune diseases. We evaluated zinc transporter 8 (ZnT8) prevalence in patients with ATD and/or CD in order to define the usefulness of ZnT8 autoantibodies for prediabetes screening. Methods: Eighty-one young patients with ATD and/or CD were included in the study; 32 subjects with clinical onset of T1DM were enrolled as a control group. GAD65, IA-2, and ZnT8 antibodies were measured. An intravenous glucose tolerance test, C-peptide, glycosylated hemoglobin levels, and genomic analysis of HLA-DQA1* and -DQB1* were also considered in patients positive for autoantibodies. Results: The ZnT8 prevalence was higher in T1DM patients than in patients with other autoimmune diseases (p < 0.001); positive ZnT8 detection was found in 2 ATD (p = 0.004) and 3 ATD + CD (p = 0.04) patients. Positive ZnT8 was associated with GAD65 (p = 0.01) but not with IA-2 positivity. No correlation between ZnT8 detection and the number of T1DM-susceptible HLA-DQ heterodimers was found. Pathological C-peptide levels and insulin response were found in subjects with islet autoimmunity and genetic susceptibility. Conclusion: ZnT8 autoantibodies detection in ATD and/or CD patients is low, and routine ZnT8 screening is not justified. ZnT8 evaluation may be recommended in subjects with autoimmune diseases as a marker for predicting compromised insulin secretion.

Background:The association between oxidative stress (OS) and metabolic syndrome (MetS) has been reported in adults. We analyzed the relation between circulating oxidized low-density lipoproteins (Ox-LDL) and MetS in pediatric ages in order to define whether plasma Ox-LDL levels are correlated to obesity and whether oxidative damage, using serum Ox-LDL levels as a proxy, are associated with MetS.Methods:We enrolled 178 children (11.8±2.6 years). On the basis of a body mass index (BMI) threshold, the subjects were classified as: normal weight BMI 97th percentile. Patients were classified as having MetS if they met three or more of the following criteria for age and sex: BMI >97th percentile, triglyceride levels >95th percentile, high-density lipoprotein (HDL) cholesterol level 95th percentile and impaired glucose tolerance.Results:Obese children showed increased MetS prevalence (p=0.001) and higher Ox-LDL levels compared to normal- and overweight subjects (pConclusions:Oxidative damage was correlated with a hypertriglyceridemic waist phenotype and can be a precocious marker of MetS and cardiometabolic risk in obese children.

Context:LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.Objective:The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4.Design and Patients:We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.Results:We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant.Conclusion:This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.

Even though autoantibodies to pancreatic islet cells are normally found in type 1 diabetes and insulin-resistance due to overweight is more reminiscent of type 2 diabetes, some studies have described β-cell antibodies also in maturity-onset diabetes of the young (MODY) and in type 2 diabetes. A 7-year-old girl was referred to our Unit for incidental hyperglycemia and family history of MODY2 and type 2 diabetes. Genetic evaluation confirmed mutation L134P in exon 4 of the glucokinase gene and a high HLA-risk of type 1 diabetes. During follow-up, she developed type 1 diabetes and overweight-induced metabolic syndrome. The coexistence of MODY, type 1 diabetes and overweight-induced metabolic syndrome confirms that diabetes subtype probably represents a continuum of immune and metabolic dysfunction modified by genetic factors.

Aim of the study Turmer syndrome (TS) patients show increased morbidity due to metabolic, autoimmune and cardiovascular disorders. A risk of neoplasia is also reported. Here, we review the prevalence of neoplasia in a cohort of Turner patients. Methods We retrospectively evaluated 87 TS women. Follow-up included periodic ultrasound of the neck, abdominal and pelvic organs, dermatologic evaluation and fecal occult blood test. Karyotype was 45,X in 46 patients. During follow-up, 63 girls were treated with growth hormone, 65 with estro-progestin replacement therapy and 20 with L-thyroxine. Autoimmune diseases were present in 29 TS. Results A total of 17 neoplasms in 14 out of 87 patients were found. Six skin neoplasia, 3 central nervous system tumors, 3 gonadal neoplasia, 2 breast tumors, 1 hepatocarcinoma, 1 carcinoma of the pancreas and 1 follicular thyroid cancer were detected. Age at tumor diagnosis was higher in 45,X pts than in those with other karyotypes (p = 0.003). Adenomioma gallbladdder (AG) was detected in 15.3% of the patients, with a lower age in girls at diagnosis with an associated neoplasia in comparison with TS without tumors (p = 0.017). No correlation between genetic make up, treatment, associated autoimmune diseases and neoplastia was found. Conclusion In our TS population an increased neoplasia prevalence was reported. A high prevalence of AG was also noted and it might be indicative of a predisposition to neoplasia. Further studies are needed to define the overall risk for neoplasia, and to determine the role of the loss of the X-chromosome and hormonal therapies.

We report here a case of a paediatric hyperthyroidism due to a micro-macro-follicular thyroid adenoma in the presence of heterozygous point mutation of TSH receptor (TSHr). We describe the case from the initial diagnosis, through laboratoristic examinations and imaging techniques, until the radical surgical treatment made by a mini-cervicotomic videoassisted technique. We also explained the genetic work-up from peripheral blood and thyroid adenoma tissue.

It has been shown that growth hormone (GH) and insulin-like growth factor-1 (IGF1) enhance steroidogenesis responsiveness to ACTH in cultured adrenal cells. To investigate the GH effect on adrenal steroidogenesis in non-GH-deficient subjects, we studied 9 girls with Turner syndrome (chronological age 5.5–7.2 years; bone age 5–7 years). In all subjects an ACTH test (Synacthen depot, 0.25 mg i.v. with blood samples at 0 and 60 min) was performed basally at 8–9 a.m. and 6 months after GH therapy (1 IU/kg/week). 17-Hydroxypregnenolone (17PGN), 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHA), its sulfate (DHA-S), androstenedione and cortisol were evaluated by radioimmunoassay. Two groups of normal girls were selected as controls: group A age-matched the patients at the start of the study, and group B age-matched the patients at the end of the study. The responsiveness of each hormone to ACTH was expressed as the difference between stimulated and basal values. A p value of < 0.01 was considered to indicate significance. There were no significant differences between pre- and posttreatment basal values of 17PGN, 17OHP, DHA, androstenedione and cortisol in the Turner syndrome patients, whereas a significant increase was observed for basal DHA-S (1.57 ± 0.31; 1.89 ± 0.43 µmol/l, p < 0.01). Comparison of increments before and after GH treatment showed a significant increase in responsiveness to ACTH after GH therapy DHA (p < 0.01). The increase in 17PGN was evident (p < 0.02), but the established significant p value was not reached. No differences for 17OHP, androstenedione and cortisol were found. The stimulated 17PGN/17OHP ratio was significantly higher (p < 0.01) after GH, whereas the 17OHP/androstenedione ratio was considerably lower, but the p value was

An increased relative risk of diabetes, ischemic heart disease, atherosclerosis, and hypertension have been reported in Turner syndrome (TS) patients. No data are currently available on the prevalence of metabolic syndrome in TS subjects. We evaluated the frequency of metabolic syndrome in obese and nonobese patients with TS.We evaluated 85 TS patients (27.05 ± 11.17 years). Obesity was defined as standard deviation score body mass index (SDS-BMI) ≥ 2 or BMI ≥ 30 kg/m(2) in adult patients. We classified metabolic syndrome according to the International Diabetes Federation (IDF). Hepatic ultrasound was performed in all girls.The prevalence of metabolic syndrome was 4.7% (12.5% obese and 4.3% nonobese, P=0.16) and associated with visceral adiposity (P=0.008). Abnormalities in glucose metabolism and hypertension were not associated with genetic or therapeutic factors. The karyotype 45,X was associated with atherogenic profile. Pathological waist circumference was more frequent in girls treated with estro-progestin (P=0.03). Evidence of fatty liver was associated with metabolic syndrome (P=0.03) and insulin resistance (P=0.05). Elevated liver enzymes were found in 15 subjects and were not related to treatment or ultrasound abnormalities.Prevalence of each component of metabolic syndrome in TS patients is partially influenced by genetic makeup and treatment. Hepatosteatosis was associated with metabolic syndrome and insulin resistance, but not to elevated liver enzymes.

Reports indicate that in plasma insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are normal in patients with Turner's syndrome (TS). The aim of our study was to evaluate both the spontaneous and the stimulated synthesis of these peptides by mesenchymal cells obtained from skin biopsies of patients affected with TS. We compared the ability of fibroblasts from six TS patients with that of fibroblasts from six age-matched control (C) subjects to synthesize in vitro IGF-I, IGF-II, and IGFBP-3 under basal and GH-, estradiol (E2)-, or GH- plus E2-stimulated conditions. Furthermore, we evaluated IGF-I, IGF-II, and IGFBP-3 messenger ribonucleic acid (mRNA) expression in fibroblasts from TS and C subjects. Fibroblasts obtained from TS patients release into the medium significantly lower amounts of IGF-I and IGF-II than C fibroblasts (P = 0.0435 and 0.0318, respectively). In TS fibroblasts, GH and E2 are able to induce a similar increase, although not significant, of IGF-I secretion into the medium (163 +/- 75% and 112 +/- 41% of control values). On the contrary, in C fibroblasts, GH is more effective (275 +/- 61%; P = 0.0277) than E2 (75 +/- 46%). In both cell lines, GH and E2 do not significantly modify IGF-II release. Interestingly, the medium conditioned by fibroblasts from TS contains, under basal conditions, significantly higher amounts (273 +/- 79 ng/1 x 10(6) cells) of IGFBP-3 than that from control fibroblasts (67 +/- 19 ng/1 x 10(6) cells; P = 0.0191). GH exerts a stimulatory effect, although it is not statistically significant, on IGFBP-3 secretion, particularly in control fibroblasts. By contrast, the effect of E2 is inhibitory in all TS fibroblast cell lines, although it does not reach statistical significance (P = 0.067). In agreement with these data, a reduced mRNA expression of the genes encoding for IGF peptides was evident in TS fibroblasts, whereas no significant difference could be demonstrated for IGFBP-3 mRNA. The results suggest a reduced autocrine/paracrine action of IGFs in TS and indicate that skin fibroblast cultures can give information on the local responsiveness to the treatment.

Ovarian tumors associated with hormonal changes of the peripheral iso-sexual precocious puberty are of common presentation. We describe here a rare case of juvenile granulosa cell tumor in a female with central precocious puberty (CPP). An 8-year old girl with CPP presented with vaginal bleeding four months after the diagnosis and before starting treatment with gonadotropin-releasing hormone (GnRH)-analogs. Suppression of basal follicle-stimulating hormone (FSH) level, elevation of serum estradiol, progesterone and Cancer Antigen-125 were documented. Abdominal ultrasound examination (US) and magnetic resonance imaging showed a pelvic mass affecting the left ovary. A left salpingo-oophorectomy was performed and the mass was totally resected. Juvenile granulosa cell ovarian tumor was diagnosed. One month post surgery, estradiol and progesterone decreased to values of the first evaluation and FSH increased, Cancer Antigen-125 resulted normal while ultrasound pelvic examination showed absence of pelvic masses. In our patient, the tumor had grown very quickly since hormonal data demonstrated a CPP without any evidence of ovarian mass on US only four months before diagnosis. The overstimulation of the FSH or aberrant activation of FSH receptors may have contributed to the development of the mass.

Introduction: Gut and adipose tissue hormones play an important role in energy balance control, particularly through the regulation at either short- or long-term food intake after bariatric surgery. Case: A 15-year-old obese female (BMI 42.2) who was unresponsive to medical treatment underwent gastroplication. Hunger hormone levels (leptin, ghrelin and insulin), weight loss and eating behavior were monitored at 3, 6 and 12 months after surgery. Results: Weight loss was obtained, progressively achieving a loss of 45.6 kg 1 year after surgery. A strong reduction in insulin concentration and insulin resistance was documented. At 3 months after the operation, a surprising leptin level drop was observed. During the following months a progressive increase in leptin levels and leptin/kg of fat mass were documented. Fasting ghrelin levels increased in the first 3 months, then fell over the next 6 months. Up to 6 months after gastroplication, we observed a less marked drop in plasma ghrelin after meal ingestion, while the values after 1 year showed a substantial fall in the postprandial period despite a further fasting ghrelin increased level. Early achievement of satiety was found. Conclusion: Hunger hormones level changes seem to be involved in weight loss and eating behavior after gastroplication in adolescents.

Chiovato L, Larizza D, Bendinelli G, Tonacchera M, Marinò M, Mammoli C, Lorini R, Severi F, Pinchera A. Autoimmune hypothyroidism and hyperthyroidism in patients with Turner's syndrome. Eur J Endocrinol 1996;134:568–75. ISSN 0804–4643 A high prevalence of autoimmune thyroid disease (AITD) has been described in Turner's syndrome (TS) but the extent of this association is controversial for the prevalence of thyroid autoantibody and the clinical impact of thyroid dysfunction. In this study we searched for thyroid disease and thyroid autoantibodies in patients with TS. Seventy-five unselected TS patients (age range 3–30 years) were studied. Sera were tested for thyroid hormones, thyrotropin (TSH), thyroglobulin (TG-ab) and thyroperoxidase (TPO-ab) antibodies. The TSH-receptor antibodies with thyroid-stimulating (TS-ab) or TSH-blocking activity (TSHB-ab) were measured in the IgG fraction using a bioassay. Ten out of 75 (13.3%) TS patients had AITD: eight had autoimmune thyroiditis (AT) (six with subclinical and two with overt hypothyroidism and one with euthyroidism) and one had Graves' disease. The prevalence of AITD increased significantly (p < 0.05) from the first (15%) to the third (30%) decade of life. The prevalence of TPO-ab and/or TG-ab (20%) was higher (p < 0.05) in TS than in age-matched female controls and increased from the first (15%) to the third (30%) decade of life. Clinical AITD was diagnosed in 46% of TS patients with TPO-ab and/or TG-ab. Thyroid-stimulating antibody was detected in the hyperthyroid patient, and TSHB-ab was found in one of eight patients with hypothyroid AT. It was concluded that: TS patients are at higher than average risk of developing AITD not only in adolescence and adult age but also in childhood; hypothyroidism, mainly subclinical, is the most frequent thyroid dysfunction; elevated TPO-ab and/or TG-ab alone do not imply thyroid dysfunction; TS-ab or TSHB-ab are always associated with thyroid dysfunction although most cases of autoimmune hypothyroidism are not due to the latter antibody. Luca Chiovato, Istituto di Endocrinologia, Università di Pisa, Viale del Tirreno, 64, 56018 Tirrenia, Pisa, Italy

Objective. To describe a biochemical growth hormone (GH) deficiency and to evaluate therapeutic result in a six-year-old male with Becker muscular dystrophy (BMD).Methods. GH peak was evaluated after response to arginine and insulin. Bone age was evaluated according to Greulich and Pyle method.Results. The GH-supplementary therapy was very effective in terms of growth gain.Conclusion. The possibility of a growth hormone deficiency and treatment with GH in patients with BMD cannot be excluded, especially considering the good therapeutic response.

Context:Agenesis of the internal carotid artery and hypoplasia of the internal carotid artery are rare congenital abnormalities, involving less than 0.01% of the general population. Congenital hypopituitarism is also a rare condition; thus, the association of the two entities is unlikely to be casual. We describe one pediatric case of agenesis of the internal carotid artery with hypopituitarism and review other known cases.Evidence Acquisition and Synthesis:In this brief clinical case seminar, we summarize the current understanding of this association based on a MEDLINE search of all peer-reviewed publications (original articles and reviews) on this topic between 1980 and 2011. We found nine other cases, mainly diagnosed during childhood. Defects of pituitary function varied among cases; in four, midline anomalies were present.Conclusion:There are two theories that are not mutually exclusive to explain the association of congenital vascular malformation and pituitary hypoplasia with hypopituitarism: the first involves hemodynamic mechanisms, and the second, complex neural-crest differentiation and/or migration disorders. Whatever the real physiopathological mechanism responsible for this condition, it could be considered as a new clinical entity.

Physical activity may protect from the adverse effects of obesity. In obese children, an increased adherence and a decreased drop-out rate during exercise could be achieved with adapted activities. We studied a recreational 12-week controlled training program for sedentary obese children, including interactive video games. We enrolled 22 obese subjects (13.23±1.76 years) in an exercise program, implemented twice a week for a 12-week period. The program consisted of a combination of circuit-based aerobics, strength and resistance exercises; specifically soccer, rugby, volleyball and basketball and interactive video game exercises. Outcome measurements included body composition, metabolic profile and cardiorespiratory fitness. During the 12-week training program there was a significant decrease in body mass index (BMI) (p=0.002), SDS-BMI (p=0.003), waist circumference (p=0.004), waist circumference/height ratio (p=0.001),% fat mass (p=0.001), blood glucose (p=0.001), homeostasis model assessment for insulin resistance (HOMA-IR) (p=0.04), triglycerides (p=0.03) and systolic pressure (p=0.04) before and after exercise. Improvement in estimated maximum oxygen consumption (VO2max) (p

Aim The prevalence of Turner syndrome (TS) at birth has been estimated as approximately 1 in 2500 live female births. An increased risk of TS in subsequent pregnancies for couples who already have a daughter with TS has not been reported. Methods We reviewed the records of 140 patients to evaluate the presence of familial TS occurrence. Results Recurrence of TS was observed in 1.4% of our case series, which represents a 35-fold increased probability of having a second child with TS compared to no recurrence. Conclusion This observation suggests that a risk of recurrence is possible, even though it is generally assumed that the likelihood of recurrent pregnancies with TS is similar to that in the general population. A wider study would be useful to confirm these data to improve genetic counseling for families with a daughter with TS.

Introduction: Obesity is often associated with increased serum alanine aminotransferase (ALT), and elevation of ALT is a marker of non-alcoholic fatty liver disease which is caused in part by insulin resistance, the essential characteristic of metabolic syndrome (MS). We evaluated the prevalence of MS in prepubertal obese children and the usefulness of ALT as an MS marker. Patients: 120 obese children (6.3 ± 1.6 years old) and 50 normal-weight controls (5.3 ± 2.0 years old) were included. Patients were classified as having MS if they met ≧3 of the following criteria: body mass index >97th percentile, triglycerides >95th percentile, high-density lipoprotein cholesterol 95th percentile, fasting blood glucose 100 mg/dl and/or impaired insulin sensitivity with homeostasis model assessment for insulin resistance >97.5th percentile. ALT levels were also evaluated. Results: MS occurred in 16.6% of obese patients. Significant differences were present in body mass index (p < 0.001), SBP (p = 0.002) and DBP (p < 0.001) between non-MS and MS obese patients; laboratory data, except total cholesterol, were significantly different in the two groups. The strongest association with MS (as evaluated by the c-statistic) was found for insulin and homeostasis model assessment for insulin resistance (c = 0.92 and 0.91, respectively); also, DBP and SBP showed good discrimination ability (c = 0.73 and 0.72, respectively). ALT levels in the MS group were higher than in the non-MS group (p = 0.02) and associated with MS (p = 0.001; c = 0.69). Conclusion: MS is a consequence of obesity already in very young children. Also, pathological serum ALT levels were significantly correlated with MS and might be considered a marker for defining MS, though confirmation in a longitudinal study is called for.

Turner syndrome (TS) affects one in 2500–3000 live-born girls, and is the most prevalent female sex chromosomal disorder in humans, resulting from the loss of all or part of one of the two X chromosomes (Sybert and McCauley 2004). About 50% of TS patients carry a 45, X monosomy, the rest being mosaics or structural chromosome abnormalities. TS patients’ phenotype is variable, and the wide spectrum of clinical features includes: short stature, ovarian dysgenesis, lymphedema, cardiovascular defects and renal malformation. Diabetes mellitus is also present at a rate two to four times higher than in the general population (Elsheikh et al. 2002), consistent with the finding of a relative insulin deficiency in TS on a non-immune basis, suggesting that haploinsufficiency for X-chromosome gene(s) impairs beta-cell function predisposing to diabetes mellitus in TS (Bakalov et al. 2004). The loss of the short arm of chromosome X (Xp), common to all TS, generally results in the full syndrome phenotype (Elsheikh et al. 2002). So far, a correlation between karyotype and phenotype in TS patients has not been clearly defined. Haploinsufficiency of several genes mapped to the short arm of X chromosome has been related to the clinical signs observed in TS patients; for example, the SHOX (short stature homeobox-containing gene) responsible for the short stature characteristic of the patients. Association of renal abnormalities and TS varies from 33% to 70% (Matthies et al. 1971). These include horseshoe kidney, duplication of collecting system, ectopic kidney, ureteropelvic stenosis, renal agenesis and renal cysts. Two forms of cystic kidney disease have been described in

Objective Genetic factors are the most important determinant of final height in developed countries, while in underprivileged countries food intake is crucial. Nutrients, in turn, may importantly affect IGF–IGFBP system which is a critical regulator of growth. The aim of this study was to evaluate the influence of nutrition on IGF system components, as well as on growth by comparing these variables in two selected populations of children living either in poor or in privileged environmental conditions. Design Height and weight were recorded in 38 normal African children, living in a Catholique Mission in Ivory Coast, and in 93 normal Italian children. IGF-I, IGF-II, IGFBP-3 and ALS were evaluated in all subjects. Results A normal height in spite of markedly reduced IGF-I, IGFBP-3, ALS and BMI was observed in African children, while the ratio IGF-I/IGFBP-3 was comparable in the two populations. IGF-II was slightly but significantly higher in Africans than in Italians. Conclusions In Africans a suboptimal nutritional condition may produce a dramatic reduction of IGF-I, ALS and IGFBP-3, although the final height results minimally affected. This suggests that only a small fraction of the circulating IGF-I is sufficient for growth and confirms what has been reported on liver IGF-I–deficient and ALS knock-out mice. The secular statural trend observed in developed countries is probably due to the increase of IGF-I consequent to the improved nutritional conditions.

Pathological breast conditions are rare in childhood and adolescence. The spectrum of breast disease in pediatric patients is different from that in adults and most lesions are benign. Fibroadenomas are the most common type of breast tumor in adolescent girls and young women. These lesions occasionally develop into very large masses, particularly in adolescent girls. Such masses are called solitary giant juvenile fibroadenomas, and local recurrence is unusual. We report here a case of recurrent juvenile giant breast fibroadenoma in a girl with Turner's syndrome.

Hypothalamic-pituitary function was studied in 45 patients with idiopathic GH deficiency (GHD), 33 of whom had pituitary abnormalities on magnetic resonance imaging: pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe in 8 patients with isolated GHD (IGHD) (group I) and in 12 patients with multiple pituitary hormone deficiency (MPHD) (group II); isolated pituitary hypoplasia in 13 patients with IGHD (group III); no evidence of pituitary abnormalities in the remaining 12 patients with IGHD (group IV). Sellar and pituitary volumes were significantly lower in groups I, II, and III than in group IV (P less than 0.001). No significant differences were observed between group I and group II in the GH response to GHRH1-44 expressed both as peak serum GH and area under the curve. Mean GH peak in group III and IV was significantly higher than that in group I (P less than 0.005) and II (P less than 0.001), as were the mean AUC (P less than 0.005), suggesting hypothalamic defect. Delayed peak serum TSH after TRH was found in all patients of group II, and overt hypothyroidism in 11 of them. Furthermore, basal hyperprolactinemia was present in 6 patients and adrenal insufficiency in 7 cases of group II. Finally, a reduced response of FSH to GnRH was observed in all these patients (P less than 0.005 vs. each of the other groups), and clinical hypogonadism was present in all of them. We suggest that: 1) A high incidence of pituitary abnormalities seems to be present in idiopathic GHD patients; 2) Pituitary hormone deficiencies are more dependent on the type of the hypothalamic-pituitary abnormality than on the size of the pituitary per se: the association of pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe should possibly be considered a distinct entity reflecting an early abnormality in hypothalamic development; 3) The majority of patients with IGHD or MPHD probably have a primary hypothalamic releasing hormone deficiency even if pituitary hypoplasia is associated; 4) Magnetic resonance imaging may have a role in the diagnosis and prognosis of patients with GHD through differentiation between patients who are at risk for developing MPHD vs. those who are candidates for having a persistently isolated GHD.

Summary Objective Childhood obesity is increasingly common and is associated with health problems; in particular, obesity plays a central role in the metabolic syndrome (MS). We estimated the prevalence of MS in Caucasian children and adolescents with varying degrees of obesity. Patients and methods We studied 191 obese [body mass index (BMI) > 97th percentile] children and adolescents. Obesity was stratified on the basis of a threshold BMI z-score and subjects were classified as moderately (z-score 2–2·5) or severely obese (z-score > 2·5). Seventy-six, nonobese subjects were recruited into a comparison group. Thirty-one of them were of normal weight (BMI 97th percentile, triglyceride levels > 95th percentile, high density lipoprotein (HDL) cholesterol level 95th percentile and impaired glucose tolerance (blood glucose level: 7·8–11·1 mmol/l at 2 h). Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) and impaired insulin sensitivity was defined as a HOMA-IR ≥ 2·5 in prepubertal patients and HOMA-IR > 4 in pubertal subjects. Results The overall prevalence of MS was 13·9% and was present in 12·0% of moderately obese and 31·1% of severely obese subjects; no overweight or normal weight subjects met the criteria for MS. The rate of the MS increased progressively with increasing BMI categories (P

Background: Studies on fertility in women with Turner syndrome have shown that spontaneous pregnancies occur in about 2–7% of patients. Fertility problems and obstetrical complications are frequently observed in untreated patients with celiac disease. We report the case of a patient, affected by Turner syndrome and celiac disease, in whom a spontaneous pregnancy occurred. Case: One patient affected by Turner syndrome at the age of 30 yr conceived spontaneously. Celiac disease was diagnosed during pregnancy. The pregnancy progressed uneventfully. After 39 weeks of gestation, she vaginally delivered a normal male infant. Conclusion: Our patient had a successful pregnancy, giving birth to a healthy child, although she presented two pathological conditions affecting fertility and pregnancy outcome: Turner syndrome and celiac disease.

Mutations in hepatocyte nuclear factor-1beta (HNF-1beta) gene cause a subtype of maturity-onset diabetes of the young (MODY5), whose clinical features are pancreatic beta-cell dysfunction, renal malformations, and in some females, internal genital malformations. Recently, we reported the first case of MODY5 and horseshoe kidney. The patient was the only male in a three-generation family with five affected females carrying renal cysts or dysplastic kidney. Diabetes mellitus, horseshoe kidney, and X chromosome monosomy or mosaicism can be observed in Turner syndrome (TS). In particular, diabetes mellitus affects about 50% and horseshoe kidney occurs in approximately 16% of patients. To investigate whether mutations/polymorphisms of HNF-1beta and X monosomy influence horseshoe kidney development, we evaluated HNF-1beta gene sequence in 13 patients with TS and several kidney abnormalities. Analysis of the nine exons including intron-exon boundaries of HNF-1beta revealed the presence in two subjects (15%) of a known intronic polymorphism, IV8+48insC. No specific variants were found. We conclude there is no direct relationship between horseshoe kidney in TS and mutation or polymorphism of HNF-1beta gene, but we speculate that target gene(s) of HNF-1beta, likely mapped on the X chromosome, is/are responsible of the horseshoe kidney formation in TS.

Pathogenesis of autoimmune thyroid disease (ATD) is multifactorial. Helicobacter pylori (Hp) infection has been proposed to be involved in nongastrointestinal conditions and reported more frequently in ATD adult patients. We evaluated the prevalence of Hp antibodies in young ATD patients and investigated the possibility that a susceptible immunogenetic profile could influence the development of ATD in subjects with Hp infection.We retrospectively studied 90 children with ATD (median age 11.2 yr), 70 age- and sex-matched healthy subjects as controls, and 65 patients with Turner syndrome (median age 18.8 yr). Antibodies to Hp were determined at diagnosis in ATD patients and, in Turner patients, at the last control in cases without ATD and before the appearance of thyroid autoantibodies in the others. Serological and molecular human leukocyte antigen (HLA) typing for classes I and II polymorphisms was performed.Prevalence of positive Hp serology resulted significantly higher in ATD patients than controls (P = 0.032). No association was found between individual HLA alleles and Hp serology. HLA-A1, B8, and DRB1*0301 were found significantly associated with ATD. A significant interaction between HLA-DRB1*0301 and Hp infection was present in ATD patients and not controls (P = 0.007), suggesting that the copresence of these two factors might favor ATD development. A similar phenomenon was observed in Turner syndrome patients (P = 0.02; cumulative Mantel test, P = 0.0001).Another target of Hp-elicited immune inflammatory response might be the thyroid gland in subjects with a peculiar immunogenetic profile so that ATD may be a consequence. Our findings suggest the opportunity of eradicating Hp infection in children with ATD and/or susceptible HLA alleles.

To the Editor: GnRH-receptor agonists are used for treatment of central precocious puberty (CPP) and relative safety and tolerability in children are reported [1]. In experimental studies, hypertensive crisis during treatment with triptorelin is described and attributed to hypoestrogenism [2]. Postmenopause is associated with increased incidence of hypertension; estrogen low levels have important effects on venous system that reverse in animal model by hormone replacement therapy [3]. We report a “suggested” association between hypertension and triptorelin therapy in a girl with CPP. A 5-y-old girl presented with breast enlargement (Tanner B2), without any other sign of sexual maturation and with prepubertal hormonal status. At the age of 7y, she showed progressive breast development (Tanner B3), bone age advancement (SDS-BA 2.5), elevated height velocity (SDS-v 3.17). Blood pressure (BP) was 105/70 mmHg (50th centile for systolic and 90th centile for diastolic [4]). Endocrine examination revealed GnRH-stimulated serum LH peak 14.7 mIU/ml and β-estradiol level 25.6 pg/ml. Magnetic Resonance Imaging showed a 1.8×1.0×1.2 cm pineal cyst, with homogeneous content and slightly thickened wall with focal irregularity. Alpha-feto-protein and human-chorionic-gonadotropin levels were negative. Therapy with Triptorelin 3.75 mg/4 wk was started. No neurosurgical intervention was planned immediately. At the age of 10y–8 mo, we noted asymptomatic hypertension (150/110 mmHg, >99th centile [4]). Ambulatory BP monitoring confirmed severe hypertension, with 24-h mean systolic and diastolic BP>3SD [5]. Transthoracic echocardiographic evaluation showed concentric hypertrophy of the left ventricle, with increased thickness of interventricular septum and posterior wall. Renovascular and renal parenchymal diseases, endocrine causes of hypertension, coartaction of aorta were excluded. We discontinued GnRH-analog and started anti-hypertensive therapy (ramipril 5mg/die and nifedipine retard 40 mg/die). Progressively, the girl showed normalization of BP values and reduction of left ventricle wall thickness. Anti-hypertensive treatment was modified during follow-up; nifedipine retard and ramipril were stopped after 4 and 8 mo, respectively. At the age of 11y-8-mo the girl had menarche. Normal BP values persist. Considering the normotensive condition at the start therapy, the reversibility of hypertension and cardiac hypertrophy after discontinuation of triptorelin and the persistence of V. Calcaterra :D. Larizza Department of Internal Medicine, University of Pavia and Department of Pediatrics, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

We investigated a possible influence on birth weight in Turner's syndrome of many clinical, hormonal, genetic and immunogenetic variables. We considered 97 patients with Turner's syndrome. Patients with parents with identical GM (Gamma heavy chains Marker) phenotype had a significantly lower birth weight than those with parents with different GM phenotype. Karyotype other than 45,X, HLA (Human Leukocyte Antigen) parental sharing, mother-patient compatibility and elevated 17-hydroxyprogesterone (17OHP) serum level after adrenocorticotropin hormone (ACTH) and absence of heart and kidney malformations and lymphedema were associated with a lower birth weight, but not significantly. Multiple interactions showed that the presence of an identical GM phenotype in parents, together with other conditions (karyotype other than 45,X, adrenal dysfunction, HLA parental sharing, mother-child compatibility, KM(3) [Kappa light chains Marker] phenotype) resulted in a further decrease of birth weight. These data might suggest a negative effect of genetic similarity on intrauterine growth in Turner's syndrome.

The de novo occurrence of germline-activating thyrotropin receptor (TSHR) gene mutations has been reported as the cause of sporadic nonautoimmune neonatal hyperthyroidism in eight children. We report the case of an Italian infant girl who presented at birth with severe hyperthyroidism and goiter. Ultrasonografic examination of the infant's thyroid showed a diffuse goiter with a normal echogenic pattern. Serum antithyroglobulin, antithyroperoxidase, and antithyrotropin receptor antibodies were undetectable. Treatment with propylthiouracyl, propranolol, and saturated potassium iodide solution started at 44 days of life with the resolution of thyrotoxic symptoms. Once euthyroidism was achieved, the dose of propylthiouracyl was tapered, but hyperthyroidism recurred. Auxological parameters showed an acceleration of linear growth and bone age. DNA was extracted from peripheral white blood cells of the patient, the sister, and the two parents. All of exon 10 of the TSHR gene was amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. In the thyrotoxic infant girl, a substitution of cytosine to thymine was detected, changing isoleucine 568 into a threonine (1568T), located in the second extracellular loop. The normal sequence could also be detected, indicating heterozygosis of the mutated allele. This mutation was previously described as a somatic mutation in a patient with toxic thyroid adenoma. The sister and the parents of the propositus, all euthyroid, showed the wild-type TSHR gene. In conclusion, we describe a case of a de novo germinal mutation of the TSHR causing severe congenital hyperthyroidism.

The prevalence of autoantibodies has been reported to be increased in both patients with Turner's syndrome and their parents. We evaluated organ-specific and non-organ-specific autoantibodies in 95 patients, ranging in age from infancy to adulthood, and in most of their parents, in order to determine the characteristics of autoimmune disorders in these families and to relate it to the genetic markers usually involved in autoimmunity (HLA, GM and KM genes). A statistically significant difference was observed between Turner patients and controls in the frequencies of organ-specific autoantibodies, in particular thyroid microsomal antibodies and thyroglobulin antibodies; however, the presence of autoantibodies was not associated with overt diseases in most cases. No significant difference was found between parents and controls. A study of the inheritance of the autoimmunity showed that transmission was preferentially paternal, since Turner patients had more chance of presenting autoantibodies when their fathers had autoantibodies rather than their mothers. A positive association was found between the presence of auto-antibodies and HLA-DR7;DQ2 and HLA-DR7;DQ9 haplotypes in Turner patients and fathers. No significant association was found between GM and KM allotype frequencies in Turner patients and their parents and the presence of autoantibodies. No epistatic interaction was demonstrated between HLA and GM or KM genes. Familial segregation was studied and a preferentially paternal transmission of HLA-DR7-carrying haplotypes and possibly also of the KM (1) allotype with autoimmunity was observed.

Permanent congenital hypothyroidism (CH) has an incidence of 1/3000-4000 newborns and is among the most frequent cause of mental retardation and neurological alterations in children. In 80% to 85% of cases CH is associated with thyroid dysgenesis. A group of 61 patients with CH (22 with agenesis, 18 with ectopy, 1 with hypoplasia, and 20 cases with CH without thyroid enlargement but not further characterized) and 30 normal subjects were examined for the presence of mutations in the gene encoding the thyroid transcription factor 1 (TTF-1). The coding-region of the TTF-1 gene was analyzed in all cases by the single stranded conformational polymorphism (SSCP) and no mutations were detected. Direct sequencing also carried out in patients with thyroid agenesis confirmed the absence of mutations or polymorphisms in the TTF-1 gene. The absence of mutations in the TTF-1 gene in our samples indicates that the mutations in the TTF-1 gene are not a frequent cause of CH.

Maghnie M, Moretta A, Valtorta A, Larizza D, Sayegh M, Greco AM, Castoldi E, Severi F. Growth hormone response to growth hormone-releasing hormone varies with the hypothalamic–pituitary abnormalities. Eur J Endocrinol 1996;135:198–204. ISSN 0804–4643 We determined growth hormone (GH) and insulin-like growth factor I (IGF-I) levels after a 3 h infusion of escalating doses of growth hormone-releasing hormone (GHRH(1-29)) followed by a bolus injection in hypopituitary patients with marked differences in pituitary features at magnetic resonance imaging (MRI) in order to evaluate further the contribution of MRI in the definition of pituitary GH reserve in GH-deficient patients. Twenty-nine patients (mean age 14.5 ±4.0 years) were studied. Group I comprised 13 patients: seven with isolated GH deficiency (IGHD) (group Ia) and six with multiple pituitary hormone deficiency (MPHD) (group Ib) who had anterior pituitary hypoplasia, unidentified pituitary stalk and ectopic posterior pituitary at MRI. Group II consisted of eight patients with IGHD and small anterior pituitary/empty sella, while in group III eight had IGHD and normal morphology of the pituitary gland. Growth hormone and IGF-I levels were measured during saline infusion at 08.30–09.00 h, as well as after infusion of GHRH (1–29) at escalating doses for 3 h: 0.2 μg/kg at 09.00–10.00 h. 0.4 μg/kg at 10.00–11.00 h. 0.6 μg/kg at 11.00–12.00 h and an intravenous bolus of 2 μg/kg at 12.00 h. In the group I patients, the peak GH response to GHRH(1–29) was delayed (135–180 min) and extremely low (median 2 mU/l). In group II it was delayed (135–180 min), high (median 34.8 mU/l) and persistent (median 37.4 mU/l at 185–210 min). In group III the peak response was high (median 30.8 mU/l) and relatively early (75–120 min) but it declined rapidly (median 14.4 mU/l at 185–210 min). In one group I patient, GH response increased to 34.6 mU/l. The mean basal value of IGF-I levels was significantly lower in group I(0.23 ± 0.05 U/ml) than in groups II (0.39 ± 0.13U/ml, p < 0.01) and III (1.54 ± 0.46 U/ml, p < 0.001) and did not vary significantly during the GHRH(1–29) infusion. The present study demonstrates that the impaired GH response to 3 h of continuous infusion of escalating doses of GHRH(1–29) was strikingly indicative for pituitary stalk abnormality, strengthening the case for use of GHRH in the differential diagnosis of GH deficiency. The low GH response, more severe in MPHD patients, might be dependent on the residual somatotrope cells, while the better response (34.6 mU/l) in the group la patients might suggest that prolonged GHRH infusion could help in evaluating the amount of residual GH pituitary tissue. Pituitary GH reserve, given the GH response to GHRH infusion in GH-deficient patients with small anterior pituitary/empty sella, seems to be maintained. M Maghnie, Department of Pediatrics, University of Pavia, IRCCS Policlinico S Matteo, I-27100 Pavia, Italy

Growth hormone (GH), alone or in combination with anabolic steroids, seems to improve the growth rate in Turner syndrome, but to exert a less striking effect on the final height (FH). Reports on the FH usually lack a control group, and the GH effect is determined using the gain in centimeters over projected height. Out of a cohort of 32 Turner syndrome girls under recombinant human GH (rhGH) therapy (0.5 IU/kg/week during the 1st year and 1 IU/kg/week subsequently), 18 (treated for 3-6 years) attained FH. The mean chronological age at the first examination was 9.6 +/- (SD) 2.1 years and at the start of GH therapy 13.0 +/- 2.0 (range 8.8-17.2) years. Eighteen untreated subjects matched for chronological age and karyotype served as control group. The FH as SDS according to Lyon and to unpublished Italian Turner syndrome girl standards was not significantly different as compared with pretreatment. In comparison with Italian cross-sectional Turner syndrome standards (FH 142.5 +/- 7.0 cm), the FH of the control group was quite similar (142.2 +/- 4.9 cm), whereas the rhGH-treated group showed a FH of 147.6 +/- 7.3 cm with a mean increment of about 5 cm. The height gain during therapy (as delta height in SDS either according to Lyon or to Italian SDS standards) was compared for each girl with that of a matched girl of the control group during a comparable observation period. A significantly different delta height was observed in the treated versus control groups: 0.3 +/- 1.1 vs. -1.0 +/- 0.8 according to Lyon (p0.001) and 0.8 +/- 0.7 vs -0.3 +/- 0.5 according to Italian standards (p0.001). If we compared the FH with the projected height according to Lyon standards, the height gain (as delta height in cm) was significantly higher than in the untreated subjects (-1.1 +/- 4.8 vs. -6.2 +/- 3.9 cm; p0.05). It seems worthwhile to undertake GH treatment in Turner syndrome girls who represent a very short stature population, even though the response is less significant than in classic GH deficiency and shows a striking variability, probably due to a sort of peripheral resistance.

We report two unrelated women with gonadal dysgenesis, and a (6;15)(p21.3;q15) and a (8;9)(p11.2;q12) balanced translocation, respectively. The patients were of normal stature and showed no phenotypic abnormality or malformation other than ovarian failure. We are not aware of other reports of balanced autosomal translocations associated with gonadal dysgenesis in women. The occurrence of chromosome anomaly and sterility in the two females may be coincidental. However, studies on mouse gametic progression indicate that balanced autosomal translocations can cause oocyte degeneration and reduction of reproductive lifespan. On the basis of these observations, we cannot exclude that the ovarian failure in our patients is the result of oocyte degeneration because of as yet unidentified consequences of the balanced translocations.

Summary OBJECTIVE Following the chance observation of congenital adrenal hyperplasia in a patient with Turner's syndrome we decided to evaluate the incidence of 21-hydroxylase deficiency (21-OHD) in patients with Turner's syndrome and in their relatives. SUBJECTS Fifty-two patients with Turner's syndrome (mean age ± SD 14.7 ± 5.6 years) and 26 relatives were studied. MEASUREMENTS 17-Hydroxy progesterone (17-OHP) serum levels before and after i.m. administration of 0.25 mg of ACTH(1-24) were evaluated in patients with Turner's syndrome and relatives. In Turner patients basal testosterone and dehydroepiandrosterone concentrations were determined. The results of ACTH tests were analysed according to HLA class I and II alleles of subjects. RESULTS The baseline 17-OHP was in the range of the classical form of 21-OHD in one Turner patient, who had severe clitoral enlargement since birth. In 11 patients the stimulated 17-OHP serum level was higher than in normal controls and similar to that found in 21-OHD heterozygous subjects. Clitoral enlargement was significantly more frequent in patients with high stimulated 17-OHP levels (P < 0.001). The frequency of heterozygous-type responses was higher in Turner subjects (1:4.6) than in the Italian population (1:47 for the classic form and 1:9.5 for the non-classic form of the disease). In our patients the frequencies of HLA antigens and haplotypes, usually associated with 21-OHD, were different compared to the controls. HLA-B8, which is negatively associated to 21-OHD, was less frequent in Turner patients than in controls and absent in those with an elevated 17-OHP level. HLA-B14, B22 and B35 were more frequent, though not significantly so, in Turner patients than in controls and even more so in the group with an elevated 17-OHP level. The same investigations performed in 26 relatives of the Turner patients showed a high frequency of carriers of 21-OHD and three subjects with the cryptic form of the disease. CONCLUSIONS Although in the literature there are only two reports of the association of Turner's syndrome and 21-OHD, on the basis of our experience this association was more frequent, in the Italian population. Since some of the typical signs of 21-OHD (short final stature, varying degrees of virilization, menstrual irregularities, amenorrhoea, infertility) in patients with Turner's syndrome could also be attributed to the chromosomal abnormality, it is therefore more difficult to diagnose 21-OHD in Turner subjects. Adrenal function should be assessed, at least in the presence of clitoral enlargement, in patients with Turner's syndrome, particularly if their karyotype does not contain a Y chromosome. The hypothesis of the presence of cryptic Y chromosome material in these patients should also be considered. Correspondence: Dr Daniela Larizza, Clinica Pediatrica, Policlinico S. Matteo, Piazzale Golgi, 27100 Pavia, Italia.

In the attempt to define possible causes of false positive GH deficiency, the role of caloric intake on GH determination was explored. The serum GH responses to insulin-induced hypoglycemia or arginine were assessed before and after 3 days of a hypocaloric diet in 23 prepubertal children of normal weight, aged 6.7-11.9 yr. Seventeen had short stature and a GH response to insulin and arginine below 10 micrograms/L, and 6 controls had normal stature and a GH peak above 10 micrograms/L in response to arginine. After diet, the serum peak GH and the area under the curve increased in both the patients (P < 0.0005 and P < 0.0005) and the controls (P < 0.005 and P < 0.025) with a GH peak greater than 10 micrograms/L in 11 of 17 patients. The patients with a persistent GH response below 10 micrograms/L also had lower mean 12-h overnight GH levels (P < 0.0005), whereas those with a normal GH response after diet had an overnight GH level greater than 3 micrograms/L. In the patients, the mean nighttime GH concentrations correlated with the serum GH peak (r = 0.85; P < 0.005) and with the area under the curve after the diet (r = 0.65; P < 0.025). The diet induced changes in plasma insulin-like growth factor-I, GH-releasing hormone levels, basal blood sugar and the nadir level obtained during insulin stimulation, total T3, and rT3. Height increased significantly during 1 and 2 yr (P < 0.005) of GH treatment only in patients with a GH response below 10 micrograms/L after the diet. These data are consistent with the hypothesis that the GH response to stimulation is strongly calorie dependent and that 3 days of a hypocaloric diet can increase the number and height of GH peaks and the total GH responses to insulin and arginine. The clear correlation of the GH response to stimulation after a hypocaloric diet with the mean nighttime GH and also with the growth response to GH treatment indicates that GH deficiency may be overdiagnosed in many children with short stature.

The case of a girl carrying a balanced X/autosome translocation: 46,X,t(X;18)(q22.3;q23),inv(9)(p11q13) and pituitary hormone deficiency (growth hormone and gonadotropin) is described. The patient had a doll-like facies, with frontal bossing and poor development of the nasal bridge, increased adipose tissue especially of the trunk, short stature and absence of pubertal development without Ullrich-Turner stigmata apart from urinary tract malformation. The lack of spontaneous puberty seems related both with gonadotropin deficiency, as suggested by hormonal data and MRI of the pituitary region, and with gonadal dysgenesis, due to the X/autosome translocation, involving the critical region of the X chromosome essential for normal ovarian function. Growth velocity was unsatisfactory during growth hormone treatment; a higher dose of growth hormone similar to that used in Ullrich-Turner patients, would probably have improved her growth rate.

The posterior pituitary lobe and stalk were studied by magnetic resonance imaging in 20 children with diabetes insipidus of different origins: primary familial autosomal dominant (n = 2) or idiopathic (n = 2), and secondary to craniopharyngioma (n = 6, resected in 5), to Langerhans cell histiocytosis (n = 5), to excessive water intake (dipsogenic; n = 3), to renal vasopressin insensitivity (n = 1), and to osmoreceptor dysfunction (n = 1). Of the four children with primary diabetes insipidus, the posterior bright signal was recognizable in two with the familial autosomal dominant form and one with the idiopathic form; in the latter, the pituitary stalk was thin, while it was normal in the first two patients; no posterior hyperintense signal with enlarged and gadolinium-enhanced pituitary stalk was observed in the fourth. The posterior hyperintense signal was absent without evidence of ectopic posterior pituitary tissue regeneration in five children with surgically removed craniopharyngioma and was doubtful in the child with unresected craniopharyngioma; the stalk was unrecognizable in all patients. In the five children with Langherans cell histiocytosis, the posterior bright signal was absent, while the stalk was normal in two and unexpectedly enlarged in three (uniformly in two and mainly at the level of median eminence and hypothalamus in one). All five patients with dipsogenic or nephrogenic diabetes insipidus or osmoreceptor dysfunction had normal images of posterior pituitary lobe and stalk. Normal posterior pituitary bright signal and stalk were found in all 25 healthy control children. Plasma vasopressin was undetectable in all patients except in nephrogenic one, in the child with osmoreceptor dysfunction, and in two of three dipsogenic children, the third mimicking partial neurogenic diabetes insipidus.(ABSTRACT TRUNCATED AT 400 WORDS)

To delineate the effects of human chorionic gonadotropin (hCG) administration on immune responsiveness, immunological parameters including serum immunoglobulins, total and differential white blood cell count T and B lymphocyte membrane phenotype, in vitro, proliferative response to phytohaemagglutinin, Concanavalin A (ConA) and pokeweed mitogen were studied in 13 prepubertal cryptorchid boys before, during, and 3 months after hCG therapy. Before treatment, all the immunological parameters were normal except for an unexpected high percentage of T suppressor-cytotoxic cells (CD8+). During therapy, the absolute number of total peripheral blood lymphocytes, and that of total T-cells, T helper-inducer cells and of CD8+ subsets were diminished. The percentage of CD8+ cells and lymphocyte response to ConA decreased significantly and returned to normal after hCG withdrawal. The possible effects of long-term hCG treatment remain to be determined.