Volume 26, Issue 7-8

There is compelling evidence that carbohydrate quality has important influences on cardiovascular disease, the metabolic syndrome, type 2 diabetes, and obesity. Cohort and interventional studies indicate that dietary fiber is an important determinant of satiation, satiety, and weight gain, and also protects against cardiovascular disease. Cohort studies have shown that vegetables and fruits protect against coronary heart disease, whereas whole grains provide protection against cardiovascular disease, type 2 diabetes, and weight gain. Dietary glycemia within the range eaten by most of the population seems not to have a significant influence on body weight, although it may influence waist circumference. There is strong evidence from interventional trials that dietary glycemia does influence insulin resistance and diabetes control. Moreover, replacing saturated fat with high-glycemic carbohydrate may increase cardiovascular risk. Soft drink consumption is a proven cause of weight gain, which may relate to the lack of satiation provided by these drinks. In large amounts, dietary fructose leads to greater adverse metabolic changes than equivalent amounts of glucose, although the extent to which fructose per se is contributing to many of the metabolic changes found in the obese, as distinct from the calories it provides, is still a matter of debate.

Background: Acute gonadotropin responses following depot leuprolide acetate injection are useful for monitoring therapeutic efficacy in central precocious puberty. Similar monitoring of therapy in patients treated with another widely used GnRH agonist, depot triptorelin, has not yet been reported. Objective: The objective of this study was to test the use of gonadotropin levels after therapeutic injections of depot triptorelin for evaluating efficacy of therapy. Patients and methods: Thirty-two patients (29 girls and three boys) were treated with triptorelin depot, 3.75 mg per vial, between 2006 and 2010. Treatment was initiated at 8.27±1.76 years (range, 4.6–11.6 years). Blood was drawn before and at variable times between 30 min and 2 h after injections. Clinical tests were retrospectively collected. Results: After the first injection, the 60-min mean luteinizing hormone (LH) level was 21.6.1±18.0 IU/L and the follicle-stimulating hormone (FSH) was 13.5±3.6 IU/L. After subsequent injections, for those who showed clinical suppression, the standard deviations above the mean were 3.6 IU/L for FSH and 2.1 IU/L for LH. The LH levels of two patients who did not suppress sufficiently were at these limits or higher. Conclusions: Sixty-minute postinjection depot triptorelin levels of LH can be successfully used to evaluate the efficacy of treatment with this agent. Limits for suppressed levels have been determined.

Background: Vaspin is a visceral adipose tissue-derived serine protease inhibitor that has an insulin-sensitizing effect. It is correlated with insulin resistance and glucose metabolism, and it improves glucose tolerance. Aim: The aim of this study was to determine and compare serum vaspin and insulin concentrations in small-for- gestational age (SGA), appropriate-for-gestational age (AGA), and large-for-gestational age (LGA) infants at birth and fifth postnatal day. Patients and methods: Eighty-two neonates were divided into three groups: SGA (n=22), AGA (n=30), and LGA (n=30). Mothers’ age, gestational week, mode of delivery, and maternal diseases, such as diabetes, pre-eclampsia, and eclampsia were recorded. Blood for vaspin, insulin, and glucose was collected from the cord at birth and from a peripheral vein on the fifth postnatal day. Results: At birth, there were no statistically significant difference in serum insulin concentrations among the three groups, whereas cord serum vaspin concentrations were significantly higher in the SGA group (χ 2 =8.158, p<0.05). Serum glucose and vaspin levels on the fifth postnatal day had no significant difference among three groups (p<0.05). Circulating vaspin concentrations were not associated with the sex of the infant and delivery route. Conclusion: Cord vaspin levels are significantly higher in SGA neonates than in AGA or LGA neonates. The fetal programming hypothesis proposes that many adulthood diseases originate from the adaptation that the fetus makes when it is undernourished. High cord-vaspin levels in SGA infants may be one of the adaptations for increased risk for adult metabolic diseases.

Objective: This study aims to describe the final adult height (FAH) and pubertal growth patterns in human immunodeficiency virus (HIV)-infected adolescents and to compare these to an age-matched population of seroreverting HIV-exposed, uninfected (HEU) adolescents. It further aims to evaluate the interplay of proinflammatory cytokines with insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), and IGFBP-1 during the pubertal growth spurt. Methods: HIV-infected (n=34) and HEU (n=12) adolescents who had achieved FAH were evaluated. Auxologic data, viral load, CD4+ T-lymphocyte (CD4) count, and the use of highly active antiretroviral therapy were obtained via a retrospective chart review. Serum interleukin (IL)-1α, IL-6, tumor necrosis factor (TNF)-α, IGFBP-1, IGFBP-3, and IGF-1 were assessed. Results: The mean FAH standard deviation score for the HIV-infected group was –0.78 (±1.1) compared to 0.05 (±0.78) for the HEU (p=0.034). There was a positive correlation between CD4 count and FAH (p=0.019). The mean age and magnitude of peak growth velocity (GV) was within normal limits. IL-1α, IL-6, TNF-α, IGFBP-3, and IGF-1 were not significantly correlated with HIV RNA or height. IGFBP-1 was detectable in 100% of poorly controlled HIV-infected patients and 25% of the HEU cohort (p=0.0003). Conclusions: The FAH of HIV-infected patients was significantly shorter than that of HEU patients, and it positively correlated with CD4 count. Our cohort demonstrated normal timing and magnitude of peak GV during puberty.

Objective: Estrogen is the final key factor that triggers the onset of puberty. The raised sensitivity of estrogen receptor, which may be caused by an estrogen receptor α ( ERα ) gene mutation or polymorphism, has been implicated in the etiology of precocious puberty. The aim of this study is to identify ERα gene mutations or polymorphisms in girls with central precocious puberty (CPP). Methods: A total of 204 Korean girls with CPP were included in this study along with 102 healthy Korean female adults as controls. All coding exons and exon-intron boundaries of the ERα gene were sequenced. The relationship between identified sequence variations and CPP were evaluated via comparison of allele frequencies between the two groups. Results: Eight polymorphisms were identified in the ERα gene. Among the eight polymorphisms in this study, five have been previously reported, whereas the other three were novel polymorphisms. Two of the three novel polymorphisms, p.G145S in exon 1 and p.R555H in exon 8 were only identified in the patient group. The subgroup with p.G145S showed a significantly higher level of peak luteinizing hormone than the subgroup without p.G145S in girls with CPP. Conclusion: The scanning and typing of ERα polymorphism has uncovered several potentially meaningful polymorphisms. However, no solid conclusion can be made from this study and further studies are necessary to validate the function of these polymorphisms.

Background: Excessive increases in percentage body fat (%BF) according to sex may pose greater risks of chronic diseases. Objective: To evaluate trends of body composition according to sexual maturation stage and body mass index (BMI) of adolescents. Method: Data about weight, height, lean mass, fat mass, %BF, BMI and sexual maturation of 1345 private school students (685 girls) aged from 7 to 18 years were collected in 2001 and compared with data of 1450 students (750 girls) collected in 2010 in Campinas, Brazil. χ 2 -test, ANOVA and logistic regression were used for statistical analyses (p<0.05). Results: Obesity prevalence increased, and number of boys and girls with normal BMI (p=0.0183 and p=0.0041) decreased. Differences in the median values of the study variables according to time point and nutritional diagnosis were not significant, except for lean mass (p=0.0484) and height (p=0.0275) in B2 (Breast stage) and %BF (p=0.0324) in G5 (Genitalia stage). Conclusion: Body composition did not change significantly, although overweight increased.

Objectives: Children with obesity have a high cardiovascular risk and an impaired oxidant-antioxidant status, which may lead to endothelial dysfunction and increased carotid intima media thickness (IMT) even in childhood. The aim of this study was to investigate the circulating oxidized low-density lipoprotein (LDL) concentrations and the IMT of carotid arteries in prepubertal obese children, and also to search for its possible association with carotid atherosclerosis. Methods: Twenty-seven prepubertal obese children (age, 7.48±2.05 years; boys, 59%) and 30 healthy children (age, 7.80±2.19 years; boys, 55%) were included in the study. Serum concentrations of oxidized LDL, total cholesterol, triglyceride, high-density lipoprotein, LDL, and glucose were measured, and carotid IMT was determined by ultrasound. Results: Serum oxidized LDL levels were significantly higher in prepubertal obese children than in healthy children (p<0.01). No significant correlation was observed between oxidized LDL levels and carotid IMT measurements. However, a significant positive correlation was found between oxidized LDL levels and body mass index, total cholesterol, and LDL-cholesterol. Conclusion: Our findings revealed that the oxidation of LDL starts early in obese children but the carotid IMT is not significantly affected. Also, oxidized LDL levels are more strongly associated with obesity and dyslipidemia than the carotid IMT in prepubertal children.

Obesity is a chronic inflammatory condition with numerous metabolic consequences to the organism, highlighting its influence on bone mass. Therefore, the aim of this study was to verify the role of visceral fat, leptin, adiponectin and ghrelin on bone mineral density in obese post-puberty adolescents girls, submitted to an interdisciplinary therapy. The study involved 20 post-puberty obese adolescent girls: 16±1.5 years of age, 98.9±15.8 kg (weight), 1.60±0.72 m (height) and 37.2±4.8 kg/m 2 [body mass index (BMI)]. Anthropometric measurements, body composition, visceral fat, subcutaneous fat, bone mineral density and content were determined. Ghrelin, leptin and adiponectin were analyzed and the leptin/adiponectin ratio was calculated. Our findings showed a significant increase in adiponectin concentration and a reduction in body weight, BMI, total fat mass, visceral and subcutaneous fat. In addition, ghrelin (r 2 =–0.53; p=0.02) visceral fat (r 2 =–0.46, p=0.04) (r 2 –0.66, p=0.001) and leptin/adiponectin ratio (r 2 –0.56, p=0.01) were negative predictors for bone mineral density and content in obese adolescent girls, respectively. It provides a novel physiologically concept that may shed light on the etiology of osteoporosis and help to identify new therapeutic targets. However this should be confirmed in a large cohort study.

Objective: To evaluate the effect of intensive art therapy in youth with poorly controlled type 1 diabetes mellitus (T1DM). Methods: A retrospective report of the characteristics and outcomes of all patients who were offered to receive individual art therapy sessions because of behavioral difficulties. Results: The study population included 29 participants. The main behavioral difficulties were needle phobia and lack of compliance with nutritional recommendations or with insulin administration. The intervention group included 16 patients, with a mean age of 9.3±2.5 years, average intervention length of 0.77±0.41 years, and long-term data of 2.27±1.13 years. The control group included 13 patients, with a mean age of 9.3±3.4 years. Improvement was observed in 56% of the case group and in 23% of the control group. Art therapy was associated with a decrease in hemoglobin A1c in the intervention group compared with a similar control group (–0.79%, ±0.24%; r=0.17, p=0.025). Conclusions: The addition of intensive art therapy for poorly controlled youth with T1DM may improve their glycemic control.

Aim: To reveal the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in the integration of the redox signal in the oxidative molecular regulation mechanism in phenylketonuria (PKU). Methods : The blood samples were obtained from Pah enu2 -BTBR PKU and wild-type mice, respectively. Phe concentration, total antioxidant capacity (T-AOC), glutathione (GSH) and maleic dialdehyde (MDA) were analyzed. After collection of the mononuclear cells, reverse transcription polymerase chain reaction (RT-PCR) for NOX was performed. In addition, NOX activity and superoxide in mononuclear cells were determined. Results : Compared to the control group, Phe concentration, T-AOC and MDA were markedly increased in PKU mice (p<0.01, p<0.05, p<0.01, respectively). However, the GSH level in PKU mice was less than that in control group (p<0.05). The mRNA level of subunits of NOX included p47 phox and p67 phox , were increased in PKU mice (p<0.05), however, the gp91 phox had no obvious change in the two groups (p>0.05). NOX activity and superoxide were also remarkably elevated in PKU mice (p<0.05). Conclusion : NOX may play an important role in the integration of the redox signal in the oxidative molecular regulation mechanism in PKU.

Aim: The purpose of this prospective study was to evaluate whether surgical treatment of adenotonsillar hypertrophy has an effect on growth patterns and circulating concentrations of leptin, ghrelin and neuropeptide Y, which are all significant in energy balance. Materials and methods: The study group consisted of 20 children who underwent tonsillectomy with or without adenoidectomy due to chronic adenotonsillar hypertrophy. The ages ranged from 4.3 to 9.2 years with normal weight. The healthy control subjects consisted of 30 age- and sex-matched children (control group) with ages between 3.2 and 8.1 years. Serum levels of leptin ghrelin and neuropeptide Y were measured in the preoperative period and at the end of the postoperative period, which was 6 months in the study group, serum levels were only measured during the first examination in the control group. Results: When the study group (preoperative) is compared with the control group, it is observed that the leptin and ghrelin levels were higher in the study group and that the neuropeptide Y levels were similar (p=0.01, p=0.005, p=0.19, respectively). When the preoperative and postoperative anthropometric data were compared, it was observed that weight, height, body mass index (BMI) and BMI-standard deviation score (SDS) values increased in the 6th month postoperatively (p<0.001, p<0.001, p=0.01, p=0.03, respectively). However, the leptin, ghrelin and neuropeptide Y levels were similar (p=0.70, p=0.12, p=0.60, respectively). Conclusion: Following adenotonsillectomy, an increase in weight and height occurred in the children. In the postoperative period, dietary and lifestyle suggestions as well as growth monitoring might be useful.

Inborn errors of metabolism (IEM) have greater repercussions in neonatology units. The aim of our study was to evaluate the impact of IEM in a neonatal intensive care unit (NICU) and the resources required to care for these neonates. All patients with IEM admitted in our unit during a 4-year period were evaluated for specific diagnosis, demographic data, clinical features, biochemical characteristics at admission, need for mechanical ventilation, use of extracorporeal removal therapy, and outcome at NICU discharge. The study group comprised 2742 infants, 39 of which required admission to the NICU (1.42% of admissions) because of severe symptoms and/or newborn screening. Five of the 39 had an earlier diagnosis and treatment because of expanded newborn screening. The average age at admission was 5 days [interquartile range (IQR, 3–9 days)] and the median length of stay in the NICU for the study population was 5 days (IQR, 3–12 days). Aggressive support was often necessary (extracorporeal removal therapy, mechanical ventilation). Ten patients died; thus the death rate was 25.6%. Overall mortality in the NICU was 10.4% during the study period. These observations shown that IEM may be very common in our population. Most patients with IEM admitted to a NICU require aggressive support (including mechanical ventilation and extracorporeal removal therapies), and consume significant resources for relatively shorter stays.

There are few large-scale studies on the utility of peripheral dual energy X-ray absorptiometry (pDXA) in children. As central dual energy X-ray absorptiometry (cDXA) equipment is not commonly available in the developing world, we assessed the correlation of bone mineral density (BMD) with cDXA and pDXA in children to determine the optimal Z-score thresholds of pDXA for predicting two predefined Z-score cutoffs (≤–1, ≤–2) of cDXA in 844 subjects (441 boys, 403 girls) aged 10–18 years. The BMD of antero-posterior lumbar spine (L1–L4), proximal femur and forearm was measured by cDXA, while the peripheral BMD of forearm and calcaneus was estimated using pDXA. The correlation was statistically significant at all sites (p<0.01). The coefficients ranged from 0.56 to 0.79 in boys and 0.17 to 0.32 in girls. A significant positive correlation was observed between BMD by pDXA and cDXA in Indian children, with a strong gender difference in both the extent of correlation and the ability of peripheral BMD to predict central BMD.

Objective: In recent years, there has been increasing focus on thyroid function in pediatric obese patients. Our aims were to investigate whether there is an association between serum thyroid-stimulating hormone (TSH) within the normal range and body mass index (BMI), and to determine if TSH levels correlate with metabolic risk factors in children. Methods: A retrospective cross-sectional analysis was carried out on 528 euthyroid, age- and sex-matched lean, overweight, or obese children. Anthropometric indices, blood pressure, fasting blood glucose, hepatic enzymes, lipid profiles, TSH, free triiodothyronine (fT3), and free thyroxine (fT4) were assessed from medical records and compared among groups. Subjects with known presence of diabetes, using medications altering blood pressure and glucose or lipid metabolism, with TSH levels >97.5 or <2.5 percentile, or with autoimmune thyroid disease were excluded. Results: Hypertension, dyslipidemia, and elevated levels of hepatic enzymes were found to be more common in overweight and obese children (p<0.001), and those metabolic changes were significantly correlated with the increase in BMI (p<0.05). Serum concentrations of TSH and fT3 within the normal range were higher in overweight and obese children (p<0.01), and TSH was positively correlated with total cholesterol, triglycerides, and systolic blood pressure (p<0.05). Conclusion: Our findings suggest that obese children have higher serum TSH and fT3 levels even within the normal range, and that an increase in TSH is associated with dyslipidemia and higher systolic blood pressure. It remains to be seen whether TSH might serve as a potential marker of metabolic risk factors in obese pediatric patients.

Hepatocyte growth factor (HGF) is a potent mitogen and morphogen expressed in fetal organs. It requires activation by specific serine proteases. The role of activated HGF during fetal development has not been evaluated. We hypothesized that the serum levels of activated HGF would be increased in preterm neonates. Cord blood total HGF and activated HGF levels were measured in 19 preterm (gestational age, 28.04±2.39 weeks) and 24 term (gestational age, 39.37±0.95 weeks) newborns. Anthropometric parameters and metabolic indices were evaluated. Activated HGF was higher in preterm than in term neonates (0.81±0.05 vs. 0.61±0.06 ng/mL, p<0.05), whereas total HGF levels did not differ significantly between groups. In addition, total and activated HGF further increased by ∼40% in preterm neonates 12 h after birth. Finally, activated HGF correlated inversely with gestational age (r=–0.369; p=0.015) and birth weight (r=–0.440; p=0.003). Our study demonstrates that regulation of HGF activity and circulating HGF levels differ between term and preterm neonates along fetal development.

Causes of hyperglycemia in critically ill non-diabetic children may differ from those in adults. The objective of this study was to investigate the pathogenesis of critical illness hyperglycemia (CIH) in terms of insulin resistance and β-cell dysfunction. Critically ill children with blood glucose (BG) levels of >150 mg/dL (8.3 mmol/L) were enrolled in the study. Insulin sensitivity and β-cell function in the hyperglycemic and euglycemic periods were analyzed with BG/insulin and BG/C-peptide ratios, and utilizing homeostasis model assessment (HOMA). A total of 40 patients were enrolled in the study. BG/insulin and BG/C-peptide ratios were significantly higher in the hyperglycemic period. The HOMA-B and S scores for the hyperglycemic period revealed that out of all the patients who survived (n=30), 20 had β-cell dysfunction, while the remaining (n=11) had insulin resistance. β-cell dysfunction was significantly higher in the hyperglycemic period (p<0.001). As in adults, β-cell dysfunction may play a major role in the pathophysiology of CIH in children.

We explored the influence of exposure to maternal diabetes in utero on β cell decline measured by fasting C-peptide (FCP) among 1079 youth <20 years with diabetes, including 941 with type 1 and 138 with type 2 diabetes. Youths exposed to maternal diabetes had FCP levels that were 17% lower among youth with type 2 diabetes [95% confidence interval (CI): –34%, +6%] and 15% higher among youth with type 1 diabetes (95%CI: –14%, +55%) than their unexposed counterparts, although differences were not statistically significant (p=0.13 and p=0.35, respectively). Exposure to maternal diabetes was not associated with FCP decline in youth with type 2 (p=0.16) or type 1 diabetes (p=0.90); nor was the effect of in utero exposure on FCP modified by diabetes type. Findings suggest that exposure to maternal diabetes in utero may not be an important determinant of short-term β-cell function decline in youth with type 1 or type 2 diabetes.

Aim: Léri-Weill dyschondrosteosis (LWD) is a mesomelic dysplasia with disproportionate short stature associated with short stature homeobox-containing gene (SHOX) haploinsufficiency. The objective of this study was to improve the diagnosis of patients with suspected LWD through molecular analysis. Methods: Twelve patients from 11 families with a clinical diagnosis of LWD were analyzed with multiplex ligation-dependent probe amplification to detect deletions and duplications of SHOX and its enhancer regions. High resolution melting and sequencing was employed to screen for mutations in SHOX coding exons. Results: The molecular-based screening strategy applied in these patients allowed detection of five SHOX deletions and two previously unreported SHOX missense mutations. Conclusion: Molecular studies confirmed the clinical diagnosis of LWD in seven out of 12 patients, which provided support for therapeutic decisions and improved genetic counseling in their families.

The aim of this study is to investigate whether abdominal aorta intima media thickness (aIMT), increases in obese children and to determine risk factors. Ninety-six children aged 5–16 (51 obese and 45 non-obese) were enrolled in this prospective and cross-sectional study. Age, gender, and relative body mass index (BMI) were recorded. Their serum lipids, thyrotropin, fasting glucose and insulin levels were analyzed. The homeostasis model assessment (HOMA-IR) score was calculated for insulin resistance. Anthropometric and biochemical data were assessed along with aIMT. Findings in obese children were compared with those of non-obese control subjects. The aIMT was significantly greater in obese children. Similar trends were observed in both prepubertal children and adolescents. In obese children, the mean aIMT (mm) was 0.021 (years of age) +0.519. In non-obese children, the mean aIMT (mm) was 0.017 (years of age) +0.381. Our data suggests a relationship between glucose metabolism and aIMT in obese children. BMI was an independent risk factor for increasing aIMT. In conclusion, when compared with non-obese controls, obese children demonstrated significantly increased aIMT. Higher BMI, insulin, HOMA-IR and increased systolic blood pressure seem to be the main factors contributing to increased aIMT and risk for developing vascular disease. Childhood obesity contributes to the development of an increased aIMT.

The ATP-sensitive K + channel controls insulin secretion from the islet. Mutations in KCNJ11 can cause permanent and transient neonatal diabetes. To date, more than 30 KCNJ11 mutations have been revealed as related to the onset of neonatal diabetes mellitus (NDM), most of which are responsive to glibenclamide treatment. In the present study, we sequenced the KCNJ11 gene in a Chinese girl diagnosed with NDM and in her parents. An in-frame 15-bp KCNJ11 deletion was identified in the patient, whereas no KCNJ11 deletions were found in her parents, indicating that this deletion was de novo. The patient was responsive to the treatment of glibenclamide. Ten months of follow-up showed that, besides permanent NDM, the motor and intelligence development of the girl was normal and she suffered no onset of convulsions. The result, to some degree, improved our knowledge on NDM.

Background: Diffuse muscle hypertrophy is a rare complication of acquired hypothyroidism. When accompanied by stiffness, weakness, and painful muscle cramps, the condition is known as Hoffmann’s syndrome (HS). HS is usually seen in young adults due to long-standing untreated primary hypothyroidism. We report a very rare case of HS with muscle hypertrophy and pituitary hyperplasia complicating hypothyroidism in an adolescent. Case: A 12-year-old male admitted with muscle pain, headache, and fatigue. He had marked hypertrophy of both calf and shoulder muscles. Laboratory tests indicated elevated muscle enzymes and lipids with an elevated thyrotropin and low thyroxine levels. Hashimoto thyroiditis was confirmed on thyroid studies. He had also papilledema bilaterally and magnetic resonance imaging showed an enlargement of the pituitary gland. Treatment with thyroid hormone resulted in complete improvement of symptoms within 3 months. Conclusions: HS is a rare but treatable form of acquired myopathies and can be seen in children due to untreated hypothyroidism. All patients with an acquired myopathy and muscular pseudohypertrophy should be screened regarding thyroid hormones.

We present a case of late diagnosis of an adolescent female with Cushing’s disease or excess glucocorticoid secretion due to the presence of an adrenocorticotropic hormone (ACTH) secreting tumor on the pituitary. Her main complaints at first presentation in 2008 were short stature and weight gain. Although these are the main criteria for testing for Cushing’s syndrome outlined by the 2008 Endocrine Society guidelines, they were not enough to lead to a timely diagnosis. The reasons may include the endocrinologists believing that additional more common symptoms needed to be present to test for Cushing’s syndrome. Consequently, the guidelines were not followed leading to placing the child on growth hormone (GH) with no further evaluation until well after 1 year of minimal growth. While Cushing’s syndrome is rare in children and hard to diagnose, a more collaborative effort among pediatricians, endocrinologists, radiologists, surgeons, as well as parents, is required to diagnose and help cure children with this disease.

Wolcott-Rallison syndrome (WRS) is a rare condition characterized by permanent neonatal diabetes (PND), skeletal dysplasia, and recurrent hepatitis. Other features, including central hypothyroidism, have been reported. We compared the phenotype of five patients from two families with WRS caused by the same EIF2AK3 mutation who have been followed up since diagnosis. Direct sequencing of the EIF2AK3 gene identified a homozygous frameshift mutation (c.1259delA) in all patients that has been reported only in these families. All patients presented with PND and four experienced recurrent hepatitis. A 3.5-year-old girl has isolated PND, whereas her younger sister has typical WRS features. Two children developed skeletal abnormalities and two had transient central hypothyroidism. Other reported features of WRS were not detected. The EIF2AK3 c.1259delA mutation results in a variable phenotype, ranging from isolated PND to typical WRS. Thyroid dysfunction in WRS is a transient phenomenon reflecting euthyroid sickness.

A 14-month-old female infant presented with recurrent episodes of acute gastroenteritis accompanied by severe metabolic acidosis and hypoglycemia. Physical examination showed hepatomegaly. Laboratory evaluation revealed elevated hepatic enzymes, prolonged prothrombin time, hyperuricemia, and extremely elevated lactate and alanine levels. Glucagon injection during hypoglycemia resulted in a further decrease of blood glucose. She was treated with glucose-containing intravenous fluids, with rapid improvement and normalization of her blood pH and glucose levels. Hormonal assessment during two episodes of hypoglycemia indicated growth hormone (GH) deficiency. However, as isolated GH deficiency could not explain all other concomitant features, such as severe lactic acidosis, hepatomegaly, impaired liver function, and hyperuricemia, the possibility of a combined defect was suggested. Further lymphocytic enzymatic investigation revealed fructose-1,6-diphosphatase deficiency and molecular genetic analysis demonstrated frame shift mutation in the FBP1 gene. This enzyme deficiency causes a rare metabolic disorder not previously described in combination with GH deficiency.

The Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http:www.imm.Ki.se/CYPalleles/cyp21.htm) has created a CYP21A2 database which include a list of all reported CYP21A2 mutations and the last update of this database was in 2006. The most up to date list of the CYP21A2 mutations reported over the last four years was published in a recent article by Concolino et al. We report a previously undescribed mutation detected by sequence analysis of CYP21A2 gene in an infant resulting in salt wasting congenital adrenal hyperplasia.

Sialidosis is a lysosomal storage disease caused by deficiency of α-N-acetyl neuraminidase-1. Sialidosis is classified into two main clinical variants: type I, the milder form of the disease, and type II, which can in turn be subdivided into three forms: congenital, infantile, and juvenile. We report a female patient with sialidosis type II, presenting with the congenital form of the disease with thrombocytopenia, pulmonary interstitial thickening, and transient secondary neonatal hyperparathyroidism.

We report the case of a boy affected by severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphisms and postnecrotic cirrhosis, diagnosed at birth as having Seckel syndrome, and subsequently confirmed as Majewski osteodysplastic primordial dwarfism type II (MOPD II) on the basis of clinical and radiological features of skeletal dysplasia. At our observation (6 years 7 months) he presented height –10.3 standard deviation score (SDS), weight –22.1 SDS, head circumference –8 SDS, delayed bone age of 4 years with respect to chronological age. In consideration of the low levels of insulin-like growth factor-1 (IGF-1) as well as of hepatic insufficiency, we started the treatment with recombinant human IGF-1 (rhIGF-1) at the dose of 0.04 mg/kg in 2 doses/day, with an increase of 0.04 mg/kg after 1 week until the maximum dose of 0.12 mg/kg. We observed an early response to rhIGF-1 treatment, with a shift of height velocity from 1.8 cm/year (–4.6 SDS) at 4 cm/year (–1.9 SDS), and an increase in bone age of 1.5 years during the first 6 months. rhIGF-1 treatment does not seem to be able to replace the physiological action of IGF-1 in patients with MOPD II and hepatic insufficiency, however, it seems to preserve the typical growth pattern of MOPD II patients, avoiding a further widening of the growth deficiency in these subjects.

Background: The sex chromosome composition of the primordial gonad, either 46XX or 46XY, determines its differentiation as ovaries or testes. Local hormones secreted by developing gonads and tissue specific transcription factors influence the differentiation of external and internal genital structures. Dosage sensitive sex reversal adrenal hypoplasia congenita critical region (DAX1) on Xp21 is a gene which is expressed in the developing adrenals, gonads, hypothalamus and pituitary gland. Duplication of this area causes dosage sensitive male-to-female sex reversal while mutation or deletion leads to adrenal hypoplasia congenita with hypogonadotropic hypogonadism in affected males. Aim: To report a case with duplication of the X chromosome segment within the region of Xp21.1–22.2 resulting in 46 XY sex reversal and a literature review on DAX1 and dosage sensitive sex reversal (DSS). Methods and results: We present the clinical history, physical findings, laboratory, and imaging study results in a newborn baby. This infant was sex assigned as female at birth and had normal female external genitalia. Chromosome analysis was done due to multiple minor malformations and showed a karyotype of 46 Xp+Y. Fluorescent in situ hybridization analysis revealed the duplication in the DSS area. Conclusion: Duplication of the DAX1 gene on the X chromosome with normal sex determining region of Y (SRY) results in 46 XY sex reversal. This was inherited from the mother who had normal ovarian function. Additional problems include growth failure, mental retardation and multiple congenital anomalies. The baby did not have a mutation or deletion of DAX1, which would have caused adrenal insufficiency and hypogonadism.

Ectopic ACTH syndrome (EAS) is rare in children and is challenging to differentiate from Cushing’s disease. A 9-year-old boy presented with a history of worsening fatigue, muscle weakness, weight gain and acne, and he appeared cushingoid with central obesity and hyperpigmentation of his palmar creases. Investigations demonstrated an elevated ACTH and an elevated morning cortisol that did not suppress with low or high dose dexamethasone suppression tests. Brain imaging inconsistently showed a small pituitary lesion. Chest and abdomen computed tomography (CT) showed adrenal hyperplasia and a liver hemangioma. [ 18 F]fluorodeoxyglucose positron emission tomography CT was normal. Ultrasound and abdominal magnetic resonance imaging (MRI) also showed a liver hemangioma. Bilateral inferior petrosal sinus sampling, however, was consistent with ectopic ACTH production. An octreotide scan revealed a small focus of increased activity in the liver, which was the likely source of ectopic ACTH production. The patient was managed with metyrapone followed by a wedge liver resection. Pathology showed a well-differentiated neuroendocrine tumor (NET) that stained positive for ACTH. Post-operatively, the signs and symptoms of EAS are resolving and his hypothalamic-pituitary-adrenal axis is recovering. This case describes the first pediatric patient with EAS caused by a liver NET. It illustrates the challenges in localizing the source of ectopic ACTH and treating this rare condition.

A 12.5-year-old Italian girl was referred to our institute for progressive growth failure from the age of 6 years, with a height of 128.2 cm (–3.37 SDS) and a bone age of 9 years. Endocrinological evaluation revealed a partial growth hormone deficiency (GHD) and GH therapy was started at a dosage of 0.25 mg/kg/week. During the first 3 years, she showed an increase in growth rate and experienced pubertal development onset. Then a poor growth rate (2 cm/year=0.43 SDS) was observed, notwithstanding an increase in GH dosage (0.35 mg/kg/week) and good compliance. We found a positive anti-GH antibody titre (1:1850, cutoff 1/100), confirmed 6 months later (1:2035); the antibodies had low binding capacity (0.63 μg/mL) and were only partially capable of inhibiting the GH effect. However, GH treatment was discontinued, and after 3 months the antibody titre decreased (1:950). In conclusion, we suggest evaluation of anti-GH antibodies in GH-treated idiopathic GHD children in whom growth response decreases after some years of therapy.

Ovotesticular disorder of sexual development (DSD) is characterized by the presence of both ovarian and testicular tissues in the same individual. The most common karyotype is 46,XX. Here, we report the case of a boy with a 46,XX/47,XXY karyotype diagnosed as ovotesticular DSD by gonadal biopsy. A 5-month-old boy presented with hypospadias, unilateral cryptorchidism, and a micropenis. Pelvic magnetic resonance imaging revealed a suspicious gonad tissue that is solid in structure in the right scrotum and a suspicious gonad that is cystic in structure in the left inguinal canal. He underwent a diagnostic laparoscopy. Cytogenetic analysis of peripheral blood revealed a 46,XX/47,XXY karyotype. Histopathologic examination of the left gonad showed ovarian tissue containing primordial follicles with ipsilateral undifferentiated tuba uterina. The right gonad showed immature testis tissue. He underwent left gonadectomy and hypospadias repair, and was raised as a male. Through this rare case, we highlight the importance of histological and cytogenetic investigation in DSD.

Patients with Albright hereditary osteodystrophy (AHO) phenotype are usually seen in pediatric endocrinology policlinics when they are evaluated for short stature and/or obesity. Brachydactyly mental retardation syndrome (BDMR, OMIM #600430) is a rare genetic disorder caused by aberrations of chromosomal region 2q37 and characterized with AHO-like phenotype without any hormone resistance. Diagnosis of BDMR is based on the detection of the deletion on the long arm of chromosome 2. Diagnosis can usually be made with karyotype analysis but sometimes chromosomal deletion can only be detected by fluorescent in situ hybridization (FISH) screening. We report a patient with the AHO phenotype whose karyotype was normal but who was diagnosed with BDMR with FISH analysis showing 2q deletion. In pediatric endocrinology practice, in patients with AHO phenotype but without parathormone (PTH) resistance, BDMR should be considered. For the diagnosis of BDMR, the subtelomeric region of chromosome 2 should be screened for deletion by FISH analysis even in patients with normal karyotypes.