Transition from pediatric to adult care in patients with Turner syndrome in Italy: a consensus statement by the TRAMITI project.

PURPOSE: Transition from pediatric to adult care is associated with significant challenges in patients with Turner syndrome (TS). The objective of the TRansition Age Management In Turner syndrome in Italy (TRAMITI) project was to improve the care provided to patients with TS by harnessing the knowledge and expertise of various Italian centers through a Delphi-like consensus process. METHODS: A panel of 15 physicians and 1 psychologist discussed 4 key domains: transition and referral, sexual and bone health and oncological risks, social and psychological aspects and systemic and metabolic disorders. RESULTS: A total of 41 consensus statements were drafted. The transition from pediatric to adult care is a critical period for patients with TS, necessitating tailored approaches and early disclosure of the diagnosis to promote self-reliance and healthcare autonomy. Fertility preservation and bone health strategies are recommended to mitigate long-term complications, and psychiatric evaluations are recommended to address the increased prevalence of anxiety and depression. The consensus also addresses the heightened risk of metabolic, cardiovascular and autoimmune disorders in patients with TS; regular screenings and interventions are advised to manage these conditions effectively. In addition, cardiac abnormalities, including aortic dissections, require regular monitoring and early surgical intervention if certain criteria are met. CONCLUSIONS: The TRAMITI consensus statement provides valuable insights and evidence-based recommendations to guide healthcare practitioners in delivering comprehensive and patient-centered care for patients with TS. By addressing the complex medical and psychosocial aspects of the condition, this consensus aims to enhance TS management and improve the overall well-being and long-term outcomes of these individuals.

The TRansition Age Management in Turner syndrome in Italy (TRAMITI) project aims to improve care for individuals with Turner Syndrome (TS) during their transition from pediatric to adult care. A team of 15 physicians and 1 psychologist collaborated to create a comprehensive set of 41 consensus statements, covering four key areas: transition and referral, sexual and bone health and oncological risks, social and psychological aspects and systemic and metabolic disorders. The consensus statements highlight the importance of patient-centered care, early intervention and long-term monitoring. They emphasize a multidisciplinary approach to address the complex medical and psychosocial aspects of TS. During the critical transition period, tailored approaches and early disclosure of the diagnosis are recommended to promote self-reliance and healthcare autonomy. To mitigate long-term complications, the consensus addresses fertility preservation and bone health strategies. It also recommends psychological or psychiatric evaluations to tackle the increased prevalence of anxiety and depression in patients with TS. In addition, strategies for addressing the heightened risk of metabolic, cardiovascular and autoimmune disorders in patients with TS are proposed. Regular screenings and interventions are advised to effectively manage these conditions. Furthermore, cardiac abnormalities, including aortic dissections, require close monitoring and early surgical intervention if specific criteria are met. Overall, the TRAMITI consensus statement provides valuable insights and evidence-based recommendations. It offers guidance for healthcare practitioners in delivering comprehensive and patient-centered care for individuals with TS. By addressing both medical and psychosocial aspects, the consensus aims to enhance TS management and improve the well-being and long-term outcomes of those affected by this genetic disorder.

MKRN3 circulating levels in girls with central precocious puberty caused by MKRN3 gene mutations.

PURPOSE: MKNR3 is a paternally expressed gene whose mutations are the main cause of central precocious puberty (CPP). Protein circulating levels can be easily measured, as demonstrated in idiopathic CPP and healthy controls. No data are available for patients harboring an MKRN3 mutation. Our aim was to perform MKRN3 mutation screening and to investigate if circulating protein levels could be a screening tool to identify MKRN3 mutation in CPP patients. METHODS: We enrolled 140 CPP girls and performed MKRN3 mutation analysis. Patients were stratified into two groups: idiopathic CPP (iCPP) and MKRN3 mutation-related CPP (MKRN3-CPP). Clinical characteristics were collected. Serum MKRN3 values were measured by a commercially available ELISA assay kit in MKRN3-CPP and a subgroup of 15 iCPP patients. RESULTS: We identified 5 patients with MKRN3 mutations: one was a novel mutation (p.Gln352Arg) while the others were previously reported (p.Arg328Cys, p.Arg345Cys, p.Pro160Cysfs*14, p.Cys410Ter). There was a significant difference in circulating MKRN3 values in MKRN3-CPP compared to iCPP (p < 0.001). In MKRN3-CPP, the subject harboring Pro160Cysfs*14 presented undetectable levels. Subjects carrying the missense mutations p.Arg328Cys and p.Gln352Arg showed divergent circulating protein levels, respectively 40.56 pg/mL and undetectable. The patient with the non-sense mutation reported low but measurable MKRN3 levels (12.72 pg/mL). CONCLUSIONS: MKRN3 defect in patients with CPP cannot be predicted by MKRN3 circulating levels, although those patients presented lower protein levels than iCPP. Due to the great inter-individual variability of the assay and the lack of reference values, no precise cut-off can be identified to suspect MKRN3 defect.

High levels of LIGHT/TNFSF14 in patients with Prader-Willi syndrome.

PURPOSE/METHODS: Prader-Willi syndrome (PWS) is a rare genetic disorder displaying different clinical features, including obesity and bone impairment. LIGHT/TNFSF14 is a cytokine produced by immune cells affecting both fat and bone metabolism. The present study aimed to evaluate LIGHT serum levels in 28 children and 52 adult PWS patients compared to age and sex-matched controls, as well as correlations with parameters of bone and fat metabolism. RESULTS: Median serum LIGHT levels were significantly increased in pediatric PWS with respect to controls [255.82 (284.43) pg/ml vs 168.11 (76.23) pg/ml, p ≤ 0.02] as well as in adult PWS compared to controls [296.85 (895.95) pg/ml vs 134.18 (141.18) pg/ml, p ≤ 0.001]. In pediatric PWS, LIGHT levels were positively correlated with weight-SDS, height-SDS, and glucose levels, and negatively with total 25 (OH) vitamin D, cholesterol, LDL cholesterol and triglycerides. Additionally, LIGHT levels were negatively correlated with total BMD and fat mass. In adult PWS, LIGHT levels were positively correlated with weight, HDL cholesterol and PTH, and negatively with glucose, insulin, HOMA-IR, total cholesterol, LDL cholesterol, triglycerides, calcium, phosphorus, 25(OH)Vitamin D as well as with instrumental parameters of bone and fat quality. Consistently, multiple regression analysis showed that LIGHT serum levels in pediatric and adult PWS were predicted by different parameters including 25 (OH) Vitamin D as well as DXA parameters of bone and fat quality. CONCLUSIONS: In PWS children and adults the high levels of LIGHT could represent a marker of the altered bone and fat metabolism.

Multicentric Italian case-control study on 25OH vitamin D levels in children and adolescents with Prader-Willi syndrome.

PURPOSE: 25OHD levels in patients with Prader-Willi Syndrome (PWS), the most frequent cause of genetic obesity with a peculiar fat mass distribution, are still debated. Insulin resistance (IR), Body Mass Index-SDS (BMI-SDS), Growth Hormone Therapy (GHT), and puberty onset seem to interact with 25OHD levels. The objectives of the study are: (1) To analyze 25OHD levels in pediatric PWS patients in comparison with a control group (CNT) (2) To evaluate a possible correlation between BMI-SDS, HOMA-IR, puberty, GHT, and 25OHD levels. METHODS: This is a retrospective case-control, multicenter study. Data were collected among 8 different Italian Hospitals (outpatient clinics), over a period of four years (2016-2020). We included 192 genetically confirmed PWS and 192 CNT patients, aged 3-18 years, matched 1:1 for age, gender, BMI-SDS, Tanner stage, sun exposure, and month of recruitment. RESULTS: No statistically significant differences in 25OHD levels were observed between the PWS population and the CNT (PWS 24.0 ng/mL vs CNT 22.5 ng/mL, p > 0.05), OR = 0.89 (95% CI 0.58-1.35). We observed a slight, although non-significant, reduction in 25OHD levels comparing NW and OB populations. HOMA-IR, puberty onset, genotype and GHT (previous or ongoing) did not show statistically significant correlation with 25OHD levels. CONCLUSIONS: Our findings could be useful for clinicians to optimize the therapeutic management as well as to increase awareness of PWS.

A new DLK1 defect in a family with idiopathic central precocious puberty: elucidation of the male phenotype.

PURPOSE: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. METHODS: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. RESULTS: A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8 years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. CONCLUSION: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.

Phenotypes of prediabetes and metabolic risk in Caucasian youths with overweight or obesity.

PURPOSE: To assess the prevalence of pre-diabetes phenotypes, i.e., impaired fasting glucose (IFG), impaired glucose tolerance (IGT), increased HbA1c (IA1c), and their association with metabolic profile and atherogenic lipid profile in youths with overweight/obesity (OW/OB). METHODS: This cross-sectional study analyzed data of 1549 youths (5-18 years) with OW/OB followed in nine Italian centers between 2016 and 2020. Fasting and post-load measurements of glucose, insulin, and HbA1c were available. Insulin resistance (IR) was estimated by HOMA-IR and insulin sensitivity (IS) by reciprocal of fasting insulin. The atherogenic lipid profile was assessed by triglycerides-to-HDL ratio or cholesterol-to-HDL ratio. Insulinogenic index was available in 939 youths, in whom the disposition index was calculated. RESULTS: The prevalence of overall pre-diabetes, IFG, IGT and IA1c was 27.6%, 10.2%, 8% and 16.3%, respectively. Analyzing each isolated phenotype, IGT exhibited two- to three-fold higher odds ratio of family history of diabetes, and worse metabolic and atherogenic lipid profile vs normoglycemic youths; IFG was associated only with IR, while IA1c showed a metabolic and atherogenic lipid profile intermediate between IGT and IFG. CONCLUSION: Prevalence of pre-diabetes was high and IA1c was the most prevalent phenotype in Italian youths with OW/OB. The IGT phenotype showed the worst metabolic and atherogenic lipid profile, followed by IA1c. More studies are needed to assess whether HbA1c may help improving the prediction of diabetes.

Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome.

PURPOSE: Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS: Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS: bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION: TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.

The genetic background and vitamin D supplementation can affect irisin levels in Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is associated to distinctive clinical symptoms, including obesity, cognitive and behavioral disorders, and bone impairment. Irisin is a myokine that acts on several target organs including brain adipose tissue and bone. The present study was finalized to explore circulating levels of irisin in children and adult PWS patients. METHODS: Seventy-eight subjects with PWS, 26 children (15 females, mean age 9.48 ± 3.6 years) and 52 adults (30 females, mean age 30.6 ± 10.7) were enrolled. Irisin serum levels were measured in patients and controls. Its levels were related with anthropometric and metabolic parameters, cognitive performance and bone mineral density either in pediatric or adult PWS. Multiple regression analysis was also performed. RESULTS: Irisin serum levels in PWS patients did not show different compared with controls. A more in-depth analysis showed that both pediatric and adult PWS with DEL15 displayed significantly reduced irisin levels compared to controls. Otherwise, no differences in irisin concentration were found in UPD15 patients with respect to controls. Our study revealed that in pediatric PWS the 25(OH) vitamin-D levels affected irisin serum concentration. Indeed, patients who were not supplemented with vitamin D showed lower irisin levels than controls and patients performing the supplementation. Multiple regression analysis showed that irisin levels in pediatric and adult PWS were predicted by the genetic background and 25(OH)-vitamin D levels, whereas in a group of 29 adult PWS also by intelligent quotient. CONCLUSION: We demonstrated the possible role of genetic background and vitamin-D supplementation on irisin serum levels in PWS patients.

Polyphenols and obesity prevention: critical insights on molecular regulation, bioavailability and dose in preclinical and clinical settings.

Obesity represents one of the most important public health challenges of the 21st century and is characterized by a multifactorial etiology in which environmental, behavioral, metabolic, and genetic factors work together. Despite the rapid increase in prevalence of obesity in the last decades, especially in children, it remains a preventable disease. To battle obesity a multisector approach promoting healthier lifestyle in terms of physical activity and nutrition is needed. Specifically, biologically active dietary compounds, as polyphenols, are able to modulate the expression of genes involved in the development and progression of obesity and its comorbidities as demonstrated by multiple studies using different obesity models. However, human studies focusing on the transcriptomic modulation by polyphenols in obese patients are still limited and do not often recapitulate the results obtained in preclinical setting likely due to the underestimation of some variables such as bioavailability, dose and form (native vs. metabolized) of polyphenols used. The aim of this review is to summarize the state-of-art of nutrigenomic in vitro, in vivo and ex vivo studies as well as clinical trials based on dietary polyphenols to fight obesity. We also critical discuss the variables to be considered to fill the gap between preclinical and clinical settings.

17ß-hydroxysteroid dehydrogenase type 3 deficiency: female sex assignment and follow-up.

BACKGROUND: Deficiency of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is a rare autosomal recessive 46,XY disorder of sex development (DSD). It is due to pathogenetic variants in the HSD17B3 gene. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Δ4-androstenedione (Δ4-A) to testosterone (T) in the fetal testis. Affected individuals are usually raised as females and diagnosis is made at puberty, when they show virilization. METHODS: A girl with a presumptive diagnosis of complete androgen insensitivity syndrome underwent endocrine and genetic assessment. Long-term follow-up was reported. RESULTS: The diagnosis of 17ß-HSD3 deficiency was made (stimulated T/Δ4-A ratio: 0.15; HSD17B3 gene analysis: c.277+4A>T in intron 3/c.640_645del (p.Glu214_Glu215del) in exon 9. After extensive information, parents decided to maintain female sex. Gonadal removal was performed and histological evaluation demonstrated deep fibrosis of testicular tissue. Follow-up till 8.5 years of age showed somatic and neuro-psychological development fitting with the female sex. CONCLUSIONS: Management of a child with the rare 17ß-HSD3 deficiency remains challenging. Any decision must be carefully evaluated with parents. Long-term follow-up must be warranted by a multidisciplinary DSD team to evaluate the adequacy of the choices made on quality of life in later life.

Pilot study on circulating miRNA signature in children with obesity born small for gestational age and appropriate for gestational age.

BACKGROUND: Children born small for gestational age (SGA) are at increased risk of metabolic dysfunction. Dysregulation of specific microRNAs (miRNAs) contributes to aberrant gene expression patterns underlying metabolic dysfunction. OBJECTIVE: We aimed to determine and compare circulating miRNA (c-miRNA) profile of SGA and appropriate for gestational age (AGA) children with obesity and with normal weight, in order to identify biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity. METHODS: Small non-coding RNAs from serum of 15 SGA children with obesity (OB-SGA), 10 SGA children with normal weight (NW-SGA), 17 AGA children with obesity (OB-AGA) and 12 AGA children with normal weight (NW-AGA) (mean age 11.2 ± 2.6) have been extracted and sequenced in order to detect and quantify miRNA expression profiles. RESULTS: RNA-seq analyses showed 28 miRNAs dysregulated in OB-SGA vs. NW-SGA and 19 miRNAs dysregulated in OB-AGA vs. NW-AGA. Among these, miR-92a-3p, miR-122-5p, miR-423-5p, miR-484, miR-486-3p and miR-532-5p were up regulated, and miR-181b-5p was down regulated in both OB-SGA and OB-AGA compared with normal weight counterparts. Pathway analysis and miRNA target prediction suggested that these miRNAs were particularly involved in insulin signalling, glucose transport, insulin resistance, cholesterol and lipid metabolism. CONCLUSION: We identified a specific profile of c-miRNAs in SGA and AGA children with obesity compared with SGA and AGA children with normal weight. These c-miRNAs could represent specific biomarkers for early detection of increased risk of developing metabolic dysfunction in SGA and AGA children with obesity.

Analysis of Circulating Mediators of Bone Remodeling in Prader-Willi Syndrome.

We tested the hypothesis that the levels of bone remodeling mediators may be altered in Prader-Willi syndrome (PWS). We assessed RANKL, OPG, sclerostin, DKK-1 serum levels, and bone metabolism markers in 12 PWS children (7.8 ± 4.3 years), 14 PWS adults (29.5 ± 7.2 years), and 31 healthy controls matched for sex and age. Instrumental parameters of bone mineral density (BMD) were also evaluated. Lumbar spine BMD Z-scores were reduced in PWS children (P < 0.01), reaching osteopenic levels in PWS adults. PWS patients showed lower 25(OH)-vitamin D serum levels than controls (P < 0.001). Osteocalcin was increased in PWS children but reduced in adults respect to controls (P < 0.005 and P < 0.01, respectively). RANKL levels were higher in both pediatric and PWS adults than controls (P < 0.004), while OPG levels were significantly reduced (P < 0.004 and P < 0.006, respectively). Sclerostin levels were increased in children (P < 0.04) but reduced in adults compared to controls (P < 0.01). DKK-1 levels did not show significant difference between patients and controls. In PWS patients, RANKL, OPG, and sclerostin significantly correlated with metabolic and bone instrumental parameters. Consistently, with adjustment for age, multiple linear regression analysis showed that BMD and osteocalcin were the most important predictors for RANKL, OPG, and sclerostin in children, and GH and sex steroid replacement treatment in PWS adults. We demonstrated the involvement of RANKL, OPG, and sclerostin in the altered bone turnover of PWS subjects suggesting these molecules as markers of bone disease and new potential pharmacological targets to improve bone health in PWS.

Growth hormone treatment improves final height and nutritional status of children with chronic kidney disease and growth deceleration.

PURPOSE: Growth retardation is a common complication of chronic kidney disease (CKD) in children. Treatment with recombinant human growth hormone (rhGH) has been used to help short children with CKD to attain a height more in keeping with their age group, but the scientific evidence regarding the effect of rhGH on final height is scarce. METHODS: Final heights of children with CKD receiving rhGH treatment (cases) were compared with final heights of a matched cohort of children with CKD that did not receive rhGH therapy (controls). RESULTS: Sixty-eight rhGH-treated cases (44 boys) were compared with 92 untreated controls (60 boys). Mean duration of rhGH therapy was 4.2 ± 0.9 years; rhGH dose was 0.3 ± 0.07 mg/kg/week. Height SDS at baseline was lower in rhGH-treated patients than in controls (-2.00 ± 1.02 versus -0.96 ± 1.11, p < 0.001). Baseline height SDS was significantly lower than target height SDS in both groups. Height SDS significantly improved from baseline to final height attainment in rhGH-treated patients, while it slightly decreased in controls (mean SDS variation 0.69 ± 1.05 in rhGH-treated cases versus -0.15 ± 1.2 in controls). Final height SDS was -1.25 ± 1.06 in rhGH-treated cases and -1.06 ± 1.17 in controls (p = 0.29). Target adjusted final height SDS was -0.91 ± 1.03 in rhGH-treated cases and -0.61 ± 1.17 in controls (p = 0.1). CONCLUSIONS: Long-term rhGH therapy is able to reduce the linear growth deceleration of children with CKD, and ultimately to improve their final height, reducing the difference with target height.

Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α.

UNLABELLED: In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI. INTRODUCTION: Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate. METHODS: Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls. RESULTS: DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients. CONCLUSIONS: Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects with OI untreated and treated with bisphosphonates. These cytokines could represent new pharmacological targets for OI patients.

Evaluation of impact of steroid replacement treatment on bone health in children with 21-hydroxylase deficiency.

There are conflicting data regarding the potential impact of chronic glucocorticoid (GC) therapy on the bone mineral density of patients with congenital adrenal hyperplasia (CAH). Previous studies performed by dual-energy X-ray absorptiometry reported conflicting results. The purpose of this study was to assess the impact of chronic GC replacement treatment in children with classical and non classical CAH due to 21-hydroxylase deficiency (21-OHD) by quantitative ultrasonometry (QUS), an easy, cheap, and radiation-free technique. The study population consisted of nineteen 21-OHD patients (nine males) on lifelong GC treatment. Anthropometric, hormonal, and treatment data were recorded for each patient, and bone quality was assessed by QUS measurements. QUS findings (amplitude-dependent speed of sound and bone transmission time) were normal in 21-OHD patients and did not correlate with duration of treatment, daily, total, and yearly hydrocortisone dose. Furthermore, no significant correlation was found between QUS findings and 17α-hydroxy progesterone, Δ4-androstenedione, and testosterone levels. In conclusion, our results provide reassurance that currently used replacement doses of GC do not have a major impact on bone in patients with CAH. QUS seems to be a reliable tool for screening of bone health in children with 21-OHD.

Regulation of IGFBP3 gene expression in short children born small for gestational age.

OBJECTIVE: Approximately 6% of newborns at term are small for gestational age (SGA) and present a birth weight and/or length less than -2SD from the mean. SGA infants are at increased risk for perinatal morbidity, associated psychological and/or mental problems, persistent short stature (about 15% of subjects) and metabolic alterations. Insulin-like growth factors (IGFs), their common receptor (IGF1R) and their binding proteins (IGFBPs) play a critical role in fetal and postnatal growth. In these genes common polymorphisms, such as single nucleotide polymorphisms and variable number of tandem repeats, have been investigated with conflicting results with respect to SGA-related outcomes, and the functional role of these gene variants remains to be elucidated. DESIGN: The study group consisted of 100 pre-pubertal short children born SGA and 94 healthy controls, matched for sex and age, recruited at the Department of Biomedicine of Development Age of the Bari University and at the Paediatric Department of the Messina Hospital. In the present study we analyzed the allelic frequency of the polymorphisms -795 G/A, -667 G/A, -396 C/T in the IGFBP3 in SGA children and their influence on the basal and insulin-stimulated transcriptional activity of the gene. RESULTS: We found that the polymorphisms -667 G/A and -396 C/T in the IGFBP3 promoter region are capable of having an effect on the transcriptional activity of the gene, although with opposing effects. Interestingly, the -667 G/A polymorphism has a negative impact on the IGFBP3 transcription, while the -396 C/T polymorphism determines an increase of the transcriptional activity of the IGFBP3 gene promoter. Interestingly, we found that the -396 C/T polymorphism correlates with lower birth length in SGA children. Most importantly, while the diminished IGFBP3 transcriptional activity induced by the -667A polymorphism was significantly recovered after insulin administration (p-value<0.05), the increased transcriptional activity caused by the -396T polymorphism was not restored to baseline levels by insulin. CONCLUSIONS: Altogether our results demonstrated that the -667 G/A and the -396 C/T polymorphisms in IGFBP3 promoter region influence the basal transcriptional activity of the gene.

Thyroid function and thyroid autoimmunity in childhood acute lymphoblastic leukemia off-therapy patients treated only with chemotherapy.

OBJECTIVE: Scanty data are available about the thyroid function in childhood acute lymphoblastic leukemia (ALL) off-therapy patients treated only with chemotherapy. We aimed to assess the prevalence of thyroid autoimmunity and thyroid dysfunction in such patients. DESIGN: Case-control cross-sectional study. METHODS: Eighty-four patients diagnosed with ALL and treated only with chemotherapy. Mean age at diagnosis 5.9+/-3.6 yr, at recruitment 12.1+/-4.3 yr. The treatment had been stopped 4.3+/-3.2 yr before recruitment. A control group of 60 subjects was recruited. Free T4, TSH, anti-thyroperoxidase, and anti-thyroglobulin antibodies were measured. RESULTS: Anti-thyroglobulin and anti-thyroperoxidase antibodies were negative in all patients. TSH was increased in 7 patients (8.3%) and 3 controls (5.0%). Free T4 was within the normal limits in all patients and controls.Mean TSH and free T4 levels did not statistically differ between controls and ALL offtherapy patients. TSH was negatively correlated with the age at the diagnosis (p=0.01) and the age at the end of therapy (p=0.008). Anti-thyroglobulin and/or anti-thyroperoxidase antibodies were detected in 3 controls (5%; vs study group: p=0.038), 1 of them with increased TSH. CONCLUSIONS: Some patients present hyperthyrotropinemia, without anti-thyroid antibodies, with a prevalence comparable to the control group. The thyroid gland seems more prone to be damaged by chemotherapy at a younger age. We think that a thyroid follow- up in ALL off-therapy patients may be advisable and should be differentiated on the basis of the age at the end of treatment, with more frequent tests for younger patients.

17beta-Hydroxysteroid dehydrogenase-3 deficiency: from pregnancy to adolescence.

OBJECTIVE: Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17beta-hydroxysteroid-dehydrogenase type 3 (17beta-HSD3) deficiency in Italy. SETTING: Pediatric Endocrine Departments, University Hospitals. PATIENTS: The cases of 5 Italian subjects affected by 17beta-HSD3 deficiency are presented in this study. INTERVENTIONS: Laboratory and genetic assessment. Gonadectomy and female sex assignment (4 patients) or GnRH analog therapy to regress puberty and gender identity disorder (1 patient). RESULTS: Presentation lasted from pregnancy (pre-natal diagnosis of a 46,XY fetus with female external genitalia) to infancy (inguinal hernia containing testes/clitoromegaly) and adolescence (virilisation). All subjects but one (subject 1, Central-Northern Italy) were from small areas of Southern Italy. Endocrine data (baseline and/or stimulated testosterone/ Delta4-androstenedione ratio) were informative. Two girls were homozygous for 17beta-HSD3 gene mutations (G289S/G289S; R80W/R80W), while the others were compound heterozygous (IVS325+4 A>T/A203V; L212Q/M235V; R80W/A235E). Four patients were confirmed as females and were well-adjusted with assigned sex; gender identity disorder improved during treatment with GnRH analog in the last subject. CONCLUSIONS: 17betaHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/Delta4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCGstimulation is mandatory in pre-puberty. Molecular analysis of 17beta-HSD3 gene should be performed to confirm the diagnosis. Temporary GnRH analog treatment may regress gender identity disorder and provide time to confirm or change the birth sex assignment. Female individuals seems to be compliant with their sex, providing that virilisation does not occur. In Italy, the disorder seems to be more prevalent in the Southern regions and shows genetic heterogeneity.

Effects of moderate-severe exercise on blood glucose in Type 1 diabetic adolescents treated with insulin pump or glargine insulin.

BACKGROUND: Few papers focus on exercise-related blood glucose (BG) in patients on continuous sc insulin infusion (CSII) or multiple daily injections (MDI) with glargine. AIM: The main objective was to evaluate the degree of glycemic control in Type 1 diabetes mellitus adolescents on CSII doing physical activity with pump switched on or off. These findings were also compared with a small group of patients on MDI with glargine. SUBJECTS AND METHODS: Eight patients on CSII (basal rate continued or turned off in alternating sessions) and 5 on MDI joined 4 sessions of moderate-severe exercise. RESULTS: Post-exercise BG significantly increased with the pump off and was unchanged/decreased with the pump on and MDI groups vs baseline. The hypoglycemia rate was not different among the 3 groups at any time. Pump on: hypoglycemias more frequent both at bedtime (p=0.031) and at awakening (p<0.001) than before dinner and at awakening than at bed-time (p=0.044). Pump off: hypoglycemias more frequent both at bed-time (p=0.010) and at awakening (p=0.031) than before dinner. MDI: no differences. CONCLUSIONS: Glargine is safe and reducing the pre-lunch insulin is unnecessary. Subjects on insulin pump should not stop the basal rate. If they stop the pump, some actions are advisable: pre-exercise insulin bolus, pre-sleeping snack rich in carbohydrates, slight reduction of the overnight basal rate. On the other hand, if the basal rate is unmodified, the ingestion of sugary drinks during the exercise, the reduction of the overnight basal rate, a reduction of the pre-dinner insulin bolus and/or a pre-sleeping snack should be considered.

Clinical, endocrine, and molecular findings in 17beta-hydroxysteroid dehydrogenase type 3 deficiency.

The 17beta-hydroxysteroid dehydrogenases (17betaHSD) gene family comprises different enzymes involved in the biosynthesis of active steroid hormones. The 17betaHSD type 3 (17betaHSD3) isoenzyme catalyzes the reductive conversion of the inactive C19-steroid, Delta4-androstenedione (Delta4- A), into the biologically active androgen, testosterone (T), in the Leydig cells of the testis. It is encoded by the 17beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) gene, which maps to chromosome 9q22. Mutations in the HSD17B3 gene are associated with a rare form of 46,XY disorder of sex development referred to as 17betaHSD3 deficiency (or as 17-ketosteroid reductase deficiency), due to impaired testicular conversion of Delta4-A into T. 46,XY patients with 17betaHSD3 deficiency are usually classified as female at birth, raised as such, but develop secondary male features at puberty. Diagnosis, and consequently early treatment, is difficult because clinical signs from birth until puberty may be mild or absent. Biochemical diagnosis of 17betaHSD3 deficiency requires measurement of serum T/Delta4-A ratio after hCG stimulation test in pre-pubertal subjects, while baseline values seem to be informative in early infancy and adolescence. However, low basal T/Delta4-A ratio is not specific for 17betaHSD3 deficiency, being sometimes also found in patients with other defects in T synthesis or with Leydig cells hypoplasia. Mutational analysis of the 17HSDB3 gene is useful in confirming the clinical diagnosis of 17betaHSD3 deficiency. This review describes clinical findings, diagnosis, and molecular basis of this rare disease.