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.

The effect of obesity-related allostatic changes on cardio-metabolic risk in euthyroid children.

PURPOSE: The hormonal thyroid changes related to obesity, even when in the euthyroid state, may contribute to the unfavorable cardio-metabolic profile of obese patients. In this retrospective study, we aim to investigate the biochemical thyroid changes and the association between serum TSH, FT4, FT3 and cardio-metabolic risk factors in euthyroid obese youths. METHODS: Four hundred ninety-one Caucasian euthyroid obese children and adolescents aged 9.93 ± 2.90 years were recruited. Each patient underwent clinical and auxological examination and laboratory workup including an OGTT and the measurement of thyroid function and lipid profile. Homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride to high-density lipoprotein cholesterol ratio, total cholesterol to HDL ratio, atherogenic index of plasma, insulinogenic index, area under the glucose and insulin curves were calculated. RESULTS: We found that TSH was positively correlated with BMI-SDS values and significantly associated with hypercholesterolemia and hyperinsulinemia; FT4 resulted negatively correlated with BMI-SDS; FT3 was positively correlated with BMI-SDS and the area under the curve of insulin and negatively correlated with HDL. FT3 and FT4 resulted significantly associated with severe obesity. In addition, children with high-normal TSH values showed higher triglyceride to high-density lipoprotein cholesterol ratio values than those with normal TSH levels. CONCLUSIONS: Our data showed that thyroid hormones could influence obesity, lipid and glycemic parameters in euthyroid youths. These findings could carry implications regarding optimal TSH levels in obese children and confirm the importance of evaluating the thyroid function as possible adjunctive cardio-metabolic risk factor related to obesity.

Safety and effectiveness of a somatropin biosimilar in children requiring growth hormone treatment: second analysis of the PATRO Children study Italian cohort.

PURPOSE: To investigate the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the somatropin biosimilar Omnitrope®. METHODS: PATRO Children is an ongoing, multicenter, observational, post-marketing surveillance study. Children who received Omnitrope® for any indication were included. Adverse events (AEs) were evaluated in all study participants. Auxological data, including height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS), were used to assess effectiveness. In this snapshot analysis, data from the Italian subpopulation up to August 2017 were reported. RESULTS: A total of 291 patients (mean age 10.0 years, 56.0% male) were enrolled at 19 sites in Italy. The mean duration of Omnitrope® treatment was 33.1 ± 21.7 months. There were 48 AEs with a suspected relationship to the study drug (as reported by the investigator) that occurred in 35 (12.0%) patients, most commonly headache, pyrexia, arthralgia, insulin-like growth factor above normal range, abdominal pain, pain in extremity and acute gastroenteritis. There were no confirmed cases of type 1 or type 2 diabetes; however, two patients (0.7%) had impaired glucose tolerance that was considered Omnitrope® related. The mean HSDS increased from - 2.41 ± 0.73 at baseline (n = 238) to - 0.91 ± 0.68 at 6.5 years (n = 10). The mean HVSDS increased from - 1.77 ± 1.38 at baseline (n = 136) to 0.96 ± 1.13 at 6.5 years (n = 10). CONCLUSIONS: In this sub-analysis of PATRO Children, Omnitrope® appeared to have acceptable safety and effectiveness in the treatment of in Italian children, which was consistent with the earlier findings from controlled clinical trials.

Subclinical hypothyroidism in children: is it always subclinical?

Aim of this commentary is to report current knowledges on the main clinical and metabolic abnormalities which might be observed in children with longstanding and untreated subclinical hypothyroidism (SH) and to comment the most recent views about natural evolution of thyroid function in the cases with either idiopathic or Hashimoto's thyroiditis-related SH. On the basis of these preliminary remarks, the essential guidelines for an appropriate and tailored management of SH children are also proposed.

Phenotypical and genotypical expression of Wolfram syndrome in 12 patients from a Sicilian district where this syndrome might not be so infrequent as generally expected.

BACKGROUND: Since the original description, there have been only few epidemiological studies of Wolfram syndrome (WS). AIM: Aims of the present paper are to ascertain WS prevalence and expression in a district of North-eastern Sicily, i.e. a geographic area where consanguineous unions are not very unusual. MATERIALS AND METHODS: Prevalence rates of WS in the Messina district were calculated by taking into consideration both the total population (653,737) and the populations included within the 0-30 year age range (202,681). We estimated the relative prevalence of WS among patients with youth-onset insulin-dependent diabetes mellitus (DM) who are currently aged under 30 years (256). RESULTS: Global WS prevalence in our district is 1:54,478, whereas prevalence among individuals under 30 is 1:16,890 and relative prevalence among patients with juvenile-onset insulin-dependent DM is 1:22.3. When compared with the patients with insulin-dependent DM of Messina district, WS patients did not exhibit significant differences in terms of biochemical features at DM onset, whereas age at DM diagnosis was significantly earlier in WS group. CONCLUSIONS: (a) WS prevalence is not so infrequent as generally expected; (b) in our series, DM presented before 10 years in 11/12 patients and ten cases have already developed all the four peculiar manifestations of WS by 26 years; (c) 9/12 patients exhibited a homozygous frameshift/truncation mutation (Y454_L459del_fsX454), which is the one most frequently found also in patients from other Italian regions; (d) age at DM diagnosis was significantly earlier in WS group than in the patients with insulin-dependent DM of Messina district.

Subclinical hyperthyroidism when presenting as initial manifestation of juvenile Hashimoto's thyroiditis: first report on its natural history.

BACKGROUND: Due to the lack of specific pediatric studies, no data are available about natural history of endogenous subclinical hyperthyroidism (SH) in childhood. AIMS: (a) To investigate for the first time the natural history of SH [suppressed thyrotropin (TSH) and normal free thyroxine free thyroxine (FT4) levels] when presenting as initial manifestation of Hashimoto's thyroiditis (HT) in childhood (group A); (b) to compare spontaneous evolution of HT-related SH with that observed in age-matched patients with HT-related frank hyperthyroidism (suppressed TSH and elevated FT4 levels), i.e., Hashitoxicosis Htx (group B). RESULTS: In the 11 patients of group A, TSH normalization spontaneously occurred 1-24 months after diagnosis, while in the 10 patients of group B it occurred 3-9 months after diagnosis, with no differences between the 2 groups in terms of time interval from entry to TSH normalization. In group A, this time interval was related to baseline thyroid peroxidase antibodies (r=0.78, p = 0.04). During follow-up, eight patients of each group remained euthyroid, whereas two became hypothyroid (in both groups) and one developed Graves' disease (in group A). CONCLUSION: (a) HT should be included among the causes of endogenous SH in pediatric age; (b) in children with HT-related SH, spontaneous normalization of TSH levels occurs within the first 24 months after diagnosis, as well as in age-matched patients with Htx; (c) in both these conditions, a further deterioration of thyroid function might re-present in some patients during follow-up; (d) Ht-related SH and Htx might be possibly seen as different biochemical stages along the same continuum.

Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood-brain barrier disruption: implications for the pathogenesis of multiple sclerosis.

AIM: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized by demyelination of white matter, loss of myelin forming oligodendrocytes, changes in the blood-brain barrier (BBB) and leucocyte infiltration. Myelin basic protein (MBP) is a component of the myelin sheath. Degradation of myelin is believed to be an important step that leads to MS pathology. Transmigration of leucocytes across the vasculature, and a compromised BBB participate in the neuroinflammation of MS. We examined the expression and regulation of the chemokine (C-C motif) ligand 2 (CCL2) and the cytokine interleukin-6 (IL-6) in human endothelial cells (EC), a component of the BBB, after treatment with MBP. METHODS: EC were treated with full-length MBP. CCL2 and IL-6 protein were determined by ELISA. Western blot analysis was used to determine signalling pathways. A BBB model was treated with MBP and permeability was assayed using albumin conjugated to Evan's blue dye. The levels of the tight junction proteins occludin and claudin-1, and matrix metalloprotease (MMP)-2 were assayed by Western blot. RESULTS: MBP significantly induced CCL2 and IL-6 protein from EC. This induction was partially mediated by the p38 MAPK pathway as there was phosphorylation after MBP treatment. MBP treatment of a BBB model caused an increase in permeability that correlated with a decrease in occludin and claudin-1, and an induction of MMP2. CONCLUSION: These data demonstrate that MBP induces chemotactic and inflammatory mediators. MBP also alters BBB permeability and tight junction expression, indicating additional factors that may contribute to the BBB breakdown characteristic of MS.

Increased large artery intima media thickness in adolescents with either classical or non-classical congenital adrenal hyperplasia.

BACKGROUND: Increased artery intima-media thickness (IMT) was found in adults with classical congenital adrenal hyperplasia (CAH). No data are available in patients with non-classical (NC) CAH. AIMS: To evaluate IMT in adolescents with classical and NC CAH and to compare the results with those recorded in a control population. PATIENTS AND METHODS: Eighteen adolescents with either classical (Subgroup A1) or NC CAH (Subgroup A2) were compared with 16 controls (Group B). All subjects underwent IMT ultrasonography measurement at different sites; results were correlated with clinical, metabolic, and insulin resistance (IR) data. RESULTS: When compared with Group B, both subgroups exhibited higher IMT values at all sites. No differences were found between classical and NC CAH. Univariate analysis of factors impacting on IMT of CAH patients demonstrated that: a) abdominal aorta (AA) IMT was positively correlated with cumulative glucocorticoid doses, triglyceride serum levels, and diastolic blood pressure SD score and negatively with androstenendione and ACTH levels; b) common carotid (CC) IMT was positively associated with triglycerides and triglyceride/HDL ratio. At multiple regression analysis, the independent positive predictors of AA and CC IMT were respectively triglyceride levels and triglyceride/HDL ratio. CONCLUSIONS: a) Even adolescents with NC CAH and not only those with classical form may be at higher risk of artery alterations; b) this risk is not necessarily associated with either obesity or waist/height ratio or dyslipidemia; c) an important role in the pathogenesis of artery alterations in CAH may be played by intermittent iatrogenic hypercortisolism and secondary IR.

Prevalence, presentation and clinical evolution of Graves' disease in children and adolescents with type 1 diabetes mellitus.

AIMS: To ascertain the prevalence of Graves' disease (GD) in 1,323 Caucasian children with type 1 diabetes mellitus (T1DM), and to compare the course of GD in T1DM patients with the one observed in 109 Caucasian peer patients with GD but without T1DM (group B). RESULTS: Only 7 patients (0.53%) of the T1DM series also presented with GD (group A)which was diagnosed many years after diabetes presentation. At GD diagnosis, the prevalence of preclinical hyperthyroidism was higher in group A (p = 0.0001), whereas serum TSH receptor antibodies (TRABs) were higher in group B (p = 0.04). The subsequent course with methimazole therapy and after its withdrawal was very similar in both groups. CONCLUSIONS: GD prevalence in T1DM patients was 0.53%, i.e. almost identical to the one reported in the general population. GD was diagnosed many years after T1DM presentation. At GD diagnosis, the clinical picture was milder and TRAB serum levels were lower in diabetic patients. Preclinical diagnosis and early treatment of GD were not associated with better responsiveness to therapy. Screening programs based on periodical TRAB assessments are not useful in T1DM.

In the Italian population sexual dimorphism affects pre-natal thyroid migration but not biochemical severity of gland ectopia and pre-natal bone maturation.

UNLABELLED: The aim of the present study was to retrospectively re-evaluate a population of selected infants with congenital hypothyroidism (CH), in order to investigate whether sexual dimorphism affects: a) CH etiology; b) its biochemical severity at the time of screening and recall; c) patients' biochemical response to replacement treatment during the 1st yr of life; d) their bone maturation (BM) at birth; e) their psychomotor status at 1 yr. This retrospective study covers 192 infants (116 females) with persistent CH who were selected from a larger population of CH patients identified during a 10-yr period (1990-1999) by the screening programs of 5 northern, central, and southern regions of Italy. Thirty boys (39.5%) and 66 girls (56.9%) were found to have ectopia, whereas the remaining 46 boys and 50 girls exhibited the other causes of CH. When compared with the prevalence of the remaining causes that of ectopia was significantly higher in girls than in boys (66/116 vs 30/76; chi2=5.57, p<0.025), and sex ratio in ectopia was significantly different also compared with the orthotopic gland group only (66/84 vs 30/51; chi2=6.02, p<0.025). No differences between males and females were detected in the groups with either athyreosis or orthotopic gland. In no groups were there differences between sexes for gestational age, birth auxological data, percentage of newborns with bone retardation or developmental quotient at 1 yr. Thyroid tests at birth, age at TSH normalization and average thyroid tests under L-T4 treatment during the 1st yr did not differ between sexes in any of the groups. CONCLUSIONS: a) in the Italian population sexual dimorphism affects pre-natal thyroid migration but neither biochemical severity of ectopia, nor pre-natal bone maturation and psychomotor development; b) girls with CH do not require higher doses of initial therapy in order to achieve TSH normalization; c) future developmental and molecular studies on ectopia etiology in CH need to take into account the effect of sexual dimorphism.

Neurocognitive profile in Turner's syndrome is not affected by growth impairment.

Turner's syndrome (TS) is a chromosomal disorder that results from the loss of the entire or a part of the X-chromosome and occurs in 1/2,500 female births. According to the majority of specific reports, intelligence in TS is generally found to be normal and the prevalence of mental retardation does not seem to be increased in TS except for those patients with a small ring X-chromosome. We evaluated 33 girls with TS with chronological age from 6-18 years. Intellectual assessment included the WISC III and the WAIS-R scales. Our results showed: 1) mean full scale intelligence quotient (FSIQ) was significantly lower than expected based on normative data (p < 0.0005); 2) no correlation was present between height and general intellectual ability; 3) mean performance intelligence quotient (PIQ) was significantly lower than both mean verbal intelligence quotient (VIQ) and FSIQ (p < 0.0025 and p < 0.01, respectively), and most patients had a VIQ-PIQ discrepancy; 4) the frequency of mental retardation in our study group was significantly higher than that observed in the general population (15.1% vs 2.3%, p < 0.025); 5) a significant association was found between karyotype and VIQ, and the best score was achieved in the subgroup of patients with structural abnormalities of the X-chromosome. In the light of these findings we conclude that the clinical picture in TS may encompass a slightly reduced FSIQ, VIQ and especially an inadequate PIQ, but this neurocognitive profile is not significantly affected by statural impairment. Since these neurocognitive defects can be responsible for misdiagnosed school difficulties, we suggest that girls with TS should receive specialized educational support and multidisciplinary care.

NeuroAIDS: contributions of the human immunodeficiency virus-1 proteins Tat and gp120 as well as CD40 to microglial activation.

Microglia are the resident phagocytes of the brain and are an important source of proinflammatory mediators. Human immunodeficiency virus (HIV)-1 infects the central nervous system early in the course of disease, and it is believed that this occurs, in part, through the transmigration of HIV-1-infected cells across the blood-brain barrier. Infected cells release viral proteins, such as Tat and gp120. After microglia interact with these proteins, they become activated and secrete chemokines; up-regulate key surface receptors, such as CD40, and also activate resident cells. This review focuses on the consequences of microglial activation in NeuroAIDS, with an emphasis on chemokine production and CD40 up-regulation after interaction with tat or gp120. The importance of microglial CD40 in two other neurological diseases, Alzheimer's disease and multiple sclerosis, is also discussed.

MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis.

Acquired immunodeficiency syndrome (AIDS)-associated dementia is often characterized by chronic inflammation, with infected macrophage infiltration of the CNS resulting in the production of human immunodeficiency virus type 1 (HIV-1) products, including tat, and neurotoxins that contribute to neuronal loss. In addition to their established role in leukocyte recruitment and activation, we identified an additional role for chemokines in the CNS. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to protect mixed cultures of human neurons and astrocytes from tat or NMDA-induced apoptosis. Neuronal and astrocytic apoptosis in these cultures was significantly inhibited by co-treatment with MCP-1 or RANTES but not IP-10. The protective effect of RANTES was blocked by antibodies to MCP-1, indicating that RANTES protection is mediated by the induction of MCP-1. The NMDA blocker, MK801, also abolished the toxic effects of both tat and NMDA. Tat or NMDA treatment of mixed cultures for 24 h resulted in increased extracellular glutamate ([Glu]e) and NMDA receptor 1 (NMDAR1) expression, potential contributors to apoptosis. Co-treatment with MCP-1 inhibited tat and NMDA-induced increases in [Glu]e and NMDAR1, and also reduced the levels and number of neurons containing intracellular tat. These data indicate that MCP-1 may play a novel role as a protective agent against the toxic effects of glutamate and tat.

Mechanisms of leukocyte trafficking into the CNS.

HIV-1 encephalitis occurs in up to one-third of HIV-1-infected individuals. The mechanisms through which this pathology develops are thought to involve viral passage across the blood-brain barrier (BBB), as well as entry of HIV-infected and/or uninfected inflammatory cells into the central nervous system (CNS). Viral proteins and cytokines may also contribute to the pathogenesis of encephalitis. We show that the chemokines SDF-1 and MCP-1 induce transmigration of uninfected human lymphocytes and monocytes across our model of the BBB, a co-culture of human fetal astrocytes and endothelial cells. We also demonstrate that the HIV-1 protein Tat induces adhesion molecule expression and chemokine production by human fetal astrocytes and microglia, which could further contribute to leukocyte entry into the CNS. Finally, our data indicate that inflammatory cytokines modulate the expression of CXCR4, a co-receptor for HIV-1, on human fetal astrocytes, suggesting that these cytokines may potentially modulate the infectability of astrocytes by HIV-1. These findings support the hypothesis that there may be several different mechanisms that contribute to the development and progression of HIV-1 encephalitis.

Disruption of IcsP, the major Shigella protease that cleaves IcsA, accelerates actin-based motility.

Shigella pathogenesis involves bacterial invasion of colonic epithelial cells and movement of bacteria through the cytoplasm and into adjacent cells by means of actin-based motility. The Shigella protein IcsA (VirG) is unipolar on the bacterial surface and is both necessary and sufficient for actin-based motility. IcsA is inserted into the outer membrane as a 120-kDa polypeptide that is subsequently slowly cleaved, thereby releasing the 95-kDa amino-terminal portion into the culture supernatant. IcsP, the major Shigella protease that cleaves IcsA, was identified and cloned. It has significant sequence similarity to the E. coli serine proteases, OmpP and OmpT. Disruption of icsP in serotype 2a S. flexneri leads to a marked reduction in IcsA cleavage, increased amounts of IcsA associated with the bacterium and altered distribution of IcsA on the bacterial surface. The icsP mutant displays significantly increased rates of actin-based motility, with a mean speed 27% faster than the wild-type strain; moreover, a significantly greater percentage of the icsP mutant moves in the cytoplasm. Yet, plaque formation on epithelial monolayers by the mutant was not altered detectably. These data suggest that IcsA, and not a host protein, is limiting in the rate of actin-based motility of wild-type serotype 2a S. flexneri.