Search

Context: Nationwide data on children diagnosed with craniopharyngioma (CP) are not available in Italy. Objective: Identify patients' characteristics, type of surgical approach, complications and recurrences, number of pituitary deficits and number of patients starting GH treatment. Methods: Retrospective multicenter collection of 145 patients aged 0-18 years underwenting surgery for CP between 2000-2018, followed-up in 17 Italian centers of Pediatric Endocrinology. Results: Age at diagnosis was 8.4±4.1 years. Duration of symptoms was 10.8±12.5 months and headache was most frequent (54%), followed by impaired growth (48%) and visual disturbances (44%). Most lesions were suprasellar (85%) and histology was adamantinomatous in all cases but two. Surgical approach was transcranic (TC) in 67.5% of cases and transphenoidal (TS) in 31.%. TC approach was prevalent in all age groups. Post-surgery complications occurred in 53% of cases with water-electrolyte disturbances most frequent. Radiotherapy was used in 39% of cases. All patients but one presented at least one hormone pituitary deficiency, with TSH deficit as most frequent (98.3%), followed by ACTH (96.8%), AVP (91.1%) and GH (77.4%). BMI significantly increased over time. A hypothalamic disturbance was present in 55% of cases. GH therapy was started during follow-up in 112 patients at a mean age of 10.6 years and 54 developed a recurrence or regrowth of the residual lesion. Conclusions: CP is often diagnosed late also in Italy with TC more frequent than TS surgical approach. Post-surgery complications were not rare and hypopituitarism developed almost in all cases. BMI shows a tendency to increase overtime.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named autoimmune regulator gene (AIRE) which results in a failure of T cell tolerance within the thymus. Chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison’s disease are the hallmarks of the syndrome. APECED is also characterized by several autoimmune endocrine and nonendocrine manifestations, and the phenotype is often complex. Moreover, even though APECED is a monogenic disease, its clinical picture is generally dominated by a wide heterogeneity both in the severity and in the number of components even among siblings with the same AIRE genotype. The variability of its clinical expression implies that diagnosis can be challenging, and a considerable delay often occurs between the appearance of symptoms and the diagnosis. Since a prompt diagnosis is essential to prevent severe complications, clinicians should be aware of all symptoms and signs of suspicion. The aim of this paper is to give an overview on the clinical presentation and diagnostic criteria of APECED and to focus on current knowledge on genotype-phenotype correlation.

The aim of the replacement therapy with levothyroxine in congenital hypothyroidism (CH) is to correct hypothyroidism and ensure normal growth and neuropsychological development. Few data are available about the appropriate dose during childhood and early adolescence; therefore, we performed a multicenter observational study in a large population of patients with CH to assess the required levothyroxine dose to obtain euthyroidism. We recruited 216 patients with permanent CH classified into three groups (agenesia, ectopia, and in situ gland) on the basis of the thyroid imaging. The levothyroxine dose was recorded at 6 and 12 months and then yearly until 12 years of age. The daily levothyroxine requirement progressively decreased during the follow-up, irrespective of etiology. It was significantly lower in patients with in situ gland than in patients with athyreosis during the entire study period and with ectopic gland from the age of 1 year. The levothyroxine requirement at 6 months of age was correlated with the requirement at each later time-point. The daily dose was modified less frequently in patients with in situ thyroid (36 %) than in patients with ectopic gland (41.4 %) or with athyreosis (43.6 %). Patients with in situ gland required a lower dose than the other two subgroups. The dose at 6 months seems predictive of the requirement until 12 years of age. Euthyroidism may be achieved in pre-school and in-school patients by 3-4 and 2-3 µg/kg/day (70-90 and 60-80 µg/m(2)/day) of levothyroxine, respectively.

ObjectivesWe designed a multicentre open prospective randomized trial to evaluate the risk-benefit profile of two different initial treatment schemes with levothyroxine (L-T4), 10-12.5 μg/kg/day vs 12.6-15 μg/kg/day, on growth and neurodevelopmental outcomes in children with congenital hypothyroidism (CH) detected by neonatal screening to identify the best range dose to achieve optimal neurocognitive development.Design, patients and methodsChildren detected by neonatal screening were randomly assigned to receive an initial L-T4 dose of 10-12.5 μg/kg/day (Low) or 12.6-15 μg/kg/day (High). All patients underwent periodical clinical examination with measurement of growth parameters and measurement of TSH and FT4. Neurocognitive development was evaluated at the age of 24 months using Griffiths Mental Development Scales (GMDS) and cognitive and behavioral assessment was performed at 48 months of age using Wechsler Preschool and Primary scale of Intelligence (WIPPSI-III). The study was registered with clinicaltrials.gov (NCT05371262).ResultsTreatment schemes below or above 12.5 μg/kg/day were both associated with rapid normalization of TSH and thyroid hormone levels in most patients with no differences in the risk of over- and under-treatment episodes in the first months of life. Growth parameters were normal and comparable between the two groups. Developmental quotients at 24 months of age were normal in both groups (Low 100.6 ± 15.5 vs High 96.9 ± 16.6). Likewise, at 4 years of age IQ and subtest scores were comparable between patients from Low and High (Total IQ 104.2 ± 11.4 vs 101.0 ± 20.3, Verbal IQ 103.9 ± 11.5 vs 98.7 ± 15.1, Performance IQ 105.3 ± 10.4 vs 100.3 ± 19.8). 6/45 CH patients (13.3%) showed a total IQ below 85 (73.7 ± 5.9) regardless of age at diagnosis, L-T4 starting dose, time of FT4 and TSH normalization and episodes of over and undertreatment. Worse socioeconomic status and delayed bone age at diagnosis were the only predictors of an increased risk of having suboptimal IQ at 24 and IQ at 48 months.ConclusionsOur results indicate that initial treatment with L-T4, 10-12.5 μg/kg/day vs 12.6-15 μg/kg/day, are both associated with normal growth and neurodevelopmental outcomes in children with CH detected by neonatal screening. Further studies with a long-term follow-up on a larger number of patients are needed to confirm these results.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT05371262?term=NCT05371262&draw=2&rank=1 identifer NCT05371262.

Context Growth hormone deficiency (GHD) in children may be associated with early cardiovascular risk factors and alterations in left ventricular (LV) structure and function; data on cardiopulmonary functional capacity are lacking. Objectives Aim of the study was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiopulmonary functional capacity, left and right cardiac structure and function, and body composition in children and adolescents. Design Prospective, case-control study. Patients and Methods Twenty-one untrained GHD children (11.3 ± 0.8 years) underwent cardiopulmonary exercise testing, echocardiography and dual-energy x-ray absorptiometry, before and after 12 months of GH therapy. Twenty-one controls matched for sex, pubertal status, body mass index, and physical activity (PA) were evaluated at baseline and after 1 year. Results At baseline, GHD patients showed reduced LV mass (LVM; 63.32 ± 7.80 vs 80.44 ± 26.29 g/m2, P = 0.006), peak oxygen consumption (VO2peak; 22.92 ± 4.80 vs 27.48 ± 6.71 mL/Kg/min, P = 0.02), peak workload (80.62 ± 29.32 vs 103.76 ± 36.20 W, P = 0.02), and O2 pulse (4.93 ± 1.30 vs 7.67 ± 2.93 mL/beat, P = 0.0003), compared with controls. GHD patients also exhibited lower lean body mass (LBM 65.36 ± 7.84% vs 76.13 ± 8.23%, P < 0.001), and higher fat mass (FM 30.84 ± 7.92% vs 22.19 ± 8.18%, P = 0.001) than controls. GH therapy resulted in a significant increase of LVM (72.01 ± 15.88, P = 0.03), VO2peak (26.80 ± 4.97; P = 0.01), peak workload (103.67 ± 32.24, P = 0.001), O2 pulse (6.64 ± 1.68, P = 0.0007), and LBM (75.36 ± 7.59%, P = 0.0001), with a reduction in FM (22.62 ± 7.73%, P = 0.001). No difference was found in either left or right ventricular function. Conclusion Our results suggest that cardiac structure, body composition and cardiopulmonary functional capacity are impaired in children with untreated GHD and can be restored after short-term GH replacement therapy.

Aims: We aimed at evaluating a standard multiplex ligation-dependent probe amplification (MLPA) probe set for the detection of aneuploidy to diagnose Turner syndrome (TS). We first fixed an MLPA ratio cutoff able to detect all cases of TS in a pilot TS group. We then tested this value on a second group of TS patients and a short-stature population to measure specificity and sensitivity. Methods: 15 TS patients with X mosaicism or X structural abnormalities (Pilot TS Group), 45 TS karyotype-assessed patients (TS Group), and 74 prepubertal female patients with apparent idiopathic short stature (Short-Stature Group) were enrolled. All subjects underwent MLPA and karyotype analysis. In the TS and Short-Stature Groups, MLPA testing was performed in blind. Results: The choice of an MLPA threshold ratio of 0.76 for at least 1 probe allowed us to detect all TS cases, including mosaicisms. Sensitivity and specificity were 100% (CI 95%, 0.92-1) and 88.89% (CI 95%, 0.79-0.94), respectively. The positive predictive value was 88.5%, and the negative predictive value was 100%. MLPA detected the presence of Y chromosome material in 2 patients. Conclusion: MLPA is an accurate and inexpensive tool to screen for TS in girls with short stature. A customized MLPA kit may be useful for the screening of an even larger population.

PURPOSE: To evaluate glucose homeostasis in children with growth hormone (GH) deficiency (GHD) receiving long-term replacement therapy. METHODS: We evaluated glucose, insulin, HOmeostasis Model Assessment (HOMA-IR), and HbA1c in 100 GHD children at diagnosis and during 5 years of therapy. One hundred healthy children comparable to patients were evaluated at baseline and after 1 and 5 years. RESULTS: No difference was detected at baseline between GHD patients and controls in glucose (79.58 ± 9.96 vs. 77.18 ± 8.20 mg/dl), insulin (4.50 ± 3.24 vs. 4.30 ± 2.60 µU/ml), HbA1c (5.20 ± 0.31 vs. 5.25 ± 0.33%) levels, and HOMA-IR (0.93 ± 0.72 vs. 0.86 ± 0.61). One year of GH was associated with a significant increase in insulin (7.21 ± 4.84, p

Background: Whether the course of thyroid function in Hashimoto's thyroiditis (HT) differs in children who present with either euthyroidism or subclinical hypothyroidism (SH) has been incompletely investigated. Aim: Using a five-year prospective evaluation of 234 children with HT and no prognostic risk factors, this study investigated whether the evolution of the thyroid status is influenced by the biochemical pattern at initial diagnosis. Results: In the entire series, thyrotropin values significantly increased during follow-up, while free thyroxine values decreased and the proportion of children with a thyroid dysfunction increased from 27.3% to 47.4% (p = 0.0001). An increasing proportion of cases with severe thyroid dysfunction was identified, especially among the 64 patients presenting with SH (group B), but also among the 170 children presenting with euthyroidism (group A) at initial diagnosis. At the end of follow-up, the prevalence of children with overt hypothyroidism was 12.3% in group A compared with 31.2% in group B (p = 0.0007). In the overall population, however, the majority of patients (52.6%) exhibited biochemical euthyroidism at the end of follow-up. Conclusions: Children with HT may develop a deterioration of thyroid status during the first five years of disease. Such a trend may be observed, even in the patients who initially present with a mild biochemical picture (either SH or euthyroidism). A total of 57.1% of initially euthyroid children remain euthyroid, and 40.6% of patients with initial SH normalize thyroid function within five years after HT diagnosis. The patients presenting with SH are more prone to the risk of developing severe thyroid dysfunction over time.

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED), formerly known as Autoimmune Polyendocrine Syndrome type 1 (APS-1), is a paradigm of a monogenic autoimmune disease caused by mutations of a gene, named autoimmune regulator (AIRE). AIRE acts as a transcription factor that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens. Although the syndrome is a monogenic disease, it is characterized by a wide variability of the clinical expression with no significant correlation between genotype and phenotype. Indeed, many aspects regarding the exact role of AIRE and APECED pathogenesis still remain unraveled. In the last decades, several studies in APECED and in its mouse experimental counterpart have revealed new insights on how immune system learns self-tolerance. Moreover, novel interesting findings have extended our understanding of AIRE’s function and regulation thus improving our knowledge on the pathogenesis of APECED. In this review, we will summarize recent novelties on molecular mechanisms underlying the development of APECED and their clinical implications.

The aim of our prospective case-control study was to evaluate long-term effects of GH replacement therapy on erythrocytes parameters, leukocytes, and platelets numbers in a large cohort of children with isolated GH deficiency (GHD). Hemoglobin (Hb) concentration, hematocrit (Hct), mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, number of erythrocytes, leukocytes, neutrophils, lymphocytes, monocytes and platelets, ferritin, and C-reactive protein were evaluated in 85 children with isolated GHD (10.20 ± 3.50 years) before and annually during the first 5 years of GH replacement therapy and in 85 healthy children age and sex comparable to patients during 5 years of follow-up. Compared with controls, GHD children at study entry showed lower Hb (-1.18 ± 0.87 vs. -0.40 ± 0.90 SDS, p

SummaryObjective Growth hormone (GH) deficiency (GHD) in adults is associated with increased cardiovascular (CV) risk. Although some authors have documented the presence of early CV risk factors in untreated GHD children, results are still inconsistent. Aim of this study was to evaluate the effects of GHD and GH therapy on early cardiometabolic risk factors in a large cohort of children. Subjects and Methods Waist-to-height ratio (WHtR), triglycerides, total-, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, atherogenic index (AI = total /HDL cholesterol), homocysteine, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP) and fibrinogen were evaluated in seventy-one GHD children (9·8 ± 3·6 years) before and after 2 years of GH therapy. Seventy-one healthy controls comparable with patients for age, sex and body mass index (BMI) were enrolled. Results Compared with controls, GHD children at study entry had higher WHtR (0·52 ± 0·05 vs 0·45 ± 0·19, P = 0·004), triglycerides (0·44 ± 0·98 vs −0·03 ± 0·73 SDS, P = 0·012), total cholesterol (0·28 ± 1·08 vs −0·46 ± 0·98 SDS, P

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named Autoimmune regulator gene (AIRE) which results in a failure of T-cell tolerance. Central tolerance takes place within the thymus and represents the mechanism by which potentially auto-reactive T-cells are eliminated through the negative selection process. The expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) in the thymus is a key process in the central tolerance and is driven by the protein encoded by AIRE gene, the transcription factor autoimmune regulator (AIRE). A failure in this process caused by AIRE mutations is thought to be responsible of the systemic autoimmune reactions of APECED. APECED is characterized by several autoimmune endocrine and non-endocrine manifestations and the phenotype is often complex. Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression even between siblings with the same genotype, thus implying that additional mechanisms, other than the failure of Aire function, are involved in the pathogenesis of the disease. Unraveling open issues of the molecular basis of APECED, will help improve diagnosis, management, and therapeutical strategies of this complex disease.

Summary It has been reported that interferon (IFN)-γ-secreting T cells reactive to gluten can be detected in the peripheral blood of individuals with treated coeliac disease (CD) after a short consumption of wheat-containing food. By contrast, very little is known about the reproducibility of this in-vivo procedure in the same patient cohort which underwent two, or more, gluten consumptions. Fourteen coeliac patients in remission consumed wheat bread for 3 days; 13 underwent a second gluten challenge after a wash-out of 3–10 months on a strict gluten-free diet. Immune reactivity to gluten was analysed in peripheral blood by detecting IFN-γ before and 6 days after commencing a gluten diet. Gliadin-specific IFN-γ-secreting CD4+ T cells increased significantly on day 6 of the first challenge. These cells resulted as prevalently human leucocyte antigen (HLA)-DQ restricted and with a phenotype of gut homing, as suggested by the expression of β7-integrin. Similarly, reactiveness to gliadin was observed after the second wheat consumption, although with an individual variability of responses at each challenge. Our findings confirmed that the short wheat challenge is a non-invasive approach to investigate the gluten-related immune response in peripheral blood of subjects intolerant to gluten. Furthermore, we demonstrated that the in-vivo procedure can be reproduced in the same subject cohort after a gluten wash-out of at least 3 months. Our study has important implications for the application of this procedure to clinical practice.

Growth hormone (GH), in addition to promote linear growth during childhood, exerts a key role in several processes of substrate metabolism. Adults with untreated GH deficiency and adolescents who discontinued GH therapy at completion of growth, exhibit a cluster of cardiovascular risk factors such as impaired cardiac performance, alteration in body proportion with increased visceral fat, dyslipidemia and hypertension, that could place them at higher risk of cardiovascular morbidity. Although studies on adolescents and children are still scarce, there is evidence that early markers of cardiovascular disease can be already detected in untreated children with GH deficiency and that, as in adults, GH replacement therapy exerts a beneficial role on metabolic alterations. Untreated GH deficiency in childhood and adolescence seems to be associated with reduced cardiac size and impaired cardiac function, dyslipidemia, abnormalities in body composition and in peripheral inflammatory markers. GH replacement therapy exerts a beneficial effects on most of these alterations. Aim of this review is to summarize the current findings on the effects of GH deficiency and GH treatment on early cardiovascular risk factors in children and adolescents.