In vivo magnetic resonance spectroscopy for the differential diagnosis of a cerebral mass in a boy with precocious puberty: a case report and review of the literature.

PURPOSE: To highlight the role of in vivo magnetic resonance spectroscopy (MRS) as a non-invasive tool that can clarify the etiology of sellar tumors by presenting the case of a boy with central precocious puberty (CPP) and to review the current literature. METHODS: A 4-year-old boy was admitted to our hospital due to repeated episodes of focal and gelastic seizures in the previous year. Clinical examination (testicular volume 4-5 ml bilaterally, penile length of 7.5 cm, and absence of axillary or pubic hair) and laboratory tests (FSH, LH, and testosterone) were indicative of CPP. The combination of gelastic seizures with CPP in a 4-year-old boy raised the suspicion of hypothalamic hamartoma (HH). Brain MRI revealed a lobular mass in the suprasellar-hypothalamic region. The differential diagnosis included glioma, HH, and craniopharyngioma. To further investigate the CNS mass, an in vivo brain MRS was performed. RESULTS: Οn conventional MRI, the mass demonstrated isointensity to gray matter on T1 weighted images but slight hyperintensity on T2-weighted images. It did not show restricted diffusion or contrast enhancement. On MRS, it showed reduced N-acetyl aspartate (NAA) and slightly elevated myoinositol (MI) compared with values in normal deep gray matter. The MRS spectrum, in combination with the conventional MRI findings, were consistent with the diagnosis of a HH. CONCLUSION: MRS is a state-of-the-art, non-invasive imaging technique that compares the chemical composition of normal tissue to that of abnormal regions by juxtaposing the frequency of measured metabolites. MRS, in combination with clinical evaluation and classic MRI, can provide identification of CNS masses, thus eliminating the need for an invasive biopsy.

High frequency of autoimmune thyroiditis in euthyroid girls with premature adrenarche.

Objective: The purpose of this study was to investigate the frequency of autoimmune thyroiditis (AT) among euthyroid prepubertal girls presenting with premature adrenarche (PA). We also aimed to identify the clinical, metabolic, and endocrine profile of girls with AT and concurrent PA and compare them to girls with AT without PA, PA alone and healthy controls. Methods: Ninety-one prepubertal girls aged 5-10 years, who attended our department for AT, PA and normal variants of growth and puberty were recruited for the study: 73 girls had PA, 6 AT without PA and 12 were referred for investigation of growth. All girls underwent clinical examination, detailed biochemical and hormonal screen. Standard dose Synachten stimulation test (SDSST) and oral glucose tolerance test (OGTT) were performed in all girls with PA. The whole study population was divided in 4 groups: Group PA-/AT+ included 6 girls with AT without PA; Group PA+/AT- PA subjects without AT; Group PA+/AT+ girls with PA and concomitant AT; Group PA-/AT- twelve healthy girls without PA nor AT (controls). Results: Among 73 girls presenting with PA 19 had AT (26%). BMI, systolic blood pressure (SBP) and the presence of goiter significantly differed between the four groups (p = 0.016, p = 0.022 and p < 0.001, respectively). When comparing hormonal parameters among the four groups significant differences were found in leptin (p = 0.007), TSH (p = 0.044), anti-TPO (p = 0.002), anti-TG (p = 0.044), IGF-BP1 (p = 0.006), Δ4-Α (p = 0.01), DHEA-S (p = <0.001), IGF-1 (p = 0.012) and IGF-BP3 (p = 0.049) levels. TSH levels were significantly higher in Group PA+/AT+ compared to PA+/AT- and PA-/AT- (p = 0.043 and p = 0.016, respectively). Moreover, girls with AT (Groups PA-/AT+ and PA+/AT+) had higher TSH levels than those in Group PA+/AT- (p = 0.025). Girls in Group PA+/AT + showed higher cortisol response at 60 min post-SDSST than girls in Group PA+/AT- (p = 0.035). During the OGTT, insulin concentrations at 60 min were significantly higher in Group PA+/AT + compared to Group PA+/AT- (p = 0.042). Conclusion: A high frequency of AT among euthyroid prepubertal girls with PA was observed. The combination of PA with AT even in euthyroid state may be associated with a greater degree of insulin resistance, than PA alone.

Incidence of Type 1 diabetes and factors associated with presence and severity of ketoacidosis at onset in children.

BACKGROUND AND AIM: To assess the incidence of Type 1 Diabetes Mellitus (T1DM) during the period 2012-2017, the frequency and severity of ketoacidosis (DKA) at diabetes onset, and the factors associated with DKA in children and adolescents younger than 18 years old in the Abruzzo region, Italy. METHODS: All incident cases of T1DM (0-17 years old) diagnosed between January 2012 and December 2017 were included. Data about the patients were obtained from two independent sources; insulin prescriptions and medical records. Clinical data at diabetes onset, as well as demographic and non-demographic data, including center of first hospitalization, distance to regional reference center and number of pediatricians (per 1000 residents younger than 18 years) were collected and evaluated. RESULTS: During 2012-2017 period, 177 patients were diagnosed with T1DM. In 2012, T1DM incidence was 15.6 per 100,000/year; in 2013, 16.4 per 100,000/year; in 2014, 11.6 per 100,000/year; in 2015, 14.2 per 100,000/year; in 2016, 16.2 per 100,000/year and in 2017, 12.2 per 100,000/year. DKA was present in 29.3% of patients, 6.9% with severe DKA. The DKA presence was correlated to age (p<0.02), ethnicity (p<0.04), being transferred to a specialist center instead of being directly admitted to one (p<0.002) and the number of pediatricians in the population (p<0.01). The DKA severity was associated with the delay of transfer (p<0.04). CONCLUSIONS: Being admitted directly to a specialist center is very important and it could be expression of high alertness of pediatricians. Availability of well-trained pediatricians is necessary for the prevention of DKA. (www.actabiomedica.it).

Progress in Fertility Preservation Strategies in Turner Syndrome.

Growth retardation and gonadal dysgenesis are two of the most important clinical manifestations of Turner syndrome (TS). As premature ovarian failure generally occurs early in life in women with TS, these patients should be counseled and evaluated as early as possible for discussion of optimal and individualized fertility preservation strategies. Infertility seriously affects the quality of life of women with TS. For those who have ovarian reserve, the theoretical options for future fertility in TS patients include cryopreservation of oocytes, ovarian tissues, and embryos. For those who have already lost their ovarian reserve, oocyte or embryo donation, gestational surrogacy, and adoption are strategies that allow fulfillment of desire for parenting. This review describes the etiologies of infertility and reviews the fertility preservation strategies for women with TS.

Menstrual Disorders and Androgen-Related Traits in Young Women with Type 1 Diabetes Mellitus: a Clinical Study.

OBJECTIVE: To investigate possible causes of menstrual disorders and androgen-related traits in young women with type 1 diabetes mellitus (T1DM). METHODS: Fifty-three women with T1DM (duration 8.0±5.6 years), 41 women with (polycystic ovary syndrome) PCOS, and 51 controls matched for age (19.4±4.3 years vs. 21.2±2.7 years vs. 20.8±3.1 years; P>.05) and body mass index (BMI) (22.2±2.7 kg/m2 vs. 21.9±2.0 kg/m2 vs. 21.4±1.9 kg/m2; P>.05) were prospectively recruited. RESULTS: Two women (3.8%) in the T1DM group had not experienced menarche (at 15.5 and 16.6 years); of the rest, 23.5% had oligomenorrhea, 32.1% hirsutism, and 45.3% had acne. The age at menarche was delayed in the T1DM group compared to controls (12.7±1.3 vs. 12.0±1.0 years; P = .004), while no difference was observed with the polycystic ovary syndrome (PCOS) group (12.4±1.2 years). There were no differences in total testosterone (0.43±0.14 ng/mL vs. 0.39±0.14 ng/mL; P>.05), dehydroepiandrosterone sulfate (DHEA-S) (269 ± 112 µg/dL vs. 238 ± 106 µg/dL; P>.05) or Δ4-androstenedione (2.4±1.3 ng/mL vs. 1.9±0.5 ng/mL; P>.05) concentrations between T1DM and controls. However, patients with T1DM had lower sex hormone binding globulin (SHBG) concentrations than controls (61 ± 17 nmol/L vs. 83 ± 18.1 nmol/L; P = .001), which were even lower in the PCOS group (39.5±12.9 nmol/L; P = .001 compared with T1DM). The free androgen index (FAI) was higher in the PCOS group compared with both other groups (T1DM vs. PCOS vs. controls: 2.53±0.54 vs. 7.88±1.21 vs. 1.6 ± 0.68; P<.001). FAI was higher in patients with T1DM compared to controls as well (P = .038). There was no difference in DHEA-S concentrations between T1DM and PCOS patients (269 ± 112 µg/dL vs. 297 ± 100 µg/dL; P>.05). CONCLUSION: Menstrual disorders and androgen-related traits in young women with T1DM may be attributed to an increase in androgen bioavailability due to decreased SHBG concentrations.

PCSK9 and Lp(a) levels of children born after assisted reproduction technologies.

PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipoprotein (a) (Lp[a]) levels are associated with cardiovascular risk. To investigate PCSK9 and Lp(a) levels of children born after assisted reproduction technologies (ART) compared with naturally conceived (NC) controls. METHODS: In this exposure-matched cohort study, 73 racial-, sex-, and age-matched children (mean age 98 ± 35 months) of ART (intracytoplasmic sperm injection [ICSI] n = 33, classic in vitro fertilization [IVF] n = 40) and 73 NC children were assessed. Blood lipid profile, including PCSK9 and Lp(a) levels, was measured. Children were grouped according to age (< 8 years, 8-10 years, ≥ 10 years). RESULTS: In the overall population, PCSK9 levels were related to total cholesterol, low-density lipoprotein, and systolic blood pressure, while Lp(a) levels were related to age, apolipoprotein-B, birth weight, height, waist-to-hip ratio, insulin resistance, insulin, and high-sensitivity C-reactive protein. No significant differences were observed regarding lipid biomarkers between ART and NC children. However, a significant interaction was found between age groups and conception method (p < 0.001) showing that PCSK9 levels increase with age in ART children, while they decline with age in NC offspring. IVF children showed higher levels of adjusted mean Lp(a) than ICSI (13.5 vs. 6.8 mg/dl, p = 0.010) and NC children (12.3 vs. 8.3 mg/dl, p = 0.048). CONCLUSIONS: We show that PCSK9 levels increase with age in ART children, indicating a gradual deterioration of lipidemic profile that could lead to increased cardiovascular risk. Moreover, our results indicate that ART method may be of importance given that classic IVF is associated with higher levels of Lp(a).

The influence of treatment, age at onset, and metabolic control on height in children and adolescents with type 1 diabetes-A SWEET collaborative study.

OBJECTIVE: To describe the association between height, demographics, and treatment in youths with type 1 diabetes participating in an international network for pediatric diabetes centers (SWEET). METHODS: Data were collected from 55 centers with documented patients' height. All subjects below 20 years of age, diabetes duration >1 year, and without celiac disease were included. World Health Organization growth charts were used to calculate height and body mass index z-scores. Multiple hierarchic regression models adjusting for known confounders were applied. RESULTS: Data on 22 941 subjects (51.8% male) were analyzed with a median and interquartile range for age 14.8 years (11.2, 17.6), diabetes duration 5.6 years (3.1, 8.9), and height z-score 0.34 (-0.37, 1.03). Children were taller in the youngest age groups: adjusted height z-scores of 0.31 (±0.06) and 0.39 (±0.06), respectively; with shorter diabetes duration (<2 years: 0.36 [±0.06]; 2-<5 years: 0.34 [±0.06]; ≥5 years: 0.21 [±0.06]) and if they were pump users: 0.35 ± 0.05 vs 0.25 ± 0.05 (>three injections/day and 0.19 ± 0.06 [0-3 injections daily]), respectively. High hemoglobin A1c (HbA1c) and low to normal weight were associated with a lower height z-score. Trends were identical in all models except for gender. No gender differences were found except in the final height model where females exhibited higher z-score than males. CONCLUSION: For youths treated at centers offering modern diabetes management, major growth disturbances are virtually eliminated. For children with a young age at onset, high HbA1c, injections, and/or non-intensive diabetes, treatment still requires attention in order to attain normal growth.

Pediatric endocrine and metabolic diseases and proteomics.

The principles of Predictive, Preventive and Personalized Medicine (PPPM) dictate the need to recognize individual susceptibility to disease in a timely fashion and to offer targeted preventive interventions and treatments. Proteomics is a state-of-the art technology- driven science aiming at expanding our understanding of the pathophysiologic mechanisms that underlie disease, but also at identifying accurate predictive, diagnostic and therapeutic biomarkers, that will eventually promote the implementation of PPPM. In this review, we summarize the wide spectrum of the applications of Mass Spectrometry-based proteomics in the various fields of Pediatric Endocrinology, including Inborn Errors of Metabolism, type 1 diabetes, Adrenal Disease, Metabolic Syndrome and Thyroid disease, ranging from neonatal screening to early recognition of specific at-risk populations for disease manifestations or complications in adult life and to monitoring of disease progression and response to treatment. SIGNIFICANCE: Proteomics is a state-of-the art technology- driven science aiming at expanding our understanding of the pathophysiologic mechanisms that underlie disease, but also at identifying accurate predictive, diagnostic and therapeutic biomarkers that will eventually lead to successful, targeted, patient-centric, individualized approach of each patient, as dictated by the principles of Predictive, Preventive and Personalized Medicine. In this review, we summarize the wide spectrum of the applications of Mass Spectrometry-based proteomics in the various fields of Pediatric Endocrinology, including Inborn Errors of Metabolism, type 1 diabetes, Adrenal Disease, Metabolic Syndrome and Thyroid disease, ranging from neonatal screening, accurate diagnosis, early recognition of specific at-risk populations for the prevention of disease manifestation or future complications.

Turner Syndrome: transition from childhood to adolescence.

Transition from pediatric to adult care for young women with Turner Syndrome (TS) is characterized by high drop-out rates and inadequate follow-up, leading to increased morbidity and mortality. The complexity of the health issues young women with TS face or new problems that may arise warrants a well-structured and efficiently coordinated gradual transition plan, which is adapted to the individual needs of the emerging young adult and is based on interdisciplinary communication between physicians. In order to achieve a high level of care, it is important for the patient to be sincerely informed about her condition but also supported throughout this critical period of rising responsibility and autonomy by an experienced, multidisciplinary team. In this review, we present the basic concepts that should characterize transition and the major health issues that should be thoroughly addressed, including growth, Hormone Replacement Treatment and fertility options, cardiovascular disease, bone health, gastrointestinal disorders, autoimmunity, orthopaedic and ENT issues, as well as the overall psychological well-being of the young adult with TS.

Proteomics of Children Born After Intracytoplasmic Sperm Injection Reveal Indices of an Adverse Cardiometabolic Profile.

CONTEXT: Assisted reproduction technologies (ART), classic in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) are increasingly used. Several studies have demonstrated an unfavorable cardiometabolic profile of the ART offspring. Proteomics is a state-of-the-art technology used for the identification of early biomarkers of disease. OBJECTIVES: To investigate the proteomic profile of children born after ICSI compared with naturally conceived (NC) controls in search of cardiometabolic risk markers. DESIGN: Cross-sectional case-control study: qualitative, comparative proteomic plasma analysis. SETTING: Pediatric Endocrinology and IVF Outpatient Clinics, University of Athens and the Biomedical Research Foundation of the Academy of Athens. PARTICIPANTS: Forty-two sex- and age-matched couples of ICSI and NC children were assessed. Ten pairs additionally matched for birth weight and twin/single pregnancies were submitted to proteomic analysis. INTERVENTION: Medical history, clinical examination, and blood biochemical, hormonal, and proteomic analyses. MAIN OUTCOME MEASURES: (1) Differences in auxological and laboratory data between groups. (2) Differences in plasma proteomic profile in 10 individual pairs and pooled samples. RESULTS: The ICSI group had shorter gestation, more cesarean sections, smaller birth weight/length, and advanced maternal age. No major differences were observed regarding biochemical markers. Proteomic analysis revealed 19 over- and three underexpressed proteins in ICSI. Most overexpressed proteins are implicated in acute-phase reaction, blood coagulation, complement pathway activation, and iron and lipid metabolism, suggesting a subclinical unfavorable cardiometabolic profile. CONCLUSIONS: This study applies proteomics in ICSI-conceived children, providing evidence for an early adverse cardiometabolic profile and supporting the necessity of their long-term monitoring.

The Use of Proteomics in Assisted Reproduction.

Despite the explosive increase in the use of Assisted Reproductive Technologies (ART) over the last 30 years, their success rates remain suboptimal. Proteomics is a rapidly-evolving technology-driven science that has already been widely applied in the exploration of human reproduction and fertility, providing useful insights into its physiology and leading to the identification of numerous proteins that may be potential biomarkers and/or treatment targets of a successful ART pregnancy. Here we present a brief overview of the techniques used in proteomic analyses and attempt a comprehensive presentation of recent data from mass spectrometry-based proteomic studies in humans, regarding all components of ARTs, including the male and female gamete, the derived zygote and embryo, the endometrium and, finally, the ART offspring both pre- and postnatally.

Possibilities and challenges of a large international benchmarking in pediatric diabetology-The SWEET experience.

AIM: Despite the existence of evidence-based guidelines for the care of children with diabetes, widespread gaps in knowledge, attitude, and practice remain. The purpose of this paper is to present a review of benchmarking practices and results of this process within SWEET, moreover focusing on current challenges and future directions. METHODS: Biannually, members electronically transfer de-identified clinic data for 37 parameters to the SWEET database. Each center receives benchmarking and data validation reports. RESULTS: In 2015, 48 centers have contributed data for 20 165 unique patients (51.6% male). After exclusion for missing data 19 131 patients remain for further analysis. The median age is 14.2 years, with a median diabetes duration 4.8 years; 96.0% of patients have type 1, 1.1% type 2, and 2.9% other diabetes types. Data completeness has increased over time. In 2015, median HbA1c of all patients' (diabetes type 1) medians was 7.8% (61.7 mmol/mol) with 39.1%, 41.4%, and 19.4% of patients having HbA1c < 7.5% (58 mmol/mol), 7.5%-9% (58-75 mmol/mol) and >9% (75 mmol/mol), respectively. Although HbA1c has been stable over time [7.7%-7.8% (60.7-61.7 mmol/mol)], there remains wide variation between centers. Fourteen centers achieve a median HbA1c <7.5% (58 mmol/mol). CONCLUSIONS: Our vision is that the participation in SWEET is encouraging members to deliver increasingly accurate and complete data. Dissemination of results and prospective projects serve as further motivation to improve data reporting. Comparing processes and outcomes will help members identify weaknesses and introduce innovative solutions, resulting in improved and more uniform care for patients with diabetes.

NGAL and cystatin C: two possible early markers of diabetic nephropathy in young patients with type 1 diabetes mellitus: one year follow up.

OBJECTIVE: Diabetic nephropathy constitutes a major long-term complication in patients with type 1 diabetes mellitus (T1D) and its diagnosis is based on microalbuminuria. The aim of this observational follow-up study was to explore the role of neutrophil-gelatinase-associated lipocalin (NGAL) and cystatin C in unravelling early diabetic nephropathy even in patients with normoalbuminuria. DESIGN: Fifty-six euthyroid patients with T1D, with mean age 13.1 (SD: 3.2) years, and 49 healthy controls with mean age 12.8 (SD: 6.6) were recruited. Besides standard blood chemistry and urinary albumin excretion, serum NGAL (ELISA) and cystatin C (nephelometry) were measured at enrollment and after 12-15 months. GFR was calculated with the bedside Schwartz formula (eGFR) and the Lund strategy formula (L-eGFR). RESULTS: At baseline, mean NGAL levels were not significantly different between children with diabetes and controls. At re-evaluation, mean NGAL value and mean eGFR value in patients with diabetes were increased (p=0.032 and p=0.003 respectively). At both baseline and reevaluation, NGAL was positively correlated with cystatin C (r=0.41, p<0.001), systolic arterial pressure z-score (r=0.3, p=0.031) and creatinine (r=0.32, p=0.010). NGAL correlated negatively with eGFR (r=-0.26, p=0.049) and L-eGFR (r=-0.33, p=0.010). Cystatin C had a negative correlation to eGFR (r=-0.29, p=0.025) and a positive one with creatinine (r=0.35, p=0.009) at reevaluation. No statistically significant correlation was found between cystatin C and microalbuminuria (p=0.736). CONCLUSIONS: NGAL and cystatin C, known markers of renal injury, correlate with renal function decline in T1D, suggesting that they may be used as supplementary tests to urine albumin excretion in order to unmask early renal dysfunction.

Plasma metabolomic profiling suggests early indications for predisposition to latent insulin resistance in children conceived by ICSI.

BACKGROUND: There have been increasing indications about an epigenetically-based elevated predisposition of assisted reproductive technology (ART) offspring to insulin resistance, which can lead to an unfavorable cardio-metabolic profile in adult life. However, the relevant long-term systematic molecular studies are limited, especially for the IntraCytoplasmic Sperm Injection (ICSI) method, introduced in 1992. In this study, we carefully defined a group of 42 prepubertal ICSI and 42 naturally conceived (NC) children. We assessed differences in their metabolic profile based on biochemical measurements, while, for a subgroup, plasma metabolomic analysis was also performed, investigating any relevant insulin resistance indices. METHODS & RESULTS: Auxological and biochemical parameters of 42 6.8±2.1 yrs old ICSI-conceived and 42 age-matched controls were measured. Significant differences between the groups were determined using univariate and multivariate statistics, indicating low urea and low-grade inflammation markers (YKL-40, hsCRP) and high triiodothyronine (T3) in ICSI-children compared to controls. Moreover, plasma metabolomic analysis carried out for a subgroup of 10 ICSI- and 10 NC girls using Gas Chromatography-Mass Spectrometry (GC-MS) indicated clear differences between the two groups, characterized by 36 metabolites linked to obesity, insulin resistance and metabolic syndrome. Notably, the distinction between the two girl subgroups was accentuated when both their biochemical and metabolomic measurements were employed. CONCLUSIONS: The present study contributes a large auxological and biochemical dataset of a well-defined group of pre-pubertal ICSI-conceived subjects to the research of the ART effect to the offspring's health. Moreover, it is the first time that the relevant usefulness of metabolomics was investigated. The acquired results are consistent with early insulin resistance in ICSI-offspring, paving the way for further systematic investigations. These data support that metabolomics may unravel metabolic differences before they become clinically or biochemically evident, underlining its utility in the ART research.