Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome.

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Endocrine, auxological and metabolic profile in children and adolescents with Down syndrome: from infancy to the first steps into adult life.

Down syndrome (DS) is the most common chromosomal disorder worldwide. Along with intellectual disability, endocrine disorders represent a remarkable share of the morbidities experienced by children, adolescents and young adults with DS. Auxological parameters are plotted on syndrome-specific charts, as growth rates are reduced compared to healthy age- and gender-matched peers. Furthermore, children with DS are at increased risk for thyroid dysfunctions, diabetes mellitus, osteopenia and obesity compared to general population. Additionally, male individuals with DS often show infertility, while women tend to experience menopause at an overall younger age than healthy controls. Given the recent outstanding improvements in the care of severe DS-related comorbidities, infant mortality has dramatically decreased, with a current average life expectancy exceeding 60 years. Accordingly, the awareness of the specificities of DS in this field is pivotal to timely detect endocrine dysfunctions and to undertake a prompt dedicated treatment. Notably, best practices for the screening and monitoring of pediatric endocrine disorders in DS are still controversial. In addition, specific guidelines for the management of metabolic issues along the challenging period of transitioning from pediatric to adult health care are lacking. By performing a review of published literature, we highlighted the issues specifically involving children and adolescent with DS, aiming at providing clinicians with a detailed up-to-date overview of the endocrine, metabolic and auxological disorders in this selected population, with an additional focus on the management of patients in the critical phase of the transitioning from childhood to adult care.

Wiskott-Aldrich Syndrome: A study on 577 patients defining the genotype as a predictive biomarker for disease severity.

WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.

Association between Physical Activity and Menstrual Cycle Disorders in Young Athletes.

Our study aims to evaluate clinical predictors of menstrual cycle disorders in female athletes who compete in running disciplines. This is a prospective observational study. Women were recruited between January and May 2022. Fifty-three patients were enrolled and completed a questionnaire about menstrual cycle, physical activity, and food habit characteristics. Of the women in our population, 39.6% had menstrual irregularities and reported a significantly higher number of kilometers run per week (67 vs. 35, p:0.02). The number of kilometers run per week was associated with menstrual irregularities (for 10 km, OR 1.35; IC95% 1.05-1.73; p: 0.02) after adjusting for BMI, age, level of sport and caloric intake. The variable of "km run per week" appeared as a diagnostic indicator of irregular menstrual cycle with statistical significance (AUC ROC curve 0.71, IC95% 0.54-0.86, p-value=0.01) and the cut-off of 65 km run per week is a good indicator of the presence of irregular menstrual cycle (sensitivity (SE) and specificity (SP) of 55% and 81.48%). Menstrual cycle disorders are very frequent in female athletes, and the variable of km run per week may play a role in screening endurance athletes at high risk for these disorders.

SMC1A epilepsy syndrome: clinical data from a large international cohort.

SMC1A epilepsy syndrome or developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85, OMIM #301044) is an X-linked neurologic disorder associated with mutations of the SMC1A gene, which is also responsible for about 5% of patients affected by Cornelia de Lange syndrome spectrum (CdLS). Only described in female patients, SMC1A epilepsy syndrome is characterized by the onset of severe refractory epileptic seizures in the first year of life, global developmental delay, a variable degree of intellectual disability, and dysmorphic facial features not typical of CdLS. This was a descriptive observational study for the largest international cohort with this specific disorder. The main goal of this study was to improve the knowledge of the natural history of this phenotype with particular attention to the psychomotor development and the epilepsy data. The analyzed cohort shows normal prenatal growth with the subsequent development of postnatal microcephaly. The incidence of neonatal problems (seizures and respiratory compromise) is considerable (51.4%). There is a significant prevalence of central nervous system (20%) and cardiovascular malformations (20%). Motor skills are generally delayed. The presence of drug-resistant epilepsy is confirmed; the therapeutic role of a ketogenic diet is still uncertain. The significant regression of previously acquired skills following the onset of seizures has been observed. Facial dysmorphisms are variable and no patient shows a classic CdLS phenotype. To sum up, SMC1A variants caused drug-resistant epilepsy in these patients, more than two-thirds of whom were shown to progress to developmental and epileptic encephalopathy. The SMC1A gene variants are all different from each other (apart from a couple of monozygotic twins), demonstrating the absence of a mutational hotspot in the SMC1A gene. Owing to the absence of phenotypic specificity, whole-exome sequencing is currently the diagnostic gold standard.

Long-Term Complications after Allogeneic Hematopoietic Stem Cell Transplantation with Treosulfan- or Busulfan-Based Conditioning in Pediatric Patients with Acute Leukemia or Myelodysplastic Syndrome: Results of an Associazione Italiana Ematologia Oncologia Pediatrica Retrospective Study.

Patients undergoing hematopoietic stem cell transplantation (HSCT) for hematologic malignancies during childhood have an increased risk of developing long-term sequelae that are in part attributable to the conditioning regimen. The present study aimed to assess the occurrence of long-term toxicities in a population of children who underwent HSCT for hematologic malignancies using either treosulfan or busulfan in the conditioning regimen. The cumulative incidences of growth impairment, altered gonadal function, altered thyroid function, cataracts, secondary malignant neoplasia, and altered pulmonary function were evaluated retrospectively by univariable and multivariable analyses in a population of 521 pediatric patients with acute leukemias or myelodysplastic syndromes treated in 20 Italian transplant centers affiliated with the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP). The median duration of follow-up for the entire study population was 7.1 years (range, 1 to 16 years). Overall, a larger proportion of patients given busulfan developed long-term toxicities compared to patients treated with treosulfan (34% versus 20%; P = .01). In univariable analysis, gonadal toxicity developed in 10% of patients who received treosulfan (95% confidence interval [CI], 3% to 15%), compared with 38% (95% CI, 24% to 39%) of busulfan-treated patients (P = .02), and this finding was confirmed by multivariable analysis (relative risk, .51; 95% CI, .34 to .76; P = .0009). We did not find any statistically significant associations between the occurrence of other long-term toxicities and the use of either busulfan or treosulfan. This study provides evidence that the use of treosulfan is correlated with a reduced incidence of gonadal toxicity in children undergoing HSCT for hematologic malignancies.

Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment.

Introduction: Impaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty. Methods: Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded. Results: Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30). Conclusions: a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.

Current practices of follow-up programs for childhood cancer survivors in Italy.

INTRODUCTION: Quality of life in childhood cancer survivors is largely affected by survivorship care and transition from treatment to long-term follow-up (LTFU). Referring to evidence-based recommendations, we wanted to evaluate LTFU care for survivors through a survey among the Italian Association for Pediatric Hematology-Oncology (AIEOP) centers. The project aimed to evaluate the availability of services in Italy, investigate strengths and weaknesses, analyze improvements of awareness in the field, and identify the gaps that need to be addressed by different centers. METHODS: Together with the family representatives, on behalf of AIEOP's Late Effects Working Group, we developed a questionnaire on assisting childhood cancer survivors. All AIEOP centers received one questionnaire including information on local health system organizations; LTFU for childhood cancer survivors; services for adult survivors of childhood cancer; information provided to survivors/caregivers and care plan delivery. RESULTS: Forty-eight AIEOP centers were contacted and 42 replied, with a response rate of 87.5%. The majority of respondents confirmed their interest in assisting patients with a survivorship care plan (95.2%), regardless of a clinic or dedicated staff. DISCUSSION: This is the first overview of LTFU in Italy, which provides detailed results at national levels, prompting consideration of improvements in the last decade. Although there is a high level of interest in survivorship care, many centers lack resources to implement such programs. The identification of these challenges is useful for planning future strategies.

Thyroid Function Tests in Children and Adolescents With Trisomy 21: Definition of Syndrome-Specific Reference Ranges.

CONTEXT: The lack of syndrome-specific reference ranges for thyroid function tests (TFT) among pediatric patients with Down syndrome (DS) results in an overestimation of the occurrence of hypothyroidism in this population. OBJECTIVE: To (a) outline the age-dependent distribution of TFT among pediatric patients with DS; (b) describe the intraindividual variability of TFT over time; and (c) assess the role of elevated thyrotropin (TSH) in predicting the future onset of overt hypothyroidism. METHODS: In this retrospective, monocentric, observational analysis, we included 548 patients with DS (0-18 years) longitudinally assessed between 1992 and 2022. Exclusion criteria were abnormal thyroid anatomy, treatments affecting TFT, and positive thyroid autoantibodies. RESULTS: We determined the age-dependent distribution of TSH, FT3, and FT4 and outlined the relative nomograms for children with DS. Compared with non-syndromic patients, median TSH levels were statistically greater at any age (P < .001). Median FT3 and FT4 levels were statistically lower than controls (P < .001) only in specific age classes (0-11 for FT3, 11-18 years for FT4). TSH levels showed a remarkable fluctuation over time, with a poor (23%-53%) agreement between the TSH centile classes at 2 sequential assessments. Finally, the 75th centile was the threshold above which TSH values predicted future evolution into overt hypothyroidism with the best statistical accuracy, with a satisfactory negative predictive value (0.91), but poor positive predictive value (0.15). CONCLUSION: By longitudinally assessing TFT in a wide pediatric DS population, we outlined the syndrome-specific reference nomograms for TSH, FT3, and FT4 and demonstrated a persistent upward shift of TSH compared to non-syndromic children.

Towards an individualized management of pubertal induction in girls with hypogonadism: insight into the best replacement outcomes from a large multicentre registry.

OBJECTIVE: An evidence-based pubertal induction scheme in hypogonadal girls is still to be established. Interestingly, literature data report a suboptimal uterine longitudinal diameter (ULD) in >50% of treated hypogonadal women, negatively influencing their pregnancy outcomes. This study aims to investigate auxological and uterine outcomes of pubertal induction in girls in the light of underlying diagnosis and therapeutic schemes used. DESIGN: Retrospective analysis of longitudinal data from a multicentric registry. METHODS: Auxological, biochemical, and radiological data were collected at baseline and during follow-up in 95 hypogonadal girls (chronological age > 10.9 years, Tanner stage ≤ 2) treated with transdermal 17ß-oestradiol patches for at least 1 year. Induction was started at a median dose of 0.14 mcg/kg/day with a 6-monthly increase and was considered completed for 49/95 patients who started progesterone with a concomitant oestrogen adult dose. RESULTS: At the end of induction, the achievement of the complete breast maturation was associated with a 17ß-oestradiol dose at progesterone introduction. ULD showed a significant correlation with a 17ß-oestradiol dosage. Final ULD was >65 mm in only 17/45 girls. At multiple regression analysis, pelvic irradiation represented the major determinant of reduced final ULD. After correction for uterine irradiation, ULD was associated with the 17ß-oestradiol dose at progesterone introduction. Final ULD was not significantly different from the one assessed after progesterone introduction. CONCLUSIONS: Our results provide evidence that progestins, hampering further changes in uterine volume and breast development, should be introduced only in the presence of a concomitant adequate 17ß-oestradiol dose and an appropriate clinical response.

The Complex Cyto-Molecular Landscape of Thyroid Nodules in Pediatrics.

Thyroid fine-needle aspiration (FNA) is a commonly used diagnostic cytological procedure in pediatric patients for the evaluation of thyroid nodules, triaging them for the detection of thyroid cancer. In recent years, greater attention has been paid to thyroid FNA in this setting, including the use of updated ultrasound score algorithms to improve accuracy and yield, especially considering the theoretically higher risk of malignancy of these lesions compared with the adult population, as well as to minimize patient discomfort. Moreover, molecular genetic testing for thyroid disease is an expanding field of research that could aid in distinguishing benign from cancerous nodules and assist in determining their clinical management. Finally, artificial intelligence tools can help in this task by performing a comprehensive analysis of all the obtained data. These advancements have led to greater reliance on FNA as a first-line diagnostic tool for pediatric thyroid disease. This review article provides an overview of these recent developments and their impact on the diagnosis and management of thyroid nodules in children.

The bronchiolitis epidemic in 2021-2022 during the SARS-CoV-2 pandemic: experience of a third level centre in Northern Italy.

BACKGROUND: The aim of this study is to compare the 2021-2022 bronchiolitis season to the four previous years (2017-2018, 2018-2019, 2019-2020, 2020-2021) to see if there was an anticipation of the peak, an overall increase of cases, and an increased need of intensive care. METHODS: A retrospective single-centre study in the San Gerardo Hospital Fondazione MBBM, Monza, Italy was performed. Emergency Departments (ED) visits of patients aged < 18 years and ≤ 12 months were analyzed: the incidence of bronchiolitis on total assessments, the urgency level at triage and the hospitalization rate were compared. Data of children admitted to the Pediatric Department due to bronchiolitis were analyzed in terms of need of intensive care, respiratory support (type and duration), length of hospital stay, main etiological agent, patient characteristics. RESULTS: During 2020-2021 (first pandemic period) an important reduction in the ED attendance for bronchiolitis was observed, while in 2021-2022 there was an increase in incidence of bronchiolitis (13% of visits in infants < 1 year) and in the rate of urgent accesses (p = 0.0002), but hospitalization rates did not differ compared to previous years. Furthermore, an anticipated peak in November 2021 was observed. In the 2021-2022 cohort of admitted children to the Pediatric Department, a statistically significative increased need of intensive care unit was detected (Odds Ratio 3.1, 95% CI 1.4-6.8 after adjustment for severity and clinical characteristics). Instead, respiratory support (type and duration) and length of hospital stay did not differ. RSV was the main etiological agent and RSV-bronchiolitis determined a more severe infection (type and duration of breathing support, intensive care need and length of hospital stay). CONCLUSIONS: During Sars-CoV-2 lockdowns (2020-2021), there was a dramatic decrease of bronchiolitis and others respiratory infections. In the following season, 2021-2022, an overall increase of cases with an anticipated peak was observed and data analysis confirmed that patients in 2021-2022 required more intensive care than children in the four previous seasons.

Iron Overload Following Hematopoietic Stem Cell Transplantation: Prevalence, Severity, and Management in Children and Adolescents with Malignant and Nonmalignant Diseases.

Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) that has been investigated extensively in the field of hemoglobinopathies but has not been thoroughly characterized after HSCT in pediatric malignancies. Our aim was to assess prevalence, severity, risk factors, and management of IOL, as defined using biochemical (serum ferritin) and radiologic tools (T2*-weighted magnetic resonance imaging [MRI]), in a cohort of pediatric patients who underwent HSCT for either malignant or benign diseases. This monocentric, retrospective, observational study included all the 163 patients alive and in continuous remission at 24 months post-HSCT out of the 219 consecutive children and adolescents who underwent HSCT at our institution between 2012 and 2018, were included in the study. IOL was classified into 4 categories: absent, mild, moderate, and severe. Among the 163 patients, 73% had some degree of IOL (mild in 37%, moderate in 29%, and severe in 7%). Moderate/severe IOL was more frequent among patients diagnosed with a malignant disease versus those with a benign disease (43% versus 19%; P = .0065). Trend lines for serum ferritin showed a "bell-shaped" distribution, with the highest levels recorded during the first 6 months post-HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 ng/mL versus 617 ng/mL; P < .001) and maximum post-HSCT (2473 ng/mL versus 1591 ng/mL; P < .001) median ferritin levels were statistically higher in the patients with malignancies. Radiologic assessment of IOL confirmed a more severe degree in patients with malignant disorders compared to those with benign disorders (median T2*-MRI, 4.20 msec [interquartile range (IQR), 3.0 to 6.40 msec] versus 7.40 msec [IQR, 4.90 to 11.00 msec]; P = .008). T2* levels were associated with the number of transfusions performed (P = .0006), with a steeper drop in T2* values for the first 20 transfusions and a milder slope for subsequent transfusions. T2* and ferritin values showed a statistically significant negative exponential relationship (P < .0001), although a ferritin level ≥1000 ng/mL showed poor specificity (48%) and low positive predictive value (53%) for discriminating moderate-to-severe IOL from absent-mild IOL as assessed by T2*-MRI, but with high sensitivity (92%) and negative predictive value (91%). In a multivariable model, >20 transfusions (odds ratio [OR], 4.07; 95% confidence interval [CI], 1.61 to 10.68; P = .003) and higher pre-HSCT ferritin level (P < .001) were associated with the risk of developing moderate-to-severe IOL. Use of a sibling donor (OR, .29; 95% CI, .10 to .77; P = .015) and a nonmalignancy (OR, .27; 95% CI, .08 to .82; P = .026) were protective factors. Phlebotomy (66%), low-dose oral chelators (9%), or a combined approach (25%) were started at a median of 12 months after HSCT in 78% of the patients with IOL. Six percent of the patients treated exclusively with phlebotomy (median, 14, significantly higher in patients >40 kg) discontinued phlebotomy owing to poor venous access, lack of compliance, or hypotension, whereas 39% of patients treated with chelators developed mild renal or hepatic side effects that resolved after tapering or discontinuation. Patients with malignancies showed statistically higher pre-HSCT and post-HSCT ferritin levels and lower T2* values. High ferritin level recorded on T2*-MRI showed unsatisfactory diagnostic accuracy in predicting IOL; thus, T2*-MRI should be considered a key tool for confirming IOL after HSCT in patients with an elevated serum ferritin level. IOL treatment is feasible after HSCT.

Case report: Fluctuating tumor markers in a boy with gonadotropin-releasing hormone-independent precocious puberty induced by a pineal germ cell tumor.

GnRH-independent precocious puberty (GIPP) can be the presenting clinical picture experienced by patients with secreting germ cell tumor (GCT). Indeed, as luteinizing hormone (LH) and human chorionic gonadotropin (hCG) share identical α-subunits and similar ß-subunits, an increased secretion of ß-hCG may result in a precocious activation of Leydig cells. Though the co-occurrence of raised ß-hCG levels and signs of precocious virilization usually prompts a complete oncological work-up, the diagnostic and therapeutic management of GCT-induced GIPP may be challenging. We report the case of a 6.2 year-old boy presenting with clinical and biochemical findings consistent with GIPP (discrepancy between overt virilization and pre-pubertal testicular volume, suppressed gonadotropins and remarkably raised testosterone). Brain imaging detected a bilobed cyst of the pineal gland, while serum and cerebrospinal baseline assessment initially ruled out raised alpha-fetoprotein or ß-hCG levels. Nevertheless, a strict biochemical follow-up highlighted a fluctuant trend of tumor markers, with a more aggressive behavior and recurrent erections occurring as a result of unpredictable phases of raised testosterone and serum/cerebrospinal ß-hCG, followed by sudden spontaneous decrease. Accordingly, a secreting pineal GCT was suspected. Given the fluctuating trend of tumor markers, surgery was initially kept on hold and a combined treatment with bicalutamide (androgen receptor blocker) and anastrozole (aromatase inhibitor) was undertaken in order to prevent the patient from experiencing further virilization and excessive bone age maturation. Subsequently, a progression in the size of the pineal tumor prompted surgical resection and a diagnosis of secreting GCT was histologically confirmed. Accordingly, the patient was started on adjuvant chemo- and radiotherapy. Antineoplastic treatment was followed by persistent and remarkable decrease of tumor markers and by a complete pubertal arrest. We reported the challenging diagnosis of a secreting pineal GCT in a patient with GIPP and a fluctuating trend of tumor markers, testosterone levels and associated clinical signs, hence prompting the indication for a systematic assessment and a strict monitoring whenever a patient with GnRH-independent precocious puberty shows clinical or radiological markers potentially consistent with a GCT.

Exaggerated mini-puberty in a preterm girl: a case report and review of literature.

OBJECTIVES: Mini-puberty is the physiological and transient activation of the hypothalamic-pituitary-gonadal axis occurring during the first months after birth. In preterm infants, the hormonal surge is more pronounced and longer-lasting than in at-term-peers. To date, only few cases of vaginal bleeding in the setting of an exaggerated mini-puberty have been reported. CASE PRESENTATION: At the corrected age of 3 months, an ex-very-preterm girl presented with breast enlargement and recurrent vaginal bleeding. A remarkable increase in gonadotropins and estradiol levels was detected, while pelvic ultrasound highlighted a large right ovarian cyst. As brain and pituitary MRI showed negative findings, an exaggerated mini-puberty was suspected and no additional investigations were undertaken. The subsequent progressive regression of clinical, biochemical and sonographic findings confirmed the diagnosis. CONCLUSIONS: Although exaggerated mini-puberty of infancy in ex-preterm girls is a rare event, it is important to raise knowledge of this para-physiological condition in order to avoid unnecessary investigations and treatment.

Thyroid Disorders Following Hematopoietic Stem Cell Transplantation in Childhood: Impact of Conditioning Regimen on Thyroid Dysfunction, Volume Changes, and Occurrence of Nodules.

Thyroid late effects are among the most frequent sequelae reported after pediatric hematopoietic stem cell transplantation (HSCT). Although the detrimental effects of radiotherapy on the developing thyroid gland have been extensively assessed, the role of chemotherapy-only conditioning regimens remains controversial. We aimed to describe the occurrence, monitoring, and management of thyroid function disorders (ie, Graves disease, Hashimoto thyroiditis, and nonautoimmune hypothyroidism), nodules, and volumetric changes over a 20-year observation period in a single pediatric transplantation unit. In addition, we assessed the impact of different conditioning regimens on thyroid health. The study population for this retrospective observational analysis comprised 244 pediatric patients who underwent HSCT for malignant or nonmalignant diseases between 1999 and 2018 and for whom at least 4 thyroid function tests and 1 or more thyroid ultrasound(s) assessed sequentially after HSCT were available. The 15-year cumulative incidence of either autoimmune or nonautoimmune thyroid dysfunctions (34%, SE 5.3%) did not differ statistically between total body irradiation (TBI)-based and chemotherapy-based regimens (P = .23). Indeed, the cumulative incidence after busulfan (Bu)-based conditioning was overall superimposable to that recorded after TBI (10-year cumulative incidence, 22.2% versus 25.9%, respectively). Nevertheless, the cumulative incidence of nonautoimmune hypothyroidism was statistically higher after Bu-based conditioning (12.4%, SE 3.7%) than after other chemotherapy-only-based conditioning regimens (3.1%, SE 3.1%; P = .02, 5-year cumulative incidence), treosulfan (Treo) included. The overall cumulative incidence of nodules was low for the first 5 years after HSCT (1.9%, SE .9%) but subsequently increased steeply over time, with a 15-year cumulative incidence as high as 52.1% (SE 7.5%). TBI-conditioned patients had a higher 15-year cumulative incidence of nodules (66.8%, SE 9.1%) compared with patients receiving chemotherapy-only regimens (33.6%, SE 9.5%; P = .02), whereas age >10 years at transplantation showed a protective effect (hazard ratio, .42, 95% confidence interval, .2 to .88). Finally, a systematic sonographic follow-up highlighted a progressive statistically significant reduction in thyroid anteroposterior diameter among patients conditioned with TBI (P = .005), but not in those who received chemotherapy-only regimens. TBI and younger age at HSCT have a statistically significant detrimental effect on the occurrence of thyroid nodules, both benign and malignant. TBI and Bu expose patients to a higher cumulative incidence of thyroid dysfunction compared with other chemotherapy-only regimens, Treo included. Accordingly, Bu can be considered the most thyrotoxic agent among those administered as a part of a chemotherapy-only conditioning regimen. Finally, patients conditioned with TBI, but not those with other regimens, show a progressive decrease in thyroid volume over time, as assessed by sequential ultrasound examinations.

Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child.

Mucopolysaccharidosis-plus syndrome (MPS-PS) is a novel autosomal recessive disorder caused by a mutation in the VPS33A gene. This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders. To date, twenty-four patients have been described. There is no specific therapy for MPS-PS; clinical management is therefore limited to symptoms management. The clinical course is rapidly progressive, and most patients die before 1-2 years of age. We describe a currently 6-year-old male patient with MPS-PS presenting with multiorgan involvement. Symptoms started at four months of age when he progressively suffered from numerous acute and potentially life-threatening events. When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids. To date, this child represents the oldest patient affected by MPS-PS described in the literature and the first one presenting with a life-threatening secondary HLH. The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life. HLH should be suspected and adequately treated in MPS-PS patients presenting with suggestive symptoms of the disease. The usefulness of a prolonged steroid treatment to improve the clinical course of children with MPS-PS deserves further investigation.

Proposal of an Algorithm to Early Detect Attenuated Type I Mucopolysaccharidosis (MPS Ia) among Children with Growth Abnormalities.

Background and Objectives: Diagnostic delay is common in attenuated Mucopolysaccharidosis Type I (MPS Ia) due to the rarity of the disease and the variability of clinical presentation. Short stature and impaired growth velocity are frequent findings in MPS Ia, but they rarely raise suspicion as paediatric endocrinologists are generally poorly trained to detect earlier and milder clinical signs of this condition. Materials and Methods: Following a consensus-based methodology, a multidisciplinary panel including paediatric endocrinologists, paediatricians with expertise in metabolic disorders, radiologists, and rheumatologists shared their experience on a possible clinical approach to the diagnosis of MPS Ia in children with short stature or stunted growth. Results: The result was the formation of an algorithm that illustrates how to raise the suspicion of MPS Ia in a patient older than 5 years with short stature and suggestive clinical signs. Conclusion: The proposed algorithm may represent a useful tool to improve the awareness of paediatric endocrinologists and reduce the diagnostic delay for patients with MPS Ia.

High levels of physical activity in female adolescents with anorexia nervosa: medical and psychopathological correlates.

PURPOSE: While overexercise is commonly described in patients who experience anorexia nervosa (AN), it represents a condition still underestimated, especially in the paediatric population. METHOD: The present study aims at assessing the possible associations between levels of physical activity (PA) and clinical features, endocrinological data and psychopathological traits in a sample of 244 female adolescents hospitalised for AN subdivided into two groups according to PA levels (high PA vs. no/low PA). The two groups were compared through multivariate analyses, while multiple regression analysis was conducted to determine whether physical activity predict specific outcomes. RESULTS: No significant differences were found between the two groups in terms of last Body Mass Index (BMI) before illness, BMI at admission and disease duration, while a difference emerged in delta BMI(rapidity of weight loss), significantly higher in high-PA group (p = 0.021). Significant differences were observed in Free triiodothyronine- (p < 0.001), Free thyroxine (p = 0.046), Follicle-stimulating hormone (p = 0.019), Luteinising hormone (p = 0.002) levels, with values remarkably lower in high-PA group. Concerning psychopathological scales, the high-PA group showed worst Children's Global Assessment Scale (CGAS) scores (p = 0.035). Regression analyses revealed that higher PA predicts higher delta BMI (p = 0.021), presence of amenorrhea (p = 0.003), lower heart rate (p = 0.012), lower thyroid (Free triiodothyronine p < 0.001, Free thyroxine p = 0.029) and gynaecological hormones' levels (Follicle-stimulating hormone p = 0.023, Luteinising hormone p = 0.003, 17-Beta estradiol p = 0.041). Concerning psychiatric measures, HPA predicts worst scores at CGAS (p = 0.019), and at scales for evaluation of alexithymia (p = 0.028) and depression (p = 0.004). CONCLUSIONS: Results suggest that high levels of physical activity in acute AN associate with worst clinical conditions at admission, especially in terms of endocrinological and medical features. LEVEL OF EVIDENCE: Level III.

Evidence of Treatment Benefits in Patients with Mucopolysaccharidosis Type I-Hurler in Long-term Follow-up Using a New Magnetic Resonance Imaging Scoring System.

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.