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Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzyme deficiencies required for cortisol biosynthesis in the adrenal cortex. The majority of CAH are due to the deficiency of the 21-hydroxylase enzyme, while 3β-hydroxysteroid dehydrogenase type 2 deficiency accounts for less than five percent of all CAH cases. We report two Moroccan twins from a spontaneous triplet pregnancy. The 46,XY newborn exhibited a disorder of sexual differentiation (DSD) with hypo virilization, while the 46,XX newborn had normal female external genitalia. In the first week of life, they showed hyponatremia and primary adrenal insufficiency with a slight 17OHP elevation and increased DHEAS and renin levels. The aCGH-SNP analysis disclosed a 8.36 Mb long contiguous stretch of homozygosity (LCSH) on chromosome 1p13.2-p11.2 including the candidate HSD3B2 gene, a LCSH of 7.3 Mb on 14q31.1-q32.11, and a 7 Mb duplication on 10q22.3-q23.2. Clinical exome sequencing revealed the biallelic c.969T > G (p.Asn323Lys) HSD3B2, likely pathogenic, variant in both of the affected twins. This case emphasizes the importance of a prompt molecular diagnosis performed through the combination of aCGH and clinical exome, both for establishment of correct therapy and for follow-up, as the newborns also carry a genomic rearrangement with possible clinical implications.

Objective Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

INTRODUCTION: Subjects with hypo- or hypergonadotropic hypogonadism need hormone replacement therapy (HRT) to initiate puberty and maintain it with a normal hormonal status. While general recommendations for the management of HRT in adults have been published, no systematic suggestions focused on adolescents and young adults. The focus of this review is the HRT in males and females with hypogonadism, from puberty to late reproductive age, covering the different management options, encompassing sex steroid or gonadotropin therapy, with discussion of benefits, limitations and specific considerations of the different treatments. EVIDENCE ACQUISITION: We conducted an extensive search in the 3 major scientific databases (PubMed, EMBASE and Google Scholar) using the keywords "hormonal replacement therapy," "hypogonadism," "bone mineral density," "estradiol/testosterone," "puberty induction," "delayed puberty." Case-control studies, case series, reviews and meta-analysis published in English from 1990 to date were included. EVIDENCE SYNTHESIS: By considering the available opportunities for fertility induction and preservation, we hereby present the proposals of practical schemes to induce puberty, and a decisional algorithm to approach HRT in postpubertal adolescents. CONCLUSIONS: A condition of hypogonadism can underlie different etiologies involving the hypothalamic-pituitary-gonadal axis at different levels. Since the long-terms effects of hypogonadism may vary and include not only physical outcomes related to sex hormone deficiencies, but also psychological problems and implications on fertility, the initiation, maintenance and consolidation of puberty with different pharmaceutical options is of utmost importance and beside pubertal development, optimal uterine and testicular growth and adequate bone health should consider also the psychosocial wellbeing and the potential fertility.

Introduction.Despite progress obtained with current treatments,the event-free survival of high-risk neuroblastoma(HR-NB)patients does not exceed 40-50% and the prognosis in refractory or relapsed patients is poor,still representing a challenge for pediatric oncologist.Therapeutic Iodine-131 meta-iodobenzylguanidine(Th-131I-MIBG) is a recognized safe and potentially effective treatment in NB.Materials.In this retrospective study,we report outcome of 28 MIBG-avid NB patients with advanced disease,because refractory or relapsed,underwent,from 1996 to 2014,to Th-131I-MIBG administered shortly before(median of 17 days) high-dose chemotherapy with Busulfan and Melphalan(HD-BuMel) and autologous stem cell transplantation(ASCT)at Gaslini Institute in Genoa,with the aim to analyze feasibility,safety and efficacy of this approach.Results.Engraftment occurred in all patients after a median of 14(11-29)and 30 days(13-80)from ASCT for neutrophil and platelet respectively.No treatment-related deaths were observed.The main high grade(3-4)toxicity observed was oral and gastrointestinal mucositis in 78.6% and 7.1% of patients respectively,while high grade hepatic toxicity was observed in 10.7%;two patients developed veno-occlusive-disease(7.1%),completely responsive to defibrotide.Hypothyroidism was the main late complication occurred in 9 patients(31.1%).After Th-131MIBG and HD-BuMel, 19 patients(67.8%) showed an improvement of disease status.Over a median follow-up of 15.9 years,the 3-year and 5-year overall survival(OS)probability were 53%(CI 0.33-0.69)and 41%(CI 0.22-0.59)and the 3-year and 5-year rates of cumulative risk of progression/relapse were 64%(CI 0.47-0.81)and 73%(CI 0.55-0.88),respectively.MYCN amplification emerged as the only risk factor significantly associated with OS(HR 3.58;p0.041).Conclusion.Th-131I-MIBG administered shortly before HD-BuMel turned out to be a safe and effective regimen,suggesting it should be included in a sequential approach in patients with advanced MIBG-avid NB.These patients could be benefit to be manage in centers with proven expertise in these treatments.

OBJECTIVE To evaluate whether the diagnosis of pediatric type 1 diabetes or its acute complications changed during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Italy. RESEARCH DESIGN AND METHODS This was a cross-sectional, web-based survey of all Italian pediatric diabetes centers to collect diabetes, diabetic ketoacidosis (DKA), and COVID-19 data in patients presenting with new-onset or established type 1 diabetes between 20 February and 14 April in 2019 and 2020. RESULTS Fifty-three of 68 centers (77.9%) responded. There was a 23% reduction in new diabetes cases in 2020 compared with 2019. Among those newly diagnosed patients who presented in a state of DKA, the proportion with severe DKA was 44.3% in 2020 vs. 36.1% in 2019 (P = 0.03). There were no differences in acute complications. Eight patients with asymptomatic or mild COVID-19 had laboratory-confirmed severe acute respiratory syndrome coronavirus 2. CONCLUSIONS The COVID-19 pandemic might have altered diabetes presentation and DKA severity. Preparing for any “second wave” requires strategies to educate and reassure parents about timely emergency department attendance for non–COVID-19 symptoms.

Aims Anti-CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti-CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions. Methods We investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid-dependent and steroid/calcineurin inhibitor-dependent disease) treated at a national referral centre over a 9-year period (400 treatments; follow-up 1-9 years). Results Infusion reactions were mainly absent in children with steroid-dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short-term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3-9 months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein-Barr virus and John Cunningham virus activation markers were occasionally observed. Conclusion Overall, the toxicity of anti-CD20 monoclonal antibodies was limited to post-infusion side effects in children with more complex disease. The relatively safe profile of anti-CD20 antibodies supports their use as steroid-sparing agents in children with INS.

Minimal change disease (MCD) is a pathological condition characterized by subtle glomerular lesions causing massive and reversible proteinuria that is usually steroid sensitive. Recurrence of symptoms of active disease following successful treatment (including proteinuria, oedema and oliguria) and steroid toxicity requires the use of other drugs to attain or maintain remission. Unresolved MCD is considered the initial step in the pathological pathway leading to focal and segmental glomerulosclerosis (FSGS). Historically, cyclophosphamide, chlorambucil, mycophenolate and calcineurin inhibitors have been utilized with success in MCD; however, the chronic nature of the disease and the toxicity of long-term use of these medications has pushed the development of new therapies. Synthetic corticotropin (adrenocorticotropic hormone) and anti-CD20 monoclonal antibodies, for example, are currently under investigation in clinical trials. In addition, these new interventions have dramatically impacted our understanding of the mechanisms of the disease. Phase II-IV clinical trials targeting new mechanisms and/or molecules are in progress. The list is long and includes drugs blocking the adaptive immune system (abatacept and anti-CD40 antibodies), as well as retinoids and the sialic acid precursor N-acetyl-D-mannosamine (ManNAc), two agents that affect the sieving properties of the glomerular basement membrane. Other drugs are being tested against FSGS and, if successful, could also be utilized against MCD. Clinical trials currently in progress should furnish a proper solution to what appears to be a solvable problem.

AIMS: Anti‐CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti‐CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions. METHODS: We investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid‐dependent and steroid/calcineurin inhibitor‐dependent disease) treated at a national referral centre over a 9‐year period (400 treatments; follow‐up 1–9 years). RESULTS: Infusion reactions were mainly absent in children with steroid‐dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short‐term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3–9 months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein–Barr virus and John Cunningham virus activation markers were occasionally observed. CONCLUSION: Overall, the toxicity of anti‐CD20 monoclonal antibodies was limited to post‐infusion side effects in children with more complex disease. The relatively safe profile of anti‐CD20 antibodies supports their use as steroid‐sparing agents in children with INS.

Magnetic resonance imaging (MRI) is the radiological examination method of choice for evaluating hypothalamo-pituitary-related endocrine disease and is considered essential in the assessment of patients with suspected hypothalamo-pituitary pathology. Physicians involved in the care of such patients have, in MRI, a valuable tool that can aid them in determining the pathogenesis of their patients' underlying pituitary conditions. Indeed, the use of MRI has led to an enormous increase in our knowledge of pituitary morphology, improving, in particular, the differential diagnosis of hypopituitarism. Specifically, MRI allows detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. MRI recognition of pituitary hyperintensity in the posterior part of the sella, now considered a marker of neurohypophyseal functional integrity, has been the most striking finding in the diagnosis and understanding of certain forms of 'idiopathic' and permanent growth hormone deficiency (GHD). Published data show a number of correlations between pituitary abnormalities as observed on MRI and a patient's endocrine profile. Indeed, several trends have emerged and have been confirmed: (i) a normal MRI or anterior pituitary hypoplasia generally indicates isolated growth hormone deficiency that is mostly transient and resolves upon adult height achievement; (ii) patients with multiple pituitary hormone deficiencies (MPHD) seldom show a normal pituitary gland; and (iii) the classic triad of ectopic posterior pituitary, pituitary stalk hypoplasia/agenesis and anterior pituitary hypoplasia is more frequently reported in MPHD patients and is generally associated with permanent GHD. Pituitary abnormalities have also been reported in patients with hypopituitarism carrying mutations in several genes encoding transcription factors. Establishing endocrine and MRI phenotypes is extremely useful for the selection and management of patients with hypopituitarism, both in terms of possible genetic counselling and in the early diagnosis of evolving anterior pituitary hormone deficiencies. Going forward, neuroimaging techniques are expected to progressively expand and improve our knowledge and understanding of pituitary diseases.

Ofatumumab is an anti‐CD20 humanized monoclonal antibody utilized in the treatment of several clinical conditions resistant to other treatments. In spite there was a general expectation that ofatumumab was less toxic compared to rituximab, side effects have been reported that resemble those of its anti‐CD20 chimeric precursor. Here, we describe the first case of Ofatumumab associate lung injury occurring in a 14‐year‐old boy affected by nephrotic syndrome dependent to prednisone plus cyclosporine A who had been treated with the dose of drug utilized in nephrotic syndrome (1500 mg/173 m2). The patient developed the full blown picture of rituximab associated lung injury (RALI) after 45 days from ofatumumab infusion at the end of the steroid tapering: severe exertional dyspnea, mild fever and cyanosis, with CT scan showing diffuse ground glass areas in both lungs and DLCO (diffusing capacity of transfer factor of the lung for carbon monoxide) test suggestive for reduction of CO diffusion. Clinical outcome was good with rapid improvement and normalization of all parameters without any specific therapy. After 60 days, chest CT and CO diffusion tests were normal. In conclusion, we describe here the first case of acute pneumonitis associated with ofatumumab that presents the same clinical, laboratory, and radiology features of the lung injury reported for rituximab. Like RALI occurring in patients treated for nephrotic syndrome, this case had a mild clinical expression and recovered in a few months.

Central diabetes insipidus (CDI) is the end result of a number of conditions that affect the hypothalamic-neurohypophyseal system. The known causes include germinoma/craniopharyngioma, Langerhans cell histiocytosis (LCH), local inflammatory, autoimmune or vascular diseases, trauma resulting from surgery or an accident, sarcoidosis, metastases and midline cerebral and cranial malformations. In rare cases, the underlying cause can be genetic defects in vasopressin synthesis that are inherited as autosomal dominant, autosomal recessive or X-linked recessive traits. The diagnosis of the underlying condition is challenging and raises several concerns for patients and parents as it requires long-term follow-up. Proper etiological diagnosis can be achieved via a series of steps that start with clinical observations and then progress to more sophisticated tools. Specifically, MRI identification of pituitary hyperintensity in the posterior part of the sella, now considered a clear marker of neurohypophyseal functional integrity, together with the careful analysis of pituitary stalk shape and size, have provided the most striking findings contributing to the diagnosis and understanding of some forms of ‘idiopathic’ CDI. MRI STIR (short-inversion-time inversion recovery sequencing) is a promising technology for the early identification of LCH-dependent CDI.

ObjectiveControversies exist about posterior pituitary (PP) function in subjects with ectopic PP (EPP) and with cerebral midline defects and/or their co-occurrence. We investigate water and electrolyte disturbances in patients at risk for PP dysfunction.DesignThe study was conducted in a single Pediatric Endocrinology Research Unit.MethodsForty-two subjects with childhood-onset GH deficiency were subdivided into five groups: normal magnetic resonance imaging (n=8, group 1); EPP (n=15, group 2); septo-optic dysplasia (SOD) with normal PP (n=4, group 3); EPP and SOD without (n=7, group 4), and with additional midline brain abnormalities (n=8, group 5). At a mean age of 16.0±1.1 years, they underwent a 120 min i.v. infusion with hypertonic 5% saline and evaluation of plasma osmolality (Posm), arginine vasopressin (AVP), thirst score (in groups 1 and 2), and urinary osmolality were performed.ResultsMean Posm and AVP significantly increased from baseline scores (284.7±4.9 mosm/kg and 0.6±0.2 pmol/l) to 120 min after saline infusion (300.5±8.0 mosm/kg and 10.3±3.3 pmol/l, PPConclusionsPatients with midline brain abnormalities and EPP have defective osmoregulated AVP. Patients with EPP and congenital hypopituitarism have normal PP function.