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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 the progress in current treatments, the event-free survival of high-risk neuroblastoma (HR-NB) patients does not exceed 40%-50%, and the prognosis of refractory or relapsed patients is poor, still representing a challenge for pediatric oncologist. Therapeutic Iodine-131 meta-iodobenzylguanidine (Th-131 I-MIBG) is a recognized safe and potentially effective treatment for NB. Materials This retrospective study reports the outcomes of 28 MIBG-avid NB patients with advanced disease either refractory or relapsed, which was undertaken from 1996 to 2014. Th-131 I-MIBG was administered shortly before (median: 17 days) high-dose chemotherapy with busulfan and melphalan (HD-BuMel) and autologous stem cell rescue (ASCR) at the Gaslini Institute in Genoa, with the aim of analyzing the 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 ASCR for neutrophils and platelets, 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, whereas 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 that occurred in nine patients (31.1%). After Th-131 MIBG and HD-BuMel, 19 patients (67.8%) showed an improvement in disease status. Over a median follow-up of 15.9 years, the three-year and five-year overall survival (OS) probabilities were 53% (CI 0.33-0.69) and 41% (CI 0.22-0.59), and the three-year and five-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;P = 0.041). Conclusion Th-131 I-MIBG administered shortly before HD-BuMel is a safe and effective regimen for patients with advanced MIBG-avid NB. These patients should be managed in centers with proven expertise.

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.

MODY is a monogenic, autosomal dominant form of diabetes mellitus. MODY can be caused by mutations in several genes; glucokinase (GCK) accounts for 30-50% of the cases. The diagnosis can be suspected in early-onset diabetes with atypical features for type 1/type 2. Treatment is usually not recommended. A 5-year-old girl came to our attention for occasional episodes of hyperglycaemia. She was born at term, her birth weight was small for gestational age. At the beginning of her pregnancy, her mother was already on insulin therapy for impaired fasting glucose levels, detected before conception and confirmed in the first weeks of gestation. She was treated with insulin until the childbirth without further investigations. The patient was asymptomatic and in good clinical condition. Basal blood tests have shown a fasting plasma glucose of 125 mg/dl, an HbA1c of 6.5%. Antibodies against islet cells, anti-GAD and anti-ZNT8 antibodies were all negative. A 2-h oral glucose tolerance test was performed and underlined an impaired glucose tolerance. HLA haplotypes were screened, excluding susceptibility. GCK Sanger Sequencing identified a novel heterozygous variant. It is not described as a classical mutations. The analysis has been extended to the parents, finding out the same variant in her mother. To our knowledge this mutation has not been described previously; we believe that this variant is responsible for MODY2 due to FBG and Hb1Ac of all the affected members of family. We suggest high suspicion of an underlying GCK variant in SGA children with hyperglycaemia born to a diabetic mother.

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.

Introduction The availability of pediatric age- and sex-matched reference curves for bone markers is essential for appropriate assessment of bone turnover and treatment follow-up of bone disorders. The aim of this work was to obtain updated reference equations for collagen type I C-telopeptides (CTX-1) and bone alkaline phosphatase (BAP) by using an alternative statistical approach. The study included 1502 Italian pediatric subjects from 6 months to 16 years of age (686 females and 816 males) subjected to CTX-1 and BAP measurement during a six-year period. Methods The unselected population of patients was used for the calculation of age- and sex-matched reference curves by using a multivariate statistical analysis after an appropriate validation with a selected population of 184 healthy subjects (6 months-16 years; 88 females and 96 males). The effect of age, sex, puberty based on Tanner stage evaluation and anthropometrics on the variations of the two bone markers was then studied. Results Pediatric reference curves were obtained for CTX-1 and BAP from 3465 results retrieved by our Laboratory Information System. The equations for the calculation of reference values were obtained for boys and girls. The two bone markers markedly varied according to age, sex and pubertal stage with females displaying higher values during Tanner stages II and III and males during stages III and IV. Conclusions The application of a novel statistical approach provided reference curves for CTX-1 and BAP. This method, moreover, could be applied in pediatrics to obtain reference intervals for other biomarkers.

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.