Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.

Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I.

Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re-evaluated the NF1 gene variants found in the period 2000-2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2-11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non-homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5' end of NF1 had a lower age-related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5' end of the NF1 gene although not significant at the multivariate analysis.

Health-related quality of life and metabolic control in immigrant and Italian children and adolescents with type 1 diabetes and in their parents.

OBJECTIVE: To determine if the diabetes-specific health-related quality of life (D-HRQOL) of young people with type 1 diabetes (T1D) and their parents is influenced by migrant status. SUBJECTS AND METHODS: One hundred and twenty-five patients (12.4 ± 3.55 years, males 53.6%) with T1D and their parents (102 mothers, 37 fathers) were enrolled and categorized into: group A (both foreign parents) and group B (both native Italian parents). The Pediatric Quality of Life Inventory™ 3.0 Diabetes Module (PedsQL™ 3.0 DM) was used to evaluate the D-HRQOL. Data on diabetic ketoacidosis (DKA) at T1D onset, insulin therapy, and glycosylate hemoglobin (HbA1c) were also collected. RESULTS: Group A (n = 40), compared to group B (n = 85), had higher frequency of DKA at T1D onset (P < .001) and a lower use of sensor augmented insulin pump (P = .015). HbA1c values were higher in group A than in group B (P < .001). Patients' "Diabetes symptoms" (P = .004), "Treatment barriers" (P = .001), and "Worry" (P = .009) scales scores were lower in group A than in group B. Mothers of group A had lower scores in "Diabetes symptoms" (P = .030), "Treatment barriers" (P < .001), "Treatment adherence" (P = .018), "Communication" (P = .009) scales, and total score (P = .011) compared to the group B ones. High PedsQL™ 3.0 DM was significantly associated with being Italian, being prepubertal, and having lower HbA1c mean levels. CONCLUSIONS: Being a migrant confers disadvantages in terms of D-HRQOL and metabolic control in children and adolescents with T1D. Specific educational interventions should be considered in the clinical care of patients with migration background, to improve D-HRQOL and health status.

Endocrine Disrupting Chemicals and Type 1 Diabetes.

Type 1 diabetes (T1D) is the most common chronic metabolic disease in children and adolescents. The etiology of T1D is not fully understood but it seems multifactorial. The genetic background determines the predisposition to develop T1D, while the autoimmune process against ß-cells seems to be also determined by environmental triggers, such as endocrine disrupting chemicals (EDCs). Environmental EDCs may act throughout different temporal windows as single chemical agent or as chemical mixtures. They could affect the development and the function of the immune system or of the ß-cells function, promoting autoimmunity and increasing the susceptibility to autoimmune attack. Human studies evaluating the potential role of exposure to EDCs on the pathogenesis of T1D are few and demonstrated contradictory results. The aim of this narrative review is to summarize experimental and epidemiological studies on the potential role of exposure to EDCs in the development of T1D. We highlight what we know by animals about EDCs' effects on mechanisms leading to T1D development and progression. Studies evaluating the EDC levels in patients with T1D were also reported. Moreover, we discussed why further studies are needed and how they should be designed to better understand the causal mechanisms and the next prevention interventions.

Isolated hypoaldosteronism as first sign of X-linked adrenal hypoplasia congenita caused by a novel mutation in NR0B1/DAX-1 gene: a case report.

BACKGROUND: X-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1. Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease. CASE PRESENTATION: A 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC. CONCLUSIONS: AHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.

Anthropometric characteristics of newborns with Prader-Willi syndrome.

This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader-Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p < .0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS.

The Approach to a Child with Dysmorphic Features: What the Pediatrician Should Know.

The advancement of genetic knowledge and the discovery of an increasing number of genetic disorders has made the role of the geneticist progressively more complex and fundamental. However, most genetic disorders present during childhood; thus, their early recognition is a challenge for the pediatrician, who will be also involved in the follow-up of these children, often establishing a close relationship with them and their families and becoming a referral figure. In this review, we aim to provide the pediatrician with a general knowledge of the approach to treating a child with a genetic syndrome associated with dysmorphic features. We will discuss the red flags, the most common manifestations, the analytic collection of the family and personal medical history, and the signs that should alert the pediatrician during the physical examination. We will offer an overview of the physical malformations most commonly associated with genetic defects and the way to describe dysmorphic facial features. We will provide hints about some tools that can support the pediatrician in clinical practice and that also represent a useful educational resource, either online or through apps downloaded on a smartphone. Eventually, we will offer an overview of genetic testing, the ethical considerations, the consequences of incidental findings, and the main indications and limitations of the principal technologies.

Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

Real-life long-term efficacy and safety of recombinant human growth hormone therapy in children with short stature homeobox-containing deficiency.

Objective: This Italian survey aims to evaluate real-life long-term efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with short stature homeobox-containing gene deficiency disorders (SHOX-D) and to identify potential predictive factors influencing response to rhGH therapy. Design and methods: This is a national retrospective observational study collecting anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhGH. Data were collected at the beginning of rhGH therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3 and T4) and at near-final height (nFH) (T5), when available. Results: One hundred and seventeen SHOX-D children started rhGH therapy (initial dose 0.23 ± 0.04 mg/kg/week) at a mean age of 8.67 ± 3.33 years (74% prepubertal), 99 completed the first year of treatment and 46 reached nFH. During rhGH therapy, growth velocity (GV), standard deviation score (SDS) and height (H) SDS improved significantly. Mean H SDS gain from T0 was +1.14 ± 0.58 at T4 and +0.80 ± 0.98 at T5. Both patients carrying mutations involving intragenic SHOX region (group A) and ones with regulatory region defects (group B) experienced a similar beneficial therapeutic effect. The multiple regression analysis identified the age at the start of rhGH treatment (ß = -0.31, P = 0.030) and the GV during the first year of rhGH treatment (ß = 0.45, P = 0.008) as main independent predictor factors of height gain. During rhGH therapy, no adverse event of concern was reported. Conclusions: Our data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless the wide variety of genotype. Significance Statement: Among children with idiopathic short stature, the prevalence of SHOX-D is near to 1/1000-2000 (1.1-15%) with a wide phenotypic spectrum. Current guidelines support rhGH therapy in SHOX-D children, but long-term data are still few. Our real-life data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless of the wide variety of genotypes. Moreover, rhGH therapy seems to blunt the SHOX-D phenotype. The response to rhGH in the first year of treatment and the age when rhGH was started significantly impact the height gain.

The impact of BMI on long-term anthropometric and metabolic outcomes in girls with idiopathic central precocious puberty treated with GnRHas.

Background: Gonadotropin-releasing hormone analogs (GnRHas) are effective in increasing the final height of children with idiopathic central precocious puberty (ICPP). However, in previous years, some transient metabolic complications have been described during this treatment, for which there are no long-term outcome data. Our study aimed to evaluate the efficacy of GnRHas and clarify if body mass index (BMI) at diagnosis of ICPP could influence long-term outcomes. Methods: This was an observational, retrospective study that recruited a cohort of girls with ICPP. Data for anthropometric measures, fasting lipid profile, and glucose metabolism were collected at baseline [when GnRHas treatment started (T1)], at the end of the treatment (T2), and near-final height (nFH) or final height (FH) (T3). Predicted adult height (PAH) was calculated at T1 following Bayley and Pinneau's method. Analysis was carried out using BMI standard deviation score (SDS) categories at T1 (group A, normal weight, vs. group B, overweight/obese). Results: Fifty-seven girls with ICPP who were treated with GnRHas were enrolled in the study (group A vs. group B: 33 vs. 24 patients, aged 7.86 ± 0.81 vs. 7.06 ± 1.61 years, respectively; p < 0.05). In the study population, nFH/FH was in line with the target height (TH) (p = 0.54), with a mean absolute height gain of 11.82 ± 5.35 cm compared with PAH. Even if the length of therapy was shorter (group A vs. group B: 1.84 ± 2.15 vs. 2.10 ± 0.81 years, respectively; p < 0.05) and the age at menarche was younger (group A vs. group B: 10.56 ± 1.01 vs. 11.44 ± 0.85 years, respectively; p < 0.05) in group B than in group A, the nFH/FH gain was still comparable between the two groups (p = 0.95). At nFH/FH, BMI SDS was still greater in group B than in group A (p = 0.012), despite the fact that BMI SDS significantly increased in group A only (p < 0.05). Glucose metabolism got worst during GnRHa with a complete restoring after it, independently from pre-treatment BMI. The ratio of low-density to high-density lipoprotein cholesterol transiently deteriorated during treatment with GnRHas in group A only (p = 0.030). Conclusions: Our results confirm the effectiveness of treatment with GnRHas on growth and do not support the concern that being overweight and obese can impair the long-term outcomes of GnRHas therapy. However, the observed transient impairment of metabolic parameters during treatment suggests that clinicians should encourage ICPP girls treated with GnRHas to have a healthy lifestyle, regardless of their pretreatment BMI.

Growth hormone deficiency in a child with benign hereditary chorea caused by a de novo mutation of the TITF1/NKX2-1 gene.

OBJECTIVES: Benign Hereditary Chorea (BHC) (MIM 118700) is a rare childhood-onset movements disorder characterized by non-progressive chorea. It is usually caused by variants in the thyroid transcription factor 1 (TITF-1/NKX2-1) gene and it is associated with thyroid dysfunction and pulmonary symptoms in the brain-lung-thyroid syndrome. CASE PRESENTATION: We reported the clinical case of a toddler presenting with neurological symptoms (hypotonia, delayed motor milestones, and axial dystonia) and subclinical hypothyroidism in which we found a 'de novo' variant in the NKX2-1 gene. CONCLUSIONS: The peculiarity of our case is that the mild alteration of thyroid-stimulating hormone (TSH) levels, hypotonia, and delayed motor milestones were associated with growth hormone deficiency.

Longitudinal evaluation of endothelial markers in children and adolescents with familial hypercholesterolemia.

BACKGROUND AND AIM: Children with heterozygous familial hypercholesterolemia (heFH) are at risk of premature atherosclerosis. Aims of this study were: (a) to longitudinally evaluate the endothelial dysfunction, estimated through brachial flow mediated dilation (FMD), as first sign of subclinical atherogenesis in a group of children and adolescents affected by heFH in comparison to normo-lipidemic controls, and (b) to identify predictive factors influencing the endothelial function and its development in the same cohort of patients. METHODS: This is a prospective, longitudinal and cross-sectional study. Physical examination, plasma lipid profile and brachial artery FMD were measured at baseline and after follow-up. RESULTS: At baseline, FMD did not differ between heFH children (n.24, median age 9.71) and controls (n. 24, median age 10.29) (7.67 ± 9.26 vs. 11.18 ± 7.28 %, p 0.09). Nevertheless, during follow-up (median length of lipid-lowering diet 4.52 years), FMD got worse in 54% of heFH subjects and its worsening correlated to the increasing of low-density lipoprotein cholesterol (r -0.21, p < 0.05). Moreover, being male (ß -0.46, p 0.03), undergoing puberty (ß -0.61, p 0.03) and increasing of body mass index standard deviation score (ß -0.39, p 0.03) were identified as main independent predictor factors of FMD drop. CONCLUSIONS: During the first decades of life, not only hypercholesterolemia, but also clusters of pro-atherogenic conditions and their persistence, could affect the endothelial function and its trend. (www.actabiomedica.it).

Homozygous n.64C>T mutation in mitochondrial RNA-processing endoribonuclease gene causes cartilage hair hypoplasia syndrome in two siblings.

Cartilage hair hypoplasia syndrome (OMIM # 250250) is a rare autosomal recessive metaphyseal dysplasia, characterized by disproportionate short stature, hair hypoplasia and variable extra-skeletal manifestations, including immunodeficiency, anemia, intestinal diseases and predisposition to cancers. Cartilage hair hypoplasia syndrome has a broad phenotype and it is caused by homozygous or compound heterozygous mutation in the mitochondrial RNA-processing endoribonuclease on chromosome 9p13. Although it is well known as a primordial dwarfism, descriptions of the prenatal growth are missing. To add further details to the knowledge of the phenotypic spectrum of the disease, we report on two siblings with cartilage hair hypoplasia syndrome, presenting n.64C > T homozygous mutation in the mitochondrial RNA-processing endoribonuclease gene. We describe the prenatal and postnatal growth pattern of the two affected patients, showing severe pre- and post-natal growth deficiency.

Copy Number Variation Analysis Increases the Number of Candidate Loci Associated with Pediatric Obesity.

BACKGROUND/AIMS: Obesity is a multifactorial disease caused by the interaction of genetic, environmental, and behavioral factors. Currently, only a small number of obese children undergo genetic analysis, usually when obesity is associated with dysmorphic features. The aim of this study was to identify genomic rearrangement causing obesity. METHODS: We analyzed the DNA of children and adolescents by single-nucleotide polymorphism-array (platform CytoScan HD, Affymetrix). Patients included in this study were obese with dysmorphic features and/or intellectual disabilities and/or neuropsychomotor signs. RESULTS: Ninety-four children and adolescents with obesity (9.25 ± 4.04 years old, 60 males) were enrolled in the study. Dysmorphic features were found in 64 out of 94 subjects (68.1%), intellectual disability was found in 23 subjects (24.5%), and other neuropsychomotor signs in 31 (32.9%). Copy number variations (CNVs) were identified in 43 out of 94 patients (45.7%): among these 14 subjects showed at least 1 deletion, 22 duplication, whereas 7 patients showed both deletion and duplication. In 20 subjects (13 males), CNVs were linked or possibly related with obesity; in 23 subjects, this correlation cannot be inferred. CONCLUSION: A genetic origin of obesity was detected in about half of our obese children and adolescents with associated dysmorphic features and/or intellectual disability and/or neuropsychomotor signs. In these children, array-CGH analysis can be useful to identify causative genetic mutations, with consequent advantage in therapeutic management and follow-up of these patients.

EEG Patterns in Patients with Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a rare disease determined by the loss of the paternal copy of the 15q11-q13 region, and it is characterized by hypotonia, hyperphagia, obesity, short stature, hypogonadism, craniofacial dysmorphisms, and cognitive and behavioral disturbances. The aims of this retrospective study were to analyze interictal EEG findings in a group of PWS patients and to correlate them with genetic, clinical, and neuroimaging data. The demographic, clinical, genetic, EEG, and neuroimaging data of seventy-four patients were collected. Associations among the presence of paroxysmal EEG abnormalities, genotype, and clinical and neuroimaging features were investigated. Four patients (5.4%) presented drug-sensitive epilepsy. Interictal paroxysmal EEG abnormalities-focal or multifocal-were present in 25.7% of the cases, and the normalization of the EEG occurred in about 25% of the cases. In 63.2% of the cases, the paroxysmal abnormalities were bilaterally localized over the middle-posterior regions. Brain magnetic resonance imaging (MRI) was performed on 39 patients (abnormal in 59%). No relevant associations were found between paroxysmal EEG abnormalities and all of the other variables considered. Interictal paroxysmal EEG abnormalities-in particular, with a bilateral middle-posterior localization-could represent an important neurological feature of PWS that is not associated with genotype, cognitive or behavioral endophenotypes, MRI anomalies, or prognosis.

COVID-19 and Type 1 Diabetes: Concerns and Challenges.

Due to the current COVID-19 pandemic, worldwide population's lifestyle has changed dramatically, causing psychosocial consequences.  Patients presenting a preexisting chronic condition, as Type 1 Diabetes (T1D), are the ones suffering the most from this situation. Moreover, people affected by diabetes are the ones with the worst prognosis, if infected by SARS-CoV-2.  We analyzed why patients with T1D were poorly represented between the subjects hospitalized for COVID-19 and why the cases of diabetic ketoacidosis (DKA) were fewer and more severe compared with the past years. Furthermore, literature has showed how patients of all ages with T1D did not experience a deterioration in their glucose control throughout the lockdown. Among other causes, this is also due to the surging use of telemedicine. Finally, we tried to understand how the coronavirus tropism for endocrine tissues could influence the future epidemiology of T1D, focusing on the effects they have on pancreatic ß-cells.

Glycemic Control Improvement in Italian Children and Adolescents With Type 1 Diabetes Followed Through Telemedicine During Lockdown Due to the COVID-19 Pandemic.

Background/Objective: To minimize the wide spread of coronavirus disease (COVID-19) pandemic, Italy was placed in an almost complete lockdown state that forced people to "stay at home". Aim of this study was to evaluate the effects of lockdown on glycemic control in children and adolescents with type 1 diabetes (T1D) followed through telemedicine. Subjects/Methods: This observational study involved patients with T1D using the real-time continuous glucose monitoring (CGM) Dexcom G6®. Ambulatory glucose profile data from the 3-months before schools closure (November 26, 2019-February 23, 2020; T0) and from the 3-months of consecutive lockdown (February 24-May 18, 2020; T1) were compared. Results: Sixty-two children and adolescents (11.1 ± 4.37 years, 50% males) with T1D (median time disease 3.67 years) were enrolled in the study. Insulin total daily dose was unchanged, while time spent on physical activities was decreased (p<0.0001). Despite the lack of statistical significance, median value of the glucose management indicator decreased from 7.4% to 7.25%. Glucose standard deviation (p<0.0001) and coefficient of variation (p=0.001) improved across the study. Median time in range increased from 60.5% to 63.5% (p=0.008), time above range decreased from 37.3% to 34.1% (p=0.048), and time below range decreased from 1.85% to 1.45% (p=0.001). Conclusions: Overall, in our children and adolescents with T1D glycemic control improved during lockdown. Despite patients were confined to their homes and limited to exercise, our data suggest that the use of real-time CGM, the continuous parental management, and the telemedicine can display beneficial effects on T1D care.

Uniparental disomy and pretreatment IGF-1 may predict elevated IGF-1 levels in Prader-Willi patients on GH treatment.

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.

Low-density lipoprotein oxidizability in children with chronic renal failure.

BACKGROUND: In childhood, dyslipidemia and low-density lipoprotein (LDL) oxidation play an important role in the development of atherosclerosis. Alterations of these factors have been shown in adult uremic patients. METHODS: Nine children affected by chronic renal failure (CRF; urinary tract malformation, n = 8; polycystic kidney disease, n = 1) were studied to investigate the abnormalities of plasma lipoprotein concentration and composition and to assess the susceptibility of LDL to oxidation. All patients with CRF were on conservative treatment and, after informed consent, underwent the evaluation of (i) quantitative and qualitative plasma lipid profile; (ii) lipoprotein oxidation in vitro; and (iii) lipoprotein anti-oxidant content. These results were compared to those of an age-matched control group of eight healthy children. RESULTS: Total cholesterol, LDL and triglycerides were significantly higher in CRF than in the control group. The composition of lipoproteins was different in the two groups: the amount of anti-oxidant factors (alpha-, gamma-tocopherol and carotenoids) was different in CRF and normal controls children, while LDL susceptibility to oxidation was significantly higher in uremic children than in controls. CONCLUSIONS: CRF patients, already before dialysis, have a higher LDL oxidizability due to an altered lipoprotein composition and a low anti-oxidant content; therefore they have higher risk factors for atherosclerosis. On the basis of these data, supplementation with anti-oxidants might be useful in CRF children, but further studies are needed to evaluate the efficacy and safety of this therapeutic intervention.

Central Precocious Puberty and Response to GnRHa Therapy in Children with Cerebral Palsy and Moderate to Severe Motor Impairment: Data from a Longitudinal, Case-Control, Multicentre, Italian Study.

BACKGROUND: Children affected by neurodevelopmental disability could experience early pubertal changes at least 20 times more than the general population. Limited data about central precocious puberty (CPP) among children affected by cerebral palsy (CP) are available. METHODS: This is a longitudinal, observational, retrospective, case-control study involving 22 children affected by CPP and CP (group A), 22 paired with CP but without CPP (group B), and 22 children with CPP without CP. Auxological, biochemical, and instrumental data were collected at diagnosis of CPP and at 2 follow-up visits. RESULTS: No differences were detected between groups A (at baseline) and B. At diagnosis of CPP, height SDS adjusted for target height (H-TH SDS) was significantly reduced in A than in C (-0.63 ± 1.94 versus 1.56 ± 1.38), while basal LH and oestradiol levels were significantly elevated in A than in C. During follow-up, despite an effective treatment, growth impairment deteriorated in A than in C (Δ H-SDS from diagnosis of CPP to last follow-up: -0.49 ± 0.91 versus 0.21 ± 0.33, p = 0.023). CONCLUSIONS: Diagnosis of CPP could be partially mislead in CP due to growth failure that got worse during follow-up despite therapy. CPP in CP seems to progress rapidly along time supporting the hypothesis of a more intense activation of hypothalamic-pituitary-gonadal-axis in these patients.