Case report: Long term response to growth hormone in a child with Silver-Russell syndrome-like phenotype due to a novel paternally inherited IGF2 variant.

Silver-Russell syndrome (SRS, OMIM, 180860) is a rare genetic disorder with a wide spectrum of symptoms. The most common features are intrauterine growth retardation (IUGR), poor postnatal development, macrocephaly, triangular face, prominent forehead, body asymmetry, and feeding problems. The diagnosis of SRS is based on a combination of clinical features. Up to 60% of SRS patients have chromosome 7 or 11 abnormalities, and <1% show abnormalities in IGF2 signaling pathway genes (IGF2, HMGA2, PLAG1 and CDKN1C). The underlying genetic cause remains unknown in about 40% of cases (idiopathic SRS). We report a novel IGF2 variant c.[-6-2A>G] (NM_000612) in a child with severe IUGR and clinical features of SRS and confirm the utility of targeted exome sequencing in patients with negative results to common genetic analyses. In addition, we report that long-term growth hormone treatment improves height SDS in this patient.

Urinary Bisphenol-A (BPA) and Bis(2-ethylhexyl)phthalate (DEHP) metabolite concentrations in children with obesity: A case-control study.

Introduction Obesity is a worldwide public health problem. Experimental animal and in vitro studies suggest that the exposure to BPA and phthalates are associated to a higher risk of obesity. Objective To determine urinary excretion of bisphenol A and phthalates in obese and normal weight children. Methods A case-control study was conducted in 122 children. Sixty-six obese children 36 girls (mean age 8.41±1.27 years) and 30 boys (mean age 8.51 ± 1.33 years), and 56 normal weight children, 27 girls (mean age 7.64 ± 1.49 years) and 29 boys (mean age 7.77 ± 1.56 years) were studied. Urinary BPA and Bis(2-ethylhexyl) phthalate (DEHP) metabolites (MEHP, MEHHP and MEOHP) were measured respectively by gas chromatography and high-performance liquid chromatography. Individual determinants of exposure were evaluated through "ad hoc" questionnaires. Results BPA and DEHP metabolites were detectable in obese and normal weight children. Obese girls showed significantly higher BPA concentrations in comparison with normal weight girls (means 10.77, 95% CI 7.02-16.53 vs 5.50, 95% CI 3.93-7.71 µg/g creatinine, respectively, p< 0.02). The first step of DEHP metabolic rate was significantly higher in obese girls compared with controls (p<0.05). DEHP metabolites correlated significantly with leptin concentrations in obese girls (p< 0.03). A higher risk of obesity was found in children with BPA levels above the median values with the habit to eat food packaged (OR=11.09, 95% CI=1.28-95.78). Conclusions These findings show that a higher exposure to BPA is associated with the risk of obesity in girls. Further studies are needed to unveil the cause-effect relationship.

COVID-19 pandemic phases and female precocious puberty: The experience of the past 4 years (2019 through 2022) in an Italian tertiary center.

Objective: Since the outbreak of COVID-19 pandemic, several centers of pediatric endocrinology worldwide have observed a significant increase in the number of girls presenting with precocious or early puberty. We aimed to compare the incidence rates of female precocious puberty before and during the different phases of COVID-19 pandemic. Methods: We have retrospectively analyzed all the consultations recorded in the outpatient clinic database of the Endocrinology Unit of Bambino Gesù Children's Hospital, Rome, Italy, from the lockdown start in March 2020 up to September 2020, in comparison with the consultations recorded in the same months of 2019, 2021 and 2022. Age, height, weight, body mass index, Tanner's pubertal stage and bone age at presentation, birth weight, ethnicity, family history of central precocious puberty (CPP), maternal age at menarche, history of adoption were retrieved from clinical records. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) both at baseline and after gonadotropin-releasing hormone (GnRH) stimulation, and basal estradiol levels were collected. Results: In 2019, 78 girls with suspected precocious puberty were referred for endocrinological consultation, compared to 202 girls in 2020, 158 girls in 2021 and 112 girls in 2022. A significant increase in the proportion of girls diagnosed with rapidly progressive CPP was observed in 2020, compared to 2019 (86/202 vs. 18/78, p<0.01). In the following periods of 2021 and 2022, a gradual decrease in the number of cases of progressive CPP was evident, so much that the number of cases was not significantly different from that observed in 2019 (56/158 in 2021 and 35/112 in 2022, p=0.054 and p=0.216 respectively, compared to 2019). Conclusions: Our research suggests that drastic lifestyle changes, such as those imposed by COVID-19 lockdown, and the consequent stress may affect the regulation of pubertal timing. The remarkable increase in CPP cases observed during the 2020 first pandemic wave seems to be reduced in 2021 and 2022, concurrently with the progressive resumption of daily activities. These data seem to support the hypothesis of a direct relationship between profound life-style changes related to the pandemic and the rise in precocious puberty cases.

Governance Innovations for forest ecosystem service provision - Insights from an EU-wide survey.

This paper analyses the occurrence of governance innovations for forest ecosystem service (FES) provision in the forestry sector in Europe and the factors that influence innovation development. Based on a European-wide online survey, public and private forest owners and managers representing different property sizes indicate what type of governance innovation activities they engage in, and why. To investigate forestry innovations as systems, the analysis focuses on biophysical, social and technical factors influencing innovation development. The results of our exploratory quantitative analysis show that most innovation activities identified are largely oriented towards biomass production. Accordingly, most forest owners implement efficiency-driven optimisation strategies for forest management and technological improvement for provisioning service supply, to generate income. In contrast, the provision of regulating and cultural services is not yet a prominent part of forestry innovation activities.Reasons are rooted in a market-oriented economic rationale focusing on timber production, a lack of financial resources to compensate for other FES provisions or institutions to provide backup and security to forest owners and managers for engaging in innovation development. Given that the provision of a wide range of FES is a politically well-established objective for forest management in Europe, a strategy is needed that helps to align actors and sectors for supporting and co-financing related forest management approaches and business models. The current revision of the forest related policy framework on EU level under the EU Green deal poses a window of opportunity for better fostering novel governance approaches for more sustainable FES provision.

A novel homozygous variant in COX5A causes an attenuated phenotype with failure to thrive, lactic acidosis, hypoglycemia, and short stature.

Genetic defect in the nuclear encoded subunits of cytochrome c oxidase are very rare. To date, most deleterious variants affect the mitochondrially encoded subunits of complex IV and the nuclear genes encoded for assembly factors. A biallelic pathogenic variant in the mitochondrial complex IV subunit COX5A was previously reported in a couple of sibs with failure to thrive, lactic acidosis and pulmonary hypertension and a lethal phenotype. Here, we describe a second family with a 11-year-old girl presenting with failure to thrive, lactic acidosis, hypoglycemia and short stature. Clinical exome revealed the homozygous missense variant c.266 T > G in COX5A, which produces a drop of the corresponding protein and a reduction of the COX activity. Compared to the previous observation, this girl showed an attenuated metabolic derangement without involvement of the cardiovascular system and neurodevelopment. Our observation confirms that COX5A recessive variants may cause mitochondrial disease and expands the associated phenotype to less severe presentations.

"Impact of COVID-19 pandemic lockdown on early onset of puberty: experience of an Italian tertiary center".

At the end of 2019, an emerging atypical pneumonia called COVID-19 (coronavirus disease 2019), caused by the novel coronavirus defined as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), was first reported. COVID-19 rapidly expanded leading to an epidemic in China, followed by a global pandemic during the year 2020. In few weeks Italy was assaulted by a severe health emergency, constraining the Italian government to put in place extraordinary restrictive measures, such as school closures and a strict lockdown extended to the entire country at the beginning of March 2020. Since the beginning of lockdown, the Endocrinology Unit of Bambino Gesù Children's Hospital has recorded a rapid increase of the outpatient consultations for suspected precocious or early puberty. We have now retrospectively analyzed all the consultations recorded in the database of our outpatient clinic from March to September 2020, and compared them with the consultations recorded in the same database from March to September 2019. Our preliminary data suggest a significant increase of precocious puberty cases in girls during the first period of COVID-19 pandemic. Further investigations in larger cohorts of children are needed in order to correlate the observed increase of precocious puberty with specific pathogenic factors.

Abnormal linear growth in paediatric adrenal diseases: Pathogenesis, prevalence and management.

Abnormal adrenal function can interfere with linear growth, potentially causing either acceleration or impairment of growth in paediatric patients. These abnormalities can be caused by direct effects of adrenal hormones, particularly glucocorticoids and sex steroids, or be mediated by indirect mechanisms such as the disturbance of the growth hormone-insulin-like growth factor-1 axis and aromatization of androgens to oestrogens. The early diagnosis and optimal treatment of adrenal disorders can prevent or minimize growth disturbance and facilitate improved height gain. Mechanisms of growth disturbance in the following abnormal states will be discussed; hypercortisolaemia, hyperandrogenaemia and obesity. Prevalence and features of growth disturbance will be discussed in ACTH-dependent and ACTH-independent Cushing's syndrome, adrenocortical tumours, premature adrenarche, congenital adrenal hyperplasia and adrenal insufficiency disorders. Recommendations for management have been included.

The impact of IGF-I, puberty and obesity on early retinopathy in children: a cross-sectional study.

BACKGROUND: Childhood obesity has been correlated with coronary heart disease, but the correlation with microvascular disease remains unclear. The retinal microcirculation is affected early in the process of atherosclerosis and it offers the opportunity to indirectly study the effects of obesity on small brain vessels. Insulin-like growth factor 1 (IGF-I) is involved in angiogenesis and it has a crucial role in retinal vascularization. METHODS: A single-centre cross-sectional study was performed in 268 children and adolescents (116 males; mean age 13.03 ± 1.9 years,) with overweight/obesity, in order to identify risk factors for early retinopathy. RESULTS: Nine patients (3.3%) showed signs of retinopathy, defined as arteriovenous crossings and/or papilledema. Body mass index and fat mass, analysed by Dual X-ray Absorptiometry, were not different in patients with or without retinopathy. Patients with retinopathy were pubertal and showed higher waist circumference (107.78 ± 15.83 versus 99.46 ± 10.85 cm; p: 0.027), waist circumference/height ratio (0.66 ± 0.07 versus 0.62 ± 0.05; p: 0.04) and IGF-I SDS (0.03 ± 1.3 versus - 0.66 ± 0.9; p: 0.04). Multivariate analysis (after correction for sex, age, family history of type 2 diabetes mellitus, obesity, cardiovascular disease, hypertension and dyslipidaemia) showed that waist circumference/height ratio and IGF-I SDS were the only variables independently correlated with the presence of retinopathy. CONCLUSIONS: Retinal vascular changes may become evident as an early complication of overweight and obesity, even during childhood and adolescence. Relatively high levels of IGF-I during this phase may act as an additional risk factor for microvascular damage. The screening for retinopathy should be proposed to all children and adolescents with overweight/obesity.

The LIFE PERSUADED project approach on phthalates and bisphenol A biomonitoring in Italian mother-child pairs linking exposure and juvenile diseases.

Phthalates and bisphenol A (BPA), plasticizers used in several products of daily life, are considered as endocrine disrupters, therefore children exposure is particularly relevant. The LIFE PERSUADED project aims to define the following: (a) the evaluation of internal levels of DEHP's metabolites and BPA in Italian children and their mothers, (b) the association of the exposure with puberty development and obesity diseases, and (c) the effects of exposure in juvenile in vivo model. The cross-sectional study has involved 2160 mother-child pairs, including males and females, children and adolescents, from urban and rural areas of North, Center, and South Italy. A structured questionnaire and a food diary are designed to evaluate the association between lifestyle variables potentially related to DEHP/BPA exposure and internal levels, through univariate and multivariate analyses. Two pilot case-control studies are carried out on idiopathic premature thelarche and precocious puberty (30 girls each group, aged 2-7 years) and idiopathic obesity (30 boys and 30 girls, aged 6-10 years), matched to healthy controls. BPA and DEHP's metabolites are analyzed in urine samples from all recruited subjects. Clinical and toxicological biomarkers are evaluated in serum of case-control subjects. Moreover, the toxicity study is carried out in a juvenile rodent model exposed to mixtures of BPA and DEHP at dose levels recorded in children population. The scientific results of LIFE PERSUADED will contribute to risk assessment of BPA and DEHP.

Endocrine implications of neurofibromatosis 1 in childhood.

In 1882, von Recklinghausen described a group of patients with multiple tumors arising from the 'endoneurium' of peripheral nerves, and called them 'neurofibromas'. The term von Recklinghausen disease was used up to the end of the 20th century, when the gene of neurofibromatosis (NF1) was cloned on chromosome 17q11.2. The gene product is a cytoplasmic protein termed neurofibromin, regulating proliferation and maturation of both glial and neuronal progenitors during embryogenesis. Loss of neurofibromin function determines the hyperactivation of the proto-oncogene RAS, leading to an increased risk of tumor formation, predominantly affecting the skin, bone and the nervous system. NF1 is clinically and genetically distinct from neurofibromatosis type 2, characterized by bilateral vestibular schwannomas and other nervous system tumors. An increased incidence of central precocious puberty, diencephalic syndrome, GH deficiency and GH hypersecretion has been described in NF1 children. These conditions are commonly complications of optic pathway gliomas (OPG) involving the hypothalamic and sellar region. Nevertheless, these endocrine disorders have been observed also in children without evidence of OPG at magnetic resonance imaging. Clinical and laboratory follow-up is crucial in all children with NF1, particularly in those with an OPG, aiming at the early identification of signs suggestive of secondary endocrine alterations.

The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the progression to true precocious puberty in girls with onset of premature thelarche in the first three years of life.

CONTEXT: Premature thelarche in early childhood may evolve into true precocious puberty. The individuation of cases progressing to precocious puberty is challenging. OBJECTIVE: We analyzed the parameters predictive for progression in girls younger than 3 years. DESIGN AND SETTING: We conducted a retrospective longitudinal study. PATIENTS AND METHODS: A total of 450 girls referred for premature thelarche were initially evaluated, 353 were clinically monitored at 3-month intervals, and 97 underwent endocrine and imaging assessment. Central precocious puberty (CPP) was diagnosed in girls showing LH peak response to GnRH testing >5 mU/mL with tuber cinereum hamartoma at magnetic resonance imaging, or with normal magnetic resonance imaging but progression of puberty during follow-up. MAIN OUTCOME MEASURE: We measured the progression to precocious puberty. RESULTS: Idiopathic premature thelarche (IPT) was diagnosed in 85 of the 97 girls who underwent extensive evaluation, CPP in nine girls, and peripheral precocious puberty in three girls. The uterus was >34 mm in six (7%) IPT girls and six (66.6%) CPP girls. Basal LH was >0.2 mU/mL in one (1.17%) IPT girl and eight (88.8%) CPP girls. LH peak was >5 mU/mL in 31 (36.4%) IPT girls and nine (100%) CPP girls. LH peak/FSH peak ratio was >1 in six (66.6%) CPP girls. CONCLUSIONS: None of the available tests alone allows identification of girls who will progress to precocious puberty. Elevated LH responses to GnRH are common but are not related to progression toward puberty. The combined measurement of basal LH and longitudinal diameter of the uterus represents a reliable screening approach to identify subjects who should undergo GnRH testing.

The physical and mental health of children in foster care.

BACKGROUND: To evaluate physical and mental health in children in foster care and comparison with general population. METHODS: The study is carried out between September 2011 and April 2012 into nine group homes in Rome. It involved 112 children ranging in age 2-17 years, living in temporary care facilities or institutes. All data came out of clinical history and physical exams, validated by a pediatrician. Such data were being then compared with samples of general population. RESULTS: Significant themes were high percentage of children with psychiatric disorders in foster care (22.3%); high percentage of psychiatric disorders diagnosed immediately while arriving at the foster care (56%); no significant differences in weight, height and BMI between children in foster care and general population; significant differences (P<0.05) for allergy, gastrointestinal diseases and caries between children in foster care and general population. CONCLUSION: The results suggest that the physical health of children in group homes is no worse than that of children living care in their own homes and that the foster care provides necessary conditions to support the growth of the children and their physical, mental and social needs.

Factitious disorders and Munchausen syndrome: the tip of the iceberg.

This population-based study evaluates the prevalence of factitious disorders, Münchausen syndrome, and Münchausen syndrome by proxy in a clinical setting. All children referred to the Pediatric Unit of the Department of Pediatrics of the Catholic University Medical School (Agostino Gemelli Hospital) in Rome were recruited between November 2007 and March 2010. An experienced interdisciplinary team of medical professionals analyzed all suspected cases. A total of 751 patients were hospitalized. Factitious disorders were diagnosed in 14/751 patients, resulting in a prevalence of 1.8%. Three of 14 (21.4%) patients fulfilled the criteria for Münchausen syndrome. Münchausen syndrome by proxy was identified in four of 751 patients, resulting in a prevalence of 0.53%. The perpetrator was the mother in three of four of these cases. The epidemiological data obtained in this population-based study indicate that the prevalence of factitious disorders, Münchausen syndrome, and Münchausen syndrome by proxy is higher than previously observed. Moreover, early detection was possible thanks to the awareness of an expert interdisciplinary team. We suggest that physicians must consider the possibility of these diagnoses whenever there are discrepancies in a child's illness presentation.

Does anticonvulsant treatment influence pain perception in epileptic children?

BACKGROUND: The aims of our study were to evaluate pain perception in epileptic children and to establish the influence of anticonvulsant drugs on pain perception. METHODS: The study involved 40 children, 30 with epilepsy and 10 healthy control subjects. In the group of epileptic children, 10 were not treated and 20 assumed a single drug. From all children of each group, one sample of saliva was collected through a noninvasive device 15 minutes before (t0), during (t1), and 15 minutes after (t2) blood withdrawal, and salivary α-amylase activity was then determined. RESULTS: No statistically significant difference was found at t0 and at t1, indicating that in both groups venipuncture equally induced a state of stress. Conversely, at t2 a statistically significant difference (p = 0.0195) was found, suggesting that epileptic children presented a greater sensitization to pain and a slower recovery from stress. Comparing furthermore data obtained in children with epilepsy not treated with those registered in treated ones, we found a statistically significant difference at t0 (p = 0.012), at t1 (p = 0.037), and at t2 (p = 0.011). CONCLUSIONS: Anticonvulsant drugs do not seem to influence pain perception and enzymatic activity levels in epileptic patients.

Salivary alpha-amylase: a new non-invasive biomarker for assessment of pain perception in epileptic children.

The aim of this study was to evaluate pain perception in epileptic children during an invasive procedure as the collection of venous blood through salivary alpha-amylase (sAA) activity determination, and to compare it with that of healthy children. In the study 23 children, 12 with epilepsy and 11 healthy controls were enrolled. From all children of both groups, one sample of saliva was collected through a non-invasive device, 15 min before (t 0), during (t 1), and 15 min later (t 2) blood withdrawal, and sAA activity was then determined through a kinetic-colorimetric assay. A statistically significant difference (p < 0.001) was found at t 2 between the sAA activity in the two groups, suggesting that epileptic children have an increased sensitization to pain, while at t 0 the difference was at the limit of statistical significance and at t 1 no statistically significant difference was found indicating that in both groups the venipuncture equally induced a state of stress. Our data suggest that sAA activity could represent a new objective and non-invasive biomarker for the assessment of pain perception in epileptic children.

Efficacy and Safety of Dimeticone in the Treatment of Lice Infestation through Prophylaxis of Classmates.

BACKGROUND: We conducted a study to evaluate efficacy and safety of dimeticone 4%, a lotion with no conventional insecticide activity, to cure lice infection and to prevent spread of infestation/reinfestation by prophylaxis of classmates. METHODS: The study is carried out between April 2008 and June 2008 in Petranova International Institute in Rome. A total of 131 children, aged 3 to 13 years (median age: 7 years) were included in the study. All participants received treatment with dimeticone 4% that was applied both to children with the infestation, to cure it, and to all classmates, to prevent the spreading of the infestation. They have been controlled after 7 and 30 days from the application of dimeticone. RESULTS: At baseline we found a positivity of lice infestation in 23/131 children (17.6%), whereas 108/131 (82.4%) children were free from lice. After 7 days of treatment with dimeticone 4%, 7/23 (30.4%) positive children still had lice infestation, with a cure rate of 69.6% (16/23). At 30 days 26/131 children (19.9%) were infested: 15 children were lice free at baseline whereas 11 had lice at both evaluations; the cure rate amounted to 52.2% (12/23). The reinfestation rate (percentage of positive children that showed negativity at baseline) was 5.3% (7/131) at 7 days and 11.5% (15/131) at 30 days. CONCLUSION: The lower reinfestation rate showed in our trial suggests that this approach could be effective in reducing spreading of head lice in small communities. More studies are needed to confirm our findings.

Nephrotic Syndrome Following H1N1 Influenza in a 3-Year-Old Boy.

BACKGROUND: The pandemic influenza A/H1N1, spread through the world in 2009, producing a serious epidemic in Italy. Complications are generally limited to patients at the extremes of age (<6 months or >65 years) and those with comorbid medical illness. The most frequent complications of influenza involve the respiratory system. CASE PRESENTATION: A 3-year-old boy with a recent history of upper respiratory tract infection developed a nephrotic syndrome. Together with prednisone, furosemide and albumin bolus, a therapy with oseltamivir was started since the nasopharyngeal swab resulted positive for influenza A/H1N1. Clinical conditions and laboratory findings progressively improved during hospitalization, becoming normal during a 2 month follow up. CONCLUSION: The possibility of a renal involvement after influenza A/H1N1 infection should be considered.