Increased risk of nephrolithiasis: an emerging issue in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PURPOSE: To investigate the incidence of nephrolithiasis in a cohort of children with congenital adrenal hyperplasia (CAH), and to study if there is an association with the metabolic control of the disease. METHODS: This study was designed as a multicenter 1 year-prospective study involving 52 subjects (35 males) with confirmed molecular diagnosis of CAH due to 21-hydroxylase deficiency (21-OHD). Each patient was evaluated at three different time-points: T0, T1 (+6 months of follow-up), T2 (+12 months of follow up). At each follow up visit, auxological data were collected, and adrenocorticotrophic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione, dehydroepiandrosterone sulfate (DHEAS) serum levels, and urinary excretion of creatinine, calcium, oxalate and citrate were assayed. Moreover, a renal ultrasound was performed. RESULTS: The incidence of nephrolithiasis, assessed by ultrasound was 17.3% at T0, 13.5% at T1 and 11.5% at T2. At T0, one subject showed nephrocalcinosis. In the study population, a statistically significant difference was found for 17-OHP [T0: 11.1 (3.0-25.1) ng/mL; T1: 7.1 (1.8-19.9) ng/mL; T2: 5.9 (2.0-20.0) ng/mL, p < 0.005], and Δ4-androstenedione [T0: 0.9 (0.3-2.5) ng/mL; T1: 0.3 (0.3-1.1) ng/mL; T2: 0.5 (0.3-1.5) ng/mL, p < 0.005] which both decreased over the follow up time. No statistically significant difference among metabolic markers was found in the group of the subjects with nephrolithiasis, even if 17-OHP, DHEAS and Δ4-androstenedione levels showed a tendency towards a reduction from T0 to T2. Principal component analysis (PCA) was performed to study possible hidden patterns of associations/correlations between variables, and to assess the trend of them during the time. PCA revealed a decrease in the amount of the variables 17-OHP, Δ4-androstenedione, and ACTH that occurred during follow-up, which was also observed in subjects showing nephrolithiasis. CONCLUSIONS: our data demonstrated that children affected with 21-OHD can be at risk of developing nephrolithiasis. Additional studies are needed to clarify the pathogenesis and other possible risk factors for this condition, and to establish if regular screening of kidney ultrasound in these patients can be indicated.

Comparison of Performance in the Six-Minute Walk Test (6MWT) between Overweight/Obese and Normal-Weight Children and Association with Haemodynamic Parameters: A Cross-Sectional Study in Four Primary Schools.

Physical activity plays a pivotal role in preventing obesity and cardiovascular risks. The six-minute walk test (6MWT) is a tool to assess functional capacity and predict cardiovascular events. The aim of this cross-sectional study was to compare the performance and haemodynamic parameters before and after a 6MWT between obese/overweight vs. normal-weight children (average age 8.7 ± 0.7 years) participating in a project involving four primary schools in South Verona (Italy). Validated questionnaires for physical activity and diet, as well as blood drops, were collected. Overweight or obese children (OW&OB; n = 100) covered a shorter 6MWT distance compared to normal-weight children (NW, n = 194). At the test's conclusion, the OW&OB group exhibited a higher Rate Pulse Product (RPP = Systolic Blood Pressure × Heart Rate) as compared to the NW. Body Mass Index, waist-to-height ratio, fat mass by electrical impedance, and trans fatty acids showed direct correlations with pre and post-test haemodynamic parameters, such as RPP, and inverse correlations with oxygen saturation. OW&OB children demonstrated lower performance in this low-intensity exercise test, along with an elevated haemodynamic response. Excess fat in childhood can be considered a risk factor for haemodynamic stress, with potential deleterious consequences later in life. Efforts should be initiated early to break this cycle.

Central Precocious Puberty in Italian Boys: Data From a Large Nationwide Cohort.

CONTEXT: There are only a few nationwide studies on boys with central precocious puberty (CPP) and the last Italian study is a case series of 45 boys that dates back to 2000. OBJECTIVE: We aimed to evaluate the causes of CPP in boys diagnosed during the last 2 decades in Italy and the relative frequency of forms with associated central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) compared to idiopathic ones. METHODS: We performed a national multicenter retrospective study collecting data from 193 otherwise normal healthy boys with a diagnosis of CPP. Based on MRI findings, the patients were divided into: Group 1, no CNS abnormalities; Group 2, mild abnormalities (incidental findings) unrelated to CPP; and Group 3, causal pathological CNS abnormalities. RESULTS: The MRI findings show normal findings in 86%, mild abnormalities (incidental findings) in 8.3%, and causal pathological CNS abnormalities in 5.7% of the cases. In Group 3, we found a higher proportion of patients with chronological age at diagnosis < 7 years (P = .00001) and body mass index greater than +2 SDS (P < .01). Gonadotropin-releasing hormone analogue therapy was started in 183/193 subjects. The final height appeared in the range of the target height in all groups and in 9 patients in whom the therapy was not started. CONCLUSION: In our study on a large nationwide cohort of boys referred for precocious puberty signs, the percentage of forms associated with CNS abnormalities was one of the lowest reported in the literature.

Decreased vitamin D levels in the pediatric population after COVID-19 lockdown.

BACKGROUD: SARS-Cov2 infection began to spread worldwide since December 2019; on March 2020, the World Health Organization characterized its related disease, named COVID-19, as a pandemic. In Italy, to contain the spread of infection a severe lockdown in the spring 2020 was instituted. Other less severe restrictions were imposed in the winter 2020-2021 and in the spring 2021. The containment measures caused a series of consequences for the population and, in particular, for children and adolescents that presented psychophysical problems. The aim of this manuscript is to investigate the serum levels of vitamin D in children and adolescents before, during and after the lockdown consequent to COVID-19 pandemic. METHODS: This is a retrospective cross-sectional study, including all children and adolescents between 1 to 18 years referring to the Pediatric Endocrinology Service of the University Hospital of Verona, Italy, between January 2019 and December 2021. All patients affected by clinical conditions that involve vitamin D metabolism or assuming vitamin D supplementation were excluded. RESULTS: In total, 491 children (36.7% males and 63.3% females) were enrolled in this study. The vitamin D levels decreased over time: 28.3 ± 10.2 ng/mL in 2019; 28.2 ± 11.4 ng/mL in 2020 and 24.9 ± 10.1 ng/mL in 2021 (p < 0.05). The vitamin D levels are significant higher in summer and in autumn in comparison with the levels of winter and spring, regardless of the examined years. CONCLUSIONS: The measures adopted to contain the COVID-19 pandemic led to a reduction of serum levels of vitamin D in pediatric population, probably due to the reduced solar exposure. This may have severe consequences on the bone metabolism of those children who did not present optimal vitamin D levels even before the lockdown. Therefore, an adequate supplementation of vitamin D is necessary from the end of fall to the beginning of spring (November-April) in all children and adolescents living in Northern Italy.

Autoimmune adrenal insufficiency in children: a hint for polyglandular syndrome type 2?

BACKGROUND: Primary adrenal insufficiency (PAI) in childhood is a life-threatening disease most commonly due to impaired steroidogenesis. Differently from adulthood, autoimmune adrenalitis is a rare condition amongst PAI's main aetiologies and could present as an isolated disorder or as a component of polyglandular syndromes, particularly type 2. As a matter of fact, autoimmune polyglandular syndrome (APS) type 2 consists of the association between autoimmune Addison's disease, type 1 diabetes mellitus and/or Hashimoto's disease. CASE PRESENTATION: We report the case of an 8-year-old girl who presented Addison's disease and autoimmune thyroiditis at an early stage of life. The initial course of the disease was characterized by numerous crises of adrenal insufficiency, subsequently the treatment was adjusted in a tertiary hospital with improvement of disease control. CONCLUSIONS: APS type 2 is a rare condition during childhood, probably because it may remain latent for long periods before resulting in the overt disease. We recommend an early detection of APS type 2 and an adequate treatment of adrenal insufficiency in a tertiary hospital. Moreover, we underline the importance of a regular follow-up in patients with autoimmune diseases, since unrevealed and incomplete forms are frequent, especially in childhood.

Vitamin D and Osteogenesis Imperfecta in Pediatrics.

Osteogenesis Imperfecta (OI) is a heterogeneous group of inherited skeletal dysplasias characterized by bone fragility. The study of bone metabolism, in these disease, is problematic in terms of clinical and genetic variability. The aims of our study were to evaluate the importance of Vitamin D levels in OI bone metabolism, reviewing studies performed on this topic and providing advice reflecting our experience using vitamin D supplementation. A comprehensive review on all English-language articles was conducted in order to analyze the influence of vitamin D in OI bone metabolism in pediatric patients. Reviewing the studies, contradictory data were found on the relationship between 25OH vitamin D levels and bone parameters in OI, and in several studies the baseline levels of 25OH D were below the threshold value of 75 nmol/L. In conclusion, according to the literature and to our experience, we highlight the importance of adequate vitamin D supplementation in children with OI.

The influence of growth hormone on pediatric body composition: A systematic review.

Background: Growth hormone (GH) affects metabolism and regulates growth in childhood. The most prominent feature of GH deficiency (GHD) in children is diminished height velocity that eventually leads to short stature. In adult-onset GHD, lean body mass (LBM) is reduced, and visceral fat mass (FM) increased. Beneficial effects of GH treatment on body composition in adults with GHD, including an increase in muscle mass and a decrease in FM, are well established. Relatively few studies have investigated the effects of GH treatment on the body composition of pediatric patients with idiopathic or hypothalamic-pituitary disease-associated GH deficiency. This systematic review aimed to summarize available evidence relating to the effects of GH treatment on body composition in children with GHD. Methods: The PubMed, Science Direct, Cochrane Trials, and Embase databases, were searched with keywords including "GH", "body composition", "children", and "growth hormone" for English-language articles, published between January 1999 and March 2021. Two reviewers independently evaluated the search results and identified studies for inclusion based on the following criteria: participants had a confirmed diagnosis of GHD (as defined in each study); participants were pediatric patients who were receiving GH or had stopped GH treatment, regardless of whether they were pre- or post-pubertal; the intervention was recombinant human GH (rhGH; somatropin); and outcomes included changes in body composition during or after stopping GH therapy. Data extracted from each study included study quality, study sample characteristics, study interventions, and body composition. Data on fat-free mass and LBM were combined into a single category of LBM. Results: Sixteen studies reporting changes in body composition (i.e., FM and LBM) associated with GH treatment in children with GHD were identified and included in the review. Collectively, these studies demonstrated that FM decreased, and LBM increased in response to GH replacement therapy. Conclusion: Despite study limitations (i.e., potential effects of diet and physical activity were not considered), we concluded that a periodic body composition assessment is required to ensure that a satisfactory body composition is achieved during GH replacement therapy in children with GHD.

Complex relationship between growth hormone and sleep in children: insights, discrepancies, and implications.

Growth hormone (GH) is crucial to growth and development. GH secretion is regulated by a complex feedback system involving the pituitary gland, hypothalamus, and other organs, and predominantly occurs during deep sleep. Isolated and idiopathic growth hormone deficiency (GHD) is a condition characterized by GHD without any other signs or symptoms associated with a specific syndrome or disease. The aim of this narrative review was to evaluate the relationship between GH and sleep in children using published data. Various databases (Medline/PubMed, Scopus, and Web of Science) were systematically searched for relevant English language articles published up to April 2023. Search strategies included the terms 'children/pediatric', 'growth hormone', 'growth hormone deficiency' and 'sleep'. Data were extracted by two independent reviewers; 185 papers were identified of which 58 were duplicates and 118 were excluded (unrelated n=83, syndromic/genetic GHD n=17, non-English n=13, abstract n=1, case report n=1). Overall, nine studies (six clinical studies, two case series, and one survey) were included. GHD appears to have an adverse effect on sleep in children, and GH therapy has only been shown to have a beneficial effect on sleep parameters in some individuals. Notably, identified data were limited, old/poor quality, and heterogenous/inconsistent. Further research of GHD in pediatric populations is necessary to improve the understanding of GHD impact on sleep and its underlying mechanisms, and to determine the specific impacts of GH therapy on sleep in children.

Benefits of rescreening newborns of mothers affected by autoimmune hypothyroidism.

Introduction: Infants of mothers with autoimmune hypothyroidism (AH) are at risk of developing late-onset hypothyroidism, often escaping at newborn screening. This condition might be caused both by the action of maternal antibodies and/or by maternal treatment. Objectives: The aim of this study is to evaluate the prevalence of AH in the mothers of children born in Veneto region, Italy, and to define what is the most appropriate management for these newborns. Methods: Newborns of six different hospitals with a mother suffering from AH and with negative neonatal screening for congenital hypothyroidism (CH) were included in the study. Between 15 and 20 days of life, we collected a serum sample for the evaluation of thyroid function (thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3)) and anti-thyroid antibodies. On the same occasion, a capillary blood sampling was performed for a second screening test. Results: Maternal AH has a prevalence of 3.5%. A total of 291 newborns were enrolled from November 2019 to May 2021. Whereas the 11.4% of infants had a slight elevated serum TSH (>6 mU/L) and required a follow-up, only 2 children presented an elevated TSH level at the second screening test. One of these, with the gland in situ, showed persistently elevated serum TSH levels and required treatment with levothyroxine. Conclusions: Maternal AH rarely caused neonatal thyroid dysfunction. We suggest to reassess newborns from mothers with AH 15 days after birth by means of a second neonatal screening test. This procedure avoids false negatives due to maternal thyroid status, is less invasive and cheaper than the serum TSH evaluation, and prevents a long follow-up.

Twenty Years of Neonatal Screening for Congenital Adrenal Hyperplasia in North-Eastern Italy: Role of Liquid Chromatography-Tandem Mass Spectrometry as a Second-Tier Test.

BACKGROUND: Newborn screening for congenital adrenal hyperplasia (CAH) based on 17-hydroxyprogesterone (17-OHP) concentration in dried blood spots has been taking place in North-Eastern Italy since 2001. Since 2017, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been introduced, for the first time in Italy, as a second-tier test. AIMS: Our study aims to evaluate, on the one hand, the effectiveness of the newborn screening for CAH after 20 years of testing and, on the other, the impact that the introduction of the second-tier test had on the diagnostic accuracy of the screening program. METHODS: Since 2001 dried blood spots taken from newborns have been screened with a time-resolved fluoroimmunoassay for 17-OHP determination. Over the years, the cut-off levels of 17-OHP were adjusted according to gestational age. Since 2017, a second-tier test in LC-MS/MS was introduced for samples displaying fluoroimmunoassay 17-OHP exceeding the cut-off. RESULTS: In total, 862,521 newborns have been screened over a period of 20 years. The total incidence of 21-hydroxylase deficiency (21-OHD) was 1:25,368, moreover, a case of 11-ß-hydroxylase deficiency was identified. All these diagnoses were genetically confirmed. The sensitivity and specificity of the screening program were 97% and 99.4%, respectively. The use of LC-MS/MS as a second-tier test significantly reduced the recall rate and increased the positive predictive value. CONCLUSIONS: Screening for CAH is useful in the neonatal diagnosis of a classic form of 21-OHD, allowing a precocious treatment of affected children. The introduction of an LC-MS/MS second-tier reduced the recall rate, avoiding unnecessary blood withdrawal and medical evaluations and preventing stress to families. Furthermore, it helped identify rarer forms of CAH.

A complex pheotype in a girl with a novel heterozygous missense variant (p.Ile56Phe) of the GNAS gene.

BACKGROUND: GNAS is a complex gene that encodes Gsα, a signaling protein that triggers a complex network of pathways. Heterozygous inactivating mutations in Gsα-coding GNAS exons cause hormonal resistance; on the contrary, activating mutations in Gsα result in constitutive cAMP stimulation. Recent research has described a clinical condition characterized by both gain and loss of Gsα function, due to a heterozygous de novo variant of the maternal GNAS allele. PATIENTS AND METHODS: We describe a girl with a complex combination of clinical signs and a new heterozygous GNAS variant. For the molecular analysis of GNAS gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples. In silico analysis was performed to predict the possible in vivo effect of the detected novel genetic variant. The activity of Gsα protein was in vitro analyzed from samples of erythrocyte membranes, recovered from heparinized blood samples. RESULTS: We found a new heterozygous missense c.166A > T-(p.Ile56Phe) GNAS variant in exon 2, inherited from the mother that determined a reduced activity of 50% of Gsα protein function. The analysis of her parents showed a 20-25% reduction in Gsα protein activity in the mother and a normal function in the father. Clinically our patient presented a multisystemic disorder characterized by hyponatremia compatible with a nephrogenic syndrome of inappropriate antidiuresis, subclinical hyperthyroidism, subclinical hypercortisolism, precocious thelarche and pubarche and congenital bone abnormalities. CONCLUSIONS: This is the first time that the new variant c.166A > T (p.Ile56Phe) on exon 2 of GNAS gene, originated on maternal allele, has been described as probable cause of a multisystemic disorder. Although the mutation is associated with a reduced activity of the function of Gsα protein, this unusual phenotype on the contrary suggests a mild functional gain.

Supportive treatment of vascular dysfunction in pediatric subjects with obesity: the OBELIX study.

INTRODUCTION: Overweight or obese children develop abnormal endothelial cell dysfunction and arterial intima-media thickening with increased vasomotor tone and inflammation. Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D have shown beneficial effects on endothelial function. We test, among overweight and obese pediatric subjects, the effects on the endothelium of a combination of curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D. METHODS: Forty-eight subjects (6-17 years) were randomized into two groups (placebo vs treatment) attended three visits at 0, 3, and 6 months (±15 days). Endothelial function was assessed by means of a post-occlusive release hyperemic (PORH) test for estimation of delta flow (DF) and hyperemic AUC index, and a heat provocation test (HPT) to measure DF HPT (DFHPT). RESULTS: Significant DF difference was noted at 6 months in both groups (p < 0.001). Overall time trend was significantly different between baseline, 3 months, and 6 months both in placebo (p < 0.05) and treatment (p < 0.001) groups and their comparison (p < 0.001). No differences were noted in hyperemic AUC index (3 and 6 months), whilst there were significant differences in time trends of rreatment (p < 0.001) and placebo (p < 0.05) groups and their comparison (p < 0.001). DFHPT difference between groups was significant at 3 and 6 months (p < 0.05). The overall time trend was significant exclusively in Treatment group between 3 and 6 months (p < 0.05). Correlation with anthropometrics was found for DF and body mass index (r = 0.677 6 months, p < 0.05), as well as for hyperemic AUC index and males (r = 0.348, p < 0.05), while DFHPT showed no correlation. CONCLUSION: Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D appear to be promising in enhancing endothelial function by improvement of both DF in the PORH test and DF in the HPT, lowering the risk of developing cardiovascular diseases in overweight and obese pediatric subjects.

Treatment of congenital hypothyroidism: comparison between L-thyroxine oral solution and tablet formulations up to 3 years of age.

OBJECTIVE: Oral solution and tablet formulations of levothyroxine (L-T4) are both used in the treatment of congenital hypothyroidism (CH). However, few studies and with a limited follow-up period have been published comparing these two formulations in children. DESIGN: The aim of this multicenter study was to compare the effectiveness of L-T4 oral solution (with ethanol as excipient) and tablet formulation in children with CH up to 3 years of age. METHODS: Children diagnosed with CH between 2006 and 2015 were enrolled and divided into two groups according to the L-T4 formulation used: solution in drops (group D) or tablets (group T). Auxological parameters, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) values and L-T4 dose were collected at diagnosis and at 15 days, 1, 3, 6, 12, 24 and 36 months of treatment. The developmental quotient (DQ) at 1 and 3 years of age was evaluated using Griffiths' Scale. RESULTS: In this study, 254 children were enrolled among which 117 were treated with solution and 137 with tablets. Auxological parameters, dose and thyroid function values at diagnosis, 3, 6, 12, 24, 36 months were not significantly different. TSH at 15 days (P = 0.002) and 1 month (P = 0.009) was significantly reduced in group D. At 2-year follow-up, median TSH was significantly lower in group T (P = 0.03). No statistical difference was detected between the median DQ; however, group D showed lower values in the language subscale at 12 months and in eye-hand coordination at 36 months. CONCLUSIONS: Both therapeutic strategies are effective in the treatment of CH. A higher risk of overtreatment in the first months of therapy seems to be associated with oral solution L-T4; therefore, a different strategy should be considered when starting and adjusting the dose. No negative effects on cognitive development were observed. The data obtained are encouraging but long-term follow-up is needed.

Case Report: Long-Term Tolvaptan Treatment in a Child With SIADH and Suprasellar Arachnoid Cyst.

Suprasellar arachnoid cysts represent a rare occurrence in the pediatric population and usually cause symptoms related to mass effect and can occasionally cause endocrine dysfunctions. The association between SAC and the syndrome of inappropriate antidiuretic hormone (SIADH) in the pediatric population has rarely been described previously. In most cases, SIADH is temporary and resolves by treating the underlying cause. The first-line treatment consists of fluid restriction in asymptomatic children. Oral urea and demeclocycline are other effective treatment options. Vaptans are a new class of medication for the management of SIADH. These agents are a nonpeptide vasopressin V2 receptor antagonist that selectively antagonizes the antidiuretic effect of AVP, resulting in excretion of diluted urine or "aquaresis." Their efficacy has been shown in adult patients with euvolemic or hypervolemic hyponatremia. However, evidence is lacking in pediatric patients with SIADH. We report the case of a 9-year-old female child with a SAC, who underwent endoscopic fenestration at the age of 2 years. After surgery she developed chronic hyponatremia due to SIADH. Hyponatremia was refractory to treatment with fluid restriction, oral sodium, and urea. In order to normalize serum sodium levels, tolvaptan treatment was started on a compassionate-use basis; 24-48 h later serum sodium levels returned to normal. To date, tolvaptan has been used regularly for 6 years with no side effects occurring during the treatment period. This is the first case of a child with chronic SIADH secondary to SAC successfully treated with tolvaptan. Further studies are needed to demonstrate its usefulness on a broader case series.

Case Report: SARS-CoV-2 Infection in a Child With Suprasellar Tumor and Hypothalamic-Pituitary Failure.

In early 2020, a novel coronavirus leading to potentially death was discovered. Since then, the 2019 coronavirus disease (COVID-19) has spread to become a worldwide pandemic. Beyond the risks strictly related to the infection, concerns have been expressed for the endocrinological impact that COVID-19 may have, especially in vulnerable individuals with pre-existing endocrinological health conditions. To date new information is emerging regarding severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in children but the literature is still scarce concerning this infection in patients with intracranial malignant neoplasms. We report a 9-year-old child infected with SARS-CoV-2 and recent diagnosis of suprasellar non-germinomatous germ cell tumor also suffering from diabetes insipidus and hypothalamic-pituitary failure (hypothyroidism, adrenal insufficiency, hypothalamic obesity and growth hormone deficiency) and its clinical course. The patient remained asymptomatic for the duration of the infection without requiring any change in the replacement therapeutic dosages taken before the infection. We then discuss the proposed approach to treat a pediatric patient with SARS-CoV-2 infection and hypothalamic-pituitary failure and we include a review of the literature. Our report suggests that SARS-CoV-2 infection is usually mild and self-limiting in children even those immunocompromised and with multiple endocrinological deficits. Patients are advised to keep any scheduled appointments unless informed otherwise.

Central precocious puberty in a girl with LEGIUS syndrome: an accidental association?

BACKGROUND: Central precocious puberty is a condition characterized by precocious activation of the hypothalamic-pituitary-gonadal axis. It may be idiopathic or secondary to organic causes, including syndromes such as Neurofibromatosis type 1 (NF1). CASE PRESENTATION: We presented a girl of 6 years and 10 months with almost 11 café-au-lait skin macules, without other clinical or radiological signs typical of NF1, and with a central precocious puberty. Genetic analysis evidenced the new variant NM-152594.2:c.304delAp. (Thr102Argfs*19) in SPRED1 gene, which allowed to diagnose Legius syndrome. CONCLUSIONS: We report for the first time a case of central precocious puberty in a girl with Legius syndrome. The presence of central precocious puberty in a child with characteristic café-au-lait macules should suggest pediatricians to perform genetic analysis in order to reach a definitive diagnosis. Further studies on timing of puberty in patients with RASopathies are needed to better elucidate if this clinical association is casual or secondary to their clinical condition.

DYSMORPHIC features and adult short stature: possible clinical markers of KBG syndrome.

BACKGROUND: Growth monitoring is an essential part of primary health care in children and short stature is frequently regarded as a relatively early sign of poor health. The association of short stature and dysmorphic features should always lead to exclude an underlying syndromic disorder. CASE PRESENTATION: We report the case of an Indian school-aged boy with dysmorphic features, intellectual disability and a clinical history characterized by seizures and hearing problems. Although his height was always included in the normal range for age and sex throughout childhood, he presented a short near-adult stature in relation to his mid-parent sex-adjusted target height. This is probably due to a rapidly progressive pubertal development. CONCLUSIONS: In the presence of characteristic dysmorphic features, intellectual disability, seizures and hearing problems, KBG syndrome should always be considered. This emergent condition presents a wide spectrum of clinical phenotypes and is often associated with adult short stature.