Fifteen-minute consultation: The approach to the child with precocious puberty.

Precocious puberty has traditionally been defined as the onset of secondary sexual characteristics occurring before age 8 years in girls and 9 years in boys. This earlier onset of puberty may have significant physical and psychological consequences if left untreated. Moreover, it should be excluded that pubertal signs are not secondary to malignancies, other organic aetiologies or associated syndromic phenotypes. Initial assessment involves a thorough medical history and physical examination; a hand and wrist X-ray to determine bone age, and hormonal tests might be indicated to confirm the diagnosis and to determine the origin of hormonal production. Treatment options depend on the underlying cause. Given the complexity of the differential diagnosis, this article aims to familiarise clinicians with the different steps that can be taken when precocious puberty is suspected.

The real-life management of glucose homeostasis abnormalities in pediatric onco-hematological diseases: data from a national survey.

Glycemic abnormalities are a frequent finding in pediatric oncological patients, both during treatment and after its discontinuation. Moreover, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG) and diabetes mellitus (DM) are not rarely diagnosed in non-oncological hematological diseases. To explore the current pediatric Italian approach to the diagnosis and the management of the glycemic alterations in this clinical setting and, thus, to identify and enforce current clinical needs, we submitted an online 23-items survey to all the Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers, and surveys were descriptively analyzed. Thirty-nine AIEOP centers were involved in the study. In 2021, among 75278 children and adolescents affected by an oncological or a hematological disease, 1.2 and 0.65% developed DM, while IGT or IFG were widespread in 2.3 and 2.8%, respectively. The main causes of DM were the use of corticosteroids in patients with cancer and the iron overload in patients with thalassemia. Venous fasting plasma glycemia was the most used tool to detect glycemic abnormalities. The performance of oral glucose tolerance test (OGTT) was extremely limited, except when IFG occurred. Despite the diagnosis of DM, ∼45% of patients with cancer and 30% of patients with one hematological disease did not receive an appropriate treatment. In the other cases, insulin was the drug of first choice. Emerging technologies for diabetes care (glucose sensors and insulin pumps) are not largely used yet. The results of our study support the standardization of the care of the glycemic abnormalities during or after onco-hematologic diseases in the pediatric age. Despite the scarce data in pediatric literature, proper guidelines are needed.

The treatment of obesity in children and adolescents: consensus position statement of the Italian society of pediatric endocrinology and diabetology, Italian Society of Pediatrics and Italian Society of Pediatric Surgery.

This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder.

A Short-Duration Gonadotropin-Releasing Hormone Stimulation Test for the Diagnosis of Central Precocious Puberty.

Background and Objectives: The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard method for diagnosing central precocious puberty (CPP), although it requires multiple blood samplings over 120 min. This study aimed to evaluate if a shorter test may have an equivalent diagnostic accuracy. Materials and Methods: We retrospectively reviewed the GnRH tests of 188 consecutive pediatric patients (169 females) referred for signs of early pubertal development. The diagnostic accuracy of the hormonal levels was evaluated at different time points (15, 0, 60, 90, and 120 min after the GnRH stimulus). Results: A diagnosis of CPP was made in 130 cases (69%), with 111 (85%) being female. Sensitivity and specificity ratings higher than 99% for the diagnosis of CPP were achieved for LH levels ≥4.7 mU/mL at 30 and 60 min after the stimulus (area under the ROC curve (AUC) = 1), with no further increase in the diagnostic accuracy in the remaining time points. No sex differences in diagnostic accuracy were found. The LH/FSH ratio at 30 min showed a sensitivity of 94.9%, with an AUC of 0.997 and a value ≥0.76. Conclusions: A short-duration GnRH test of 60 min provided optimal results for the diagnosis of CPP. Extending the test for an extra hour is therefore unnecessary and inadvisable.

Reduction in pediatric growth hormone deficiency and increase in central precocious puberty diagnoses during COVID 19 pandemics.

BACKGROUND: While several studies have been published so far on the effect of COVID-19 pandemic on health care for non-COVID-19 diseases, to date no study evaluated the impact of the COVID-19 pandemic on the entire field of pediatric endocrinology. This study aimed to evaluate differences in pediatric endocrine stimulation tests after the advent of COVID-19 pandemics. METHODS: Retrospective study with data collection for pediatric endocrine stimulation tests performed in 2019 and 2020 in a tertiary center. RESULTS: Overall, 251 tests were performed on 190 patients in 2020, compared to 278 tests on 206 patients in 2019 (- 10% tests; - 8% children evaluated). A significant reduction was found in tests to diagnose growth hormone deficiency (GHD) (- 35%), while LHRH tests increased (+ 22%). A reduction of 30% in GHD diagnosis was observed. Central precocious puberty (CPP) diagnosis increased by 38% compared to 2019, mainly in females. CONCLUSION: This study found a significant reduction of tests investigating GHD during COVID-19 pandemics. It also showed a clinically meaningful increase in cases of CPP in girls. These results suggest the need for families and pediatricians to monitor children's growth during isolation and enlighten new perspectives towards conditions associated with lockdown restrictions as increased screen time, social isolation, and children's anxiety as possible triggers of CPP.

Clinical and Cytometric Study of Immune Involvement in a Heterogeneous Cohort of Subjects With RASopathies and mTORopathies.

RASopathies and mTORopathies are groups of genetic syndromes associated with increased activation of the RAS-MAPK or the PI3K-AKT-mTOR pathway, resulting in altered cell proliferation during embryonic and postnatal development. The RAS-MAPK and the PI3K-AKT-mTOR pathways are connected to each other and play a crucial role in adaptive immunity. However, with the exception of Activated PI3K delta syndrome (APDS), immune function has not been deeply studied in these disorders. We collected clinical and immunophenotypic data of a cohort of patients with RASopathies and mTORopathies. Overall, we enrolled 47 patients (22 females, 25 males, age 2-40 years): 33 with neurofibromatosis type 1, 11 Noonan syndrome and 3 Bannayan-Riley-Ruvalcaba syndrome. 8 patients reported a history of invasive infections requiring hospitalization and intravenous antibiotic therapy. Only 3 patients reported a history of unusual, difficult-to-treat or deep-seated infection. Adenotonsillectomy was performed in 11 patients (24%). However, in most cases (83%) patients' parents did not perceive their child as more prone to infections than their peers. Lymphocyte subpopulations were analyzed in 37 of the 47 patients (16 female, 21 males, age 1-40 years). Among the studied lymphocyte subsets, the only consistent alteration regarded an increased percentage of immature B cells (recent bone marrow emigrants) in 34 out of 37 (91,9%) patients, and an increased percentage of double negative T cells in 9 patients. In conclusion, although borderline immune abnormalities were present in a significant proportion of subjects and adenotonsillectomy was performed more frequently than expected for the general population, no major immune disturbance was found in this cohort of patients.

Albuminuric and non-albuminuric reduced eGFR phenotypes in youth with type 1 diabetes: Factors associated with cardiometabolic risk.

BACKGROUND AND AIM: Albuminuria and reduced eGFR are hallmarks of Diabetic Kidney Disease in adults. Our aim was to analyze factors associated with albuminuric and non-albuminuric mildly reduced eGFR phenotypes in youths with type 1 diabetes. METHODS AND RESULTS: This multicenter cross-sectional study included 1549 youths (age 5-17 years) with type 1 diabetes enrolled at 14 Italian Pediatric Diabetes Centers. Albuminuria, creatinine, glycosylated hemoglobin (HbA1c), lipids, blood pressure (BP), neutrophils (N) and lymphocytes (L) count were analyzed. Uric acid (UA) was available in 848 individuals. Estimated GFR (eGFR) was calculated using bedside Schwartz's equation. The sample was divided in three phenotypes: 1) normoalbuminuria and eGFR ≥90 mL/min/1.73 m2 (reference category, n = 1204), 2) albuminuric and normal GFR phenotype (n = 106), 3) non-albuminuric mildly reduced GFR (MRGFR) phenotype (eGFR 60-89 mL/min/1.73 m2, n = 239). Albuminuric and non-albuminuric reduced eGFR phenotypes were significantly associated with autoimmune thyroiditis (P =0.028 and P=0.044, respectively). Albuminuric phenotype showed high risk of high HbA1c (P=0.029), high BP (P < 0.001), and low HDL-C (P =0.045) vs reference category. Non-albuminuric MRGFR phenotype showed high risk of high BP (P < 0.0001), low HDL-C (P =0.042), high Triglycerides/HDL-C ratio (P =0.019), and high UA (P < 0.0001) vs reference category. CONCLUSION: Non albuminuric MRGFR phenotype is more prevalent than albuminuric phenotype and shows a worst cardiometabolic risk (CMR) profile). Both phenotypes are associated with autoimmune thyroiditis. Our data suggest to evaluate both albuminuria and eGFR earlier in type 1 diabetes to timely identify young people with altered CMR profile.

Topical Clobetasol: An Overlooked Cause of Cushing Syndrome.

BACKGROUND: We describe the case of an 11-year-old boy affected by chronic granulomatous disease complicated by a Crohn's like colitis needing prolonged treatment with oral corticosteroids. CASE PRESENTATION: His therapy for the control of severe oral mucositis was based on topical clobetasol, which did not decrease once the steroids were discontinued. Two years after the oral interruption of the steroids, cushingoid characteristics persisted, the cause of which, after a thorough investigation, was found to be the persistence of the topical clobetasol oral gel. CONCLUSION: Several studies investigated the efficacy of topical clobetasol for immuno-related mucositis, but little is known about its pharmacokinetics and side effects. In this report, we have reviewed the literature, defining a maximum putative dose of clobetasol mucosal gel to avoid Cushing syndrome.

An unusual diagnosis for an usual test.

BACKGROUND: Hereditary multiple osteochondromas (HMO) is a genetic condition characterized by the presence of multiple osteochondromas, usually at the lateral side of the most active growth plate of a long bone. These lesions may persist, be asymptomatic during childhood, and may increase in number and size until growth plates close. Therefore, diagnosis of HMO in children and young people can be challenging; while short stature can be more evident at the onset of puberty, asymptomatic ostheocondromas can progress into different degrees of orthopedic deformity. Moreover, multiple complications may arise due to the presence of osteochondromas, including tendon and compression muscle pain, neurovascular disorders, obstetric problems, scoliosis and malignant transformation into secondary peripheral chondrosarcoma in adulthood. CASE PRESENTATION: We report the case of a girl admitted to our Institute for growth delay. While laboratory tests, including growth hormone stimulation test, were normal, left hand X-ray revealed multiple osteochondromas, suggestive for HMO. The genetic test for EXT1 and EXT2 genes confirmed the radiological diagnosis, with a mutation inherited from the mother who displayed the same radiological abnormalities along with recurrent limb pain episodes. CONCLUSIONS: HMO is a genetic condition whose diagnosis can be challenging, especially in females. Every pediatricians should consider a skeletal dysplasia in case of unexplained growth delay and a skeletal survey might be fundamental in reaching a diagnosis.

Unilateral testicular enlargement in a teenager with Beckwith-Wiedemann syndrome: a case report.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth disorder. A major feature is lateralized overgrowth, which can variably involve a single body district up to the entire hemisome. Visceral asymmetrical involvement has been observed, commonly represented by enlargement of one kidney or adrenal gland, rather than one gonad. CASE PRESENTATION: We report the case of a pubertal boy affected by BWS, who developed a progressive testicular enlargement, ipsilateral to the pre-existing external body overgrowth. Asymptomatic unilateral testis enlargement started after regular pubertal onset and worsened over time, without any associated pathological findings in a long-term follow-up. Since biopsy is not indicated in case of benign macro-orchidism, we hypothesize that this asymmetric enlargement could be an expression of visceral lateralized overgrowth in BWS. CONCLUSIONS: At the best of our knowledge, this is the first detailed report of unilateral testicular overgrowth in BWS. We revised common causes of painless unilateral scrotal masses in the pediatric age. Considering both the overall frequency of neoplasia and the malignancies predisposition in BWS, a testicular cancer should be carefully ruled out through a close follow-up, before stating a benign condition. A normal ultrasound pattern, together with normal serum hormonal levels and negative tumor markers, make testicular neoplasms highly unlikely.

Impact of the 2017 Blood Pressure Guidelines by the American Academy of Pediatrics in overweight/obese youth.

OBJECTIVES: The aim of this study was to compare the impact of the European Society of Hypertension Guidelines 2016 (ESHG2016) and the American Academy of Pediatrics Guidelines 2017 (AAPG2017) on the screening of hypertension and classification of abnormal left ventricular geometry (ALVG) in overweight/obese youth. METHODS: This study included 6137 overweight/obese youth; 437 had echocardiographic assessment. Hypertension was defined using either ESHG2016 or AAPG2017. ALVG was defined using 95th percentile for age and sex of left ventricular mass index (LVMi) and/or relative wall thickness (RWT) more than 0.38 (juvenile cut-offs) according to ESHG2016 or LVMi more than 51 g/h and/or RWT more than 0.42 (adult cut-offs) according to AAPG2017. RESULTS: Prevalence of youth at a high risk of hypertension was 13% higher using AAPG2017 than ESHG2016. The increase was larger in overweight youth at least 13 years of age (+43%). Using the juvenile cut-offs for ALVG, youth at a high risk of hypertension by ESHG2016 had an odds ratio [95% confidence interval (95% CI)] of 3.03 (1.31-7.05) for left ventricular concentric remodelling (LVcr) and 2.53 (1.43-4.47) for concentric left ventricular hypertrophy (cLVH) as compared with youth with normal LVG. Similarly, in youth at a high risk of hypertension by AAPG2017, the odds ratio for LVcr was 3.28 (1.45-7.41, P < 0.001) and 3.02 (95% CI: 1.73-5.27, P < 0.001) for cLVH. Using the adult cut-offs, no significant difference in ALVG was found with both guidelines. CONCLUSION: The prevalence of overweight/obese youth at a high risk of hypertension increased by 13% comparing AAPG2017 vs. ESHG2016. The juvenile cut-offs for ALVG were more effective than the adult criteria in intercepting individuals with a potentially higher cardiovascular risk.

MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study.

BACKGROUND: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. METHODS: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2-8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17ß-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. RESULTS: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). CONCLUSIONS: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.

MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study.

PURPOSE: Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty. METHODS: We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2-8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2-8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9-14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients. RESULTS: No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:-0.35; p:0.02), Luteinizing Hormone (r:-0.35; p:0.03), FSH (r:-0.37; p:0.02), and (17)estradiol (r: -0.36; p:0.02). CONCLUSIONS: We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

Long-term safety and efficacy of Omnitrope®, a somatropin biosimilar, in children requiring growth hormone treatment: Italian interim analysis of the PATRO Children study.

BACKGROUND: PATRO Children is an ongoing observational, longitudinal, non-interventional, global post-marketing surveillance study, which is investigating the long-term safety and effectiveness of Omnitrope®, a somatropin biosimilar to Genotropin®, in children with growth disturbances. The primary endpoint of PATRO Children is long-term safety and the secondary endpoint is effectiveness, which is assessed by analysing auxological data such as height (HSDS) and height velocity (HVSDS) standard deviation scores. Here, we report the data from the Italian interim analysis of PATRO Children data up to August 2015. METHODS: PATRO Children is enrolling children who are diagnosed with conditions of short stature requiring GH treatment and are receiving Omnitrope®. Adverse events (AEs) are assessed in all Omnitrope®-treated patients. Height is evaluated yearly to near-adult (final) height, and is herein reported as HSDS; height velocity is also assessed and reported as a standard deviation score (HVSDS). RESULTS: Up to August 2015, a total of 186 patients (mean age 10.2 years, 57.5 % males) were enrolled :156 [84 %] had growth hormone deficiency, 12 [6.5 %] were born small for gestational age, seven [3.8 %] had Prader-Willi syndrome, one [0.5 %] had Turner syndrome and one [0.5 %] had chronic renal insufficiency; seven [3.8 %] patients had other indication profiles. The mean treatment duration with Omnitrope® was 28.1 ± 19.1 months. AEs were reported in 35.6 % of patients and included headache, pyrexia, arthralgia, abdominal pain, leg and/or arm pain and increased blood creatine phosphokinase. Two serious AEs in two patients were thought to be drug-related; one patient experienced a minimal increase in a known residual craniopharyngioma, and another a gait disturbance with worsening of walking difficulties. Similar to investigational studies, Omnitrope® treatment was associated with improvements in both HSDS and HVSDS. CONCLUSIONS: Omnitrope® appears to be well tolerated and effective for the treatment of a wide range of paediatric indications, which is consistent with the outcomes from controlled clinical trials. These results need to be interpreted with caution until the data from the global PATRO Children study are available.

Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy.

Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.