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.

Pubertal boy presenting with mild disproportionate short stature.

A boy aged 12 years was referred with short stature. He was born at term, of adequate weight (10-25th centile) and length (10-25th centile), which settled to just below the third centile from 18 months of age, with a growth deceleration in the last 6 months (growth velocity -2.1 standard deviation score, according to Tanner charts). He was otherwise asymptomatic. His mother's height was 155 cm, and father's height 158 cm, and he was growing near his target height centile (-2.26 SDS, <3rd centile).On examination, his height was -2.22 SDS, with normal weight and body mass index (BMI). Pubertal stage corresponded to Tanner 2, with a testicular volume of 4 mL. His legs and forearms appeared shorter, with arm span/height ratio 0.93 (normal value >0.965) and sitting height/height ratio 0.56 (slightly above the normal upper value of 0.55). He resembled his father, whose wrists were abnormally curved (figure 1). The patient's hand X-ray showed that bone age was similar to chronological age.

Endoscopic and Histologic Healing in Children With Inflammatory Bowel Diseases Treated With Thalidomide.

BACKGROUND & AIMS: Mucosal healing, determined by endoscopic evaluation, is one of the most important prognostic markers for patients with inflammatory bowel diseases. Findings from histologic evaluation, however, could complement findings from endoscopy in assessing mucosal responses to treatment. We analyzed long-term results of children treated with thalidomide to determine the association between clinical response and histology and endoscopy findings. METHODS: We collected data from 2 multicenter trials of 70 children with refractory Crohn's disease (CD) or ulcerative colitis (UC) (2-18 years old; ileocolonic or colonic disease) given thalidomide or placebo (NCT00720538). Clinical remission and clinical response at 8 weeks were defined as a pediatric CD activity index scores 10 points or lower and a decrease of at least 50% from baseline, respectively, for patients with CD; and as a pediatric UC activity index score below 10 and a decrease of at least 20 points from baseline, respectively, for patients with UC. Patients with a clinical response to 8 weeks' treatment with thalidomide underwent endoscopic examination with biopsy collection at study weeks 12 and 52. Severity of inflammation in patients with UC was assessed by Mayo score and in patients with CD by 4-grade system. Biopsies were assessed for signs of active inflammation, erosion or ulceration, and crypt abscesses and assigned a histologic score. RESULTS: Clinical remission was observed in 42 patients (60.0%) and clinical response in 45 patients (64.2%) at Week 8. At Week 52, a total of 38 patients (54.3%) were still in clinical remission or still had a clinical response; 29 patients (41.4%) had mucosal healing, defined as complete healing of erosions or ulcerations, and 20 patients (27.7%) had histologic healing, defined as complete absence of markers of inflammation. Of patients with clinical remission or clinical response, 75.3% also had mucosal healing and 52.6% also had histologic healing. The probability of achieving mucosal healing decreased significantly with increasing values of erythrocyte sedimentation rate (adjusted odds ratio, 0.96; 95% CI, 0.93-0.98; P = .006). CONCLUSIONS: In a long-term analysis of data from 2 clinical trials of pediatric patients with CD or UC, 52 weeks' treatment with thalidomide led to clinical remission in 54.3% of patients with ileocolonic or colonic disease; of these patients, 75.3% had mucosal healing and 52.6% also had histologic healing. Further studies are needed to determine how thalidomide therapy affects long-term progression of inflammatory bowel diseases. (ClinicalTrials.gov number NCT00720538).

Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial.

IMPORTANCE: Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. OBJECTIVE: To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease. DESIGN, SETTING, AND PATIENTS: Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy. INTERVENTIONS: Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. MAIN OUTCOMES AND MEASURES: Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response. RESULTS: Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event. CONCLUSIONS AND RELEVANCE: In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00720538.

Acute febrile cholestatic jaundice in children: keep in mind Kawasaki disease.

Kawasaki disease (KD) is characterized by persistent fever in addition to 4 of 5 signs of mucocutaneous inflammation. Although gastrointestinal involvement does not belong to the classic diagnostic criteria, it has been often associated with KD onset. We reviewed patients who were admitted for febrile cholestatic jaundice between 2003 and 2010 in 2 tertiary pediatric care centers. KD was the second most frequent cause (21%) after viral infections. Considering the relative high frequency of this condition, a high index of suspicion of KD should be maintained in patients presenting with febrile cholestatic jaundice.

Pediatric Adrenal Insufficiency: Challenges and Solutions.

Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason.

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.

Candidate Biomarkers for the Detection of Serious Infections in Children: A Prospective Clinical Study.

Serious bacterial infections (SBI) in children are associated with considerable morbidity and mortality, and their early identification remains challenging. The role of laboratory tests in this setting is still debated, and new biomarkers are needed. This prospective, observational, single-center study aims to evaluate the diagnostic role of blood biomarkers in detecting SBI in children presenting with signs of systemic inflammatory response syndrome (SIRS). A panel of biomarkers was performed, including C-reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), absolute neutrophil count (ANC), interleukin (IL)-6, IL-8, IL-10, human terminal complement complex (C5b-9), Plasmalemma-Vesicle-associated protein 1 (PV-1), Intercellular Adhesion Molecule-1 (ICAM-1), and Phospholipase A2 (PLA2). Among 103 patients (median age 2.9 years, 60% males), 39 had a diagnosis of SBI (38%). Significant predictors of SBI were CRP (p = 0.001) and ICAM-1 (p = 0.043). WBC (p = 0.035), ANC (p = 0.012) and ANC/WBC ratio (p = 0.015) were also significantly associated with SBI in children without pre-existing neutropenia. ROC curves, however, revealed suboptimal performance for all variables. Nevertheless, a model that combined CRP and ANC/WBC ratio had more in-depth diagnostic accuracy than either of the two variables. Overall, this study confirms the limited usefulness of blood biomarkers for the early diagnosis of SBI. WBC, ANC, ANC/WBC ratio, CRP, and ICAM-1 showed the best, albeit moderate, diagnostic accuracy.

Definition and prevalence of familial short stature.

OBJECTIVE: To verify the prevalence of novel definitions of familial short stature on a cross-sectional cohort of children referred for short stature when their height and that of both parents were measured. METHODS: We consecutively enrolled 65 individuals referred for short stature when both parents were present. We defined "target height-related short stature" (TH-SS) when child's height is ≤ - 2 SDS and included in the range of target height; suspected "autosomal dominant short stature" (AD-SS) when child height and at least one parent height are ≤ - 2 SDS; "constitutional familial short stature" (C-FSS) when a child with TH-SS does not have any parents with height ≤ - 2 SDS. RESULTS: Of 65 children referred for SS, 48 individuals had a height ≤ - 2 SDS. Based on the parents' measured heights, 24 children had TH-SS, 16 subjects AD-SS, and 12 individuals C-FSS. If we had considered only the parents' reported height, 3 of 24 children with TH-SS, 9 of 16 with AD-SS, and 10 of 12 with C-FSS would have been lost. CONCLUSION: We suggest novel definitions to adequately detect and approach the cases of FSS since C-FSS (25%) might not need any specific investigation, while on the contrary, AD-SS (33%) should undergo genetic evaluation. Moreover, this study underlines that adequate measurement and consideration of children's and parents' heights (individually and together) are crucial in the clinical evaluation of every child with short stature.

Should Pediatric Endocrinologists Consider More Carefully When to Perform a Stimulation Test?

Introduction: Pediatric endocrinology rely greatly on hormone stimulation tests which demand time, money and effort. The knowledge of the pattern of pediatric endocrinology stimulation tests is therefore crucial to optimize resources and guide public health interventions. Aim of the study was to investigate the distribution of endocrine stimulation tests and the prevalence of pathological findings over a year and to explore whether single basal hormone concentrations could have saved unnecessary stimulation tests. Methods: Retrospective study with data collection for pediatric endocrine stimulation tests performed in 2019 in a tertiary center. Results: Overall, 278 tests were performed on 206 patients. The most performed test was arginine tolerance test (34%), followed by LHRH test (24%) and standard dose Synachthen test (19%), while the higher rate of pathological response was found in insulin tolerance test to detect growth hormone deficiency (81%), LHRH test to detect central precocious puberty (50%) and arginine tolerance test (41%). No cases of non-classical-congenital adrenal hyperplasia were diagnosed. While 29% of growth hormone deficient children who performed an insulin tolerance test had a pathological peak cortisol, none of them had central adrenal insufficiency confirmed at low dose Synacthen test. The use of basal hormone determinations could save up to 88% of standard dose Synachthen tests, 82% of arginine tolerance + GHRH test, 61% of LHRH test, 12% of tests for adrenal secretion. Conclusion: The use of single basal hormone concentrations could spare up to half of the tests, saving from 32,000 to 79,000 euros in 1 year. Apart from basal cortisol level <108 nmol/L to detect adrenal insufficiency and IGF-1 <-1.5 SDS to detect growth hormone deficiency, all the other cut-off for basal hormone determinations were found valid in order to spare unnecessary stimulation tests.

Prevalence of children born small for gestational age with short stature who qualify for growth hormone treatment.

BACKGROUND: Recombinant human growth hormone (rhGH) is approved in Europe as a treatment for short children born small for gestational age (SGA) since 2003. However, no study evaluated the prevalence of SGA children with short stature who qualify for rhGH in Europe so far. This study aimed to investigate in an Italian population the prevalence of children born SGA, of short stature in children born SGA, and of SGA children who qualify for rhGH treatment at 4 years of age. METHODS: We conducted a population-based study on primary care pediatricians' databases in Trieste, Italy. Data was collected on 3769 children born between 2004 and 2014. SGA was defined as birth weight and/or birth length ≤ - 2 SDS. Data on height and weight were registered at the closest well-being visit to 1, 2, 3, 4 years of age. Short stature was defined as height ≤ - 2 SDS. Short children born SGA who qualify for rhGH treatment were identified according to Note AIFA #39 criteria (age ≥ 4 years; height ≤ - 2.5 SDS; growth velocity < 50th percentile). RESULTS: Full data at birth were available for 3250 children. The SGA prevalence was 3.6% (0.8% SGA for weight, 2.2% SGA for length, 0.6% SGA for both weight and length). The prevalence of short stature among SGA children was 9% at 1 year of age, 6% at 2 years (significantly higher in preterm in the first 2 years), 4% at 3 years, 3% at 4 years (all born at term). At 4 years of age, median height SDS was - 0.52. One child born SGA was eligible for GH treatment (0.8% among SGA children). CONCLUSIONS: The prevalence in a general pediatric population of children born SGA who qualify for GH treatment was 1:3250. Although the prevalence of SGA in our population was similar to previous studies, catch-up growth was recorded earlier in our sample compared to previous reports, and term babies had late catch-up. Height SDS of children born SGA at 4 years of age was lower than expected (- 0.52 SDS).

Pediatric endocrinology through syndromes.

In everyday practice, a pediatric endocrinologist will face a variety of different endocrine issues (such as short or tall stature, dysthyroidism, abnormal pubertal timing or impaired glucose metabolism), which relevantly contribute to the global care of a number of syndromic conditions. On the other hand, the presence of endocrine features may assist in the diagnostic process, leading to final diagnosis of a syndromic disorder. The intention of this review is to provide a referenced overview of different genetic syndromes characterized by endocrine features, and to present a possible classification, based on whether the endocrinopathy or the syndrome is typically recognized first. Thus, the first part of the manuscript deals with the most common syndromes associated with endocrine dysfunctions, while the second part describes the conditions by which a syndrome is most frequently diagnosed after an endocrine finding. The aim is to provide a practical overview of the assessment of syndromic patients, so that they can be recognized and managed in an integrated, multidisciplinary fashion.

Pattern and Features of Pediatric Endocrinology Referrals: A Retrospective Study in a Single Tertiary Center in Italy.

Introduction: The knowledge of the pattern and the features of pediatric endocrinology referrals is crucial to optimize resources and guide public health interventions. We explored the numbers and the reasons for referral to a pediatric endocrinology outpatient clinic and investigated their features in terms of assignment of priority ranks, sex, age differences, the prevalence of pathological findings among referred cases, and the agreement among referrals, final diagnosis, treatment, and follow-up. Methods: Retrospective study with data collection for pediatric endocrinology first visits between November 2012 and February 2019 in a tertiary center. Results: A total of 1930 first visits were performed with an overall number of referrals of 2,165, and an increasing trend over the years. The most frequent referral reasons were slow growth, precocious puberty, and obesity; 14% of visits were classified as "urgent" (<7 days), 35% as "deferrable" (<30 days), and 51% as "planned" (<180 days). Sex and age differences among referrals were detected, with criticality in the appropriate timing for referral. Thirty-eight percent of patients had pathological findings. In 4% of the cases the final diagnosis was not concordant with the reason for referral. Treatment was prescribed in 35% of cases, and 67% returned at least for one follow-up visit. Conclusion: The study highlighted the need to target medical education of primary care on the definition of priority ranks, the need for more extended observation periods for subclinical or para-physiological conditions, the appropriate timing for referral, based on the definition of conditions or the best window of intervention.

A case report of glucose transporter 1 deficiency syndrome with growth hormone deficiency diagnosed before starting ketogenic diet.

BACKGROUND: Growth failure and growth hormone deficiency (GHD) have been reported as one accessory feature of GLUT1 deficiency syndrome (GLUT1DS), considered so far as a long-term adverse effects of ketogenic diet which is used to treat this condition. CASE PRESENTATION: We report the case of a 10-year-old Caucasian boy referred for short stature (height - 2.56 SDS) and delayed growth (growth velocity - 4.33 SDS) who was diagnosed with GHD and started treatment with recombinant human growth hormone (rhGH). Because of his history of seizures with infantile onset, deceleration of head growth with microcephaly, ataxia, and moderate intellectual disability, a lumbar puncture was performed, which revealed a low CSF glucose concentration with a very low CSF-to-blood glucose ratio (< 0.4), and genetic tests detected a SLC2A1 gene exon 1 deletion confirming a diagnosis of GLUT1DS. Ketogenic diet was started. After 5.5 years of rhGH treatment his height was normalized (- 1.15 SDS). No side effects were reported during treatment, particularly on glycemic metabolism. CONCLUSIONS: This is the first case of GHD in a Caucasian boy with GLUT1DS diagnosed before starting ketogenic diet, with a good response to rhGH treatment and absence of side effects. We speculate that GHD may represent a poorly recognized clinical feature of GLUT1DS rather than a complication due to ketogenic diet. Under-diagnosis may derive from the fact that growth failure is usually ascribed to ketogenic diet and therefore not further investigated. Pediatric neurologists need to be alerted to the possible presence of GHD in patients with GLUT1DS with slow growth, while pediatric endocrinologist need to refer GHD patients with additional features (motor and cognitive developmental delay, seizures with infantile onset, deceleration of head growth with acquired microcephaly, movement disorder with ataxia, dystonia, and spasticity) that may suggest GLUT1DS.

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.