Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Clinical Characteristics of Pathogenic ACAN Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data.

INTRODUCTION: Heterozygous variants in the ACAN gene may underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or early-onset osteoarthritis (OA). METHODS: The objective of this study was to describe phenotype, analyze genotype-phenotype correlations, and assess the response of growth hormone (GH) treatment in children with a heterozygous ACAN variant. Thirty-six subjects (23 boys, 13 girls) with ACAN deficiency and treated for ≥1 year with GH were identified in the Dutch National Registry of GH treatment in children. RESULTS: We identified 25 different heterozygous ACAN variants in 36 subjects. Median (interquartile range) height SDS at start of GH was -2.6 SDS (-3.2 to -2.2). Characteristic features such as disproportion, advanced BA, early-onset OA, and dysmorphic features like midface hypoplasia and brachydactyly were present in the majority of children, but in ∼20%, no specific features were reported. Subjects with a truncating ACAN variant had a shorter height SDS compared to subjects with a non-truncating variant (-2.8 SDS and -2.1 SDS, respectively, p = 0.002). After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS (0.9-1.4). In pubertal children, height SDS remained relatively stable. CONCLUSION: The phenotype of subjects with pathogenic heterozygous ACAN variants is highly variable, and genetic testing for ACAN deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement. Furthermore, children with ACAN deficiency may benefit from GH with a modest but significant response, which is sustained during 3 years of treatment.

Bone health in children with Angelman syndrome at the ENCORE Expertise Center.

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of -1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (-2.24 SDS) versus non-deletion (-1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (-2.60 vs -1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes.  Conclusions: Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. What is Known: • Children with neurological disorders often have a low bone health and higher risk of fractures. • Little is known about bone health in children with Angelman syndrome (AS). What is New: • Children with AS showed a reduced bone health and this was significantly associated with having a deletion, not being able to walk independently, and late onset of puberty. • Longitudinal analysis showed a significant decrease in bone health as children got older.

Hyperphagia, Growth, and Puberty in Children with Angelman Syndrome.

Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal disomy, imprinting center defect, or pathogenic variant in the UBE3A gene. Characteristics are developmental delay, epilepsy, behavioral, and sleep problems. There is some evidence for hyperphagia, shorter stature, and higher BMI compared to neurotypical children, but longitudinal studies on growth are lacking. In this study, we analyzed prospectively collected data of 145 children with AS, who visited the ENCORE Expertise Center between 2010 and 2021, with a total of 853 visits. Children showed an elevated mean score of 25 on the Dykens Hyperphagia questionnaire (range 11-55) without genotype association. Higher scores were significantly associated with higher body mass index (BMI) standard deviation scores (SDS) (p = 0.004). Mean height was -1.2 SDS (SD 1.3), mean BMI-SDS was 0.6 (SD 1.7); 43% had a BMI-SDS > 1 and 20% had a BMI-SDS > 2. Higher BMI-SDS was significantly associated with non-deletion genotype (p = 0.037) and walking independently (p = 0.023). Height SDS decreased significantly with age (p < 0.001) and BMI-SDS increased significantly with age (p < 0.001. Onset of puberty was normal. In conclusion, children with AS showed moderate hyperphagia, lower height SDS, and higher BMI-SDS compared to norm data, with increasing deviation from the norm with age. It is uncertain how loss of maternal UBE3A function may influence growth. Attention to diet, exercise, and hyperphagia from an early age is recommended to prevent obesity and associated health problems.

De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues.

The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier-Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.

Computer-aided facial analysis as a tool to identify patients with Silver-Russell syndrome and Prader-Willi syndrome.

Genetic syndromes often show facial features that provide clues for the diagnosis. However, memorizing these features is a challenging task for clinicians. In the last years, the app Face2Gene proved to be a helpful support for the diagnosis of genetic diseases by analyzing features detected in one or more facial images of affected individuals. Our aim was to evaluate the performance of the app in patients with Silver-Russell syndrome (SRS) and Prader-Willi syndrome (PWS). We enrolled 23 pediatric patients with clinically or genetically diagnosed SRS and 29 pediatric patients with genetically confirmed PWS. One frontal photo of each patient was acquired. Top 1, top 5, and top 10 sensitivities were analyzed. Correlation with the specific genetic diagnosis was investigated. When available, photos of the same patient at different ages were compared. In the SRS group, Face2Gene showed top 1, top 5, and top 10 sensitivities of 39%, 65%, and 91%, respectively. In 41% of patients with genetically confirmed SRS, SRS was the first syndrome suggested, while in clinically diagnosed patients, SRS was suggested as top 1 in 33% of cases (p = 0.74). Face2Gene performed better in younger patients with SRS: in all patients in whom a photo taken at a younger age than the age of enrollment was available, SRS was suggested as top 1, albeit with variable degree of probability. In the PWS group, the top 1, top 5, and top 10 sensitivities were 76%, 97%, and 100%, respectively. PWS was suggested as top 1 in 83% of patients genetically diagnosed with paternal deletion of chromosome 15q11-13 and in 60% of patients presenting with maternal uniparental disomy of chromosome 15 (p = 0.17). The performance was uniform throughout the investigated age range (1-15 years). CONCLUSION: In addition to a thorough medical history and detailed clinical examination, the Face2Gene app can be a useful tool to support clinicians in identifying children with a potential diagnosis of SRS or PWS. WHAT IS KNOWN: • Several genetic syndromes present typical facial features that may provide clues for the diagnosis. • Memorizing all syndromic facial characteristics is a challenging task for clinicians. WHAT IS NEW: • Face2Gene may represent a useful support for pediatricians for the diagnosis of genetic syndromes. • Face2Gene app can be a useful tool to integrate in the diagnostic path of patients with SRS and PWS.

Objective Home-Monitoring of Physical Activity, Cardiovascular Parameters, and Sleep in Pediatric Obesity.

Introduction: Clinical research and treatment of childhood obesity is challenging, and objective biomarkers obtained in a home-setting are needed. The aim of this study was to determine the potential of novel digital endpoints gathered by a home-monitoring platform in pediatric obesity. Methods: In this prospective observational study, 28 children with obesity aged 6-16 years were included and monitored for 28 days. Patients wore a smartwatch, which measured physical activity (PA), heart rate (HR), and sleep. Furthermore, daily blood pressure (BP) measurements were performed. Data from 128 healthy children were utilized for comparison. Differences between patients and controls were assessed via linear mixed effect models. Results: Data from 28 patients (average age 11.6 years, 46% male, average body mass index 30.9) and 128 controls (average age 11.1 years, 46% male, average body mass index 18.0) were analyzed. Patients were recruited between November 2018 and February 2020. For patients, the median compliance for the measurements ranged from 55% to 100% and the highest median compliance was observed for the smartwatch-related measurements (81-100%). Patients had a lower daily PA level (4,597 steps vs. 6,081 steps, 95% confidence interval [CI] 862-2,108) and peak PA level (1,115 steps vs. 1,392 steps, 95% CI 136-417), a higher nighttime HR (81 bpm vs. 71 bpm, 95% CI 6.3-12.3) and daytime HR (98 bpm vs. 88 bpm, 95% CI 7.6-12.6), a higher systolic BP (115 mm Hg vs. 104 mm Hg, 95% CI 8.1-14.5) and diastolic BP (76 mm Hg vs. 65 mm Hg, 95% CI 8.7-12.7), and a shorter sleep duration (difference 0.5 h, 95% CI 0.2-0.7) compared to controls. Conclusion: Remote monitoring via wearables in pediatric obesity has the potential to objectively measure the disease burden in the home-setting. The novel endpoints demonstrate significant differences in PA level, HR, BP, and sleep duration between patients and controls. Future studies are needed to determine the capacity of the novel digital endpoints to detect effect of interventions.

Broadening the Spectrum of Loss-of-Function Variants in NPR-C-Related Extreme Tall Stature.

CONTEXT: Natriuretic peptide receptor-C (NPR-C, encoded by NPR3) belongs to a family of cell membrane-integral proteins implicated in various physiological processes, including longitudinal bone growth. NPR-C acts as a clearance receptor of natriuretic peptides, including C-type natriuretic peptide (CNP), that stimulate the cGMP-forming guanylyl cyclase-coupled receptors NPR-A and NPR-B. Pathogenic variants in CNP, NPR2, and NPR3 may cause a tall stature phenotype associated with macrodactyly of the halluces and epiphyseal dysplasia. OBJECTIVE: Here we report on a boy with 2 novel biallelic inactivating variants of NPR3. METHODS: History and clinical characteristics were collected. Biochemical indices of natriuretic peptide clearance and in vitro cellular localization of NPR-C were studied to investigate causality of the identified variants. RESULTS: We identified 2 novel compound heterozygous NPR3 variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. In silico analysis indicated decreased stability of NPR-C, presumably resulting in increased degradation or trafficking defects. Compared to other patients with NPR-C loss-of-function, the phenotype seemed to be milder: pseudo-epiphyses in hands and feet were absent, biochemical features were less severe, and there was some co-localization of p.(Ile432Phe) NPR-C with the cell membrane, as opposed to complete cytoplasmic retention. CONCLUSION: With this report on a boy with tall stature and macrodactyly of the halluces we further broaden the genotypic and phenotypic spectrum of NPR-C-related tall stature.

Approach to Diagnosing a Pediatric Patient With Severe Insulin Resistance in Low- or Middle-income Countries.

Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli-Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and, therefore, our approach is especially applicable to low- or middle-income countries.

Predicting Malignancy in Pediatric Thyroid Nodules: Early Experience With Machine Learning for Clinical Decision Support.

OBJECTIVE: To develop a machine learning tool to integrate clinical data for the prediction of non-benign thyroid cytology and histology. CONTEXT: Papillary thyroid carcinoma is the most common endocrine malignancy. Since most nodules are benign, the challenge for the clinician is to identify those most likely to harbor malignancy while limiting exposure to surgical risks among those with benign nodules. METHODS: Random forests (augmented to select features based on our clinical measure of interest), in conjunction with interpretable rule sets, were used on demographic, ultrasound, and biopsy data of thyroid nodules from children younger than 18 years at a tertiary pediatric hospital. Accuracy, false-positive rate (FPR), false-negative rate (FNR), and area under the receiver operator curve (AUROC) are reported. RESULTS: Our models predict nonbenign cytology and malignant histology better than historical outcomes. Specifically, we expect a 68.04% improvement in the FPR, 11.90% increase in accuracy, and 24.85% increase in AUROC for biopsy predictions in 67 patients (28 with benign and 39 with nonbenign histology). We expect a 23.22% decrease in FPR, 32.19% increase in accuracy, and 3.84% decrease in AUROC for surgery prediction in 53 patients (42 with benign and 11 with nonbenign histology). This improvement comes at the expense of the FNR, for which we expect 10.27% with malignancy would be discouraged from performing biopsy, and 11.67% from surgery. Given the small number of patients, these improvements are estimates and are not tested on an independent test set. CONCLUSION: This work presents a first attempt at developing an interpretable machine learning based clinical tool to aid clinicians. Future work will involve sourcing more data and developing probabilistic estimates for predictions.

Serum hepcidin concentrations in relation to iron status in children with type 1 diabetes.

Chronic low-grade inflammation in type 1 diabetes (T1D) might increase hepcidin synthesis, possibly resulting in functional iron deficiency (FID). We hypothesized that in T1D children with FID, hepcidin concentrations are increased compared to those with normal iron status and those with absolute iron deficiency (AID). We evaluated hepcidin concentrations in T1D children in relation to iron status, and investigated whether hepcidin is useful in assessing FID. A cross-sectional study was conducted. FID was defined as elevated zinc protoporphyrin/heme ratio and/or red blood cell distribution width, and AID as low serum ferritin concentration. Post-hoc analyses with different definitions of FID were performed, using transferrin saturation and reticulocyte hemoglobin content. Serum hepcidin concentrations were measured using mass-spectrometry. The IRODIAB-study is registered at www.trialregister.nl (NTR4642). This study included 215 T1D children with a median age of 13.7 years (Q1-Q3: 10.1-16.3). The median (Q1-Q3) hepcidin concentration in patients with normal iron status was 1.8 nmol/l (0.9-3.3), in AID-patients, 0.4 nmol/l (0.4-0.4) and in FID-patients, 1.6 nmol/l (0.7-3.5). Hepcidin concentrations in FID-patients were significantly higher than in AID-patients (p < 0.001). Irrespective of FID-definition used, hepcidin concentrations did not differ between FID-patients and patients with normal iron status. This might be explained by the influence of various factors on hepcidin concentrations, and/or by differences in response of iron parameters over time. Single hepcidin measurements do not seem useful in assessing FID in T1D children. Multiple hepcidin measurements over time in future studies, however, might prove to be more useful in assessing FID in children with T1D.

An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature.

CONTEXT: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type). DESIGN: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant. RESULTS: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B. CONCLUSIONS: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.

[Growth failure as a symptom of inflammatory bowel disease]. / Afbuigende lengtegroeicurve bij inflammatoire darmziekte.

BACKGROUND: Growth failure can be a unique manifestation of untreated intestinal inflammation in children with inflammatory bowel disease (IBD). It can, however, be difficult to diagnose IBD in the absence of symptoms or in the presence of aspecific gastrointestinal symptoms. A delay in diagnosis is a risk factor for lower adult height. CASE DESCRIPTION: A 15--year-old boy was referred to a paediatric endocrinologist for growth failure and delayed puberty. Additional investigations were performed and he was diagnosed with Crohn's disease. CONCLUSION: IBD needs to be considered in a child presenting with growth failure and delayed puberty. A detailed medical history of any gastrointestinal symptoms should be taken. One should perform additional investigations according to the guidelines in a patient who fulfils criteria of short stature.

Central congenital hypothyroidism caused by maternal thyrotoxicosis.

Central congenital hypothyroidism (CCH) is a rare and underdiagnosed disease that sometimes is caused by maternal Graves' disease. We report a case of CCH caused by undiagnosed, initially antibody-negative maternal thyrotoxicosis with possible disruption of fetal hypothalamic-pituitary-thyroid axis maturation. In CCH, maternal thyroid disease should be considered.

The influence of food order on postprandial glucose levels in children with type 1 diabetes.

OBJECTIVE: To evaluate the effect of the order of intake of carbohydrates, protein, and fat on postprandial glucose levels in children with type 1 diabetes (T1D). Our hypothesis was that postprandial glucose levels would be lower when fat and protein are consumed prior to carbohydrates, compared to a meal where all macronutrients are combined. METHODS: A randomized, open-label, within-subject crossover study was conducted. Twenty patients aged 7 to 17 years diagnosed with T1D for >1 year consumed 2 isocaloric meals (with similar composition) in random order. In 1 meal, the protein and fat part was consumed 15 minutes prior to the carbohydrates (test meal). In the other meal, all macronutrients were consumed together (standard meal). Capillary blood glucose measurements and continuous glucose monitoring system were used to assess multiple glucose levels during a 3-hour postprandial period. RESULTS: Overall, mean glucose levels were 1 mmol/L lower following the test meal compared to the standard meal (9.30 ± 3.20 vs 10.24 ± 3.35 mmol/L; P < .001). No significant difference in peak glucose was found. Glucose excursions were 1.5 and 1 mmol/L lower at 30 and 120 minutes following the test meal. A reduction in the total time period in which glucose levels exceeded 10 and 12 mmol/L of 28.7 (P = .001) and 22.3 minutes (P = .004), respectively, after the test meal was found. CONCLUSIONS: This study shows that consumption of protein and fat prior to carbohydrates results in lower postprandial glucose levels and reduced glycemic variability in children with T1D.

Iron status and its association with HbA1c levels in Dutch children with diabetes mellitus type 1.

Children with diabetes mellitus (DM) type 1 may be at risk for iron deficiency (ID) although this has been little studied. ID is either an absolute (depleted iron stores) or a functional (restricted iron stores due to chronic inflammation) deficiency each requiring a different therapeutic approach. Unfortunately, absolute ID is often not distinguished from functional ID. Furthermore, iron-deficient anemia may influence hemoglobin A1c (HbA1c) levels. We aimed to determine the prevalence and type of ID and investigate its association with HbA1c levels in pediatric DM type 1 patients. We performed a two-center prospective observational study in which the iron status of Dutch children with DM type 1 was determined during a regular check-up. Absolute ID and functional ID were found in 13/227 (5.7%) and 100/214 (47%) patients, respectively, while only 15/113 (13%) patients also had anemia. HbA1c levels in patients with and without a deprived iron status (absolute or functional) were not significantly different (65 ± 17 vs. 65 ± 16 mmol/mol, p = 0.815). CONCLUSION: Functional, but not absolute, ID was common in Dutch pediatric DM type 1 patients. HbA1c levels were not associated with ID, which can be explained by the relatively mild deprived iron status in our patients. TRIAL REGISTRATION: NTR4642 What is Known: • Iron deficiency is either an absolute (depleted iron stores) or a functional (restricted iron stores due to chronic inflammation) deficiency each requiring a different therapeutic approach. • Children with diabetes mellitus type 1 may be at risk for both types of iron deficiency and this can influence their hemoglobin A1c levels although this has been little studied. What is New: • In Dutch children with diabetes mellitus type 1, functional, but not absolute iron deficiency, is common and should not be treated with iron replacement therapy. • Hemoglobin A1c levels were not associated with iron deficiency, probably due to the relatively mild deprived iron status in our patients.

Utility of adult-based ultrasound malignancy risk stratifications in pediatric thyroid nodules.

BACKGROUND: Individual ultrasound (US) features have limited ability to distinguish benign from malignant thyroid nodules. Adult-based systems have been developed to integrate the sonographic features in an effort to improve diagnostic accuracy. None, however, has been validated in children, in whom the likelihood of malignancy is 2-5 times higher than adults. OBJECTIVE: To assess the performance of two adult-based sonographic (US) stratification methods for assessment of thyroid nodules in children. MATERIALS AND METHODS: This retrospective study comprised 124 children who underwent thyroid US. Three radiologists reviewed the US data using the American Thyroid Association (ATA) and the Thyroid Image Reporting and Data System (TI-RADS). Radiologists' accuracy and agreement was assessed. The reference standard was histopathology/cytology or 2-year follow-up of clinical outcome for nonoperative cases. RESULTS: We assessed 71 benign and 52 malignant nodules and excluded 1 nodule. Using the ATA pattern descriptions, 80% of malignant nodules were classified as "high" 36/52 (69%) or "intermediate" 6/52 (11%) likelihood of malignancy. A total of 20/71 (28%) benign nodules were also classified within these two categories. Using the TI-RADS, malignant nodules were classified as 2, 3, 4a, 4b, 4c and 5, with rate of malignancy of 0%, 0%, 7/52 (13.5%), 7/52 (13.5%), 32/52 (61.5%) and 6/52 (11.5%), respectively. Benign nodules were also classified in the 4a (26/71; 36.6%), 4b (17/71; 24%), 4c (14/71; 19.7%) and 5 (1/71; 1.4%) categories. The positive and negative predictive values were 68.0% and 87.5% for ATA, and 71.7% and 80.0% for TI-RADS. CONCLUSION: We validated the use of ATA and TI-RADS methods in children and showed that they have test characteristics similar to those in adults, although neither is independently sufficient to discriminate nodules' likelihood of malignancy.

RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too?

RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype-phenotype correlations, which may provide insight into pathways that regulate the timing of puberty.

Puberty and Pubertal Growth in GH-treated SGA Children: Effects of 2 Years of GnRHa Versus No GnRHa.

CONTEXT: Most studies on puberty in children born small for gestational age (SGA) report height and age at onset of puberty. GH-treated SGA children with an adult height (AH) expectation below -2.5 SDS at onset of puberty can benefit from an additional 2 years of GnRH analog (GnRHa) treatment. There are no data on puberty and growth after discontinuation of GnRHa treatment in GH-treated SGA children. OBJECTIVE: This study aimed to investigate the effects on puberty and pubertal growth of 2 years GnRHa vs no GnRHa in GH-treated SGA children. METHODS: This was a GH trial involving 76 prepubertal short SGA children (36 girls) treated with GH. Thirty-two children received additional GnRHa for 2 years. Pubertal stages were 3-monthly assessed according to Tanner. RESULTS: Age, bone age, and median height at pubertal onset were lower in girls and boys in the GH/GnRHa group compared with the GH group. In girls and boys treated with GH/GnRHa, pubertal duration after stop of GnRHa treatment was shorter than pubertal duration in those with GH only (40.9 vs 46.7 mo; P = .044; 50.8 vs 57.5 months; P = .006; respectively). Height gain from onset of puberty until AH, including height gain during 2 years of GnRHa treatment, was 25.4 cm in girls and 33.0 cm in boys, which was 6.6 cm more than girls and boys treated with GH only. AH was similar in children treated with GH/GnRHa compared with those with GH only. CONCLUSIONS: GH-treated SGA children who start puberty with an AH expectation below -2.5 SDS and are treated with 2 years of GnRHa have a shorter pubertal duration after discontinuation of GnRHa compared with pubertal duration in children treated with GH only. Height gain from onset of puberty until AH is, however, more due to adequate growth during 2 years of GnRHa treatment resulting in a similar AH as children treated with GH only.