Effects and safety of growth hormone treatment in six children with pycnodysostosis.

BACKGROUND: Pycnodysostosis is an extremely rare skeletal dysplasia caused by cathepsin K deficiency. It is characterized by extreme short stature with adult height in males typically less than 150 cm and in females less than 130 cm. Our objective was to evaluate the effect and safety of growth hormone (GH) treatment in 6 patients with pycnodysostosis treated according to the Dutch national pycnodysostosis guideline. CASE PRESENTATION: 6 subjects (4 boys, 2 girls) with pycnodysostosis, treated with GH 1.4 mg/m2/day (~0.046 mg/kg/day) for ≥1 year. Median (IQR) age at start of GH was 10.4 years (5.7; 12.2) and median height 113.5 cm (93.3; 129.3) (-4.2 SDS (-4.8; -3.6)). All children were prepubertal at start of GH. After 1 year of GH, median height gain was 7.6 cm (6.5; 8.5) (0.3 SDS (-0.3; 0.7)). Three children are still treated with GH and the other three subjects reached adult height (AH): 1 boy reached an AH of 157.0 cm (-3.8 SDS) after 6.3 years of GH, 2 girls reached an AH of 138.5 cm (-5.2 SDS) after 4.8 years of GH and 148.0 cm (-3.6 SDS) after 6.4 years of GH, respectively. This last girl received additional GnRH analogue treatment. In all subjects height SDS remained stable or improved during and after GH treatment. No serious adverse advents were found. Serum IGF-I remained below the +2 SDS. CONCLUSION: Our data suggest that GH may prevent the decline in height which can be observed in children with pycnodysostosis. Further research is needed to confirm this. Also, the effect of other growth promoting strategies such as treatment with an additional GnRH analogue warrants further investigation.

Cerebral white matter hyperintensities in adults born small for gestational age at 12 years after cessation of childhood growth hormone treatment: a prospective cohort study including untreated controls.

Background: Increased cerebrovascular morbidity was reported in adults born small for gestational age (SGA) who were treated with growth hormone (GH) during childhood compared to the general population. Yet, previous studies lacked an appropriate control group which is a major limitation. We prospectively studied cerebral white matter hyperintensities (WMHs) in adults born SGA at 12 years after cessation of childhood GH-treatment (SGA-GH), compared to appropriate controls. Methods: In this prospective cohort study, performed between May 2016 and December 2020, total WMHs, periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) were the primary outcomes of the study, they were qualitatively assessed using 3 Tesla (T) Magnetic Resonance Imaging (MRI) and scored using the Fazekas scale in SGA-GH adults and in 3 untreated control groups: adults born SGA with persistent short stature (SGA-S), adults born SGA with spontaneous catch-up growth to a normal height (SGA-CU) and adults born appropriate for gestational age with a normal height (AGA). Regression analyses were performed in the total cohort to evaluate the associations of GH-treatment and birth characteristics with WMHs. Findings: 297 adults were investigated (91 SGA-GH, 206 controls). Prevalence of total WMHs was 53.8% (95% CI 43.1-64.3) in SGA-GH, 40.5% (95% CI 25.6-56.7) in SGA-S, 73.9% (95% CI 61.9-83.7) in SGA-CU and 41.1% (95% CI 31.1-51.6) in AGA adults. No statistically significant differences in total WMHs, PVWMHs and DWMHs were found between SGA-GH compared to SGA-S and AGA adults. Highest prevalence of all type of WMHs was found in SGA-CU adults compared to all groups. Higher prevalence of total WMHs was associated with lower birth weight standard deviation score (SDS), but not with GH-treatment. Interpretation: Our findings suggest that GH-treatment in children born SGA has no negative impact on the prevalence of all type of WMHs at 12 years after GH cessation compared to appropriate controls. SGA-CU adults had the highest prevalence of all type of WMHs around age 30 years. Funding: Novo Nordisk.

Early life poly- and perfluoroalkyl substance levels and adiposity in the first 2 years of life.

IMPORTANCE: Poly- and perfluoroalkyl substances (PFASs) are nondegradable, man-made chemicals. They accumulate in humans with potential harmful effects, especially in susceptible periods of human development, such as the first months of life. We found that, in our cohort, exclusively breastfed (EBF) infants had 3 times higher PFAS plasma levels compared with exclusively formula-fed (EFF) infants at the age of 3 months. Thus, PFASs could potentially reduce the health benefits of breastfeeding. OBJECTIVE: We investigated the associations between PFAS levels at the age of 3 months and accelerated gain in fat mass during the first 6 months of life, body composition at 2 years, and whether these associations differ between EBF and EFF infants. SETTING: In 372 healthy term-born infants, we longitudinally assessed anthropometrics, body composition (by air-displacement plethysmography and dual-energy X-ray absorptiometry), and visceral and subcutaneous fat (by abdominal ultrasound) until the age of 2 years. MEASURES: The plasma levels of 5 individual PFASs were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry at the age of 3 months. MAIN OUTCOMES: We studied associations between PFAS levels and outcomes using multiple regression analyses. RESULTS: Higher early life plasma perfluorooctanoic acid and total PFAS levels were associated with an accelerated gain in fat mass percentage [FM%; >0.67 SD score (SDS)] during the first 6 months of life. Higher early life PFAS levels were associated with lower fat-free mass (FFM) SDS at the age of 2 years, but not with total FM% SDS at 2 years. Furthermore, we found opposite effects of PFAS levels (negative) and exclusive breastfeeding (positive) at the age of 3 months on FFM SDS at 2 years. CONCLUSION: Higher PFAS levels in early life are associated with accelerated gains in FM% during the first 6 months of life and with lower FFM SDS at the age of 2 years, which have been associated with an unfavorable body composition and metabolic profile later in life. Our findings warrant further research with longer follow-up times.

Measured resting energy expenditure by indirect calorimetry and energy intake in long-term growth hormone treated children with PWS.

INTRODUCTION: Severe obesity can develop in children with PWS when food intake is not controlled. Maintenance of body weight requires an energy balance, of which energy intake and energy expenditure are important components. Previous studies described a decreased resting energy expenditure (REE) in growth hormone (GH)-untreated children with PWS. In short-term studies, no difference in REE was found between GH-treated and untreated children with PWS. However, there are limited data on REE in children with PWS who were GH-treated for a long period. METHODS: This study describes measured REE (mREE), energy intake and body composition during long-term GH-treatment in children with PWS. Patients were treated with 1.0 mg GH/m2/day (~0.035mg/kg/day). REE was determined by indirect calorimetry; dietary energy intake was calculated using a 3-day dietary record. Body composition by Dual energy X-ray absorptiometry (DXA) scans. RESULTS: We included 52 GH-treated children with PWS with mean (SD) age of 8.53 (4.35) years and median (IQR) GH-treatment duration of 7 (4-11) years. mREE increased with age, but was not associated with GH-treatment duration. A higher LBM was associated with higher mREE. Mean energy intake was significantly lower compared to daily energy requirements (DER) for age- and sex-matched healthy children (p<0.001), ranging from 23-36% less intake in children aged 3.5-12 years to 49% less intake in children aged 12-18 years. Fifty percent of children had a normal REE, 17.3 % a decreased REE and 32.7% an elevated REE, according to predicted REE based on measured REE in a large group of healthy children. CONCLUSION: In children with PWS, mREE increases with age. GH-treatment duration is not associated, whereas LBM is an important determinant of mREE. Children with PWS have a low to very low energy intake compared to DER for age- and sex-matched children, with a declining intake when becoming older.

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.

Schaaf-Yang Syndrome: Clinical Phenotype and Effects of 4 years of Growth Hormone Treatment.

INTRODUCTION: Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder caused by truncating mutations of the MAGEL2 gene, located in the Prader-Willi syndrome (PWS) region. PWS and SYS have phenotypic overlap. Patients with SYS are often treated with growth hormone (GH), but evidence for the effectiveness of the treatment in patients with SYS is limited. METHODS: This study describes 7 children with SYS. We studied their phenotype, genotype, and the effect of GH treatment on height and body mass index (BMI) during 4 years and on body composition during 1 year. RESULTS: All patients had a normal birth weight. Most patients had hypotonia and feeding difficulties after birth (86%). Full-scale IQ ranged from <50 to 92. All patients above the age of 2 years had psycho-behavioral problems. There were no apparent correlations between the phenotype and the location of the defect in the MAGEL2 gene. Mean (95% CI) height SDS increased significantly from -1.74 (-3.55; 0.07) at start to -0.05 (-1.87; 1.77) after 4 years of GH treatment. Mean (95% CI) BMI SDS decreased significantly from 2.01 (1.02; 3.00) to 1.22 (0.18; 2.26) after 6 months and remained the same during the rest of the follow-up. Fat mass percentage SDS decreased and lean body mass did not change during 1 year of treatment in 3 patients. CONCLUSION: Patients presented with a phenotype of hypotonia, respiratory insufficiency, and feeding difficulties after birth, endocrine disorders, intellectual disability, and behavioral problems. Treatment with GH significantly improved height SDS and BMI over the course of 4 years.

Infant Milk Formula with Large, Milk Phospholipid-coated Lipid Droplets Enriched in Dairy Lipids Affects Body Mass Index Trajectories and Blood Pressure at School Age: Follow-up of a Randomized Controlled Trial.

BACKGROUND: Human milk comprises large fat globules enveloped by a native phospholipid membrane, whereas infant formulas contain small, protein-coated lipid droplets. Previous experimental studies indicated that mimicking the architecture of human milk lipid droplets in infant milk formula (IMF) alters lipid metabolism with lasting beneficial impact on later metabolic health. OBJECTIVES: To evaluate in a follow-up (FU) study of a randomized, controlled trial whether a Concept IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids beneficially impacts long-term body mass index (BMI in kg/m2) trajectories and blood pressure at school age. METHODS: Fully formula-fed infants were randomly assigned to Concept IMF (n = 115) or Control IMF with conventional, small lipid droplets containing vegetable oils (n = 108) for the first 4 mo of age. A group of 88 breastfed infants served as a reference. During FU, anthropometrics were collected at 1, 3, 4, and 5 y of age, and blood pressure only at the last visit. RESULTS: Compared to Control, Concept group children had consistently lower mean BMI values during FU, with the most marked difference at 1 y of age (difference in means -0.71 kg/m2, 95% confidence interval (CI): -1.13, -0.29; P = 0.001); mean values were close to the breastfed group (P > 0.05). Contrary, the mean BMI values of the Control group were higher compared with the breastfed group during FU from 1 to 5 y of age (differences in means from 0.59 to 0.96 kg/m2, respectively; P < 0.02). At 5 y of age, the Concept group had a lower mean diastolic and arterial blood pressure compared with the Control group; -4.3mm Hg (95% CI: -7.3, -1.3; P = 0.005) and -3.7 mm Hg (95% CI: -6.5, -0.9; P = 0.01), respectively. CONCLUSIONS: Early life feeding of an innovative IMF with large, milk phospholipid-coated lipid droplets enriched with dairy lipids results in a BMI trajectory closer to breastfed infants and a lower blood pressure at school age. This trial was registered at the Dutch Trial Register as NTR3683 and NTR5538.

Cerebrovascular Abnormalities in Adults Born SGA at 12 Years After Growth Hormone Cessation Compared to Controls.

CONTEXT: Increased cerebrovascular morbidity was reported in adults born small for gestational age (SGA) who were treated with growth hormone (GH) during childhood compared to the general population. However, previous studies did not have an appropriate control group, which is a major limitation. OBJECTIVE: To study cerebrovascular abnormalities (aneurysms, previous intracerebral hemorrhages and microbleeds) using magnetic resonance imaging (MRI) in adults born SGA at 12 years after cessation of childhood GH treatment (SGA-GH) compared to appropriate controls. METHODS: In this single-center, prospective study, brain MRIs were performed between May 2016 and December 2020 on a 3T MRI system. MRI images were scored by 2 neuroradiologists who were blinded to patient groupings. Participants included adults born SGA previously treated with GH and 3 untreated control groups: adults born SGA with persistent short stature (SGA-S), adults born SGA with spontaneous catch-up growth to a normal height (SGA-CU) and adults born appropriate for gestational age with a normal height (AGA). The intervention was long-term GH treatment during childhood and the main outcome measure was cerebrovascular abnormalities. RESULTS: A total of 301 adults were investigated. Aneurysms were found in 6 adults: 3 (3.6%) SGA-GH, 1 (2.9%) SGA-S and 2 (2.2%) AGA adults, without differences between SGA-GH adults and the controls. Previous intracerebral hemorrhages were only found in 2 SGA-S adults (4.8%). Microbleeds were found in 17 adults: 4 (4.3%) SGA-GH, 4 (9.5%) SGA-S, 3 (4.3%) SGA-CU and 6 (6.3%) AGA adults, without differences between SGA-GH adults and the controls. CONCLUSION: Our findings suggest that SGA-GH adults at 12 years after GH cessation have no increased prevalence of cerebrovascular abnormalities compared to appropriate controls. Further research is needed to confirm our findings.

Longitudinal changes in acylated versus unacylated ghrelin levels may be involved in the underlying mechanisms of the switch in nutritional phases in Prader-Willi syndrome.

INTRODUCTION: Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. An elevated, more unfavorable ratio between acylated and unacylated ghrelin (AG/UAG ratio) might play a role in the underlying mechanisms of this switch. We aimed to assess the evolution of the appetite regulating hormones acylated ghrelin (AG) and unacylated ghrelin (UAG) and the AG/UAG ratio and their association with the change in eating behavior in children with PWS, compared to healthy age-matched controls. METHODS: Longitudinal study in 134 children with PWS and 157 healthy controls, from The Netherlands, France and Belgium. Levels of AG and UAG and the AG/UAG ratio were measured and nutritional phases as reported for PWS were scored. RESULTS: The AG/UAG ratio was in the first years of life lower in PWS than in controls and started to increase from the age of 3 years, resulting in a high-normal AG/UAG ratio compared to controls. The AG levels remained stable during the different nutritional phases (p=0.114), while the UAG levels decreased from 290 pg/ml in phase 1a to 137 pg/ml in phase 2b (p<0.001). The AG/UAG ratio increased significantly from 0.81 in phase 2a to 1.24 in phase 2b (p= 0.012). CONCLUSIONS: The change from failure to thrive to excessive weight gain and hyperphagia in infants and children with PWS coincides with an increase in AG/UAG ratio. The increase in AG/UAG ratio occurred during phase 2a, thus before the onset of hyperphagia.

Infant formula containing large, milk phospholipid-coated lipid droplets and dairy lipids affects cognitive performance at school age.

Background: Breastfeeding has been positively associated with infant and child neurocognitive development and function. Contributing to this effect may be differences between human milk and infant formula in the milk lipid composition and milk fat globule structure. Objective: To evaluate the effects of an infant formula mimicking human milk lipid composition and milk fat globule structure on childhood cognitive performance. Methods: In a randomized, controlled trial, healthy term infants received until 4 months of age either a Standard infant formula (n = 108) or a Concept infant formula (n = 115) with large, milk phospholipid coated lipid droplets and containing dairy lipids. A breastfed reference group (n = 88) was included. Erythrocyte fatty acid composition was determined at 3 months of age. Neurocognitive function was assessed as exploratory follow-up outcome at 3, 4, and 5 years of age using the Flanker test, Dimensional Change Card Sort (DCCS) test and Picture Sequence Memory test from the National Institutes of Health Toolbox Cognition Battery. Mann-Whitney U test and Fisher exact test were used to compare groups. Results: Erythrocyte omega-6 to -3 long-chain polyunsaturated fatty acid ratio appeared to be lower in the Concept compared to the Standard group (P = 0.025). At age 5, only the Concept group was comparable to the Breastfed group in the highest reached levels on the Flanker test, and the DCCS computed score was higher in the Concept compared to the Standard group (P = 0.021). Conclusion: These outcomes suggest that exposure to an infant formula mimicking human milk lipid composition and milk fat globule structure positively affects child neurocognitive development. Underlying mechanisms may include a different omega-3 fatty acid status during the first months of life. Clinical trial registration: https://onderzoekmetmensen.nl/en/trial/28614, identifier NTR3683 and NTR5538.

Challenges in body composition assessment using air-displacement plethysmography by BOD POD in pediatric and young adult patients.

BACKGROUND & AIMS: Air-Displacement-Plethysmography (ADP) by BOD POD is widely used for body fat assessment in children. Although validated in healthy subjects, studies about use in pediatric patients are lacking. We evaluated user experience and usability of ADP measurements with the BOD POD system in healthy children and pediatric and young adult patients. METHODS: Using the experiences of seven cohort studies, which included healthy children and patients aged 2-22 years, we retrospectively evaluated the user experience with the User Experience Questionnaire (UEQ) (n = 13) and interviews (n = 7). Technical performance was studied using the quality control data collected by the ADP-system. RESULTS: From 2016 to 2022, 1606 measurements were scheduled. BOD POD was mostly rated 'user-friendly', with a generally neutral evaluation on all scales of the UEQ. However, questionable reliability and validity of the results were frequently (86%) reported. We found a high technical failure-rate of the device, predominantly in stability (17%) and accuracy of the measurement (12%), especially in the 'pediatric option' for children aged <6 years. Measurement failure-rate was 38%, mostly due to subject's fear or device failure, especially in young and lean children, and in children with physical and/or intellectual disabilities. CONCLUSION: We conclude that ADP by BOD POD in children and young adults is non-invasive and user-friendly. However, in specific pediatric populations, BOD POD has several limitations and high (technical) failure-rates, especially in young children with aberrant body composition. We recommend caution when interpreting body composition results of pediatric patients as assessed with BOD POD using the current default settings.

Cognitive function during 3 years of growth hormone in previously growth hormone-treated young adults with Prader-Willi syndrome.

CONTEXT: Most patients with Prader-Willi syndrome (PWS) have mild to moderate cognitive impairment. Growth hormone (GH) treatment has positive short- and long-term effects on cognition in children with PWS. Few studies, however, have investigated the effects of GH on cognitive functioning in adults with PWS. OBJECTIVE: To investigate the effects of 3 years of GH treatment on cognitive functioning and behavior in young adults with PWS who were treated with GH during childhood. DESIGN: Open-label, prospective study. SETTING: Dutch PWS Reference Center. METHODS: Patients were treated with 0.33 mg GH/m²/day (∼0.012 mg/kg/day; 33% of childhood dose). Cognitive functioning was measured by Wechsler Adult Intelligence (WAIS) tests. Behavior was studied by a developmental behavior checklist-parents/caregivers (DBC-P). RESULTS: Forty-six young adults with PWS with a median age of 19 (IQR 17-21) years were investigated. Estimated mean (95% CI) total, verbal, and performance IQ remained stable during 3 years of GH-treatment. Total IQ being 66 (63-69) at the start and 67 (64-71) after 3 years (P = .30); Verbal IQ being 65 (62-68) and 66 (62-70), respectively (P = .31) and performance IQ being 67 (63-70) and 67 (63-72) resp. (P = .42). Estimated mean Total DBC score did not significantly change during 3 years of GH-treatment, being 36.3 at start and 36.5 after 3 years (P = .94) (P50). CONCLUSIONS: Three years of GH-treatment in young adults with PWS with 33% of the pediatric dose, maintains total, verbal, and performance IQ. The emotional and behavioral disturbances remained stable and were similar compared to peers with other intellectual disabilities.

Acute stress response of the HPA-axis in children with Prader-Willi syndrome: new insights and consequences for clinical practice.

Background: Prader-Willi syndrome (PWS) is associated with hypothalamic dysfunction. It has been reported that the HPA axis might show a delayed response during acute stress, and it is unknown whether the response of the HPA-axis during acute stress changes with age in children with PWS. Aim: To investigate the HPA-axis response during an overnight single-dose metyrapone (MTP) test in children with PWS and to assess if the response changes with age, whether it is delayed and if it changes with repeated testing over time. In addition, we evaluated different cut-off points of ACTH and 11-DOC levels to assess stress-related central adrenal insufficiency (CAI). Methods: An overnight single-dose MTP test was performed in 93 children with PWS. Over time, 30 children had a second test and 11 children a third one. Children were divided into age groups (0-2 years, 2-4 years, 4-8 years and > 8 years). Results: Most children did not have their lowest cortisol level at 7.30h, but at 04.00h. Their ACTH and 11-DOC peaks appeared several hours later, suggesting a delayed response. When evaluated according to a subnormal ACTH peak (13-33 pmol/L) more children had an subnormal response compared to evaluation based on a subnormal 11-doc peak (< 200 nmol/L). The percentage of children with a subnormal ACTH response ranged from 22.2 to 70.0% between the age groups, while the percentage of a subnormal 11-DOC response ranged from 7.7 to 20.6%. When using the ACTH peak for diagnosing acute-stress-related CAI, differences between age groups and with repeated testing over time were found, whereas there was no age difference when using the 11-DOC peak. Conclusion: Early morning ACTH or 11-DOC levels are not appropriate to determine acute stress-related CAI in children with PWS, thus multiple measurements throughout the night are needed for an accurate interpretation. Our data suggest a delayed response of the HPA-axis during acute stress. Using the 11-DOC peak for the test interpretation is less age-dependent than the ACTH peak. Repeated testing of the HPA-axis over time is not required, unless clinically indicated.

Skinfold-based-equations to assess longitudinal body composition in children from birth to age 5 years.

BACKGROUND & AIMS: In order to identify children at risk for excess adiposity, it is important to determine body composition longitudinally throughout childhood. However, most frequently used techniques in research are expensive and time-consuming and, therefore, not feasible for use in general clinical practice. Skinfold measurements can be used as proxy for adiposity, but current anthropometry-based-equations have random and systematic errors, especially when used longitudinally in pre-pubertal children. We developed and validated skinfold-based-equations to estimate total fat mass (FM) longitudinally in children aged 0-5 years. METHODS: This study was embedded in the Sophia Pluto study, a prospective birth cohort. In 998 healthy term-born children, we longitudinally measured anthropometrics, including skinfolds and determined FM using Air Displacement Plethysmography (ADP) by PEA POD and Dual energy X-ray Absorptiometry (DXA) from birth to age 5 years. Of each child one random measurement was used in the determination cohort, others for validation. Linear regression was used to determine the best fitting FM-prediction model based on anthropometric measurements using ADP and DXA as reference methods. For validation, we used calibration plots to determine predictive value and agreement between measured and predicted FM. RESULTS: Three skinfold-based-equations were developed for adjoined age ranges (0-6 months, 6-24 months and 2-5 years), based on FM-trajectories. Validation of these prediction equations showed significant correlations between measured and predicted FM (R: 0.921, 0.779 and 0.893, respectively) and good agreement with small mean prediction errors of 1, 24 and -96 g, respectively. CONCLUSIONS: We developed and validated reliable skinfold-based-equations which may be used longitudinally from birth to age 5 years in general practice and large epidemiological studies.

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.

The Effects of 5 Years of Growth Hormone Treatment on Growth and Body Composition in Patients with Temple Syndrome.

INTRODUCTION: Temple syndrome (TS14) is a rare imprinting disorder caused by maternal uniparental disomy of chromosome 14, paternal deletion of 14q32.2, or an isolated methylation defect. Most patients with TS14 develop precocious puberty. Some patients with TS14 are treated with growth hormone (GH). However, evidence for the effectiveness of GH treatment in patients with TS14 is limited. METHODS: This study describes the effect of GH treatment in 13 children and provides a subgroup analysis of 5 prepubertal children with TS14. We studied height, weight, body composition by dual-energy X-ray absorptiometry, resting energy expenditure (REE), and laboratory parameters during 5 years of GH treatment. RESULTS: In the entire group, mean (95% CI) height SDS increased significantly during 5 years of GH treatment from -1.78 (-2.52; -1.04) to 0.11 (-0.66; 0.87). Fat mass percentage SDS decreased significantly during the first year of GH, and lean body mass (LBM) SDS and LBM index increased significantly during 5 years of treatment. IGF-1 and IGF-BP3 levels rose rapidly during GH treatment, and the IGF-1/IGF-BP3 molar ratio remained relatively low. Thyroid hormone levels, fasting serum glucose, and insulin levels remained normal. In the prepubertal group, median (interquartile range [IQR]) height SDS, LBM SDS, and LBM index also increased. REE was normal at start and did not change during 1 year of treatment. Five patients reached adult height and their median (IQR) height SDS was 0.67 (-1.83; -0.01). CONCLUSION: GH treatment in patients with TS14 normalizes height SDS and improves body composition. There were no adverse effects or safety concerns during GH treatment.

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Sleep and 24-hour rhythm characteristics in preschool children born very preterm and full term.

STUDY OBJECTIVES: Sleep impacts the quality of life and is associated with cardiometabolic and neurocognitive outcomes. Little is known about the sleep of preterm-born children at preschool age. We, therefore, studied sleep and 24-hour rhythms of preschool children born very preterm compared with full-term children. METHODS: This was a prospective cohort study comparing sleep quality and quantity of children born very preterm (gestational age [GA] < 30 weeks) with full-term children at the (corrected) age of 3 years, using (1) 2 parent-reported questionnaires (Brief Infant Sleep Questionnaire and The Munich Chronotype Questionnaire) and (2) at least 3 days of triaxial wrist actigraphy combined with sleep diary. We performed regression analyses with adjustment for sex (corrected), age, and birth weight standard deviation (SD) score. RESULTS: Ninety-seven very-preterm-born (median GA 27+5; interquartile range 26 + 3;29 + 0 weeks) and 92 full-term children (GA 39 + 3; 38 + 4;40 + 4 weeks) were included. Sleep problems and other reported sleep parameters were not different between groups. As measured with actigraphy, sleep and 24-hour rhythm were similar between groups, except for very-preterm born children waking up 21 minutes (4;38) minutes later than full-term children (adjusted P = .001). CONCLUSIONS: Based on parent reports and actigraphy, very-preterm-born children sleep quite similar to full-term controls at the corrected age of 3 years. Reported sleep problems were not different between groups. Actigraphy data suggest that preterm-born children may wake up later than children born full term. Further studies are needed to explore how sleep relates to cardiometabolic and neurodevelopmental outcomes after preterm birth and whether early interventions are useful to optimize 24-hour rhythm and sleep. CITATION: Bijlsma A, Beunders VAA, Dorrepaal DJ, et al. Sleep and 24-hour rhythm characteristics in preschool children born very preterm and full term. J Clin Sleep Med. 2023;19(4):685-693.

Does prednisone use in pregnant women with rheumatoid arthritis induce insulin resistance in the offspring?

OBJECTIVES: The use of long-term corticosteroids during pregnancy has been growing over the past decades. Corticosteroids can be given when an auto-inflammatory disease like rheumatoid arthritis (RA) is too active. Several studies have shown that long-term corticosteroids use in pregnancy is associated with maternal and fetal adverse outcomes, like preeclampsia, shorter gestational age, lower birth weight, and rapid catch-up growth. These last two outcomes could influence the insulin resistance later in life. Our objective was to investigate whether prednisone use in pregnant women with RA induces insulin resistance in offspring. METHODS: One hundred three children were included after their mother had participated in a prospective cohort study on RA and pregnancy. Forty-two children were in utero exposed to prednisone and 61 were non-exposed. To assess insulin resistance, we measured homeostasis model of assessment insulin resistance (HOMA-IR) and serum adiponectin and lipid levels, corrected for body fat distribution. RESULTS: An average of 6 mg prednisone on a daily use gave no difference in mean HOMA-IR (SD) between the children who were prednisone-exposed in utero (1.10 (0.84)) and those non-exposed (1.09 (0.49)). No difference was found in mean adiponectin level, body fat distribution, or lipid levels such as total cholesterol, fasting triglyceride, or high-density lipoprotein. CONCLUSION: Children who are prednisone-exposed in utero (low dose) have no increased risk for insulin resistance at the age of approximately 7 years. These findings are reassuring because the prednisone use during pregnancy is increasing worldwide. Further research has to be performed to evaluate if the insulin resistance remains absent in the future. Key Points • What is already known on this topic-long-term corticosteroids use in pregnancy is associated with fetal adverse outcomes, like lower birth weight and rapid catch-up growth which can influence the insulin resistance later in life. • What this study adds-long-term corticosteroids use in pregnant women with rheumatoid arthritis has no increased risk for insulin resistance in the offspring. • How this study might affect research, practice, or policy-findings are reassuring because prednisone use during pregnancy is increasing worldwide. Further research should evaluate if the insulin resistance remains absent in the future.