Thyroid hormone levels in children with Prader-Willi Syndrome: A randomized controlled Growth Hormone (GH)-trial and 10-year GH study.

CONTEXT: Several endocrine abnormalities were reported in children with Prader-Willi Syndrome (PWS), including hypothyroidism. Growth hormone (GH)-treatment may impact the thyroid-hormone-axis by direct inhibition of T4 or TSH secretion or by increased peripheral conversion of free T4 (FT4) to T3. OBJECTIVE: To evaluate thyroid function during GH-treatment in a large group of children with PWS. METHODS: Serum FT4, T3 and TSH measured in a 2-year randomized-controlled-GH-trial (RCT) and 10-year-longitudinal-GH-study. GH-treatment with 1.0 mg/m²/day (∼0.035mg/kg/day). RESULTS: Forty-nine children with PWS were included in the 2-year RCT (median (IQR) age GH-group 7.44 (5.47-11.80) years, control group 6.04 (4.56-7.39) years). During the first 6 months, median (IQR) FT4 SDS decreased in GH-group from -0.84 (-1.07 to -0.62) to -1.32 (-1.57 to -1.08) (p<0.001) and T3 SDS increased from 0.31 (-0.01 to 0.63) to 0.56 (0.32 to 0.79) (p=0.08), while in control group, FT4 and T3 SDS remained unchanged. In our 10-year-GH-study, 240 children with PWS (median (IQR) age 1.27 (0.54-4.17) years) were included. Between 2-10 years, median (IQR) FT4 SDS remained unchanged, being -0.87 (-0.98 to -0.77) after 2 years and -0.88 (-1.03 to -0.74) after 10 years (p=0.13). TSH SDS decreased from -0.35 (-0.50 to -0.21) after 2 years to -0.68 (-0.84 to -0.53) after 10 years (p<0.001). CONCLUSIONS: Our findings suggest that GH-treatment decreases FT4 levels, due to increased peripheral conversion of FT4 to T3 in the first months of treatment, but thereafter FT4 and T3 normalize and remain stable during long-term GH-treatment in almost all children and adolescents with PWS.

[The importance of early recognition of Prader-Willi syndrome]. / Het Prader-Willi-syndroom.

Due to its rare nature and subtle dysmorphisms, Prader-Willi syndrome can be challenging to recognize and diagnose in the neonatal period. Feeding difficulties and hypotonia ('floppy infant') are the most striking characteristics. Prader-Willi syndrome requires specific follow-up and treatment, emphasizing the importance of early recognition.We encountered an infant of three months old with severe hypotonia. The hypotonia ameliorated spontaneously over time, although feeding per nasogastric tube was necessary. There were no apparent dysmorphisms. Extensive genetic investigations showed a maternal uniparental disomy of chromosome 15, fitting with Prader-Willi syndrome explaining all symptoms. After excluding contraindications, treatment with growth hormone therapy was started. Parents were educated regarding medical emergencies specific for Prader-Willi syndrome ('medical alerts'). Although Prader-Willi syndrome is rare, it should always be considered in cases of neonatal hypotonia. Early recognition is paramount as specific recommendations and treatment are warranted.

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.

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.

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.

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.

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.

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.

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.

Temple Syndrome: Clinical Findings, Body Composition and Cognition in 15 Patients.

BACKGROUND: Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated methylation defect of the MEG3-DMR. Studies on phenotypical characteristics in TS14 are scarce and patients with TS14 often experience delay in diagnosis, which has adverse effects on their health. TS14 is often characterized as either Prader-Willi-like, Silver-Russell-like or as a Silver-Russell spectrum disorder. METHODS: This study describes 15 patients with TS14 who visited the Dutch Reference Center for Prader-Willi-like from December 2018 to January 2022. RESULTS: Eight patients had UPD(14)mat and seven a methylation defect. The most common symptoms were intra-uterine growth retardation (IUGR) (100%), hypotonia (100%), precocious puberty (89%), small for gestational age (SGA) birth (67%), tube feeding after birth (53%) and psycho-behavioral problems (53%). Median (interquartile range (IQR)) IQ was 91.5 (84.25; 100.0), whilst many patients were enrolled in special education (54%). The median (IQR) fat mass % (FM%) SDS was 2.53 (2.26; 2.90) and lean body mass (LBM) SDS -2.03 (-3.22; -1.28). There were no significant differences in clinical characteristics between patients with a UPD(14)mat and a methylation defect. CONCLUSIONS: Our patients share a distinct phenotype consisting of IUGR, SGA birth, precocious puberty, hypotonia, tube feeding after birth, psycho-behavioral problems and abnormal body composition with a high FM% and low LBM. Whilst similarities with Prader-Willi syndrome (PWS) and Silver-Russell syndrome (SRS) exist, TS14 is a discernible syndrome, deserving a tailored clinical approach. Testing for TS14 should be considered in patients with a PWS or SRS phenotype in infancy if PWS/SRS testing is negative.

Atypical 15q11.2-q13 Deletions and the Prader-Willi Phenotype.

Background: Prader-Willi syndrome (PWS) is a rare genetic disorder resulting from the lack of expression of the PWS region (locus q11-q13) on the paternally derived chromosome 15, as a result of a type I or II paternal deletion (50%), maternal uniparental disomy (43%), imprinting defect (4%) or translocation (<1%). In very rare cases, atypical deletions, smaller or larger than the typical deletion, are identified. These patients may have distinct phenotypical features and provide further information regarding the genotype−phenotype correlation in PWS. Methods: A prospective study in eight patients (six males and two females) with an atypical deletion in the PWS region accompanies an overview of reported cases. Results: All patients had hypotonia (100%) and many had typical PWS facial characteristics (75%), social and emotional developmental delays (75%), intellectual disabilities (50%), neonatal feeding problems and tube feeding (63%), history of obesity (50%), hyperphagia (50%) and scoliosis (50%). All males had cryptorchidism. Two patients had two separate deletions in the PWS critical region. Conclusions: Our findings provide further insight into PWS genotype−phenotype correlations; our results imply that inclusion of both SNURF-SNPRN and SNORD-116 genes in the deletion leads to a more complete PWS phenotype. A larger deletion, extending further upstream and downstream from these genes, does not cause a more severe phenotype. Conventional PWS methylation testing may miss small deletions, which can be identified using targeted next generation sequencing. PWS's phenotypic diversity might be caused by differentially methylated regions outside the 15q11.2 locus.

Long-Term Growth Hormone Treatment of Children with PWS: The Earlier the Start, the Better the Outcomes?

Long-term effects of growth hormone (GH) treatment in young children with Prader-Willi syndrome (PWS) have never been compared with untreated age-matched controls with PWS, and it is unclear if starting GH in the first year of life is safe and more effective than starting GH in early childhood. We investigated the effects of long-term GH on body composition, anthropometrics and cognition in young children with PWS compared to untreated controls and assessed whether starting GH in the first year of life is optimal and safe. An open-label, prospective study was performed, comparing GH-treated children with untreated controls, and comparing children who started GH in the first year of life (subgroup A) with children who started between 2-5 years (subgroup C). A total of 82 GH-treated children with PWS and 22 age-matched controls with PWS were included. The main outcome measures were body composition, anthropometrics, IQ, and safety parameters. After 8 years, GH-treated children had significantly better body composition and were taller than age-matched controls. Subgroup A had a lower FM% trajectory during treatment than subgroup C and showed a greater and longer-term increase in the LBM index. After 8 years, subgroup A had a lower trunk/peripheral fat ratio (p = 0.043) and higher IQ (p = 0.043). No adverse effects of starting GH in the first year were found. Children with PWS who received long-term GH had a better body composition and growth than untreated age-matched controls and starting GH in the first year of life was optimal and safe.

Prenatal and Neonatal Characteristics of Children with Prader-Willi Syndrome.

OBJECTIVE: Prader-Willi syndrome (PWS) is a rare genetic syndrome with a wide spectrum of clinical features in early life. Late diagnoses are still present. We characterized the perinatal and neonatal features of PWS, compared them with those of healthy newborns and assessed the prenatal and neonatal differences between the genetic subtypes. DESIGN: A cohort study in children with PWS. The prevalence of variables was compared with healthy infants (PLUTO cohort) and to population statistics from literature. PATIENTS: 244 infants with PWS and 365 healthy infants. MEASUREMENTS: Data on prenatal and neonatal variables in both cohorts. Population statistics were collected through an extensive literature search. RESULTS: A higher prevalence of maternal age >35 years was found in PWS compared to healthy infants and population statistics, and the highest maternal age was found in the mUPD group. Higher prevalence of polyhydramnios, caesarean section, labour induction and breech presentation, and lower birth weight SDS was found in PWS compared to healthy infants. High prevalences of decreased fetal movements (78.5%), hypotonia (100%), cryptorchism (95.9%) and poor sucking/tube feeding (93.9%) were found in PWS. CONCLUSIONS: This study presents an overview of prenatal and neonatal variables in infants with PWS compared to healthy infants. Our findings may increase clinical awareness of the early perinatal signs of PWS by obstetricians, neonatologists and all those involved in infant care, enabling early diagnosis and start of multidisciplinary treatment.

The Spectrum of the Prader-Willi-like Pheno- and Genotype: A Review of the Literature.

Prader-Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader-Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf-Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion, 15q duplication, 19p deletion, fragile X syndrome, and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%), and psychobehavioral problems (53%). In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.

Effects of 8 years of growth hormone treatment on scoliosis in children with Prader-Willi syndrome.

OBJECTIVE: Scoliosis is frequently seen in children with Prader-Willi syndrome (PWS). There is still concern that growth hormone (GH) treatment might increase the risk of onset or progression of scoliosis. Short-term data suggested no adverse effects of GH on scoliosis, but long-term effects of GH treatment on development of scoliosis in PWS are unknown. This study investigated the effects of 8 years of GH treatment on scoliosis in children with PWS. DESIGN: Open-label, prospective cohort study in 103 children with PWS receiving GH for 8 years was analyzed. Prevalence and severity of scoliosis were compared to a group of 23 age-matched GH-untreated children with PWS. METHODS: Spine X-rays and DEXA-scans were performed, and Cobb angel was measured by two independent observers. RESULTS: After 8 years of GH treatment, at median age of 10.8 years, prevalence of scoliosis was 77.7%. No difference in prevalence or severity of scoliosis was found between GH-treated and age-matched untreated children with PWS (P = 0.409 and P = 0.709, respectively). Height SDS and trunkLBM were significantly higher in GH-treated children. Higher bone mineral density of the lumbar spine was found in children without scoliosis after 8 years of GH. Bone mineral apparent density of lumbar spine (BMADLS) SDS was associated with lower Cobb angle (r = -0.270, P = 0.008). CONCLUSIONS: Eight years of GH treatment has no adverse effects on the prevalence and severity of scoliosis in children with PWS until 11 years of age. As BMADLS SDS is inversely associated with Cobb angle, it is pivotal to optimize the BMD status in children with PWS.

Appetite-regulating hormone trajectories and relationships with fat mass development in term-born infants during the first 6 months of life.

BACKGROUND: The first 6 months of life are a critical window for adiposity programming. Appetite-regulating hormones (ARH) are involved in food intake regulation and might, therefore, play a role in adiposity programming. Studies examining ARH in early life are limited. PURPOSE: To investigate ghrelin, peptide YY (PYY) and leptin until 6 months and associations with fat mass percentage (FM%), infant feeding and human milk macronutrients. PROCEDURES: In 297 term-born infants (Sophia Pluto Cohort), ghrelin (acylated), PYY and leptin were determined at 3 and 6 months, with FM% measurement by PEAPOD. Exclusive breastfeeding (BF) was classified as BF ≥ 3 months. Human milk macronutrients were analyzed (MIRIS Human Milk Analyzer). MAIN FINDINGS: Ghrelin increased from 3 to 6 months (p < 0.001), while PYY decreased (p < 0.001), resulting in increasing ghrelin/PYY ratio. Leptin decreased. Leptin at 3 months was higher in girls, other ARH were similar between sexes. Leptin at 3 and 6 months correlated with FM% at both ages(R ≥ 0.321, p ≤ 0.001) and gain in FM% from 1 to 6 months(R ≥ 0.204, p = 0.001). In BF infants, also ghrelin and ghrelin/PYY ratio correlated with this gain in FM%. Exclusively BF infants had lower ghrelin and higher PYY compared to formula fed infants at 3 months (p ≤ 0.039). ARH did not correlate with macronutrients. CONCLUSIONS: Increasing ghrelin and decreasing PYY, thus increasing ghrelin/PYY ratio, suggests an increasing orexigenic drive until 6 months. ARH were different between BF and FF infants at 3 months, but did not correlate with human milk macronutrients. Ghrelin and leptin, but not PYY, correlated with more FM development during the first 6 months, suggesting that they might be involved in adiposity programming.

Longitudinal telomere length and body composition in healthy term-born infants during the first two years of life.

OBJECTIVE: Leukocyte telomere length (LTL) is one of the markers of biological aging as shortening occurs over time. Shorter LTL has been associated with adiposity and a higher risk of cardiovascular diseases. The objective was to assess LTL and LTL shortening during the first 2 years of life in healthy, term-born infants and to associate LTL shortening with potential stressors and body composition. STUDY DESIGN: In 145 healthy, term-born infants (85 boys), we measured LTL in blood, expressed as telomere to single-gene copy ratio (T/S ratio), at 3 months and 2 years by quantitative PCR technique. Fat mass (FM) was assessed longitudinally by PEAPOD, DXA, and abdominal FM by ultrasound. RESULTS: LTL decreased by 8.5% from 3 months to 2 years (T/S ratio 4.10 vs 3.75, p<0.001). LTL shortening from 3 months to 2 years associated with FM%(R = 0.254), FM index(R = 0.243) and visceral FM(R = 0.287) at 2 years. LTL shortening tended to associate with gain in FM% from 3 to 6 months (R = 0.155, p = 0.11), in the critical window for adiposity programming. There was a trend to a shorter LTL in boys at 2 years(p = 0.056). LTL shortening from 3 months to 2 years was not different between sexes. CONCLUSION: We present longitudinal LTL values and show that LTL shortens considerably (8.5%) during the first 2 years of life. LTL shortening during first 2 years of life was associated with FM%, FMI and visceral FM at age 2 years, suggesting that adverse adiposity programming in early life could contribute to more LTL shortening.

Longitudinal human milk macronutrients, body composition and infant appetite during early life.

BACKGROUND & AIMS: Breastfeeding is the gold standard infant feeding. Data on macronutrients in relation to longitudinal body composition and appetite are very scarce. The aim of this study was to investigate longitudinal human milk macronutrients at 1 and 3 months in association with body composition and appetite during early life in healthy, term-born infants. We hypothesized that infants receiving higher caloric human milk would have more body fat mass and satiate earlier. METHODS: In 133 exclusively breastfed infants (Sophia Pluto Cohort), human milk samples at 1 and 3 months were analyzed for macronutrients (fat, protein, carbohydrate) by MIRIS Human Milk Analyzer, with appetite assessment by Baby Eating Behavior Questionnaires. Fat mass (FM) and fat-free mass (FFM) were measured by PEA POD and DXA, and abdominal FM by ultrasound. RESULTS: Milk samples showed large differences in macronutrients, particularly in fat content. Protein and energy content decreased significantly from 1 to 3 months. Fat and carbohydrate content tended to decrease (p = 0.066 and 0.081). Fat (g/100 ml) and energy (kcal/100 ml) content at 3 months were associated with FM% at 6 months (ß 0.387 and 0.040, resp.) and gain in FM% from 1 to 6 months (ß 0.088 and 0.009, resp.), but not with FM% at 2 years. Carbohydrate content at 3 months tended to associate with visceral FM at 2 years (ß 0.290, p = 0.06). Infants receiving higher caloric milk were earlier satiated and finished feeding faster. CONCLUSIONS: Our longitudinal data show decreasing milk protein and energy content from age 1 to 3 months, while fat and carbohydrate tended to decrease. Macronutrient composition, particularly fat content, differed considerably between mothers. Milk fat and energy content at 3 months associated with gain in FM% from age 1 to 6 months, indicating that higher fat and energy content associate with higher gain in FM% during the critical window for adiposity programming. As infants receiving higher caloric breastfeeding were earlier satiated, this self-regulatory mechanism might prevent intake of excessive macronutrients. ONLINE TRIAL REGISTRY: NTR, NL7833.