Gerthe F. Kerkhof

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.

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.

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 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.

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.

Early postnatal weight gain is associated with determinants of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM2) in adults born term. We aimed to investigate the association of weight gain during different periods, and weight trajectories in early life after preterm birth, with determinants of CVD and DM2 in early adulthood. Associations of first-year growth and tempo of weight gain with determinants of CVD and DM2 in 162 young adults (18-24 yr) born preterm (gestational age <36 wk) were determined and compared with data of young adults born term (n = 217). Gain in weight for length in the period from preterm birth up to term age, and in the first 3 months after term age, was positively associated with body fat percentage and waist circumference at 21 yr. Gain in weight for length in the first 3 months after term age was also positively associated with total cholesterol and low-density lipoprotein cholesterol levels in early adulthood. Subjects with the highest gain in weight from birth to term age (highest quartile) had significantly higher body fat percentage, waist circumference, acute insulin response, and disposition index in early adulthood than the subgroups with moderate and low gain in weight. Rapid catch-up in weight during the first 3 months after term age resulted in a higher fat percentage, waist circumference, and serum triglycerides level than slower catch-up in weight. Accelerated neonatal gain in weight relative to length after preterm birth (immediately after birth and during the first 3 months after term age) is associated with determinants of CVD in early adulthood and should therefore be avoided.

The association of rapid weight gain in early life with increased adiposity and obesity in later life has been established, whereas whether rapid neonatal weight gain predisposes individuals to other risk factors for cardiovascular disease and type 2 diabetes mellitus remains controversial. Gain in weight of >0.5 SD scores in the first 3 months of life (described as rapid weight gain) is associated with an unfavourable health profile in adulthood, and keeping weight gain below this threshold could reduce the risk of cardiovascular and metabolic diseases later in life. Weight gain above this threshold is not necessarily unhealthy if the increase is in proportion with the increase in length. As such, regular measurement of both the weight and length of all infants is important. Preterm infants and those who are born small for gestational age are most likely to have rapid weight gain, and are high-risk populations for unfavourable health profiles in adulthood.

Background: The relationship between low birth weight and increased risk for metabolic syndrome (MetS) in later life has been frequently described, but mechanisms underlying this association remain unknown. Methods: In 280 young adults of the PROGRAM study, aged 18–24 yr, we investigated associations of birth weight, gain in weight for length during early life, and adult IGF-I sd score (SDS), with number of MetS components (ordinal regression analyses), prevalence of MetS components and MetS (logistic regression analyses), and other metabolic parameters (linear regression analyses). Revised criteria of the National Cholesterol Educational Program (Adult Treatment Panel III) were used to determine components of MetS. The other metabolic parameters were C-reactive protein, insulin sensitivity, trunk fat mass, total cholesterol, and low-density lipoprotein cholesterol. Results: More gain in weight for length SDS in the first 3 months of life was significantly associated with an increased number of MetS components [odds ratio (OR) = 1.34], prevalence of low high-density lipoprotein cholesterol (OR = 1.49), prevalence of MetS (OR = 2.51), increased C-reactive protein levels, and lower insulin sensitivity (P = 0.007) at the age of 21 yr. Low birth weight SDS was associated with lower insulin sensitivity (P = 0.036), but low birth weight SDS and adult IGF-I SDS were not significantly associated with any of the MetS components or MetS prevalence at 21 yr. Conclusion: Our study demonstrates that higher gain in weight for length in the first 3 months of life is associated with a higher prevalence of MetS at 21 yr, whereas low birth weight and low adult IGF-I are not.

Aims: To investigate the effect of birth size and weight gain during childhood on blood pressure and carotid intima-media thickness (cIMT) in young adulthood. Methods: The relationship of birth size with systolic blood pressure (SBP), diastolic blood pressure (DBP), and cIMT was investigated in 243 adults, aged 18–24 years. SBP, DBP, and cIMT were also analyzed in 4 subgroups: subjects either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age with idiopathic short stature or with normal stature (controls). Results: Adult weight SDS and fat mass were positively related to SBP and DBP, adjusted for birthweight SDS which was not related to SBP and DBP. Birth size was also not related to cIMT. Subgroup analyses showed no differences in blood pressure between subgroups, but cIMT was significantly greater in SGA-CU subjects than in controls after correction for age, gender and artery diameter. This difference became borderline significant after additional correction for smoking and SBP. Conclusion: Not birth size but childhood weight gain, especially fat mass, determines young adult blood pressure. Postnatal catch-up growth appears to have a greater influence on cardiovascular disease markers than birth size.