Henriette A. Delemarre-van de Waal

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

We took advantage of overlapping interstitial deletions at chromosome 8p11–p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.

Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to formulate practice guidelines for endocrine treatment of transsexual persons. EVIDENCE This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence, which was low or very low. CONSENSUS PROCESS Committees and members of The Endocrine Society, European Society of Endocrinology, European Society for Paediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and World Professional Association for Transgender Health commented on preliminary drafts of these guidelines. CONCLUSIONS Transsexual persons seeking to develop the physical characteristics of the desired gender require a safe, effective hormone regimen that will 1) suppress endogenous hormone secretion determined by the persons genetic/biologic sex and 2) maintain sex hormone levels within the normal range for the persons desired gender. A mental health professional (MHP) must recommend endocrine treatment and participate in ongoing care throughout the endocrine transition and decision for surgical sex reassignment. The endocrinologist must confirm the diagnostic criteria the MHP used to make these recommendations. Because a diagnosis of transsexualism in a prepubertal child cannot be made with certainty, we do not recommend endocrine treatment of prepubertal children. We recommend treating transsexual adolescents (Tanner stage 2) by suppressing puberty with GnRH analogues until age 16 years old, after which cross-sex hormones may be given. We suggest suppressing endogenous sex hormones, maintaining physiologic levels of gender-appropriate sex hormones and monitoring for known risks in adult transsexual persons.

Cardiometabolic Differences in Children Born After in Vitro Fertilization: Follow-Up Study

CONTEXT Increasing evidence suggests that adverse conditions during early prenatal life are associated with cardiometabolic dysfunction in postnatal life. In vitro fertilization (IVF) conception may be an early prenatal life event with long-term health consequences. OBJECTIVE Our objective was to investigate several cardiometabolic measures in 8- to 18-yr-old IVF singletons and spontaneously conceived controls born from subfertile parents. DESIGN AND SETTING This follow-up study was conducted at the VU University Medical Center, Amsterdam, The Netherlands. PARTICIPANTS Blood pressure was examined in 225 IVF-conceived children and 225 age- and gender-matched spontaneously conceived control children. Several indicators of insulin resistance were studied in a pubertal subpopulation (131 IVF children and 131 controls). MAIN OUTCOME MEASURES Blood pressure, fasting glucose, and fasting insulin were determined. RESULTS Systolic and diastolic blood pressure levels were higher in IVF children than controls (109 +/- 11 vs. 105 +/- 10 mm Hg, P < 0.001; and 61 +/- 7 vs. 59 +/- 7 mm Hg, P < 0.001, respectively). Children born after IVF were also more likely to be in the highest systolic and diastolic blood pressure quartiles (odds ratio = 2.1, 95% confidence interval 1.4, 3.3; odds ratio = 1.9, 95% confidence interval 1.2, 3.0, respectively). Furthermore, higher fasting glucose levels were observed in pubertal IVF children (5.0 +/- 0.4 vs. 4.8 +/- 0.4 mmol/liter in controls; P = 0.005). Blood pressure and fasting glucose differences could not be explained by current body size, birth weight, and other early life factors or by parental characteristics, including subfertility cause. CONCLUSIONS These findings highlight the importance of continued cardiometabolic monitoring of IVF-conceived children and might contribute to current knowledge about periconceptional influences and their consequences in later life.

Monitoring and Discussing Health-Related Quality of Life in Adolescents With Type 1 Diabetes Improve Psychosocial Well-Being A randomized controlled trial

OBJECTIVE—To test the effects of monitoring and discussing of health-related quality of life (HRQoL) in adolescents with type 1 diabetes in a multicenter randomized controlled trial. RESEARCH DESIGN AND METHODS—Four centers were randomly assigned to the HRQoL intervention (46 adolescents) or control (45 adolescents) group, with three regular visits scheduled within 12 months in both groups. In the HRQoL intervention group, HRQoL of adolescents was assessed using the Pediatric Quality of Life Inventory, and outcomes were discussed face-to-face during the consultation. The control group received care as usual. Mean differences between the groups at 12 months in physical and psychosocial well-being (Child Health Questionnaire [CHQ]-CF87/PF50, Diabetes-Specific Family Conflict Scale, and Center for Epidemiological Studies Scale for Depression), satisfaction with care (Patients’ Evaluation of the Quality of Diabetes Care), and A1C were determined, controlling for baseline scores. RESULTS—Mean scores on the CHQ subscales of psychosocial health (P < 0.001), behavior (P < 0.001), mental health (P < 0.001), and family activities (P < 0.001) improved in the HRQoL intervention group, except for adolescents with the highest A1C values. Adolescents in the HRQoL intervention group reported higher self-esteem (CHQ) at follow-up (P = 0.016), regardless of A1C, and were more satisfied with care (P = 0.009) than control subjects. No significant differences between the two groups over time were observed in A1C levels. CONCLUSIONS—Periodic monitoring and discussion of HRQoL in adolescents with diabetes is appreciated and has positive effects on their psychosocial well-being, except for those in poorest control.

The Effects of Intra-Uterine Growth Retardation and Postnatal Undernutrition on Onset of Puberty in Male and Female Rats

The nutritional status, prenatally and early postnatally, plays a critical role in postnatal growth and development. Early malnutrition may change the original programming of organs, especially those in developmental phases, which can result in long-term changes in metabolism. The association between a low birth weight and the increased risk on type 2 diabetes, hypertension and cardiovascular disease is well known.In the present study we investigated whether intrauterine malnutrition or direct postnatal food restriction affects the onset of puberty in male and female rats. Intrauterine growth retardation (IUGR) was induced by uterine artery ligation on day 17 of gestation and postnatal food restriction (FR) by litter-enlargement to 20 pups per mother from day 2 after birth until weaning (24 d). Both models of malnutrition resulted in a persistent growth failure postnatally. The parameter of the onset of puberty was balano-preputial-separation (BPS) in the male rat and vaginal opening (VO) in the female rat.In both male IUGR (n = 26) and FR (n = 20) rats, the age at BPS was significantly delayed, with 48.1 ± 1.9 d (p < 0.0001) and 50.4 ± 2.9 d (p < 0.0001), respectively, compared with controls (n = 30) with 45.8 ± 1.4 d. In female IUGR rats (n = 37) the age at VO was significantly delayed, with 37.4 ± 2.7 d (p < 0.04) compared with 36.1 ± 1.5 d in controls (n = 23), but not in female FR rats (n = 18) with 36.5 ± 2.2 d. Weight at onset of puberty did not differ between male IUGR and control rats, 194.5 ± 20.0 g and 201.7 ± 16.8 g, respectively, but was significantly lower in male FR rats with a weight of 175.6 ± 17.5 g (p < 0.0001). In female IUGR as well as in female FR rats, weight at onset of puberty was significantly lower compared with controls: weight in IUGR 106.1 ± 13.1 g (p < 0.001), weight in FR 85.3 ± 7.6 g (p < 0.0001) and weight in controls 116.9 ± 9.3 g.We conclude that early malnutrition, during late gestation or direct postnatally, results in a delayed onset of puberty in IUGR and FR male rats and in IUGR female rats, but not in FR female rats. The onset of puberty in these growth retarded rats as well as in controls does not depend on the achievement of a certain, crucial weight. The perinatal period appears to be a “critical time period” for the maturational process of pubertal development.

Network Analysis of Resting State EEG in the Developing Young Brain: Structure Comes With Maturation

During childhood, brain structure and function changes substantially. Recently, graph theory has been introduced to model connectivity in the brain. Small‐world networks, such as the brain, combine optimal properties of both ordered and random networks, i.e., high clustering and short path lengths. We used graph theoretical concepts to examine changes in functional brain networks during normal development in young children. Resting‐state eyes‐closed electroencephalography (EEG) was recorded (14 channels) from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) was calculated in three different frequency bands and between each pair of electrodes to obtain SL‐weighted graphs. Mean normalized clustering index, average path length and weight dispersion were calculated to characterize network organization. Repeated measures analysis of variance tested for time and gender effects. For all frequency bands mean SL decreased from 5 to 7 years. Clustering coefficient increased in the alpha band. Path length increased in all frequency bands. Mean normalized weight dispersion decreased in beta band. Girls showed higher synchronization for all frequency bands and a higher mean clustering in alpha and beta bands. The overall decrease in functional connectivity (SL) might reflect pruning of unused synapses and preservation of strong connections resulting in more cost‐effective networks. Accordingly, we found increases in average clustering and path length and decreased weight dispersion indicating that normal brain maturation is characterized by a shift from random to more organized small‐world functional networks. This developmental process is influenced by gender differences early in development. Hum Brain Mapp, 2011.

The Treatment of Adolescent Transsexuals: Changing Insights

INTRODUCTION Treatment of individuals with gender identity disorder (GID) has in medicine nearly always met with a great deal of skepticism. Professionals largely follow the Standards of Care of the World Professional Association for Transgender Health. For adolescents, specific guidelines have also been issued by the British Royal College of Psychiatrists. AIM To describe the stepwise changes in treatment policy which, in recent years, have been made by the team of the Gender Identity Clinic at the VU University Medical Center in Amsterdam, The Netherlands. METHODS The first step taken to treat adolescents was that, after careful evaluation, (cross-sex hormone) treatment could start between the ages of 16 and 18 years. A further step was the suppression of puberty by means of gonadotropin-releasing hormone analogs in 12-16 year olds; the latter serves also as a diagnostic tool. Very recently, other clinics in Europe and North America have followed this policy. Results. The first results from the Amsterdam clinic show that this policy is promising. CONCLUSIONS Professionals who take responsibility for these youth and are willing to help should yet be fully aware of the impact of their interventions. In this article, the pros and cons of the various approaches to youngsters with GID are presented, hopefully inciting a sound scientific discussion of the issue.

Dna Methylation of Igf2, Gnasas, Insigf and Lep and Being Born Small for Gestational Age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (<32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; “AGA”). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10-13) and head circumference at birth (P=4.1x10-13). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.

Body Mass Index, Body Composition, and Leptin at Onset of Puberty in Male and Female Rats after Intrauterine Growth Retardation and after Early Postnatal Food Restriction

In this study we examined the body composition at onset of puberty in intrauterine growth retarded (IUGR), postnatal food restricted (FR), and control male and female rats. IUGR was induced by ligation of the uterine artery on d 17 of gestation and FR by litter enlargement to 20 pups per mother from d 2 after birth until weaning (d 24). We defined onset of puberty as balanopreputial separation in male rats and vaginal opening in female rats. We calculated body mass index, measured body composition with dual-energy x-ray absorptiometry, and measured leptin concentrations in serum. It was reported previously that early malnutrition, either during late gestation or immediately postnatally, results in a delayed onset of puberty in IUGR and FR male rats and in IUGR female rats, but not in FR female rats. In IUGR male rats at balanopreputial separation and in IUGR female rats at vaginal opening no differences were found in body mass index, body composition, and leptin levels compared with controls. FR male rats had a significantly lower percentage of fat and serum leptin concentrations at balanopreputial separation. FR female rats had a significantly lower body mass index, percentage of fat, and serum leptin concentrations at vaginal opening. We conclude that the onset of puberty in the rat is not dependent on a certain percentage of body fat or a certain threshold of circulating levels of leptin and that food deprivation during different “critical” time periods around birth results in different effects in later life.

Growth and development of children born after in vitro fertilization

OBJECTIVE To evaluate growth and development of children born after IVF treatment. DESIGN Literature review. CONCLUSION(S) At present there is substantial evidence that children born after IVF are at increased risk for adverse perinatal outcome, congenital malformations, and rare epigenetic defects. It is still unclear whether observed health problems originate from the IVF procedure itself or the underlying subfertility problems of the parents. Current follow-up studies regarding postnatal growth and morbidity rates are scarce with conflicting results and other areas of long-term research in children born after IVF are still in its infancy. The importance of the worldwide continuing monitoring of children born after IVF to investigate potential long-term consequences including the development of cardiovascular diseases is therefore highlighted.