Dataset Information

Brain Development in School-Age and Adolescent Girls: Effects of Turner Syndrome, Estrogen Therapy, and Genomic Imprinting.

ABSTRACT:

Background

The study of Turner syndrome (TS) offers a unique window of opportunity for advancing scientific knowledge of how X chromosome gene imprinting, epigenetic factors, hormonal milieu, and chronologic age affect brain development in females.

Methods

We described brain growth trajectories in 55 girls with TS and 53 typically developing girls (258 magnetic resonance imaging datasets) spanning 5 years. Using novel nonparametric and mixed effects analytic approaches, we evaluated influences of X chromosome genomic imprinting and hormone replacement therapy on brain development.

Results

Parieto-occipital gray and white matter regions showed slower growth during typical pubertal timing in girls with TS relative to typically developing girls. In contrast, some basal ganglia, cerebellar, and limited cortical areas showed enhanced volume growth with peaks around 10 years of age.

Conclusions

The parieto-occipital finding suggests that girls with TS may be particularly vulnerable to altered brain development during adolescence. Basal ganglia regions may be relatively preserved in TS owing to their maturational growth before or early in typical pubertal years. Taken together, our findings indicate that particular brain regions are more vulnerable to TS genetic and hormonal effects during puberty. These specific alterations in neurodevelopment may be more likely to affect long-term cognitive behavioral outcomes in young girls with this common genetic condition.

SUBMITTER: O'Donoghue S

PROVIDER: S-EPMC6925344 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Brain Development in School-Age and Adolescent Girls: Effects of Turner Syndrome, Estrogen Therapy, and Genomic Imprinting.

O'Donoghue Stefani S Green Tamar T Ross Judith L JL Hallmayer Joachim J Lin Xiaoyan X Jo Booil B Huffman Lynne C LC Hong David S DS Reiss Allan L AL

Biological psychiatry 20190809 2

<h4>Background</h4>The study of Turner syndrome (TS) offers a unique window of opportunity for advancing scientific knowledge of how X chromosome gene imprinting, epigenetic factors, hormonal milieu, and chronologic age affect brain development in females.<h4>Methods</h4>We described brain growth trajectories in 55 girls with TS and 53 typically developing girls (258 magnetic resonance imaging datasets) spanning 5 years. Using novel nonparametric and mixed effects analytic approaches, we evaluat ...[more]

PMID: 31561860

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Project description:ObjectiveMost girls and women with Turner syndrome (TS) require estrogen replacement therapy (ERT) to initiate or maintain pubertal development. Most likely, the most fundamental effect of ERT in hypogonadism is the promotion of uterine growth. The optimal ERT model is still being discussed. The present study aimed to assess uterine size in girls with TS in the prepubertal state during and after the induction of puberty and compare it to a healthy population.MethodsThe analysis encompassed 40 TS girls. The prepubertal and postpubertal control groups contained 20 healthy girls each. All patients with TS were treated with 17-ß estradiol. Uterine imaging was performed with two-dimensional (2D) transabdominal ultrasound. The uterine volume (UV) and fundocervical antero-posterior ratio (FCR) were calculated in patients with TS before the pubertal induction, after 6-12 months of estrogen replacement therapy (ERT), after ≥ 36 months of ERT or ≥ 12 months after menarche.ResultsThe average age of TS patients at estrogen introduction and at the last control visit, when the uterus was considered mature, was 12.9 years and 16.1 years, respectively. The UV in patients with TS at the beginning of ERT was 1.55 ± 1.22 cm3 and was not significantly different from the UV in the prepubertal controls. The mature UV in patients with TS was 31.04 ± 11.78 cm3 and was significantly smaller than the UV of the postpubertal controls (45.68 ± 12.51 cm3, p<0.001). The FCR in girls with TS did not differ significantly from that in the prepubertal and postpubertal control groups, respectively. No prognostic factors could be established for the final UV. By the last control visit, thelarche had advanced in most patients to Tanner 4 and 5 (37.5% and 40%, respectively).ConclusionsBefore the onset of ERT, patients with TS have a uterus similar in size to that in prepubertal healthy girls. Pubertal induction in patients with TS causes a significant increase in the UV that is detectable after 6-12 months of ERT. The mature uterus is smaller in patients with TS than in the age-matched healthy population.

Project description:Abstract Background: Turner syndrome (TS) is a disorder characterized by complete or partial absence of the second sexual chromosome and the most commonly found abnormalities are short stature and gonadal failure. Most TS patients need estrogen replacement but individual outcomes on uterine volume, breast development and vertebral bone density are highly variable. To our knowledge, the impact of polymorphisms in estrogen receptor 1 (ESR1) over the variability in the development of secondary sexual characteristics and in adult height has not yet been evaluated in TS patients. Objective: To investigate the association among five ESR1 polymorphisms (rs543650, rs1038304, rs2046210, rs2234693 and rs9340799) and breast development, uterine volume, vertebral bone density, FSH and LH levels and adult height in TS patients. Methods: We selected 80 TS patients receiving adult estrogen dose for a minimum period of one year. Patients who had spontaneous complete pubertal development or who have Y chromosome material in karyotype were excluded from analysis. They were submitted to clinical and laboratory evaluation, pelvic ultrasound, bone densitometry and genotyping of the five chosen ESR1 polymorphisms through real time PCR. These polymorphisms were selected through active search in Pubmed and in GWAS catalogs, based on the following criteria: recurrence in studies, being Tag-single nucleotide polymorphisms (Tag-SNPs) or having a minor allele frequency (MAF) which allowed the present study with the available sample. Results: 61% of patients had 45,X karyotype and their mean target height was 158.9cm. 82% of them were treated with rhGH for 5 years on average and they reached a mean adult height of 149cm. Their average age of puberty onset was 14.4 years old and 10% of them had spontaneous thelarche. Their mean uterine volume was 30.1cc but ranged from 5.9 to 83cc. 91% attained adult breast development (Tanner 5) and 93% had normal vertebral bone mass after correction for height (by using the online calculator from University of Washington: courses.washington.edu/bonephys). Only 15% had FSH and/or LH lower than 10 IU/L in two or more measurements. Considering the ESR1 polymorphisms, all of them were in Hardy-Weinberg equilibrium. Statistical analysis with multiple linear regression showed that none of the studied polymorphisms was able to predict any of the above estrogen therapy outcomes in an isolated manner. Conclusion: We could not find a relationship among the studied ESR1 polymorphisms and estrogen therapy outcomes in patients with TS. However, the high variability in estrogen replacement results suggests that genetic variants play an important role. Other efforts to identify polymorphisms associated to estrogen outcomes may allow for individualization of treatment in TS.

Dataset Information

Brain Development in School-Age and Adolescent Girls: Effects of Turner Syndrome, Estrogen Therapy, and Genomic Imprinting.

Background

Methods

Results

Conclusions

Publications

Brain Development in School-Age and Adolescent Girls: Effects of Turner Syndrome, Estrogen Therapy, and Genomic Imprinting.

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