Clinical and Genetic Aspects in Fetuses and Children With Sex Chromosome Disorders

The aim of the project is to:

1. Investigate organ development and growth in fetuses with sex chromosome disorders;
2. Investigate growth, development, and morbidity in children with sex chromosome disorders during the first years of life;
3. Delineate how variations in sex chromosome number affect the epigenetic and genetic mechanisms regulating gene expression in the placenta and in multiple tissues of the child after birth over time during early childhood;
4. Investigate the gut microbiome in children with sex chromosome disorders during the first years of life;
5. Identify the epigenetic and genetic mechanisms and placental and child-specific alterations underlying the phenotype observed in fetuses, children, and adults with sex chromosome disorders, using a deep phenotyping approach.

Study Overview

• Status: Enrolling by invitation
• Conditions: Sex Chromosome Disorders

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Recruitment of cases will take place at obstetric departments, departments of clinical genetics, and pediatric departments throughout Denmark.

Recruitment of controls will take place at the Department of Gynecology and Obstetrics and Department of Pediatrics, Aarhus University Hospital as well as via Facebook groups.

Description

Inclusion Criteria for pregnant participants in case group:

Age ≥18 years Fetus with a genetically verified sex chromosome disorder Written informed consent

Inclusion Criteria for pregnant participants in control group:

Age ≥18 years Normal first- and second-trimester ultrasound examinations Fetal growth within the normal range Written informed consent

Inclusion Criteria for mothers in the case group:

Age ≥18 years at the time of pregnancy with the child Child with a genetically verified sex chromosome disorder Written informed consent

Inclusion Criteria for mothers in the control group:

Age ≥18 years at the time of pregnancy with the child Normal first- and second-trimester ultrasound examinations during the pregnancy Normal fetal growth during the pregnancy Written informed consent

Inclusion Criteria for children in the case group:

If parents share joint custody, written informed consent must be obtained from both parents Ability to undergo a physical examination Child with a genetically verified sex chromosome disorder (prenatally or postnatally diagnosed)

Inclusion Criteria for children in the control group:

If parents share joint custody, written informed consent must be obtained from both parents Ability to undergo a physical examination

Exclusion Criteria for all groups:

Severe claustrophobia Implanted magnetic material contraindicating MRI

Study Plan

How is the study designed?

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort
Pregnant women carrying a fetus with a sex chromosome disorder
Pregnant women carrying a fetus without a sex chromosome disorder (Controls)
Mothers of a child with a sex chromosome disorder
MOthers of a child without a sex chromosome disorder (Controls)
Children with a sex chromosome disorder
Children without a sex chromosome disorder (Controls)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of DNA methylation	Levels of DNA methylation in placenta, blood, saliva, and urothelial cells	5 years
Level of RNA ekspression	Level of RNA ekspression in placenta, blood, saliva, and urothelial cells	5 years
Height	Height in centimeter (cm)	5 years
Weight	Weight in kilogram (kg) or gram (g)	5 years
Body mass index	Body mass index (BMI) in kg/m²	5 years
Head circumference	head circumference in centimeter (cm)	5 years
Fat mass and fat-free mass	Measure of fat mass and fat-free mass by PEA POD (kg)	5 years
Development	Bayley-4 will be used to measure development. Ages & Stages Questionnaires will be used to measure development including social-emotional development drawing on the parents knowledge.	5 years
Fecal microbial diversity	Measure of fecal microbial diversity	5 years
Fecal microbial composition	Measurement of fecal microbial composition	5 year
Left ventricular ejection fraction	Left ventricular ejection fraction measured by echocardiography (%)	5 years
Left ventricular diameters	Left ventricular end-diastolic and end-systolic diameters measured by echocardiography (mm)	5 years
Interventricular septal wall thickness	Interventricular septal wall thickness measured by echocardiography (mm)	5 years
Heart rate	Heart rate (beats per minute) measured by electrocardiogram	5 years
PR interval	PR interval (ms) measured by electrocardiogram	5 years
QRS duration	QRS duration (ms) measured by electrocardiogram	5 years
Corrected QT interval	Corrected QT interval (ms) measured by electrocardiogram	5 years
Blood pressure	Systolic and diastolic blood pressure (mmHg)	5 years
Congenital heart malformation	Congenital heart malformation assessed by echocardiography	5 years
Aorta diameter	Aorta diameter (mm) measured by echocardiography	5 years
Aortic valve mean gradient	Measure of aortic valve mean gradient (mmHG)	5 years
Mitral valve mean gradient	Measure of mitral valve mean gradient (mmHg)	5 years
Transaortic doppler flow	Measure of transaortic doppler flow (m/s)	5 years
Fetal brain volume	Fetal brain volume measured by MRI (cm³)	5 years
Fetal heart volume	Fetal heart volume measured by MRI (cm³)	5 years
Fetal kidney volume	Fetal kidney volume measured by MRI (cm³)	5 years
Fetal lever volume	Fetal lever volume measured by MRI (cm³)	5 years
Fetal spleen volume	Fetal spleen volume measured by MRI (cm³)	5 years
Fetal gonadal volume	Fetal gonadal volume measured by MRI (cm³)	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular mass	Calculation of left ventricular mass (g)	5 years

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital
• Investigators: Principal Investigator: Anne Skakkebæk, MD, PHD, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2024
• Primary Completion (Estimated): January 1, 2034
• Study Completion (Estimated): January 1, 2034

Study Registration Dates

• First Submitted: December 12, 2025
• First Submitted That Met QC Criteria: January 6, 2026
• First Posted (Actual): January 14, 2026

Study Record Updates

• Last Update Posted (Actual): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 6, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Turner syndrome; Klinefelter syndrome; Triple X syndrome; Double Y syndrome; 45,X/46,XY syndrome
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Genetic Diseases, Inborn; Gonadal Disorders; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Disorders of Sex Development; Urogenital Abnormalities; Chromosome Disorders; Chromosome Aberrations; Sex Chromosome Disorders of Sex Development; Gonadal Dysgenesis; Hypogonadism; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Abnormal Karyotype; Sex Chromosome Aberrations; Turner Syndrome; Klinefelter Syndrome; Sex Chromosome Disorders; Triple X syndrome; XYY Karyotype
• Other Study ID Numbers: 1-10-72-65-24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No