Cardiometabolic Profiles of Boys With Klinefelter Syndrome

Cardiometabolic Profiles of Pubertal Boys With Klinefelter Syndrome With or Without One Year of Exogenous Testosterone Treatment

This study plans to learn more about how to measure the way the the body's energy system works in boys with Klinefelter syndrome, including the heart, lungs, muscles, and liver. This is important to know so that investigators understand how hormones and an extra X chromosome relate to diseases such as diabetes, extra weight gain, heart disease and liver diseases.

Study Overview

• Status: Completed
• Conditions: Klinefelter Syndrome; 47,XXY; Sex Chromosome Aneuploidy; XXY Syndrome
• Intervention / Treatment: Other: No intervention

Detailed Description

Klinefelter syndrome (KS) is the most common chromosomal abnormality in males and is associated with primary gonadal failure in adolescence and a high morbidity and mortality from cardiovascular-related diseases (CVD) in adulthood. Recent studies in children and adolescent boys with KS have found a high prevalence of CVD risk markers, however the underlying mechanisms have not been explored. Our central hypothesis is that pubertal boys with KS have relative testosterone deficiency resulting in abnormal energy metabolism that predisposes them to later CVD, and that exogenous testosterone will modify these abnormalities.

In this study, investigators will measure markers of cardiometabolic risk in pubertal boys with KS.

• Study Type: Observational
• Enrollment (Actual): 31

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

The study will enroll 10 youth with 47,XXY who will be subdivided into 2 groups:

1. Testosterone naïve (no exogenous testosterone within the past 5 years)
2. Testosterone exposed (topical testosterone treatment for at least 1 year but no more than 2 years) Most subjects will be recruited at the completion of a monitored, double-blind randomized controlled trial ongoing at our institution. Additional subjects may be recruited to meet enrollment goals.

Description

Inclusion Criteria:

• Male, 47,XXY karyotype (non-mosaic)
• Age 12-17 years
• Tanner stage 3-5 pubic hair
• T naïve group only: No exogenous androgen exposure within the past 5 years
• T exposed group only: currently on topical testosterone, with duration of treatment between 1-2 years.

Exclusion Criteria:

• Cognitive, psychiatric, or physical impairment resulting in inability to tolerate the study procedures
• MRI incompatible metal
• Diagnosis of type 1 or type 2 diabetes
• Hypertension greater than 140/90 mm/Hg at rest (would make exercise studies unsafe)
• Weight > 300 lbs (limit for DEXA)
• Testosterone treatment for <1 year or >2 years

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Testosterone Naive; Boys with Klinefelter syndrome age 12-17 who are Tanner 3, 4, or 5. No exogenous testosterone exposure in the past 5 years	Other: No intervention
Testosterone exposed; Boys with Klinefelter syndrome age 12-17 who are Tanner 3, 4, or 5. +topical testosterone treatment for >1 year	Other: No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VO2 peak	The primary outcome will be peak oxygen consumption (VO2 peak) during exercise on a bicycle ergometer	baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body composition	Percent body fat by dual-energy x-ray absorptiometry	baseline
Liver fat	Intrahepatic fat by abdominal magnetic resonance imaging	baseline
Muscle mitochondrial metabolism	Rate of mitochondrial phosphorylation by 31-phosphorus magnetic resonance spectroscopy of the calf muscles	baseline
Insulin sensitivity	oral disposition index with Glucola	baseline

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Shanlee M Davis, MD, University of Colorado/Children's Hospital Colorado

Publications and helpful links

General Publications

• Davis SM, DeKlotz S, Nadeau KJ, Kelsey MM, Zeitler PS, Tartaglia NR. High prevalence of cardiometabolic risk features in adolescents with 47,XXY/Klinefelter syndrome. Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):327-333. doi: 10.1002/ajmg.c.31784. Epub 2020 Jun 16.

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: March 24, 2016
• First Submitted That Met QC Criteria: March 24, 2016
• First Posted (Estimate): March 30, 2016

Study Record Updates

• Last Update Posted (Actual): March 8, 2022
• Last Update Submitted That Met QC Criteria: March 4, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: exercise capacity; hypogonadism; body composition; cardiometabolic; Klinefelter syndrome; XXY; Sex chromosome aneuploidy; sex chromosome variation
• Additional Relevant MeSH Terms: Pathologic Processes; Endocrine System Diseases; Disease; Gonadal Disorders; Disorders of Sex Development; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Chromosome Disorders; Sex Chromosome Disorders; Chromosome Aberrations; Sex Chromosome Disorders of Sex Development; Hypogonadism; Syndrome; Aneuploidy; Klinefelter Syndrome
• Other Study ID Numbers: 16-0248; UL1TR001082 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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