These narrated PowerPoint lessons were used in a CME course. That course expired in 2023. We offer these as an excellent background for healthcare providers who serve adults with XXY.
Article Title: From mini‐puberty to pre‐puberty: early impairment of the hypothalamus-pituitary-gonadal axis with normal testicular function in children with non-mosaic Klinefelter syndrome
Authors: Spaziani, Granato, Liberati, Rossi, Tahani, Pozza, Gianfrilli, Papi, Anzuini, Lenzi, Tarani, and Radicioni
Date of Publication: May 6, 2020
“Purpose Klinefelter syndrome (KS) is a genetic disorder caused by the presence of an extra X chromosome in males. The aim of this study was to evaluate the hypothalamic–pituitary–gonadal (HPG) axis and the clinical profile of KS boys from mini-puberty to early childhood…Conclusions No hormonal signs of tubular or interstitial damage were found in KS infants. The presence of higher levels of gonadotropins, INHB and testosterone during mini-puberty and pre-puberty may be interpreted as an alteration of the HPG axis in KS infants.”
Article Title: Strategies to improve early diagnosis of Klinefelter syndrome
Authors: Alberto Ferlin
Date of Publication: October 2020
“Klinefelter syndrome is the most frequent chromosome disorder in men, but it is largely undiagnosed or receives a late diagnosis in adulthood. This condition is characterized by an extra X-chromosome: approximately 80%-90% of patients with Klinefelter syndrome have a 47,XXY karyotype, 10%-20% mosaicisms of two different genetic lines such as 47,XXY/46,XY, isochromosome X, and higher number of X chromosomes. Although our knowledge on this syndrome substantially improved in last years, the diagnostic rate is still low. It has been estimated that only 25% to 40% of subjects with 47,XXY Klinefelter syndrome are ever diagnosed. A prenatal diagnosis is made in 15–20% of these cases, 10% is diagnosed before puberty, 15% at puberty, and the remaining 50–60% of cases are diagnosed during adulthood, typically in the course of a fertility workup, with some cases diagnosed even after the age of 50 or 60 years. Variants with higher number of X chromosomes (48,XXXY and 49,XXXXY) have more severe phenotype and distinct clinical features, which leads to higher diagnostic rate than 47,XXY. This manuscript refers to the most common form 47,XXY syndrome and strategies to improve early and timely diagnosis.”
Click or tap on a title below to view/download the document in PDF format.
In 2015, the AXYS Board of Directors voted to approve the development of the AXYS Clinical and Research Consortium (ACRC). The two goals that AXYS defined at that time were to improve the availability and the quality of services to the X&Y variation community. As the ACRC grew, the original goals were refined to be as follows:
Though each clinic operates independently, as members of a consortium, they collaborate with one another, share informational resources, and have the opportunity to participate in joint research projects.
In addition, AXYS organizes annual meetings of the consortium at which members meet to discuss topics important to the X&Y chromosome variation community. AXYS works to ensure that all families impacted by any of the chromosome variations have access to the best available evaluation and treatment or treatment recommendations.
Timeline of the ACRC
(Click on the year to see the accomplishments for that year.)
• AXYS brought on Robby Miller as an experienced consultant to assist AXYS in creating the ACRC
First meeting of ACRC 2015
• The formation committee, Dr. Tartaglia and Susan Howell of the eXtraordinarY Kids Clinic in Colorado, Jim Moore the AXYS Executive Director and Robby met. The consortium was formed.
• First ACRC meeting held in Denver
• AXYS Clinical Needs and Desires survey, supported by AXYS, Emory University and PCORI began
• AXYS Clinical Needs and Desires survey concluded. Results presented to ACRC by lead investigator Dr. Sharron Close
• Launched with 8 founding clinics: Atlanta, Baltimore, Chicago, Denver, Los Angles, New York, Stanford, Wilmington
• ACRC meets in Denver
• Discussed need for Adult clinics
• Added clinic in Wake-Forest
• ACRC meets in Chicago
• Began Consensus Documents
• Added clinic in Philadelphia
• ACRC meets in Atlanta
• Conducted study to pilot a process to form clinics for adults, funded by the WITH Foundation Grant. Study led by Sharron Close at Emory University and Susan Howell at Colorado Children’s Hospital.
• AXYS awarded grant from the Kosloski Family Foundation to create CME course on Klinefelter Syndrome in Adults
• Added clinics in Boston and Cleveland
Photo of 2019 ACRC meeting
• First virtual ACRC meeting
• Held quarterly ACRC meetings with dedicated discussions on telehealth, Families of Color and Adult clinics
• Added clinic in New York, second clinic in Philadelphia for adults
• Added first international clinics in Vancouver, Canada and Århus, Denmark
• Expanded ACRC to include clinical researchers:
• Published first Consensus Documents
• Added international clinic in London, UK
• Supported by grants from AXYS and The XXYY Project, GALAXY Registry project launched
• The XXYY Project launches ACRC Clinic Visit Stipend
• ACRC Clinic Visit Stipend expanded for all X&Y variations
• Added 2 ACRC Clinics (Sacramento and Chicago) for a total of 18 clinics
CME Course Title: Klinefelter Syndrome: Identifying, characterizing and managing an underdiagnosed condition with serious consequences
Course Directors: Hooman Sadri, MD, PhD and Stuart Howards, MD
Reviewed by the AXYS Clinic & Research Consortium (ACRC)
Date: October 2020
“Introduction:
Have you unknowingly seen someone with Klinefelter Syndrome in your practice?
Chances are, you have. Klinefelter Syndrome (KS) is the most common sex chromosome disorder, occurring in approximately 1 out of every 600 male births. Yet an estimated 60 to 75% of those with KS will remain undiagnosed throughout their lifetimes.
Why does this matter?
It matters because KS is linked to significantly higher mortality rates and a range of physical, neurocognitive, and social/behavioral comorbidities as well as a lower quality of life and socioeconomic status. Some healthcare providers believe that delayed diagnosis can increase patient morbidity. And it matters because those with KS are getting lost in our healthcare system. Studies show that the majority of individuals with KS report being dissatisfied with their care. In addition, many with KS and their families find that their providers have outdated information about the condition, or little information at all. By learning more about the many facets of KS, providers across the healthcare system can work together to better treat and support those with this condition and their families.”
Article Title: Metabolic and cardiovascular risk factors in Klinefelter syndrome
Authors: Spaziani and Radicioni
Date of Publication: June 2020
“Klinefelter syndrome (KS), which normally presents with a 47,XXY karyotype, is the most common sex chromosome disorder in males. It is also the most common genetic cause of male infertility. KS subjects are typically tall, with small and firm testes, gynecomastia, broad hips, and sparse body hair, although a less evident presentation is also possible. KS is also characterized by a high prevalence of hypogonadism, metabolic syndrome (MetS) and cardiovascular disease. The aim of this article is to systematically review metabolic and the cardiovascular risk factors in KS patients. Hypogonadism has an important role in the pathogenesis of the changes in body composition (particularly visceral obesity) and hence of insulin resistance and MetS, but the association between KS and MetS may go beyond hypogonadism alone. From childhood, KS patients may show an increase in visceral fat with a reduction in lean body mass and an increase in glucose and impaired fat metabolism. Their increased incidence of congenital anomalies, epicardial adipose tissue, and thromboembolic disease suggests they have a higher risk of cardiovascular disease. There is conflicting evidence on the effects of testosterone therapy on body composition and metabolism.”
Article Title: Executive function in XXY: Comparison of performance-based measures and rating scales
Authors: Janusz, Harrison, C. Boada, Cordeiro, Howell, Tartaglia, and R. Boada
Date of Publication: June 2020
“Few studies have systematically assessed executive functioning (EF) skills in boys with XXY, and these are limited by small samples and restricted EF assessment. This study used a broader battery of performance-based measures as well as parent-rating scales of EF in 77 boys and adolescents with XXY (mean age = 12.5 years), recruited from a clinical trial and an outpatient clinic. Exploratory factor analyses were used to create EF domains from performance-based measures, and similar domains were measured using the Behavior Rating Inventory of Executive Function and Conners Parent-Rating Scales. The boys with XXY showed a distinct EF profile, with the greatest deficit in attention and more moderate deficits in working memory, switching, and planning/ problem solving. Parent ratings showed similar challenges, as well as impaired inhibition. Independent sample t-tests showed no difference on performance measures between boys diagnosed or not diagnosed with attention-deficit/hyperactivity disorder (ADHD), although parents of boys diagnosed with ADHD reported more difficulties. There were no differences on performance-based tests between those diagnosed pre- and postnatally, although parents of postnatally diagnosed boys reported more metacognitive problems. Language deficits, cognition, and socio-economic status did not account for EF deficits.”
Article Title: Rare sex chromosome variation 48,XXYY: An integrative review
Authors: Blumling, Martyn, Talboy, and Close
Date of Publication: April 9, 2020
“48,XXYY presents with a wide spectrum of physical, psychological, and neurocognitive symptoms, and frequently requires complex interdisciplinary care. In order to better understand this disorder and to appropriately treat the individuals affected by it, future research should focus on experimental studies and research that utilizes a variety of methods, including participant interviews and patient-report surveys.”
Article Title: Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies
Authors: Green, Flash, and Reiss
Date of Publication: January 2019
“The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.”
