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Vol. 8 Supplement 1

December 2010



Insights into the Pathogenesis of XXY Phenotype from Comparison of the Clinical Syndrome with an Experimental XXY Mouse Model

Yan-he Lue1, MD, Christina Wang1, MD, Peter Y Liu2, MD, Krista Erkilla3, MD, Ronald S Swerdloff1, MD


Klinefelter syndrome (47, XXY male) is the most common sex chromosome disorder in men. To study the underlying mechanisms of XXY phenotypes and design specific and novel therapeutic regimens for KS men, an experimental mouse model (41, XXY) was established. This manuscript compares the phenotypes of XXY men and mice and discuses the possible contributions of low androgen levels and extra X chromosome genes to the XXY phenotypes. The phenotypic similarities between XXY mouse and men suggest that the common genes that escape the X inactivation between XXY mouse and men may be responsible for the clinical manifestations in men with Klinefelter syndrome.

Ref: Ped. Endocrinol. Rev. 2010;8(suppl 1):140-144

Keywords: Klinefelter syndrome, mouse model, testicular failure, spermatogenesis, infertility, X chromosome inactivation



Considerations for Androgen Therapy in Children and Adolescents with Klinefelter Syndrome (47, XXY)

Alan D Rogol1, MD, PhD, Nicole Tartaglia2, MD


The goals of androgen therapy for adolescents are to promote linear growth and secondary sexual characteristics, at the same time as to permit the normal accrual of muscle mass, bone mineral content and the adult regional distribution of body fat. Secondary goals are mainly in the psychosocial sphere, in which pubertally delayed boys feel that they look too young, are not considered a ‘peer’ in their age group and have difficulty competing in athletic endeavors. Puberty often starts normally in adolescents with KS corresponding to the peer group with genital enlargement and pubic hair growth. The testes start to enlarge, but rarely expand beyond 6 mL, leaving a discordance between the degree of sexual development and the size of the testes. Androgen therapy is considered mainly supplemental and one usually begins with the long acting esters, testosterone enanthate or cypionate because the other forms—patches and gels--are metered for full male replacement. The dose of testosterone is escalated until the lower range of the adult dose is reached and then a choice among the various forms can be made. Treatment-emergent adverse events often represent the pharmacodynamic effects of an androgen—oily skin and acne, but as the dose is escalated more effects may be noted in the behavioral sphere, especially in adolescents with Klinefelter syndrome compared to those who receive replacement therapy with testosterone for other purposes, for example, constitutional delay of growth and puberty.

Ref: Ped. Endocrinol. Rev. 2010;8(suppl 1):145-150

Key words: Klinefelter Syndrome Testosterone Therapy; Male Hypogonadism; Adolescents



The Spectrum of the Behavioral Phenotype in Boys and Adolescents 47,XXY (Klinefelter Syndrome)

Nicole Tartaglia1,2,MD, Lisa Cordeiro3, BS, Susan Howell1,2, MS, MBA, Rebecca Wilson1,2, PsyD, Jennifer Janusz1,3 ,PhD


The behavioral phenotype of 47,XXY (Klinefelter syndrome) includes increased risks for developmental delays, language-based learning disabilities, executive dysfunction/ADHD, and socialemotional difficulties. However there is significant variability between individuals with 47,XXY, and many children and adolescents have minimal or no behavioral features while others have quite significant involvement. This paper describes behavioral features in a cohort of 57 children and adolescents with 47,XXY, including results on standardized measures of behavior (BASC-2), attention (Conner’s Rating Scales), and social skills (Social Responsiveness Scale). A subset was directly assessed for autism spectrum disorders using the ADOS and ADIR. We discuss our results within the context of previous literature, including implications for genetic counseling, recommendations for care, and areas for future research.

Ref: Ped. Endocrinol. Rev. 2010;8suppl1):151-159

Keywords: XXY, Klinefelter syndrome, behavioral phenotype, ADHD, autism, social skills, genetic counseling



Expansion of the Phenotypic Profile of the Young Child with XXY

Carole Samango-Sprouse,EdD


XXY is a common chromosomal abnormality which remains under diagnosed and not well understood, although it was first described more than 50 years ago. In the last ten years, with advancement in neuroimaging technology and the greater understanding of behavioral neurogenetics, there has been a resurgence of interest in children and adults with XXY. This homogenous population provides insight into the interaction between learning dysfunction, brain development and behavioral performance that may be investigated from birth onward. The unique attributes of the child from birth to 6 years of age with XXY is discussed in this paper. This paper postulates a novel reconceptualization of the phenotypic presentation of the boys with XXY. The neurodevelopmental profile of XXY is actually quite consistent over time with the common thread of speech and language deficits, motor dysfunction and frontal lobe deficits including attention, planning and organization. The early motor and speech disturbances are not random developmental delays, but rather the early presentation of the central nervous system dysfunction associated with XXY. Muscle tonus abnormalities are present in trunk, upper extremities and oral facial musculature in more than 80% of the infants with XXY. Androgen deficiency may be an integral part of the delays observed in boys with XXY, since androgen is influential in brain organization, neurobehavioral development, temperament and mood in humans. It is plausible that the earliest biomarker for androgen deficiency in XXY may be the decreased muscle tonus. Androgen deficiency may not be the only causative factor in the neurodevelopmental disturbance in individuals with XXY, but may promote a restorative function if timing and dosage is appropriate. The study of children with XXY offers an opportunity to observe the impact of the genetic and chromosomal influence on learning and behavior in a population with great homogeneity. XXY is a multifaceted spectrum disorder which demonstrates the complexity of the relationship between brain, behavior, genes and the environment.

Ref: Ped. Endocrinol. Rev. 2010;8(suppl 1):160-168

Key words: XXY, Sex Chromosome Disorders and Developmental Profile



The Adolescent and Young Adult with Klinefelter Syndrome: Ensuring Successful Transitions to Adulthood

Sheryl Ryan, MD


As many adolescent and young adult males with Klinefelter syndrome move into young adulthood, they will require long-term medical and mental health care for their complex and specific health care needs. Adult general medical providers and endocrinologists may feel ill-prepared to meet the medical needs of this population. In turn, many pediatric primary care and subspecialty providers may find themselves struggling to determine how best to transition the older adolescent to adult-oriented services. Working with families and their teens to consider and address current and future medical, mental health, educational and vocational needs will enhance that young adult’s independence and functioning. This chapter addresses general transition issues and those that are specific to adolescents with Klinefelter syndrome. The prognosis for these young patients is good, and can be further enhanced by supportive families and a medical team that is informed about how best to facilitate the transition to adult-oriented services.

Ref: Ped. Endocrinol. Rev. 2010;8(suppl 1):169-177

Key words: Adolescent, Transition, IDEA, ADA, Adolescents with Special Health Care Needs, Chronic Conditions, Klinefelter Syndrome



Fertility Preservation in Adolescents with Klinefelter’s Syndrome

Vincenzo De Sanctis1, MD, Sara Ciccone2, MD


Klinefelter’s syndrome (KS) is one the most common sex chromosomal abnormalities and is characterized by hypergonadotropic hypogonadism and infertility. Some men with non-mosaic syndrome have azoospermia and only few have oligospermia. In adult 47,XXY, germ cell aplasia, total tubular atrophy or hyalinising fibrosis and relative hyperplasia of Leydig cells are found. Occasionally, single foci of spermatogenesis do exist in the testes. The mechanisms leading to degeneration of seminiferous tubules are unknown. But this process accelerates dramatically at the time of puberty. Therefore, the preservation of reproductive potential for a chromosopathy that for years has been synonymous of sterility may offer to KS subjects the ability to father genetically own their child and may have significant psychological consequences in adulthood. In non-mosaic KS, pregnancy have been reported using intracytoplasmic sperm injection (ICSI) with ejaculated spermatozoa. In azoospermic KS men, ICSI using testicular spermatozoa retrieved with micro-testicular extracted sperm (TESE) is the sole mode of treatment that can be offered, besides sperm donation. These issues are addressed here with the aim of assisting physicians in the management of adolescents with KS.

Ref: Ped. Endocrinol. Rev. 2010;8(suppl 1):178-181

Key words: Klinefelter’s syndrome, adolescents, spermatogenesis, fertility issues.



Fertility in Men with Klinefleter Syndrome

Christopher P Houk1, MD, Alan Rogol2,3, MD, PhD Peter A Lee2,4, MD, PhD


Klinefelter syndrome is an important cause of infertility among men. Although early development of the testes may appear normal, there is profound loss of germ cells during early-to-mid pubertal maturation. Spermatogenesis may be preserved in a small percent of tubules and these tubules may be available to artificial reproductive techniques for the retrieval and subsequent in vitro fertilization of extracted ova. Ethical and legal issues including risk-benefit consideration must be evaluated before implementing fertility preservation procedures in minors.

Ref: Ped. Endocrinol. Rev. 2010;8(suppl 1):182-186

Key words: Klinefelter syndrome, fertility, spermatogenesis, artificial reproductive technology, testicular extraction of sperm, intra-cytoplasmic sperm injection




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