Kleinfelter's

Klinefelter Syndrome Overview
(XXY syndrome, XXY trisomy)

Page Contributors: Brynn Ashley and Amanda Romero

Sex chromosome abnormality that occurs in males with two or more X chromosomes (typically XXY, rather than the genetic male norm of XY)
Syndrome is not inherited (passed from parent to child); rather, it is caused by a cell division error in utero. Because it is not genetic, prenatal testing is not a useful tool to predict the likelihood of having a male child with Klinefelter.

Clinical Presentation

Newborn males with the XXY genetic makeup will appear phenotypically male (normal external male genitalia)
Children with Klinefelter generally present after puberty with tall stature (long legs compared to trunk), small, firm testes, small penis, decreased pubertal hair, and gynecomastia
These children are also at higher risk for developing learning disorders (particularly involving speech delay, but also ADHD and dyslexia), bone abnormalities (i.e. osteoporosis), psychiatric conditions (i.e. depression), autism spectrum disorders, and autoimmune disorders (i.e. lupus)

Basic Genetics of Klinefelter Syndrome:

The most common chromosomal makeup for Klinefelter is XXY, meaning there is only one extra X chromosome in each cell
Males with Klinefelter can have more than two X chromosomes (i.e. XXXXY); an increased number of X chromosomes is associated with a more severe version of the syndrome with increased signs and symptoms
Males can also have a milder version in which only some of their cells have the extra X chromosome (mosaicism)
School age males presenting with learning disabilities (especially speech problems) and adolescent males who are not progressing through puberty should be considered for genetic work-up. Some adult males may be diagnosed when seeking medical attention for fertility issues
Diagnosis is established by genetic testing (karyotype). When mild symptoms are present and mosaicism is suspected, it may be necessary to perform the genetic analysis on a larger number of cells (a single sample is sufficient, but the chromosomal mapping may take place on more than the standard ~20 cells)

More information on kareotypes:

Review growth chart and milestone development:

Screen for any signs of learning disabilities or speech delay, specifically any expressive language delays, dyspraxia, lower verbal IQ.

Per Bright Futures: surveillance for developmental problems at all well-child preventive care visits and routine screening with a general screening tool at the 9-, 18-, and 30-month visits, plus screening with an autism-specific tool at the age of 18 and 24 months, or at any encounter where concern is raised by parent.
ASQ (screens for communication, gross motor, fine motor, problem solving, and personal-social delays in children up to 66 months of age) ($)
MCHAT-- the AAP recommends autism screening at 18 and 24 months of age, but one must rule this out for children with Klinefelter Syndrome, therefore can be done earlier or more frequently if necessary. MCHAT is designed for children 16-30 months of age. (Free)

Screen:

Assess for autoimmune conditions (lupus, rheumatoid arthritis and Sjogren’s Syndrome).
Increased risk for male breast cancer (20 fold) compared to typical XY males (extragonadal germ cell tumor), lung disease, vascular disease (varicose veins), and osteoporosis.
Common behavioral symptoms: ADHD, withdrawn, anxiety, depression, low self-esteem.

Exam:

Complete GU exam including Tanner staging, breast development, hair growth patterns.
Assess for decreased energy, endurance, poor coordination.
Record any scoliosis.
Check for any dental decay.

Labs to consider: hormone levels: testosterone, estradiol, LH, FSH

Referrals:

Endocrinology: Testing to be performed: karyotpe, FISH, chromosome analysis, male factor infertility evaluation. Testosterone replacement therapy to be considered around age of puberty to encourage masculine development, build muscle mass, and improve bone mineral density.

Focused on symptom management; treatment varies according to the signs and symptoms experienced by the child.
May include testosterone therapy which should be managed by endocrinologist. Testosterone therapy can help improve strength, muscle development, pubertal hair growth, and improve social and emotional complications of delayed/decreased puberty (mood, self esteem, energy, etc).
School accommodations and/or locating an early intervention program for speech delays.
Refer to developmental-behavioral pediatrics and/or mental health specialists for behavioral concerns.

Peter A. Lee, Christopher P. Houk, S. Faisal Ahmed, Ieuan A. Hughes (2006). Consensus statement on management of intersex disorders. Pediatrics, 118, e488-e500.
Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. (2004). Klinefelter’s syndrome. Lancet, 364:273–83.
Khalifa MM, Struthers JL. (2002). Klinefelter syndrome is a common cause for mental retardation of unknown etiology among prepubertal males. Clin Genetics, 61:49–53.
Strategies and advantages of early diagnosis in Klinefelter's syndrome (Radicioni et al, 2010)
“47,XXY Klinefelter syndrome: Clinical characteristics and age-specific recommendations for medical management,” http://onlinelibrary.wiley.com/doi/10.1002/ajmg.c.31349/full
Cassidy SB and Allanson JE. (2010). Management of Genetic Syndromes. (3rd ed.).
Hoboken, NJ, John Wiley & Sons, Inc. Jones KL (2006). Smith’s Recognizable Patterns of Human Malformation. (6th ed.). Philadelphia, PA. Elsevier Saunders.
Moeschler JB, Shevell M. and the Committee on Genetics. (2006). Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics, 117, 2304-2316.
Rice SG and the Council on Sports Medicine and Fitness. (2008). Medical Conditions Affecting Sports Participation. Pediatrics, 121, 841-848.
American Family Physician (2005). Klinefelter Syndrome, web page.

XXYTalk.com
AAP “The Bakers Dozen,” http://www.aap.org/en-us/about-the-aap/Committees-Councils-Sections/Section-on-Uniformed-Services/Documents/The_Bakers_Dozen-Stephan.pdf
Klinefelter Fact Sheet (Center for Genetics Education)
NIH Genetic Home Reference Page on Klinefelter
National Human Genome Research Institute's overview on Klinefelter
Gene Reviews

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