In Klinefelter Syndrome Patients, What are the Common Behavioral Problems?

Patient Presentation
A 17-year-old male with known Klinefelter syndrome (KS) came to clinic for his health supervision visit. He had his attention deficit disordertreated with a stable amount of long-acting methylphenidate with good response and few side effects. He was entering his high school senior year and was doing fairly well in school with some extra time and help with reading skills. He had some friends who liked to play pickup basketball. The past medical history revealed he had been diagnosed 15 months before because of tall stature, small testes and lack of androgen pubertal changes. He was being followed by endocrinology for testosterone treatment. He had received speech therapy when he was younger and always had struggled with reading skills. The family history was positive for diabetes mellitus. The review of systems was negative.

The pertinent physical exam showed a tall male who spoke softly. His height was 185 cm (90%), weight was 90 kg (~95%) and BMI of 26.3 (85-95%) for age. He was Tanner 3 for pubic hair and had a small phallus and small testes. The rest of his examination was negative. The diagnosis of a healthy male with Klinefelter syndrome was made. As the resident and his attending physician had discussed some of the potential needs of the patient before his visit, the resident re-ordered his medications and emphasized that he should continue exercising and eating right to help with his weight. The patient had earlier noted that he wanted to go to college after high school and the resident said that it was very common for people with Klinefelter syndrome to have some academic problems and maybe the patient would benefit from formal testing so that he could get the appropriate help for school and college. The patient and resident discussed this with his mother who also thought this was a good suggestion and a referral for neuropsychiatric/educational testing was made.

Discussion
Klinefelter syndrome (KS) is a common genetic abnormaly with a prevalence of 1 in ~650 male births. It was first described in 1942 by Dr. Harry Klinefelter. It is associated with at least one extra X chromosome with the most common karyotype (~80% of patients) being 47 XXY. Other karyotypes are seen along with mosaicism. It is believed that although it is very prevalent, only about 25-33% of people with KS are identified. About 10% are identified before puberty with the rest usually identified because of hypogonadism and tall stature especially in teenage years or due to infertility in adulthood. KS is diagnosed by karyotype.

The phenotype varies but most commonly is associated with hypogonadotropic hypogonadism, infertility, gynecomastia and tall stature. The tall stature is remarkable for a lower segment > upper segment body habitus which can be noted after age 5 years. It is felt that the SHOX gene located on the X chromosome may play a part in this growth pattern.

KS patients have underdeveloped genitalia with small phallus and small testes (or cryptochidism). The testes have changes from fetal life but the testes start to enlarge at the time of puberty and then rapidly undergo fibrosis particularly of the Sertoli cells. Patients have elevated follicle-stimulating hormone and luteinizing hormone, but decreased testosterone. Decreased androgen can lead to decreased body hair or muscle strength and treatment with testosterone is usually given in adolescence if the patient is identified. Semen analysis usually reveals azospermia (>90%) but testicular sperm extraction and some other techniques can harvest active sperm. The rates of successful pregnancy still are low.

KS patients have a higher rate of gynecomastia and breast cancer than other males.
They also have higher rates of diabetes mellitus, obesity, metabolic syndrome, osteopenia/osteoporosis and autoimmune disorders especially systemic lupus erythematosus. Other features seen in KS include varicose veins and mitral valve prolapse. They also have a lower median life expectancy by 2.1 years.

Patients need comprehensive management from a variety of specialists to address their medical and psychosocial needs throughout their lifetime.

Learning Point
As noted before, the phenotype for people with KS is quite variable. KS patients overall have normal to lower intelligence with the overall IQ distribution being lowered by about 10 points relative to the general population. KS patients also overlap areas of psychological and social functioning but do have higher numbers of people with the problems listed below. Academic problems are found in 60-85% of patients.

Behavioral and educational problems found more commonly in KS include:

• *Attention problems – including attention deficit/hyperactivity disorder
• Learning disabilities – reading disabilities, spelling disabilities. Visual, spatial and math skills are usually normal.
• Psychological problems – *anxiety, *depression, somatic complaints, *social problems, autism spectrum disorder, schizophrenia
• *Speech impairment – delayed expressive speech

* some of the more common problems

Questions for Further Discussion
1. How is Klinefelter syndrome similar to Turner Syndrome?
2. What are indications for neuropsychiatric and/or educational testing?

Related Cases

Disease: Klinefelter’s Syndrome

Symptom/Presentation: Health Maintenance and Disease Prevention | Syndromes | Learning Problems | Delayed Puberty

Specialty: Endocrinology | Genetics | Psychiatry and Psychology | School

Age: Teenager

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Klinefelter’s Syndrome

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Tartaglia N, Cordeiro L, Howell S, Wilson R, Janusz J. The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome). Pediatr Endocrinol Rev. 2010 Dec;8 Suppl 1:151-9.

Wikstrom AM, Dunkel L. Klinefelter syndrome.
Best Pract Res Clin Endocrinol Metab. 2011 Apr;25(2):239-50.

Kingery SE, Wintergerst KA. Turner Syndrome and Klinefelter Syndrome. Adolesc Med State Art Rev. 2015 Aug;26(2):411-27.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital