Klinefelter Syndrome Treatment & Management

Updated: Jan 31, 2022
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Medical Care

Early identification and anticipatory guidance are extremely helpful in Klinefelter syndrome. Management and treatment should focus on 3 major facets of the syndrome: hypogonadism, gynecomastia, and psychosocial problems.

Androgen replacement therapy

Androgen (testosterone) replacement therapy is an important aspect of treatment. Historically, testosterone replacement was started at puberty, around age 12 years, with the dose increased over time, until it was sufficient to maintain age-appropriate serum concentrations of testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). [34]  Currently, the Association for X and Y Chromosome Variations (AXYS) advocates for close monitoring of development and progression of puberty, in order to properly determine if and when testosterone treatment should be initiated. For some XXY males, gender counseling may be requested. [46]

Androgen replacement therapy corrects androgen deficiency; hence, the treatment promotes normalization of body proportions and development of normal male secondary sex characteristics. Regularly scheduled testosterone injections promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis. In addition, there are the long-term beneficial effects of decreasing the risks of autoimmune disease and breast cancer. However, testosterone therapy does not treat infertility or gynecomastia. [34]

A study by Samango-Sprouse et al suggested that early hormonal therapy (EHT) can improve social behavior in boys with Klinefelter syndrome. The study participants were boys diagnosed prenatally with 47,XXY. Twenty-nine young boys each received three injections of 25 mg testosterone enanthate and were compared with 57 controls (young boys who received no EHT). As tested using the Behavior Rating Inventory of Executive Function, Social Responsiveness Scale (2nd ed), and Child Behavior Checklist for Ages 6-18, the investigators found significant social behavior improvements in the EHT group when compared with the control group. [47]  The authors of the study believe that EHT helps to significantly minimize developmental challenges and behavioral issues in 47,XXY boys.

A double-blind, randomized trial by Ross et al of low-dose androgen treatment in prepubertal boys with KS found improvement at 24 months in visual-motor function, with secondary analyses indicating that androgen therapy had also positively impacted anxiety, depression, and social problems. However, cognitive function and hyperactive and aggressive behaviors were not significantly affected. [48]

Speech and behavioral therapy

A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems. In children, early speech and language therapy is particularly helpful for developing skills in the understanding and production of more complex language.

Boys with Klinefelter syndrome should receive a comprehensive psychoeducational evaluation (IEP) to assess their learning strengths and weaknesses. The information obtained from these evaluations may be helpful in planning appropriate educational resources and classroom placement.

Physical and occupational therapy

Physical therapy is recommended for boys with hypotonia or delayed gross motor skills that may affect muscle tone, balance, and coordination. Occupational therapy is advised in boys with motor dyspraxia.

Treatment for infertility

Until 1996, men with Klinefelter syndrome were considered infertile. Since then, however, developments in microsurgical techniques and advances in artificial reproductive technologies (ART) have enabled over 50% of men with Klinefelter syndrome to sire their own children. Success has been achieved through a combination of microsurgical testicular sperm extraction (TESE) and the use of freshly retrieved sperm for in-vitro fertilization (IVF). [4, 5, 6, 7, 8]  TESE is the process of removing a small portion of testicular tissue under local anesthesia and extracting the few viable sperm present in that tissue for intracytoplasmic sperm injection (ICSI). Intracytoplasmic sperm injection (ICSI) has offered XXY men an increased chance to father a child. A study of 42 men with Klinefelter syndrome revealed a sperm retrieval rate of 72% per testicular sperm extraction attempt, with adequate sperm for ICSI found in 69% of subjects (29 of 42 men). Thus, TESE and ICSI may be considered for males with azoospermia and Klinefelter syndrome. [4]  

Men with Klinefelter mosaic cell lines may have viable sperm in their ejaculate and hence be able to father a child without assisted reproductive technology.

Genetic counseling

The etiology of 47,XXY and sex chromosome aneuploidies is due to a chromosomal nondisjunction process. Recurrence risk is not known to be increased above the risk in the general population; hence there is no increased likelihood of a nondisjunctional event reoccurring in a particular family. Physicians and genetic counselors should provide parents with information from unbiased follow-up studies of boys diagnosed with Klinefelter syndrome. Revealing the condition to an affected male is probably best at the time of mid- to late adolescence, when he is old enough to understand his condition.

Reproductive genetic counseling

Sperm from patients with presumptive nonmosaic 47,XXY karyotype have been used successfully in medically assisted reproduction. However, the origin of meiotic products of men with the nonmosaic 47,XXY karyotype remains unclear. Mosaicism cannot be excluded in the nonmosaic 47,XXY karyotype. [49]  The presence of a normal XY germ cell line in the testis could explain the production of normal haploid sperm in these apparently nonmosaic patients. Nevertheless, peripheral lymphocyte karyotyping neither predicts the chromosomal constitution of the testis cells nor the presence or absence of spermatogenesis. [50]

ICSI is associated with an increased risk of producing a chromosome anomaly in offspring. [51] IVF is also associated with an increased risk for de-novo chromosomal aberrations, especially those involving the sex chromosomes. [52, 53]

Reproductive genetic counseling of patients with the 47,XXY karyotype remains difficult. Some authors have recommended preimplantation or prenatal diagnosis after ICSI using sperm cells from patients with the 47,XXY karyotype. [54, 55, 56, 57] Arguments from authors who propose a preimplantation genetic diagnosis (PGD) include the increased risk of producing sex chromosomal–abnormal offspring (the unbalanced offsprings are 47,XXX or 47,XXY karyotypes). [58, 59, 60, 61, 57]

The genetic risk in the offspring of patients with 47,XXY karyotype remains unknown but is presumably low. This risk concerns sex chromosomal and autosomal aneuploidy. Genetic counseling should be reassuring, and management of the pregnancy should proceed with caution. [62]


Surgical Care

Mastectomy may be indicated for gynecomastia, which can place considerable psychological strain on the patient.



Consultations may include the following:

  • Clinical geneticist/genetic counselor

  • Endocrinologist (treatment approach to androgen replacement therapy)

  • Surgeon (evaluation for breast tissue removal) 

  • Dentist (focus on dental health preservation/restoration)

  • Psychologist

  • Speech therapist

In a mixed-method study by Close et al, parents reported that a lack of guidance and case coordination increased the challenges of providing childcare for their sons with Klinefelter syndrome. The study also found parental age–related differences with regard to the stress, quality of life, and family management difficulties associated with raising a son with 47,XXY. [63]  



No special diet is needed.



No activity restrictions are required.