What are the complications of Klinefelter syndrome?

Updated: Mar 23, 2020
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Patients with Klinefelter syndrome have an increased risk of extratesticular germ cell tumors and possibly increased risk of breast cancer. [63] The risk of breast carcinoma in 47,XXY men may approach 20 times that of 46,XY men. The cause may be related to the estradiol:testosterone ratio being several fold higher in 47,XXY men than in karyotypically normal men or is possibly due to an increased peripheral conversion of testosterone to estradiol in men with Klinefelter syndrome. [64]   Other neoplasias, occurring in 1.6% of patients, include acute leukemia, Hodgkin and non-Hodgkin lymphomas, chronic myelogenous leukemia, and other myeloproliferative diseases. Gonadal and extragonadal germ cell tumors (mediastinal germ cell tumors, teratoma, teratocarcinoma, choriocarcinoma) may also occur.

Psychological and psychiatric complications may occur in 47,XXY men with lower-than-average intelligence, hypogonadism, or impotence. The results of one study found that patients with Klinefelter syndrome are at elevated risk for psychopathologies such as autism and schizotypal traits, with schizotypal traits increasing with age. Deficiencies in verbal abilities are associated with increased autism traits, whereas deficiencies in visuospatial abilities are more strongly associated with increased schizotypal traits. [65]

Decreased bone density occurs in 25% of men with Klinefelter syndrome, possibly reflecting the impact of reduced bone formation, increased bone resorption, and/or hypogonadism. Vertebral collapse may result from osteoporosis. [66]

All patients with Klinefelter syndrome should be informed about the increased risk of deep vein thrombosis and should have their hematocrit levels monitored to avoid increased viscosity. [67]

Associated endocrine complications include diabetes mellitus, hypothyroidism, empty sella syndrome, hypoparathyroidism, and precocious puberty in association with human chorionic gonadotropin (hCG)–producing germ cell tumors. A study reported that prepubertal boys (aged 4-12 years) with Klinefelter syndrome are at elevated risk for truncal obesity, insulin resistance, and childhood metabolic syndrome. Reduced physical activity is associated with these risk factors. [68]

Autoimmune diseases, including systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis, are more common, with frequencies similar to those found in 46,XX females.

Benign prostatic hyperplasia may result from testosterone supplementation. Adults undergoing such therapy should be screened for prostatic enlargement starting at age 30 years.

In males with polysomic X Klinefelter syndrome, the mortality rate due to cerebrovascular diseases such as aortic valvular disease and berry aneurysm rupture is more than 6 times that in healthy males aged 25-84 years. Enhanced platelet aggregation, thrombotic disease, and hypercoagulability have been demonstrated and may be related to increased estrogen levels. Development of varicose veins and leg ulcers may result from venous stasis. [67]

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