Klinefelter’s syndrome: Better care needed

Lifelong hormonal deficits often remain undetected.

Issue: May 2006

A Danish register study has found that men suffering from Klinefelter’s syndrome had increased rates of hospitalization for a variety of disorders. This increased rate was present even before the diagnosis of Klinefelter’s syndrome.

Anders Bojesen, MD, PhD [photo]
Anders Bojesen

“This study [and others] highlights the need for better care of the Klinefelter’s patient; early diagnosis, sufficient testosterone treatment and close follow up may prevent much of the extra morbidity,” said Anders Bojesen, MD, PhD, of Aarhus University Hospital in Aarhus, Denmark. “There is also a definite need for randomized placebo-controlled trials on the effect of testosterone treatment on many aspects of Klinefelter’s syndrome,” Bojesen told Endocrine Today.

Bojesen and his colleagues conducted a study of morbidity expressed by hospitalizations in men with Klinefelter’s syndrome using three registers of Danish men. “Klinefelter’s syndrome is the most frequent sex chromosomal disorder, affecting approximately one in every 660 males,” the researchers wrote in the Journal of Clinical Endocrinology and Metabolism. “It is characterized by the presence of one or more extra X-chromosomes.”

Previous research into the morbidities and mortality associated with Klinefelter’s syndrome has shown increased incidences of a variety of diseases and disorders and an increased risk of dying from certain diseases and infections.

Three Danish registers

Researchers first created a cohort of Klinefelter’s patients from the Danish Cytogenetic Central Register, and then used discharge diagnoses from the National Register of Patients to determine morbidities among the men originally selected. These patients were then compared with an age-matched control group drawn from the Danish Civil Register.

The final patient cohort consisted of 4,865 men (832 Klinefelter’s syndrome patients and 4,033 control patients). Patients were considered at-risk between either their date of birth or January 1977 and December 2001; during this time period, a total of 3,543 patients were admitted to the hospital (709 Klinefelter’s patients and 2,834 control patients).

Overall, men with Klinefelter’s syndrome had a greater risk of being admitted to the hospital vs. control patients (HR, 1.69; 95% CI, 1.54-1.86). Researchers divided the diagnoses into 16 groups and found that the first-admission rate was significantly increased in Klinefelter’s patients for all the subgroups except one (diseases in the newborn).

The biggest risk increases were seen in hospitalizations for congenital malformations (HR, 10.7; 95% CI, 8.63-13.3), psychiatric disorders (HR, 3.65; 95% CI, 2.92-4.55) and endocrine disorders (HR, 3.17; 95% CI, 2.49-4.03). Klinefelter’s syndrome patients also had increased risk of hospitalization for neurological diseases, circulatory diseases, pulmonary diseases, some cancers, blood diseases, skin diseases, bone and connective tissue diseases and trauma.

Before and after diagnosis

Researchers also looked at the frequencies of diagnoses before and after the diagnosis of Klinefelter’s syndrome. “Before the Klinefelter’s syndrome diagnosis, all but three groups of diagnoses (infections, skin diseases and other diagnoses) were significantly more frequent among [Klinefelter’s] subjects,” they wrote. “After the Klinefelter’s syndrome diagnosis, all but cancer diagnoses were significantly more frequent.”

Bojesen told Endocrine Today that although the present study did not have any information on testosterone treatment, treatment with testosterone could possibly eliminate many problems faced by men with Klinefelter’s syndrome. “Hypogonadism may be the key aspect, and sufficient treatment with testosterone may ameliorate or prevent much of the extra morbidity these patients suffer from,” he said.

Hypogonadism could have a direct effect on a variety of problems leading to hospitalization, such as osteoporosis, unfavorable body composition and an increased risk of type 2 diabetes and metabolic syndrome. Other diagnoses could be related to factors such as socioeconomic status, which researchers pointed out could in turn be related to Klinefelter’s-associated learning disabilities and psychiatric disturbances.

Investigators also pointed out that only a minority of men with Klinefelter’s syndrome is ever diagnosed (25%) and that most are diagnosed in adulthood.

Assessing testosterone

In an accompanying editorial, David J. Handelsman, PhD, and Peter Y. Liu, MD, of ANZAC Research Institute and Concord Hospital University in Sydney, Australia, agreed on the importance of assessing the long-term effects of testosterone treatment for not only Klinfelter’s syndrome but also for the much larger group of men with age-related decline in blood testosterone. They pointed out implications of this and previous research raising concerns about possible increased risks for death from cardiovascular and prostate cancer with prolonged testosterone treatment while it might reduce risk of death and disability from fractures.

“Ultimately, only rigorous prospective, placebo-controlled clinical trials can establish the net risks and benefits of testosterone treatment for older men,” they wrote.

Another important facet of this and other related European registry studies is the remarkable failure to diagnose many men with what should be a readily identifiable disorder.

“These studies challenge future clinical research to rectify the regrettable gap in current medical practice that permits lifelong but readily correctible hormonal deficits to remain undetected in many men despite well-organized medical care systems and to seek more effective treatment of men with lifelong hypogonadism,” Handelsman and Liu wrote.

“As part of a systematic approach to more effective male reproductive health care, rectifying the underdiagnosis of Klinefelter’s syndrome could be a benchmark to be achieved either by establishing genetic screening … at birth or introducing the expectation that standard medical care for young men includes at least one genital examination during late adolescence.” – by Dave Levitan

For more information:

Bojesen A, Juul S, Birkebaek NH, et al. Morbidity in Klinefelter’s syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab. 2006;91:1254-1260.

Handelsman DJ, Liu PY. Klinefelter’s’s syndrome – a microcosm of male reproductive health. J Clin Endocrinol Metab. 2006;91:1220-1222.