Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl. 2002;23:41–48.

The article by Kamischke et al entitled “Clinical and Diagnostic Features of Patients With Suspected Klinefelter Syndrome” makes several interesting points relevant to the clinical practice of andrologists, endocrinologists, and urologists as well as primary care physicians. As is widely known, Klinefelter syndrome occurs in 1:600 males, and the characteristics of those presenting as teenagers with failure of pubertal development are well described. These tall, eunichoid boys have small, firm testes, often have gynecomastia, and may have learning difficulties as well. They have scant public hair, may not shave on a daily basis, and are not muscular. Their phenotype is a reflection of their poor androgenic axis, itself a result of the slow but steady pathological destruction of the intratesticular architecture. This leaves seminiferous tubules sclerosed and the Leydig cell compartment either hyperplastic and dysfunctional or fibrosed altogether. These young men reside on the most severely affected end of the phenotypic Klinefelter spectrum. However, there are many men who are virilized well enough at or around puberty that they escape detection and may only be recognized when presenting for an infertility evaluation many years hence. Kamischke et al retrospectively reviewed 10 134 new male patients presenting to their clinic from 1984 to 1999 for evaluation of infertility or hypogonadism. Sixty-five (65) had been diagnosed previously with Klinefelter syndrome and were appropriately excluded from the study. The authors selected 311 patients who, on the basis of clinical symptoms, physical examination, and previous laboratory assays, were suspected of having Klinefelter syndrome. In each of these patients, a Barr body examination, followed by a peripheral lymphocyte karyotype, was performed. Body size, hair distribution, and body composition were recorded. The presence of gynecomastia was noted. Testis size was measured both clinically and by scrotal ultrasound. Most patients had semen analyses and hormonal measurements (follicle-stimulating hormone [FSH], luteinizing hormone [LH], testosterone, sex hormone—binding globulin [SHBG], and estradiol). The group of Klinefelter men (47,XXY: n = 85) was then compared to the group whose karyotype turned out to be normal (46,XY; n = 224). Therefore, all of these men had at least a single feature that might suggest Klinefelter syndrome, but none had had a prior karyotype. The clinical predictive abilities of the authors were quite good actually, with 28% of the patients who they thought might have Klinefelter syndrome turning out to be positive for that diagnosis.

The authors show us that a Barr body examination is sensitive (82%) and specific (95%) and can be performed in about 1 hour in a clinical laboratory. This can provide a rapid diagnosis for patients, although confirmation with a karyotype is still necessary to be definitive. Barr body analysis may, therefore, be a useful screening tool for those in whom the diagnosis is much less likely based on clinical features but still possible (men with severe oligospermia, low normal LH, and normal testosterone). However, in the severely oligospermic or azoospermic male with elevated FSH indicative of spermatogenic dysfunction, a karyotype is still required to demonstrate other etiologic anomalies such as translocations or Y chromosomal macrodeletions. Thus, Barr body analysis cannot stand alone as a diagnostic tool. Most interestingly, the authors' comparison of those with and without Klinefelter syndrome (all were suspected to have Klinefelter syndrome) revealed that there is no way to definitively distinguish the groups. That is, there is such overlap in the clinical features of the 2 groups that it is impossible to accurately predict their karyotype results on the basis of these clinical features. For example, parental age and incidence of cryptorchidism were the same for both cohorts, while the Klinefelter group tended to be taller and had smaller testis size. While these two latter findings were significantly different between the groups, one could not simply look at the height of an individual or measure the testis size and place an individual into one of the 2 groups with any level of certainty. A Barr body analysis or karyotype should be carried out in any man with spermatogenic compromise of a severe degree and hypogonadal features or endocrine results. The authors' last point is a provocative one. Their data suggest that the younger a Klinefelter patient is, the more likely he is to have sperm production, albeit at markedly reduced levels compared to the norm. Will earlier diagnosis and cryopreservation of ejaculated sperm (or even testis sperm) lead to the preservation of future fertility? The answer is unknown at this time but is worthy of further study.