TESTIS FAILURE IV: KLINEFELTER
SYNDROME
Klinefelter syndrome is the most common genetic cause of sterility due to primary gonadal failure; it is also a relatively common genetic anomaly in the general population, occurring in 1:500 boys. It is characterized by a male phenotype with a 47,XXY chromosomal constitution. Approximately 10% of Klinefelter patients have mosaic 46,XY/47,XXY (or variants) patterns and the remainder have a pure 47,XXY or variant constitution. Clinically, it is associated with a triad of findings: small, firm testes, azoospermia (no sperm count) and gynecomastia, although the latter is not necessarily a typical feature.
Approximately half of
Klinefelter cases are paternally derived, and recent evidence suggests that its
occurrence may correlate with advanced paternal age. This syndrome may also
present with increased height, decreased intelligence, varicosities, obesity,
diabetes, leukemia, and increased likelihood of extragonadal germ cell tumors
and breast cancer (20-fold higher than normal males). It usually presents as
either delayed male puberty due to hypogonadism or with primary infertility
later in life. Although nearly always associated with infertility in the pure
chromosomal pattern, Klinefelter patients often show a wide spectrum of
masculinization ranging from a severe eunuchoid habitus to a normal male
phenotype. The degree of gynecomastia is variable. Indeed, approximately 10% of
Klinefelter patients exhibit the classic attributes of this condition.
Reproductive hormones
usually demonstrate a low testosterone and frankly elevated luteinizing hormone
(LH) and follicle-stimulating hormone (FSH). Natural paternity with this
syndrome is possible, but almost exclusively with the mosaic or milder form of
the disease. Biologic paternity in cases of pure XXY males is now possible with
assisted reproduction in conjunction with retrieval of testis sperm.
Characteristically, the
testes exhibit an irregular distribution of seminiferous tubules and tubular
sclerosis separated by connective tissue and clumps of Leydig cells. Leydig
cells are often increased in number and size and can form nests that appear as
adenomas. Among seminiferous tubules, most contain only Sertoli cells, whereas
in 60% of cases, other tubules will harbor pockets of spermatogenesis with
sperm. The seminiferous tubule basement membrane is
thickened and sclerosed, and there is significant intertubular hyalinization.
Testicular abnormalities similar to those in Klinefelter syndrome can be
brought about by radiation damage, mumps orchitis, or other testicular injury.
Such a history is not typically elicited from Klinefelter patients, however.
Prior to adolescence, the testes are relatively normal in size but fail to
develop normally in response to pubertal gonadotropin stimulation.
Interestingly, despite a
uniformly abnormal somatic genotype, 75% to 100% of mature sperm from 47,XXY
patients harbor a normal haploid sex chromosome complement (X or Y), instead of
XY or YY complements. The lack of significant gonosomal aneuploidy in the
presence of somatic aneuploidy suggests that abnormal germ cell lines may
arrest at a meiotic checkpoint within the testis or that somatic-germ line mosaicism
is more common than
previously thought.
