The Principles of Clinical Cytogenetics - Extra Materials - Springer

256 Linda Marie Randolph
In a review of the chromosomal contribution to male infertility, Van Assche et al. (20) reported on
the chromosome constitution of about 8000 infertile men and compared the findings to the chromosome
constitution of a group of newborn children. In the infertile group, the incidence of sex chromosome
abnormalities was 27 times higher (3.8% vs 0.13%), and the incidence of autosome
abnormalities was five times higher (1.3% vs 0.25%) (20). When considering men with oligospermia
only, pooled data show a frequency of chromosome abnormalities of 4.6%. For men with azoospermia,
the pooled data show a frequency of 13.7% (20).
In a separate cytogenetic study of 1007 infertile men, major chromosome abnormalities were seen
in 62, or 6.2%. Of those, 38 (3.8%) had sex chromosome abnormalities and 24 (2.4%) had autosomal
chromosome abnormalities. Of those with sex chromosome abnormalities, 28 were 47,XXY, 3 were
47,XYY, and 7 had a Y chromosome with a structural abnormality. Of the autosomal abnormalities,
10 were reciprocal translocations, 8 had Robertsonian translocations, 5 had an inversion, and 1 had a
ring chromosome. The likelihood of a chromosome abnormality was higher in men with a sperm
density of < 5 × 10 6 /mL, an FSH � 30.1 mLU/mL, an LH � 8.9 mLU/mL, a testosterone value � 2.69
ng/mL, or an average testis volume � 8 mL (21).
Sex Chromosome Abnormalities (See Also Chapter 10)
Among men with infertility, the most frequent cytogenetic findings are 47,XXY and 47,XXY/
46,XY. Men with these chromosome constitutions commonly have the clinical features of Klinefelter
syndrome, which include essentially normal appearance at birth but for a slightly small head, delayed
puberty, higher incidence of gynecomastia than other males have, and small, firm testes with hyalinization
of seminiferous tubules. Intelligence is usually normal, with performance IQ normal and
verbal IQ below normal on average. Reading skills can be a problem (22). Patients have hypergonadotropic
hypogonadism and azoospermia or very severe oligospermia. Although many of these
men are diagnosed as boys, others are not diagnosed until such time as they are seeking the cause for
their infertility. Given the incidence at newborn screening, it appears most males with 47,XXY or
47,XYY do not come to diagnosis.
Men with 47,XYY or 47,XYY/46,XY karyotypes are usually fertile and typically have normal semen
analyses (22). They are slightly taller than their chromosomally normal brothers on average and
have, on average, a normal IQ. About half have learning disabilities requiring special education (22).
The incidence of men with 47,XYY is about the same as that of 47,XXY in the general population;
each is present in about 1 in 1000 newborns (21). However, in infertility surveys [e.g., the study by
Gunduz et al. (19)], the finding of 47,XXY is about nine times as frequent as that of 47,XYY. Men
with a 47,XYY karyotype are represented more frequently among infertile men (0.26%) than in newborn
males (0.07%). Their semen analyses are usually normal, as noted above, but in a minority of
cases, they have severe abnormalities of spermatozoa number, motility, and/or morphology (23).
Autosomal Abnormalities
The most common autosomal abnormality seen in infertile men is the Robertsonian translocation
(see Chapter 9). In the above-cited review by Van Assche (20), the incidence of infertile men with
this finding was 0.7%. This was 8.5 times the incidence in the newborn survey used for comparison.
It appears that the increased frequency of the X-Y bivalent and the trivalents formed by the chromosomes
involved in the Robertsonian translocation are correlated with the extent of germ cell impairment
(24); see also Chapters 2, 9, and 10.
The review by Van Assche, which pooled data from several studies, also indicated that 0.5% of
men with infertility had reciprocal translocations, as compared to 0.1% in the newborn population.
The association between reciprocal translocations involving chromosomes 3–7, 9, 11, 13–15, 16, 17,
and 19–22 and the impairment of sperm production has been documented in several studies (13).
Chromosomes from men with reciprocal translocations involving these chromosomes have been
observed, at the pachytene stage of meiosis, to have a high frequency of centromeric contacts and