9.4.5 XYY male

Men with a 47,XYY karyotype do not present with a well-defined clinical syndrome. The diagnosis relies entirely on the cytogenetic demonstration of two Y chromosomes, accompanying an otherwise normal set of chromosomes. Cases with 47,XYY/46,XY mosaicism are also subsumed under the XYY male category. The 48,XXYY karyotype is briefly discussed in Chapter 9.4.3.

In a series of unselected male newborns, the 47,XYY karyotype had a prevalence of roughly one in 1000. In this newborn series, 20% of the XYY children were mosaics. These may have arisen postzygotically, while a non-mosaic 47,XYY state originates from an error in the paternal second meiotic division. There is no association between parental age and the likelihood of a 47,XYY karyotype in the offspring.

Most 47,XYY males lead well-adapted and productive lives, are fertile, and have no health problems distinct from those of 46,XY males. Population-based studies suggest that the majority of these individuals remain undiagnosed for their lifetimes (1). This is concordant with the clinical impression that most 47,XYY diagnoses come as unexpected chance findings when chromosomes are analysed for unrelated issues, such as recurrent pregnancy losses or congenital disorders in the family.

This notwithstanding, the 47,XYY karyotype is loosely associated with some anthropometric, behavioural, and clinical peculiarities (2). While length at birth is average, from infancy onwards almost every XYY boy grows within centiles above the 50th. This translates into an adult height 7 cm in excess of the male population mean. In a cohort of Danish XYY adolescents, the mean height at the age of 18 years was 187 cm, with some of the boys still growing. There is no disproportion between the upper and lower body segments, as is observed in Klinefelter’s syndrome. Adolescents and young men with an XYY karyotype tend to be lean. Whether their relatively low weight persists as they grow older remains to be documented. There is no increased frequency of malformations among XYY individuals.

Compared to boys with a 46,XY karyotype, the onset of puberty is delayed by six months. Otherwise, no peculiarities of pubertal development are known. Adult testicular volume is normal, as are testosterone and gonadotropin serum levels. Given the high prevalence of male infertility in the general population, it comes as no surprise that some XYY individuals have been identified when large cohorts of infertile men were karyotyped. The prevalence of the 47,XYY aberration among infertile men is approximately 0.2–0.3%; 0.6% specifically among oligozoospermic men, and 0.2% among azoospermic men. While these percentages indicate a slight overrepresentation of XYY men as compared to the newborn prevalence, infertility is certainly not a regular or even obligate sequela of this chromosome abnormality. Many XYY men are known to have fathered children, and taken in sum, the evidence suggests that most XYY males have normal fertility. However, the XYY karyotype may be a moderate risk factor for spermatogenic impairment. There is no indication that XYY males are particularly predisposed to gonadal tumours.

On testing for full scale IQ, XYY boys score an average of ten points less than age-matched peers with a normal karyotype. However, there is considerable variability in academic skills with IQ scores up reaching more than 140 (3). Mental retardation is not a feature of the XYY phenotype. In everyday life the mild cognitive impairment may translate into poor school performance. Reading ability appears to be specifically affected. Inattention and distractability also contribute to the common educational difficulties. In later life, most XYY males have lower-skilled jobs.

Behavioural problems in childhood and adolescence are more common in 47,XYY males than in peers. The most commonly cited aberrant behavioural characteristics include temper tantrums, poor social adaptation and impulse control, self-isolation, and low frustration tolerance. In later life, psychiatric problems have a higher prevalence than in the general population (4). The 47,XYY karyotype was found to be overrepresented among prison inmates. This observation fuelled speculations about an association between Y chromosomal genes and aggression. A methodologically sound population-based study demonstrated that XYY men were in fact more likely to have a criminal record than XXY or XY males, but also that a history of violent behaviour was exceptional (5).

Most 47,XYY males are healthy and need no therapy at all. For those presenting with a fertility problem, it must not be assumed that the abnormal karyotype is the sole explanation. Other causes should be sought and where possible treated. When semen parameters are profoundly subnormal, intracytoplasmic sperm injection (ICSI) may be considered.

From clinical experience it is believed that XYY males achieving natural fatherhood can expect chromosomally normal offspring with the same likelihood as normal men. This is surprising, as theoretically every second sperm should carry an abnormal 24,YY or 24,XY chromosomal complement. Sperm aneuploidy rates are in fact somewhat increased among these individuals, to a minor degree according to most studies (6), but grossly in one (7). It is prudent to offer cytogenetic prenatal diagnosis for all pregnancies induced by XYY males. ICSI with preimplantation genetic diagnosis (PGD), in countries where this is permitted, may be considered for infertile patients with a 47,XYY karyotype (7).

Through the advances in prenatal medicine the survival prognosis for XYY fetuses has become worse over the past decades. The widespread use of amniocentesis and chorionic villus biopsy has resulted in a situation where a considerable percentage of XYY individuals are now diagnosed prenatally. Between 30 and 50% of parents chose to terminate the pregnancy when confronted with the diagnosis of a 47,XYY karyotype in their unborn child. Given the normal physical and mental health of most XYY males, these high termination rates are surprising and raise questions about the adequacy of post-amniocentesis genetic counselling (8). The authors advocate the position that the prenatal recognition of a 47,XYY karyotype should not be grounds for a pregnancy termination, apart from in the most exceptional circumstances.