9.4.6 Structural chromosome abnormalities

The term ‘structural chromosome abnormalities’ encompasses pathological alterations of chromosome structure that are detectable through microscopic examination of banded metaphase preparations (Chapter 9.3.5). It excludes smaller lesions diagnosable only with molecular genetic methods. Medium-sized genomic alterations, e.g. microdeletions demonstrable through molecular-cytogenetic methods such as fluorescence in situ hybridization (FISH), may also be classified as structural chromosome abnormalities. Some structural rearrangements, such as Robertsonian translocations and marker chromosomes, imply a change in chromosome number. By convention, they are regarded as structural and not numerical chromosome abnormalities.

Reciprocal and Robertsonian translocations, inversions, marker chromosomes, X and Y isochromosomes, and Y-chromosomal deletions are of practical importance in male endocrinology (Fig. 9.4.6.1) (1–4). Other classes of structural chromosome abnormalities such as rings, insertions, duplications, three-way and other complex translocations, fragile sites, and chromosome breakage syndromes (5) play no appreciable role in clinical andrology and are not further considered here.

The distinction between balanced and unbalanced structural aberrations is pivotal. The former are characterized by a deviation from normal chromosome structure without accompanying net loss or gain of genetic material. In contrast, the genome of a carrier of an unbalanced aberration is not fully diploid, but nullisomic, monosomic, trisomic, or higher aneuploid for an entire chromosome or parts of it. If no important gene is disrupted at the breakpoints, balanced structural aberrations exert no negative effect on general health. They are of clinical importance through their potential to adversely affect fertility, and to give rise to unbalanced karyotypes in the carrier’s offspring (5).

Approximately 1 in 200–400 unselected newborns carries a structural chromosome abnormality. Among infertile men the prevalence is higher, ranging somewhere between 1 and 2%. Structural chromosome rearrangements are preferentially found in oligozoospermic individuals, but not in azoospermic patients (3). Among the latter, numerical chromosome abnormalities such as 47,XXY (Chapter 9.4.3) predominate. The likelihood that a given carrier of a structural chromosome aberration will have a fertility problem is unknown. Many such individuals never come to clinical attention, and if they do, it is commonly for repeated pregnancy losses, the birth of a chromosomally unbalanced child, or reasons other than the inability to induce a pregnancy.

Some structural chromosome abnormalities are inherited from one of the parents, and some arise de novo. To the author’s knowledge, the contribution of familial and de novo cases has not been determined in patients presenting for testicular disease. With regard to de novo abnormalities, paternal meiosis is the predominant source. For most structural chromosome aberrations it is not obvious whether they have arisen de novo or are familial. Karyotyping of the patient’s parents thus merits consideration. By doing so, other unsuspecting family members may be identified as carriers of the same structural rearrangement as the index patient.

There are no histopathologic features that distinguish infertile men who carry a structural chromosome abnormality from those who do not. However, a meiotic arrest pattern has been repeatedly observed in the former group of patients. Even if this histological finding is not specific, it should heighten the index of suspicion for an underlying chromosomal aberration. There is also no consistent correlation between a patient’s sperm concentration, morphology, or motility and his karyotype. The carrier of a structural chromosome abnormality may be azoo-, oligozoo-, or even normozoospermic. Meiotic cell preparations from infertile inversion and translocation carriers commonly display pairing abnormalities between the involved homologues. Sometimes, there is an association between unpaired autosomal elements and the XY bivalent. Whether these cytological observations indicate the basic cause of meiotic breakdown is unclear. The molecular mechanisms of spermatogenic failure in men with structural chromosome anomalies are obscure.

Only few chromosomal abnormalities such as Klinefelter’s syndrome (Chapter 9.4.3) and some unbalanced autosomal structural aberrations (see below) display a typical clinical phenotype. Therefore, the detection of a chromosomal abnormality in an infertile but otherwise healthy man often comes as a surprise. In particular, there are no clinical, endocrine or spermatological clues to detect the rare carriers of balanced autosomal rearrangements in the vast pool of male infertility cases. The clinical presentation is mostly unspecific: nonobstructive oligo- or azoospermia, normal or elevated FSH levels, normal testosterone and LH, normal or subnormal testicular volume, and no or unspecific findings upon scrotal sonography.

In essence, the likelihood that a structural chromosome abnormality is diagnosed in an infertile man with no other distinguishing clinical features depends on the use of karyotyping as a screening procedure. Box 9.3.5.1 in Chapter 9.3.5 lists some more specific indications for ordering a chromosome analysis. Measured by the standards of evidence-based medicine, these must be taken as preliminary suggestions derived more from subjective clinical impression than solid science. The prevalence of chromosome aberrations increases with decreasing sperm counts (3). It is worth emphasizing that being a carrier for a structural chromosome abnormality is compatible with normal fertility. Thus, for an individual patient, a cause-and-effect relationship between a balanced structural chromosome abnormality and a concomitant fertility problem is no more than a reasonable working hypothesis.

Unbalanced structural aberrations of the autosomes such as deletions or unbalanced translocations typically have a dramatic impact on general health (5). Their phenotypic features include dysmorphism, malformations and mental retardation. Anatomical and functional abnormalities of the male genital tract such as cryptorchidism, hypospadias, and hypogonadism are prevalent in this patient population, but exact quantitative data are lacking. In the experience of the authors, contraception more than failing reproduction is a matter of concern in the care of individuals affected with these severe constitutional disorders.

Marker chromosomes are small supernumerary chromosomal elements that contain at least one centromere. They are also referred to as ESACs, an acronym for extra structurally abnormal chromosome. Marker chromosomes are often found in mosaic state with a normal cell line. Formally, any patient carrying a marker chromosome has an unbalanced karyotype, but small markers may consist of nothing but one or more centromeres, heterochromatin, and short arm material from the acrocentric chromosomes. These components do not contain dosage-sensitive genes, or any active genes at all, and thus have no adverse effects on general health. Through unknown mechanisms, marker chromosomes can selectively interfere with spermatogenesis. Markers which contain dosage-sensitive genes have effects similar to other unbalanced autosomal rearrangements, that is, mental retardation and malformations.

If two chromosomes from the acrocentric group (chromosomes 13, 14, 15, 21, 22) fuse in a head-to-head configuration the resultant derivative chromosome is called a Robertsonian translocation (5). With a prevalence of around 50% this is the most common type of structural chromosome abnormality encountered among infertile men. One copy of chromosome 13 and one of chromosome 14 are involved in 74% of all Robertsonian translocations. With a share of 8%, the 14/21 subtype is the second most common variant. This and other Robertsonian translocations involving chromosome 21 increase the risk for Down syndrome in the carrier’s offspring. Translocation trisomy is also a concern when a Robertsonian translocation includes a chromosome 13, as in the common 13/14 subtype. Uniparental disomy (UPD) also warrants consideration in pregnancies induced by Robertsonian translocation carriers. This rare genetic oddity may affect children of such patients even though their karyotype is normal, or structurally abnormal but balanced. UPD signifies the inheritance of both homologues of a chromosome pair exclusively from the mother or the father instead of their usual biparental derivation. By demasking recessive mutations, uniparental disomy of any chromosome can result in disease. Moreover, UPD of chromosomes that harbour genes with a parent-of-origin specific ‘imprint’ regularly leads to adverse health effects. With regard to the acrocentrics that participate in Robertsonian translocations, imprinting effects are important for chromosomes 14 and 15.

This type of translocation is characterized by the reciprocal exchange of terminal segments between two nonhomologous chromosomes (5). When one of the segments is very small, the exchange may appear as unidirectional. Molecular or molecular-cytogenetic methods then demonstrate the reciprocality of the rearrangement. In contrast to Robertsonian translocations, the points of chromosome breakage and reunion may be located anywhere along the length of any chromosome. Therefore, every specific reciprocal translocation is exceedingly rare; it may in fact be unique, and limited to members of a single family. This notwithstanding, some empirical rules allow appraisal of the likely meiotic segregation patterns of reciprocal translocations, and the resultant phenotypes of malsegregants. It is beyond the scope of this text to deal further with this topic, and the reader is referred to the standard textbook by Gardner and Sutherland (5) that comprehensively covers this issue. In general terms, the reproductive risks for the carriers of reciprocal translocations are threefold: first, an increased likelihood of spontaneous abortions and stillbirths; second, an increased risk of mentally and physically handicapped liveborn offspring with an unbalanced karyotype; and third, the recurrence of infertility in male children that have inherited the parental translocation in balanced form. The magnitude of these risks varies significantly between different reciprocal translocations and has to be determined on an individual basis.

Translocations between the sex chromosomes, or between one sex chromosome and one autosome, are rare. They merit special consideration as their biological and clinical behaviour deviates from that of autosomal translocations. The majority of reported X/Y interchanges have been observed in the unbalanced form. The karyotype–phenotype correlation is complex, and for details the reader is referred to Hsu’s exhaustive review. (2) In general terms, this type of rearrangement can be associated with either male or female gender differentiation, and gonadal function is compromised irrespective of sex.

In both balanced and unbalanced forms, a translocation between the heterochromatic part of Yq and the short arm of an acrocentric chromosome leaves the general health and fertility of the carrier unimpaired. Other Y/autosome reciprocal rearrangements cause infertility in 80% of cases, and malformations and mental handicaps have also been observed. Balanced X/autosome translocations have a severely detrimental effect on spermatogenesis, but fatherhood by men carrying this type of rearrangement has been occasionally reported.

An inversion results when two breaks occur in a chromosome and the segment between the breakpoints reinserts in the reverse orientation (5). Pericentric inversions include the centromere, while paracentric ones do not. After translocations, inversions are the second most common structural chromosome abnormalities encountered among infertile men. Many inversion carriers, however, are fertile. The a priori risk that an inversion will compromise fertility to a clinically significant degree is unknown. Small pericentric inversions of the Y chromosome are not detrimental to spermatogenesis. The experience with X chromosomal inversions in men is limited. Some case reports indicate that this type of rearrangement is compatible with normal male fertility.

Meiotic pairing between an inverted autosomal chromosome and its non-inverted counterpart is brought about by a loop that forms along the inverted segment. If meiotic recombination (crossing over) occurs in this loop, an inversion can give rise to derivative chromosomes that are partly deleted and partly duplicated. Spontaneous pregnancy loss or the birth of a chromosomally unbalanced child can be the ultimate consequences. The risk for the latter outcome is higher in peri- than paracentric inversions; however, many pericentric inversions carry only a small risk. For genetic counselling, each inversion must be assessed on an individual basis. Estimation of the risks brought about by an inversion takes into consideration the size of the inverted segment, the genetic imbalance in potential recombinants, and the reproductive history of the patient and his or her family.

Short arm deletions of the Y chromosome that encompass the sex determining SRY gene result in sex reversal. These are phenotypically female individuals with somatic signs of Turner’s syndrome. Their streak gonads are prone to developing gonadoblastoma.

Loss of the heterochromatic part of the Y chromosome’s long arm (Yq12) leaves general and reproductive health unaffected. The Yq12 band is responsible for the bright fluorescence of the Y upon quinacrine staining (Chapter 9.3.5). Thus, Y chromosomes lacking the heterochromatic region are non-fluorescent (‘Ynf’). The term non-fluorescent Y is somewhat misleading, because it can signify this inconsequential loss of the genetically inactive heterochromatin, but also Yq deletions that extend more proximally into the euchromatic Yq11 band. In the latter case, azoospermia or severe oligozoospermia ensue, because Yq11 harbours loci essential for spermatogenesis (Chapter 9.3.5). Some patients with deletions extending into Yq11 also have short stature and incomplete virilization. Female phenotypic sex has been observed, but this is exceptional. In contrast, ambiguous or female external genitalia are observed in nearly 70% of patients who are mosaics for a 46,X,del(Y)(q11) and a 45,X cell line. Interstitial submicroscopic deletions (‘microdeletions’) in the long arm of the Y chromosome are dealt with in Chapter 9.3.5.

An Xq isochromosome consists of a centromere with a copy of the X chromosomal long arm on either side. This unbalanced structural abnormality is observed in a rare variant of Klinefelter’s syndrome (Chapter 9.4.3). The karyotype designation reads as 47,X,i(Xq),Y indicating a male XY sex chromosomal complement plus the isochromosome. The phenotype is indistinguishable from patients with Klinefelter’s syndrome who have the ordinary 47,XXY karyotype.

Isochromosomes of the Y-chromosomal short arm are exceedingly rare. The published clinical data are insufficient for a reliable description of the phenotype. An isochromosome of the long arm of the Y chromosome has the same consequences as a short arm deletion: female sex differentiation with streak gonads, amenorrhea, and optionally other signs of Turner’s syndrome.

An isodicentric chromosome has two centromeres, one of which may be functionally silenced. There is chromatin in between the two centromeres and telomeric to them. Ideally, an isodicentric should have a palindromic architecture with homologous chromosomal segments to both sides of the axis of symmetry. Dicentric chromosomes tend to be unstable in mitosis, and therefore commonly occur in mosaic states. A Yq isodicentric contains two copies of the complete long arm and parts of the short arm. A Yp isodicentric has two complete short arms and two copies of the partially deleted long arm. Both Yq and Yp isodicentrics are almost invariably encountered in mosaic state with a 45,X cell line. Male phenotypic sex is observed in about 30% of the cases, intersex genitalia in another 20–30%, and female phenotypic sex in 40–50%. Those with male sex differentiation mostly feature small testis size, azoospermia, and hypospadias.

A point to consider for clinical management is that several Y chromosomal aberrations confer an increased risk for the development of a gonadal tumour, most notably gonadoblastoma. The following aberrations fall into this group: Yp deletions, Yq11 deletions in mosaic state with a 45,X cell line, and Yp and Yq isodicentrics. So far, no evidence for an increased tumour risk has been brought forward for deletions of Yq heterochromatin (Yq12) and deletions of Yq extending into the euchromatic part (Yq11) without mosaicism with a 45,X cell line.

There is no causal treatment for structural chromosome abnormalities. An unknown proportion, but probably the majority, of male individuals carrying a structural aberration are fertile and need no therapy at all. Those with impaired fertility should be evaluated for other contributing and treatable factors such as infections or endocrine hypogonadism. If this fails, assisted reproduction techniques (ARTs) are an option. As discussed in Chapter 9.5.2, intracytoplasmic sperm injection (ICSI) is the most effective ART for the treatment of male factor infertility. In the case of nonobstructive azoospermia, an attempt to recover spermatozoa or spermatids from a testicular biopsy may be worthwhile.

For any carrier of a structural chromosome abnormality who considers fatherhood, genetic counselling is strongly recommended, and it should be obligatory prior to any sort of infertility treatment (6). Several points need to be considered and discussed with the patient: the risks for inadvertent reproductive outcomes such as spontaneous pregnancy loss or an unbalanced karyotype in live-born offspring, options of prenatal and, where applicable, preimplantation diagnosis, and for certain types of aberrations the possibility that other family members are also affected and should be informed accordingly. It is important to note that a negative family history does not obviate the need for a family study: female carriers of balanced structural chromosome abnormalities are almost universally fertile, very early pregnancy losses may have gone unnoticed, and other unsuccessful pregnancy outcomes are commonly not made known in the family.

For most structural chromosome abnormalities there is no information on the a priori risk that their carriers will be subfertile. The abortion rate is increased and the livebirth rate decreased in ICSI-treated couples where one of the partners carries a structural chromosome abnormality.

Structural chromosome abnormalities can imply an increased risk for the birth of a disabled child. With regard to this outcome, empirical risk figures derived from experience with naturally conceived pregnancy must be used with caution when ICSI is considered. It is conceivable (but empirically unproven) that the ICSI procedure itself could have an influence on the likelihood that a sperm with an aneuploid set of chromosomes comes to fertilization. Sperm chromosome studies can be used to estimate the percentage of chromosomally unbalanced sperm in men with abnormal karyotypes (7, 8).