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Autosomal abnormalities
From time to time, men may ask for fertility treatments including IVF/ICSI when they are already known to have an autosomal defect. In these cases, genetic counselling is also required.
Genetic counselling should be offered to all couples where the male partner is known or found to have autosomal karyotype abnormality. When there is conflict between the wishes of the couple and the interests of the future child, it may be ethically correct to withhold therapy. In general best management is to agree treatment with the couple, providing them with full information about the genetic risk.
2.5 Genetic defects
X-linked genetic disorders and male fertility
The man has only one X chromosome. This means that an X-linked recessive disorder will be manifest in males,
and that the defect will be transmitted to his daughters, but not to his sons.
Kail man n's syndrome
The commonest X-linked disorder in infertility practice is Kallmann's syndrome and the predominant form is X-linked recessive caused by a mutation in the KALIG-1 gene on Xp 22.3 [14]. Rarer forms of Kallmann's syndrome include an autosomal-dominant form [15]. Patients with Kallmann's syndrome have hypogonadotrophic hypogonadism and may have other clinical features, including anosmia, facial asymmetry, cleft palate, colour blindness, deafness, maldescended testes and renal abnormalities. It is important to note that some men with Kallmann's syndrome have an isolated gonadotrophin deficiency without any other phenotypic abnormalities. These patients may present de novo with infertility, which can be treated successfully by hormone replacement therapy.
Androgen insensitivity: Reifenstein's syndrome
The rare disorder of androgen insensitivity may first present with infertility. The condition has X-linked recessive inheritance due to a defect in the androgen receptor gene located on Xq 11-12. The phenotype varies widely, from complete testicular feminization to an apparently normal man with infertility, although the latter is rare. A structured genetic search for androgen deficiency was conducted amongst men with high testosterone and low sperm counts, but no cases were found using base pair mismatch analysis technology [16]. Several de novo mutations of the androgen receptor were noted, but in all cases, these were associated with obvious genital abnormalities such as hypospadias. It was concluded that androgen insensitivity in the infertile male in the absence of any genital abnormality is rare.
Other X-disorders
A case report exists of an azoospermic man with biopsy-proven spermatogenetic arrest, who was found to have a submicroscopic interstitial deletion on the Xp pseudoautosomal region in peripheral blood and skin fibroblast samples. Other genetic and chromosome examinations were entirely normal, including probing of the Yq region [17]. There is also a report about two men with azoospermia and X pseudoautosomal deletions [18].
X-linked disorders not associated with male infertility
A number of rare X-linked disorders are not associated with infertility. When recessive, these appear in male
babies but skip several generations and therefore family history is important. Examples of such disorders
include:
? retinitis pigmentosa, a condition that affects 1 in 3,000 people, may be recessive or dominant and
causes visual impairment [19]
? chronic granulomatous disease (CGD), a condition that predisposes to severe bacterial and fungal
infections [20]
? Menkes' syndrome, an X-linked recessive disturbance of copper metabolism associated with
progressive neurological symptoms [21]
The couple should be given choices after appropriate genetic counselling, which should include consideration about the severity of any disorder that may result. It may be appropriate to offer pre-implantation sex determination and replacement of female embryos or amniocentesis and abortion.
Y-genes and male infertility
A large number of case series of Y microdeletions have been published (Table 1) and it is clear that while microdeletions may occur in the fertile population [22], they are more prevalent in the infertile population. Microdeletions have been found in three non-overlapping regions of the Y chromosome, AZF a-b-c [23]. Several genes have been described, including RBM, DAZ, DFFRY, DBY and XXX. The most commonly reported abnormality is a microdeletion in the AZFc region which encompasses the DAZ gene. However, there is no exact correlation between DAZ deletion and the presence or absence of spermatogenesis.
Table 1: Men with microdeletions (Adapted from published case series data)
| Reference | Observation | Nr. of men | Nr. with deletion | Percentage |
| Ma et al. [24] | Various all Yq | Various | 3 azoo-oligo | |
| Mallidisef a/. [25] | 1 AZFc | 3% | ||
| Kent-First and Muallem [26] | Multiplex STS all Yq | (18-22%) | ||
| Kupker et al. [27] | 6 all Yq | 80 oligo 40 azoo | 0 3 | 7.5% azoo |
| Kobayashi et al. [28] | 16% | |||
| Najmabadi et al. [29] | 26 interval 6 | 16 fertile men 7 fertile women 50 azoo 10 oligo 15X-linked | 0 0 10 1 0 | 20% azoo 10% oligo |
| Reijo et al. [30] | 83 all Yq | 89 azoo | 13% | |
| Reijo et al. [30] | 118 probes all Yq | 35 severe oligozoo | 5.7% | |
| Qureshiefa/. [31] | 23 all Yq | 51 azoo 38< 5.0 oligo 11 > 5.0 oligo 80 fertile | 4 4 0 0 | 8% azoo 11 % < 5.0 oligo |
| Foresta et al. [32] | 16 azoo 23< 5.0 oligo | 5 6 | 31% 26% | |
| Stuppia et al. [33] | 13 probes interval 6 | 33 azoo-oligo 10 normal | 8% | |
| Vogt et al. [23] | 76 probes allYq | 370 azoo-oligo 200 | 3.2% | |
| Pryor et al. [22] | 85 probes allYq | 200 infertile 200 normal | 14 4 | 7% 2% |
| Foresta ef al. [34] | 15 probes allYq | 38 azoo-oligo 10 normal | 37.5% azoo 22.7% oligo | |
| Simoni et al. [35] | 4 probes AZFa,b,c | 168 azoo-oligo 86 normal | 0% normal 3% | |
| Girardiefa/. [36] | 36 all Yq | 160 infertile 6 fertile | 5% | |
| Stuppia ef al. [37] | 27 interval 6 | 50 azoo-oligo 10 normal | 14% |
Clinical implications of Y microdeletions
There are no reports that men with microdeletions have any phenotypic abnormalities other than abnormal spermatogenesis [23,31,38]. As there is only one Y chromosome, it may be predicted that Y microdeletions will be transmitted to male offspring, although this is likely to be rare in the normal population because, without ICSI treatment, men with very low sperm counts are less likely to father children. Nevertheless, eight such cases have been reported (Table 2). More information is needed from father/son pairs where the son has a very low sperm count, and also about the outcome of ICSI attempts where spermatozoa have been used from men with microdeletions. Long-term follow-up of any male children is also required.
Table 2: Transmission of Y chromosome deletion from father to son
| Authors | Y deletion son | Y deletion father | Phenotype |
| Kobayashi et al. [28] | AZFc | AZFc | ? |
| Vogt et al. [23] | AZFc | AZFc | <0.1x106 |
| Kent-First et al. [39] | Small near AZFc | Small near AZFc | ICSI |
| Small near AZFc Large AZFc -AZFb | Not detected Not detected | Normal | |
| Pryor et al. [22] | sY153-sY267 sY207-sY272 | sY153-sY267 | 0.3 x106 |
| Stuppia et al. [40] | AZFc | AZFc (smaller) | <2x106 |
| Mulhallefa/. [41] | Ongoing twin pregnancy | AZFc | ICSI |
| Silber et al. [42] | Two ongoing pregnancies Two ongoing 1 twin AZFc | AZFc Azoospermic AZFc Oligospermic | TESE-ICSI ICSI |
| Kamischke et al. [43] | AZFc | AZFc | ICSI Normal |
Testing for Y microdeletions
Testing for microdeletions is now widespread, but the lack of a standardized methodology makes it difficult to
directly compare the reported results (Table 1). Several centres have developed screening methodologies
[23,26,31,44].
As there is no correlation between the histopathoiogy and deletion of DAZ, it is premature to rely on detection
using specific gene probes, as this will fail to find a significant proportion of men with microdeletions.
Comparing results from 28 different European laboratories, it was concluded that use of a high number of
primers did not improve the accuracy of results. Recommendations are being produced for standardization
[45].
Testing for microdeletions is not necessary in men with obstructive azoospermia where ICSI is used, because spermatogenesis should be normal. For men with severely damaged spermatogenesis, testing for microdeletions before ICSI is desirable. However, as these men and their male children are unlikely to have any phenotypic abnormality other than impaired spermatogenesis, it is reasonable to take into account the cost and limitations of current testing methods and to discuss this with the couple. Wherever possible, testing should be encouraged and laboratories should join quality control schemes.
If a man with microdeletion and his partner wish to proceed with ICSI they can be advised that microdeletions will be passed to sons, but not to daughters. The should also be advised that it is not known to what extent a son who inherits a microdeletion will in turn have a fertility problem, although there is some evidence that the microdeletion size in sons may be larger than in their fathers. Couples may be told that there is no evidence of any other health consequences of microdeletions.
Autosomal defects with severe phenotypic abnormalities as well as infertility
There are a number of inherited disorders with severe or considerable generalized abnormalities as well as infertility (Table 3). Such patients will be well known to doctors often from childhood and any fertility problem has to be managed in the context of the care of the man as a whole and with consideration of his and his partner's ability to care for a child, should infertility treatment be successful.
Table 3. Less common inherited disorders associated with infertility and other alterations to phenotype
| Disorder | Phenotype | Geneticbasis |
| Prader-Willi syndrome | Obesity, mental retardation | Deletion of 15q12 on paternally inherited chromosome |
| Bardet - Biedle syndrome | Obesity, mental retardation, retinitis pigmentosa, polydactyly | Autosomal recessive 16q21 |
| Cerebellar ataxia and hypogonadotrophic hypogonadism | Eunuchoidism, disturbances of gait and speech | Autosomal recessive |
| Noonan's syndrome | Short stature, webbed neck, cardiac and pulmonary abnormality, cryptorchidism | Autosomal dominant |
| Myotonic dystrophy | Muscle wasting, cataract testicular atrophy | Autosomal dominant 19q13.3 |
| Dominant polycystic kidney disease | Renal cysts, obstruction from epididymal cysts | Autosomal dominant 16p13.3and 4q |
| 5-alpha reductase deficiency | Perineal or scrotal hypospadias, vaginal pouch, immature female phenotype | Autosomal recessive |
Date: 2016-06-12; view: 301
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