Clinical Aspects of Infertility

Question 1

Give 2 definitions of infertility.

Answer 1

1. The failure to conceive after 12 months (24) of regular unprotected intercourse.
2. The inability to achieve conception or the inability to sustain a pregnancy through to live birth (infecundity).

Question 2

What percentage of couples does infertility affect?

Answer 2

Infertility affects approximately 10-15% of couples.

Question 3

What percentage of infertility remains unexplained?

Answer 3

Infertility remains unexplained in approximately 25-30% of couples after investigations.

Question 4

How can we split up the causes of infertility?

Answer 4

A good way to split up the causes of infertility is into endocrine causes and anatomical causes.

Question 5

What factors in females may cause endocrine abnormalities resulting in infertility?

Answer 5

• Pituitary tumours
• Thyrotoxicosis
• Polycystic ovaries
• Extremes of weight
• Drugs
• Stress
• Premature Ovarian Failure

Question 6

What factors in females may cause anatomical abnormalities resulting in infertility?

Answer 6

• Tubal problems (e.g blockages due to infection etc)
• Problems with the uterine cavity (e.g endometriosis)
• Cervical problems (e.g anti-sperm antibodies caused by infection)
• Congenital absences

Question 7

What factors in males may cause endocrine abnormalities resulting in infertility?

Answer 7

Hormonal problems?

Question 8

What factors in males may cause anatomical abnormalities resulting in infertility?

Answer 8

• Infection
• Sperm Autoimmunity
• Cryptorchidism
• Obstruction
• Torsion / Trauma
• Chemotherapy

Question 9

What are the baseline investigations for male infertility?

Answer 9

Semen analysis (number, motility etc.)

Question 10

What are the baseline investigations for female infertility?

Answer 10

Baseline bloods looking at FSH and LH levels

Question 11

After initial baseline infertility investigations what further investigations may the couple undergo?

Answer 11

• The couple will then be referred to a fertility clinic for further investigations. This will include gathering info from history and examination.
• Hysterosalpingography (HSG) / Laproscopy and dye test which are checking to see if the tubes are physically patent.
• Karyotyping and CFTR testing may be offered if a man presents without any sperm.

Question 12

Approximately what is a normal sperm count?

Answer 12

About 20x10^6/ml is a normal sperm count.

Question 13

What is Azoospermia?

Answer 13

Azoospermia is when there are no sperm present. This may be due to obstruction preventing the sperm from getting into the ejaculate, or it may be that no sperm are actually being produced.

Question 14

What is Oligozoospermia?

Answer 14

Oligozoospermia is when there are very low levels of sperm present (less than 20 million per ml). Severe Oligozoospermia is when there are less than 5 million sperm per ml.

Question 15

What is Asthenozoospermia?

Answer 15

Asthenozoospermia is when less than 50% of sperm have normal motility, or when less than 25% have any motility.

Question 16

What is Teratozoospermia?

Answer 16

Teratozoospermia is when less then 30% of sperm have normal morphology.

Question 17

What can almost 90% of cases of male infertility be put down to?

Answer 17

Abnormalities of one or more of count, motility or morphology are found in almost 90% of infertile males.

Question 18

What are the 3 main options that an ACU may offer?

Answer 18

1. In Vitro Fertilisation
2. Intracytoplasmic sperm injection (ICSI)
3. Preimplantaiton genetic diagnosis

Other options for infertile couples include adoption or sperm/egg donation.

Question 19

If a male presents with oligo- or azoospermia, approximately what percentage will have a chromosomal abnormality?

Answer 19

About 3-13% or males presenting with oligo- or azoospermia will be found to have a chromosomal abnormality.

Question 20

Describe the clinical features of Turner Syndrome.

Answer 20

• Gonadal dysgenesis - streak ovaries, majority fail to enter puberty (primarily ovarian failure) and are infertile. As a female you need the second X-chromosome to maintain your ovaries and without it your ovaries essentially just disappear.
• Physical features include short stature, webbed neck, peripheral oedema at birth.
• Congenital heart defects occur in 15-50%. Most commonly coarctation (narrowing) of the aorta, but also ventricular septal defects.
• Structural renal abnormalities - don’t necessarily cause any problems but may predispose to infections and the like die to horse show kidneys etc.
• Relatively normal intelligence (possibly 10-15 IQ points below average for the rest of their families).
• Autoimmune disease - DM, thyroid
• High-frequency hearing loss
• Increased risk of obesity and cardiovascular disease as they get older.

Question 21

What number of live births does Turner Syndrome occur in?

Answer 21

1 in 2,500 live births.

Question 22

What are the different chromosomal explanations for the occurrence of Turner Syndrome?

Answer 22

• 49% of cases are due to a single X chromosome (45,X).
• 19% is due to mosaicism for a single X chromosome (46,XX/45,X). One cell line with normal XX and one with a single X chromosome.
• 23% of cases due to mosaicism + a structural abnormality of the second X chromosome (having a deletion in the second X chromosome for example) (45,X/46,XX).
• 8% due to a structural abnormality of the second X chromosome (46,XX/46,XX).

Question 23

How may Turner Syndrome present in a fetus during pregnancy?

Answer 23

Often present in the antenatal period due to a raised nuchal translucency - will then go on and have CVS done and identify that the fetus has Turner Syndrome.

May present with congenital heart disease.

Could be coincidental finding after a maternal age CVS/amnio or CVS/amnio for another reason and Turner Syndrome is found during this.

Question 24

Approximately what percentage of 45,X conceptions result in spontaneous miscarriage?

Answer 24

The majority of 45,X conceptions are lost as spontaneous miscarriage. If detected at 12/40 - 65% pregnancy loss before term.

Question 25

At what points may Turner Syndrome be detected?

Answer 25

1. During Pregnancy - Often present in the antenatal period due to a raised nuchal translucency - will then go on and have CVS done and identify that the fetus has Turner Syndrome.

May present with congenital heart disease.

Could be coincidental finding after a maternal age CVS/amnio or CVS/amnio for another reason and Turner Syndrome is found during this.

2. At Birth - may get a baby with swelling of feet and short neck etc.
3. Growth - may pick up that child is not growing and in girls this may indicate Turner Syndrome.
4. Puberty - failure to go into puberty.
5. Infertility - may only pick it up when they try for a baby and are found to be infertile.

Question 26

If a couple have one child with Turner Syndrome already, what is the recurrence risk to the parents?

Answer 26

• In a classical Turner Syndrome case that is 45,X the recurrence risk will be very low and parental samples will not be requested.
• In cases of Turner Syndrome arising due to a structurally abnormal second X we would need to request the maternal karyotype in order to estimate the recurrence risk.

Question 27

For a female with Turner Syndrome what will the risk to her offspring be?

Answer 27

Natural fertility in individuals with Turner Syndrome is rare, but if they have mosaic Turners they can in some cases be fertile. In these cases there is an increased risk of other chromosomal abnormalities, particularly Trisomy 21 and 45,X.

If they have an X rearrangement they may have a very high recurrence risk and it might lead to male fetal loss.

One of the options for Turners females is IVF with donor oocytes. However, Turner females that do get pregnant with donor oocytes have increased risks in pregnancy (e.g. 2% risk of aortic disease) and thus need close monitoring throughout the pregnancy.

Question 28

What kind of structural aberrations in the X chromosome can cause problems leading to Turner Syndrome?

Answer 28

• Deletions in the X chromosome can give different problems. It depends where the break points are as to what effect the deletions sill have.
• Xq deletions usually result in ovarian failure if they involve the critical region. The more proximal the deletion, the more severe it usually is. A very proximal deletion will usually lead to primary amenorrhea and failure to enter puberty. In the case of more distal deletions menarche may occur, but premature ovarian failure (POF) may develop (early menopause).
• For Xp deletions there are certain critical regions such as Xp11 and Xp21. There is the SHOX gene as Xp22.33 and if this is deleted then it can result in short stature and neurological defects. If you get deletion of Xp11 this would lead to primary amenorrhea at 50% - some females would start their periods normally but would still have problems with actual fertility. A different deletion, this time in Xp21, will likely lead to normal menarche and secondary amenorrhea infertility.

Question 29

What can be the effect of Xq deletions in Turners females?

Answer 29

Xq deletions usually result in ovarian failure if they involve the critical region. The more proximal the deletion, the more severe it usually is. A very proximal deletion will usually lead to primary amenorrhea and failure to enter puberty. In the case of more distal deletions menarche may occur, but premature ovarian failure (POF) may develop (early menopause).

Question 30

What can be the effect of proximal Xq deletions in Turners females?

Answer 30

Xq deletions usually result in ovarian failure if they involve the critical region. The more proximal the deletion, the more severe it usually is. A very proximal deletion will usually lead to primary amenorrhea and failure to enter puberty. In the case of more distal deletions menarche may occur, but premature ovarian failure (POF) may develop (early menopause).

Question 31

What can be the effect of distal Xq deletions in Turners females?

Answer 31

Xq deletions usually result in ovarian failure if they involve the critical region. In the case of more distal deletions menarche may occur, but premature ovarian failure (POF) may develop (early menopause).

Question 32

What can be the effect of Xp deletions in Turners females?

Answer 32

For Xp deletions there are certain critical regions such as Xp11 and Xp21. There is the SHOX gene at Xp22.33 and if this is deleted then it can result in short stature and neurological defects. If you get deletion of Xp11 this would lead to primary amenorrhea at 50% - some females would start their periods normally but would still have problems with actual fertility. A different deletion, this time in Xp21, will likely lead to normal menarche and secondary amenorrhea infertility. The resulting phenotype very much depends on where the break points are.

Question 33

What can be the effect of Xp11 deletions in Turners females?

Answer 33

If you get deletion of Xp11 this would lead to primary amenorrhea at 50% - some females would start their periods normally but would still have problems with actual fertility.

Question 34

What can be the effect of Xp21 deletions in Turners females?

Answer 34

An Xp21 deletion will likely lead to normal menarche and secondary amenorrhea infertility.

Question 35

Where is the SHOX gene located and what may be the phenotypic result if it is deleted?

Answer 35

The SHOX gene is located at Xp22.33.

If this region is deleted then it can result in short stature and neurological defects.

Question 36

Describe the features of Klinefleter Syndrome.

Answer 36

Klinefelter Syndrome is the clinical term describing the features that are associated with a 47,XXY karyotype. It is quite common and is estimated to have a prevalence of about 1 in 800. Relatively mild clinical features.

• Tall
• Infertility
• Increased risk of gynaecomastia
• IQ 10-15 points lower than sibs
• Decreased bone mineral density and body hair as a result of low testosterone levels
• Normal lifespan and general health
• Often not diagnosed until adulthood - fertility clinic
• Also coincidental prenatal diagnosis
• Maternal age effect

Question 37

Describe what happens to the testes, testosterone levels and gonadotrophin levels of a Klinefelters individual at puberty.

Answer 37

In Klinfelters individuals boys enter puberty normally. However, following this the testes begin to involute and become small. The testes will then only produce low levels of testosterone which produces some of the stereotypic Klinefelter features.

The low level of testosterone production from the testes is detected by the hyopthalamus by one of the feedback loops in the body and the hypothalamus then stimulated the pituitary glands to produce high levels of gonadotropins (LH and FSH) which are essentially desperately trying to stimulate the testes to produce more testosterone even though they are not able to do so. This is described as Hypertrophic Hypogonadism.

The testes in Klinefelter Syndrome produce very low levels of sperm, or no sperm, that actually get into the ejaculate so men present with azoospermia or oligospermia. It has been argued that if men have oligospermia it is probably the result of a 47,XY mosaic group of cells that is present somewhere in the testes. If you actually do a biopsy of the testes however you can find mature sperm present there and this sperm may be sufficient to enable ICSI. Some studies however have suggested caution with ICSI however because there is evidence of Klinefelter sperm having an increased chance of being XX or XY, thus leading to an increased chance of Klinefelter or Triple X syndrome. Also there is evidence of an increased chance of other aneuploidies in the children of Klinefelter individuals. However, these studies have only being done on sperm or embryos produced from ICSI and IVF. There are relatively few studies looking at the offspring of men with Klinefelter Syndrome and the increased risk of aneuploidy is not absolutely proven at this stage.

Question 38

Are males with Klinefelter Syndrome capable of producing offspring? Explain. Are there any additional risks associated with Klinefelter males producing offspring?

Answer 38

The testes in Klinefelter Syndrome produce very low levels of sperm, or no sperm, that actually get into the ejaculate so men present with azoospermia or oligospermia. It has been argued that if men have oligospermia it is probably the result of a 47,XY mosaic group of cells that is present somewhere in the testes. If you actually do a biopsy of the testes however you can find mature sperm present there and this sperm may be sufficient to enable ICSI. Some studies however have suggested caution with ICSI however because there is evidence of Klinefelter sperm having an increased chance of being XX or XY, thus leading to an increased chance of Klinefelter or Triple X syndrome. Also there is evidence of an increased chance of other aneuploidies in the children of Klinefelter individuals. However, these studies have only being done on sperm or embryos produced from ICSI and IVF. There are relatively few studies looking at the offspring of men with Klinefelter Syndrome and the increased risk of aneuploidy is not absolutely proven at this stage.

Question 39

If a child is found to have Klinefelter Syndrome would this warrant karyotyping the child’s parents?

Answer 39

No. The recurrence risk of Klinefelter Syndrome is less than 1% and therefore parents are not routinely karyotyped.

Question 40

What structural abnormalities in the Y chromosome are known to be implicated in the production of sperm?

Answer 40

It has been recognised that on the long arm of the Y chromosome (Yq) there are a number of loci that are very important for the production of sperm and that deletions in this region can lead to azoospermia. Initially this region was described as the Azoospermia Factor (AZF) Locus. Deletions in this region can lead to either azoospermia or severe oligospermia. It may also be that microdeletions in this region are present that are not able to be detected cytogenetically and as more has been discovered about this region the AZF region has been sub-divided into different regions:

• AZFa region deletion tends to lead to complete absence of germ cells (sertoli-cell-only syndrome)
• With AZFb deletion you tend to get germ cells but there is arrest of maturation at the spermatocyte stage
• AZFc deletion has variable outcomes ranging from sertoli-cell-only syndrome to severe oligozoospermia with all germ cell types present. The most common microdeletion in this region is at Yq11.23 which contains the DAZ multigene family which is important for sperm development.

Question 41

What is the AZF region of the Y chromosome?

Answer 41

It has been recognised that on the long arm of the Y chromosome (Yq) there are a number of loci that are very important for the production of sperm and that deletions in this region can lead to azoospermia.

Initially this region was described as the Azoospermia Factor (AZF) Locus.

Deletions in this region can lead to either azoospermia or severe oligospermia.

It may also be that microdeletions in this region are present that are not able to be detected cytogenetically and as more has been discovered about this region the AZF region has been sub-divided into different regions:

Question 42

What are the 2 regions of the AZF region called?

Answer 42

The AZFa region, the AZFb region, and the AZFc region.

Question 43

What may result when deletion of the AZFa region occurs?

Answer 43

AZFa region deletion tends to lead to complete absence of germ cells (sertoli-cell-only syndrome).

Question 44

What may result when deletion of the AZFa region occurs?

Answer 44

With AZFb deletion you tend to get germ cells but there is arrest of maturation at the spermatocyte stage.

Question 45

What may result when deletion of the AZFc region occurs?

Answer 45

AZFc deletion has variable outcomes ranging from sertoli-cell-only syndrome to severe oligozoospermia with all germ cell types present. The most common microdeletion in this region is at Yq11.23 which contains the DAZ multigene family which is important for sperm development.

Question 46

What is the most common deletion that is observed in the AZFc region?

Answer 46

The most common microdeletion in this region is at Yq11.23 which contains the DAZ multigene family which is important for sperm development.

Question 47

How will a male with an isodicentric Y chromosome phenotypically appear?

Answer 47

If a male has and isodicentric Y chromosome that individual will appear phenotypically as a normal male because the SRY region on the Yp arm is present which is the most important region for determining the male phenotype. However, since the whole of the Yq arm of the Y chromosome which contains the AZF region is not present there will be a complete lack of spermatogenesis.

Question 48

How common are reciprocal autosomal translocations?

Answer 48

They are thought to be fairly common with more than 1 in 100 people carrying them.

Question 49

How may individuals with reciprocal autosomal translocations present?

Answer 49

They may present with infertility. There is a clear link between reciprocal autosomal translocations and primary infertility in males and some literature has suggested that there is also an increase in female infertility.

Question 50

Is it possible to predict whether infertility will arise based on the nature of the reciprocal autosomal translocation?

Answer 50

Infertility is not predictable from the nature of the translocation, however infertility seems more likely with acrocentric translocations. The acrocentrics possibly disturb the integrity of the X-Y bivalents at meiosis because of the differenc ein acrocentrics compared to other chromosomes.

Question 51

What treatments may infertile males who are found to have translocations be offered?

Answer 51

Infertile males who have translocations might be offered ICSI and PGD. PGD can be used to select chromosomally balanced sperm.

Question 52

Other than infertility, how else may reciprocal translocations come to light?

Answer 52

1) . Recurrent Miscarriages - Reciprocal autosomal translocations may also come to light when recurrent miscarriages occur. When a couple have recurrent miscarriages it is counted as significant if they have more than 3 miscarriages (because they are not uncommon in the general pop). On issue is that a female having recurrent early miscarriages would actually present as someone having problems conceiving because she may not know she was miscarrying.
2) . Through contact tracing in family - might get a child born or pregnancy that occurs with congenital anomalies and when that child is karyotyped they are found to have an unbalanced translocation. It is then the job of the genetics department to ‘contact trace’ throught the family (parents, then siblings of the parents and so on) and they would then get referred to their local genetics service.
3) . Coincidental finding in pregnancy after CVS for another condition - e.g. may find something during a karyotype that is offered to the parents at the same time as they are having other testing done - for example if they come in for prenantal CF testing they will usually be offered the option to have karyotyping conducted at the same time. At this point would consider if the translocation was linked to any history of recurrent miscarriage or problems conceiving etc.

Question 53

Describe the main element of the work up that is conducted for a couple found to have a balanced chromosome rearrangement.

Answer 53

We would usually draw up a diagram to depict the possible inheritance patterns of the chromosomes from each parent. From this we would then work out the risk of miscarriage etc. A lot of these unbalanced conceptuses would miscarry early on - however, the possibility is that there will be a viable pregnancy with congenital malformation. What we try and do is come up with a risk figure for this happening. Usually this risk figure falls in the region of 5%-20% depending on the pedigree of the family (if there has already been a child born in that family with that chromosome pattern then you would give them a much higher risk of that chromosome pattern occurring in future). In a lot of families we often find that there is no history of malformations, but a history of miscarriages and in such cases their risk of having a life born child with malformations would be quite low.

In cases of chromosomal translocations you would not expect there to be a long line of miscarriages with no live births. It is important to remember that with miscarriages and infertility there may be more than one contributing factor. Need to keep an open mind even if you have found one possible explanation.

Question 54

If you come across a case where the couple have had a long line of miscarriages and no live births would it be safe to assume that one of them is likely to have a balanced chromosomal rearrangement?

Answer 54

In cases of chromosomal translocations you would not expect there to be a long line of miscarriages with no live births. It is important to remember that with miscarriages and infertility there may be more than one contributing factor. Need to keep an open mind even if you have found one possible explanation.

Question 55

Describe some of the complications associated with X-autosome translocations.

Answer 55

X-autosome translocations are more complicated than standard autosome translocations.

1). Balanced X-autosome translocations. This is complicated by x-inactivation. In a normal individual x-inactivation would be random (i.e. each x-chromosome would be equally likely to be inactivated in each cell). However, if a woman has a balanced x-autosome translocation you will get selection for inactivation of the normal x-chromosome. In the majority of women with this translocation there won’t be an associated phenotype, however, some may have a milder phenotype if selection or skewing is incomplete (you would have a problem if the abnormal x was inactivated because you would be inactivating some of an autosome too!).

If the critical region for POF is involved in the x-autosome translocation then the woman is at risk of gonadal dysgenesis and amenhorrhoea or POF. Quite a large proportion of these women will be infertile (about 50%). Furthermore, if the break point of the translocation disrupts a disease gene, or if the active X contains a mutation in a disease gene (such as in DMD), then the woman may manifest signs of that disease even thought she is technically just a carrier of the disease.

2). Unbalanced X-Autosome translocation - In women again you get skewed inactivation, but this time for selection of inactivation of the X chromosome with the translocation. This inactivation spreads onto the autosome sections. Essentially it is cancelling out the effect of having an extra bit of autosome stuck on your X and so you get a much milder than expected phenotype as a result of the selective X-inactivation.

Question 56

Describe the issues that may arise due to a balanced X-autosome translocation in a female.

Answer 56

1). Balanced X-autosome translocations - This is complicated by x-inactivation. In a normal individual x-inactivation would be random (i.e. each x-chromosome would be equally likely to be inactivated in each cell). However, if a woman has a balanced x-autosome translocation you will get selection for inactivation of the normal x-chromosome. In the majority of women with this translocation there won’t be an associated phenotype, however, some may have a milder phenotype if selection or skewing is incomplete (you would have a problem if the abnormal x was inactivated because you would be inactivating some of an autosome too!).

If the critical region for POF is involved in the x-autosome translocation then the woman is at risk of gonadal dysgenesis and amenhorrhoea or POF. Quite a large proportion of these women will be infertile (about 50%). Furthermore, if the break point of the translocation disrupts a disease gene, or if the active X contains a mutation in a disease gene (such as in DMD), then the woman may manifest signs of that disease even thought she is technically just a carrier of the disease.

3). The situation with men who have X-autosome translocations is simpler. They are almost invariably infertile as a result of spermatogenic arrest (although occasionally some immature spermatocytes may be found).

Question 57

Describe the issues that may arise due to an unbalanced X-autosome translocation in a female.

Answer 57

2). Unbalanced X-Autosome translocation - In women again you get skewed inactivation, but this time for selection of inactivation of the X chromosome with the translocation. This inactivation spreads onto the autosome sections. Essentially it is cancelling out the effect of having an extra bit of autosome stuck on your X and so you get a much milder than expected phenotype as a result of the selective X-inactivation.

Question 58

Describe the situation for men who have an X-autosome imbalance.

Answer 58

The situation with men who have X-autosome translocations is simpler. They are almost invariably infertile as a result of spermatogenic arrest (although occasionally some immature spermatocytes may be found).

Question 59

What structural aberrations may be associated with infertility other than translocations?

Answer 59

1) . Inversions - in rare occasions carriers may be infertile (particularly if it is males that have the inversions - this is due to a disruption of meiosis causing a problem with the spermatogenesis).
2) . Robertsonian Translocations - Can be associated with recurrent miscarriage and, depending on which chromosome it is, abnormal outcomes in the pregnancy. They can be associated with male infertility occasionally female infertility. IVF, ICSI and PGD may be an option for these couples.
3) . Complex rearrangements. -can be associated with sub-fertility and infertility, particularly in males. This is particularly the case if acrocentric chromosomes are involved. Also, ring chromosomes can be associated with problems with spermatogenesis in males.

The overall take home message is that spermatogenesis is just not as robust as oogenesis so it is usually the males who are affected with the infertility rather than the females in these cases.

Question 60

Describe what effects inversions may have on fertility.

Answer 60

1). Inversions - in rare occasions carriers may be infertile (particularly if it is males that have the inversions - this is due to a disruption of meiosis causing a problem with the spermatogenesis).

Question 61

Describe what effects Robertsonian Translocations may have on fertility.

Answer 61

2). Robertsonian Translocations - Can be associated with recurrent miscarriage and, depending on which chromosome it is, abnormal outcomes in the pregnancy. They can be associated with male infertility occasionally female infertility. IVF, ICSI and PGD may be an option for these couples.

Question 62

Describe what effects complex rearrangements may have on fertility.

Answer 62

3). Complex rearrangements. -can be associated with sub-fertility and infertility, particularly in males. This is particularly the case if acrocentric chromosomes are involved. Also, ring chromosomes can be associated with problems with spermatogenesis in males.

Question 63

Which is more robust, oogenesis or spermatogenesis?

Answer 63

Spermatogenesis is just not as robust as oogenesis so it is usually the males who are affected with the infertility rather than the females in these cases.

Question 64

What is CBVAD?

Answer 64

Congenital Bilateral Absence of the Vas Deferens.

Question 65

What is the Vas Deferens?

Answer 65

The Vas Deferens is the tube that runs from the testes and carries the sperm out so that they are present in the ejaculate.

Question 66

What patients would you usually expect to see CBAVD in?

Answer 66

You get CBAVD in men with Cystic Fibrosis. More than 95% of men with Cystic Fibrosis are infertile as a result of this condition. If both Vas Deferens are blocked the sperm cannot exit the testes to be present in the ejaculate even if they are being produced normally in the testes.

Question 67

How does CBAVD result in male infertility?

Answer 67

If both Vas Deferens are blocked the sperm cannot exit the testes to be present in the ejaculate even if they are being produced normally in the testes.

Question 68

Would you expect all men with CBAVD to present with other symptoms of Cystic Fibrosis?

Answer 68

CBAVD can also present in males without other features of cystic fibrosis, but more than half of these men are found to have mutations in the CFTR gene on testing.

Question 69

What Cystic Fibrosis alleles are most likely to be seen in males with infertility due to CBAVD but no other symptoms of Cystic Fibrosis?

Answer 69

Compared to men with traditional Cystic Fibrosis, males with CBAVD only are more likely to present with partially functional CF alleles such as R117H and 5T. It is thought that having one copy of the gene partially functioning is enough to protect them from many of the features of CF.

Question 70

Are males with CBAVD who have partially functional CF alleles considered to have Cystic Fibrosis?

Answer 70

Although not traditional CF, these males are sometimes considered to have a mild form of CF or CF-related disease. Some of these men have mild respiratory and digestive problems in addition to CBAVD - may get adult onset asthma.

Question 71

How does infertility due to CBAVD related to CFTR mutations arise?

Answer 71

CBAVD in these patients occurs because the mucus in the male genital tract is more thick and sticky than usual, which clogs up the vas deferens as they are developing.

Question 72

What is Kallmann Syndrome?

Answer 72

Kallmann syndrome is a single gene cause of infertility. It is the association of isolated gonadotrophin-releasing hormone deficiency leading to hypogonadism and therefore lack of sexual maturation. It is also associated with anosmia.

Question 73

List some of the single gene causes of infertility.

Answer 73

1) . Cystic Fibrosis
2) . Kallmann Syndrome
3) . Myotonic Dystrophy
4) . Fragile X Syndrome
5) . Primary Ciliary Dyskenesia
6. ) Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Question 74

Describe Kallmann Syndrome.

Answer 74

Kallmann syndrome is a single gene cause of infertility. It is the association of isolated gonadotrophin-releasing hormone deficiency leading to hypogonadism and therefore lack of sexual maturation. It is also associated with anosmia.

Kallmann Syndrome affects more males than females (1 in 8,000 males compared to 1 in 40,000 females).

It is usually a sporadic condition with only one individual in the family affected, but it can be AD, AR or X-linked.

Individuals affected with Kallmann Syndrome are also known to display other features such as synkinesia (missor movements).

The X-linked type of Kallmann Syndrome is usually linked to mutations in a gene called KAL-1 which encodes a protein called Anosmin 1 which is involved in the embryonic migration of the neurones which synthesis gonadotrophin-releasing hormone and also cause a lack of differentiation of the olfactory bulbs.

The 6 or 7 genes that have so far been identified to be involved in Kallmann Syndrome only account for about 25-35% of cases. This makes Kallmann Syndrome a very difficult condition to council for with regards to recurrence risk etc.

Kallmann Syndrome can be treated with hormone therapy and gonadotrophin therapy and it is possible to essentially treat the infertility. You can induce spermatogenesis by treating with gonadotrophin-releasing hormone.

Question 75

What is the incidence of Kallmann Syndrome in males and females?

Answer 75

Kallmann Syndrome affects more males than females (1 in 8,000 males compared to 1 in 40,000 females).

Question 76

What mode of inheritance does Kallmann Syndrome follow?

Answer 76

It is usually a sporadic condition with only one individual in the family affected, but it can be AD, AR or X-linked.

Question 77

How does Kallmann Syndrome result in infertility?

Answer 77

Essentially, a gene defect leads to gonadotrophin-releasing hormone deficiency which results in hypogonadism and lack of sexual maturity and thus a lack of fertility.

Question 78

What are some of the other features associated with Kallmann Syndrome other than infertility?

Answer 78

• Anosmia

- Synkinesia (mirror movements)

Question 79

What gene is usually associated with the X-linked form of Kallmann Syndrome?

Answer 79

The X-linked type of Kallmann Syndrome is usually linked to mutations in a gene called KAL-1 which encodes a protein called Anosmin 1 which is involved in the embryonic migration of the neurones which synthesis gonadotrophin-releasing hormone and also cause a lack of differentiation of the olfactory bulbs.

Question 80

Why can Kallmann Syndrome be particularly difficult to council for?

Answer 80

The 6 or 7 genes that have so far been identified to be involved in Kallmann Syndrome only account for about 25-35% of cases. This makes Kallmann Syndrome a very difficult condition to council for with regards to recurrence risk etc.

Question 81

How can Kallmann Syndrome be treated?

Answer 81

Kallmann Syndrome can be treated with hormone therapy and gonadotrophin therapy and it is possible to essentially treat the infertility. You can induce spermatogenesis by treating with gonadotrophin-releasing hormone.

Question 82

Describe Myotonic Dystrophy?

Answer 82

Myotonic Dystrophy is a condition that can lead to infertility in both males and females.

Myotonic Dystrophy is a particular type of muscular dystrophy where individuals get myotonia. This essentially means that they are unable to relax their muscles.

The classical phenotype of Myotonic Dystrophy is one where you shake hands with a patient and they are very slow to release your grip (this is classically how they are said to be diagnosed). There is actually a spectrum in the condition in that the most mildly affected people can present only with cataracts, then you get the classical adult phenotype where individuals have frontal balding and conduction defects in the heart (which has implications if they are going to have anaesthetics etc.), also have an increased risk of diabetes. Next there is the child phenotype where a child will present with learning difficulties, myopathic facial features. The most severe phenotype is the congenital myotonic dystrophy phenotype. Most babies with the congenital Myotonic Dystrophy phenotype don’t survive because they have severe respiratory problems in the neonatal period.

The size of the repeat expansion is directly correlated to the phenotype observed in the individual (fewer repeats = milder phenotype).

In terms of Myotonic Dystrophy related infertility, it can affect both males and females. There is not a lot known about the reasons for which the infertility occurs. In men it is thought to be a combination of gonadal atrophy causing reduced fertility. Females may get POF, have a higher miscarriage rate (reasons unclear) and when they do get pregnant they have a higher risk of obstetric problems (such as premature babies, failure to progress and post partum haemorrhages).

Question 83

Describe the phenotypes related to the different types of Myotonic Dystrophy.

Answer 83

The classical phenotype of Myotonic Dystrophy is one where you shake hands with a patient and they are very slow to release your grip (this is classically how they are said to be diagnosed).

There is actually a spectrum in the condition:

1) . Most mildly affected people can present only with cataracts.
2) . Then you get the classical adult phenotype where individuals have frontal balding and conduction defects in the heart (which has implications if they are going to have anaesthetics etc.), also have an increased risk of diabetes.
3) . Next there is the child phenotype where a child will present with learning difficulties, myopathic facial features.
4) . The most severe phenotype is the congenital myotonic dystrophy phenotype. Most babies with the congenital Myotonic Dystrophy phenotype don’t survive because they have severe respiratory problems in the neonatal period.

Question 84

What are the 4 different severities of Myotonic dystrophy? How does repeat expansion size link to the severity of Myotonic Dystrophy?

Answer 84

1) . Mild
2) . Adult Type
3) . Child Type
4) . Congenital Type

The longer the repeat expansion, the more sever the myotonic dystrophy phenotype that results.

Question 85

How does infertility relating to Myotonic Dystrophy occur?

Answer 85

In terms of Myotonic Dystrophy related infertility, it can affect both males and females. There is not a lot known about the reasons for which the infertility occurs. In men it is thought to be a combination of gonadal atrophy causing reduced fertility. Females may get POF, have a higher miscarriage rate (reasons unclear) and when they do get pregnant they have a higher risk of obstetric problems (such as premature babies, failure to progress and post partum haemorrhages).

Question 86

What is Fragile X Syndrome?

Answer 86

Fragile X Syndrome is the most common cause of inherited mental retardation.

It is and X-linked learning disability.

It can be quite difficult to pick up features of this condition, as classically the phenotype evolves after puberty with a triad of typical facies, mental retardation and macro-orchidism.

The prevalence of Fragile X Syndrome is 1 in 5,500 males. It is found in 4-8% of boys with an IQ of 35-70.

Fragile X syndrome is caused by an expansion of a CGG repeat of 5’ UTR of FMR1 within exon 1 which is non-coding.

Question 87

What is the prevalence of Fragile X Syndrome?

Answer 87

The prevalence of Fragile X Syndrome is 1 in 5,500 males. It is found in 4-8% of boys with an IQ of 35-70.

Question 88

What is the cause of Fragile X Syndrome?

Answer 88

Fragile X syndrome is caused by an expansion of a CGG repeat of 5’ UTR of FMR1 within exon 1 which is non-coding.

Question 89

What are the main features of Fragile X Syndrome?

Answer 89

Fragile X Syndrome is the most common cause of inherited mental retardation.

It is and X-linked learning disability.

It can be quite difficult to pick up features of this condition, as classically the phenotype evolves after puberty with a triad of typical facies, mental retardation and macro-orchidism.

Question 90

Summarise the impacts of trinucleotide repeats of different sizes with regards to Fragile X Syndrome.

Answer 90

200 repeats = Full Mutation (FM). Methylation of the FMR1 gene. All males will have learning difficulties, as will around 50% of females.

These boundaries are not distinct, they are just general sizes that are given.

Question 91

What is Premature Ovarian Failure (POF)?

Answer 91

POF can be linked to Fragile X Syndrome. POF is classified as the cessation of menses before the age of 40 (in the general population the average age of the menopause is 51). In the general population about 1% of women experience early menopause, but if you are a premutation carrier for Fragile X then you have a risk of about 1 in 5 (21%) of having POF and early menopause.

6.5% of women with POF are found to have a premutation in FMR1 when tested.

13% of women with a family history of POF will have a premutation in FMR1, compared to 3% of women who have an individual history of POF but no family history.

Question 92

If you are a female premutation carrier of Fragile X Syndrome, what is your risk of having POF and early menopause?

Answer 92

POF can be linked to Fragile X Syndrome. POF is classified as the cessation of menses before the age of 40 (in the general population the average age of the menopause is 51). In the general population about 1% of women experience early menopause, but if you are a premutation carrier for Fragile X then you have a risk of about 1 in 5 (21%) of having POF and early menopause.

Question 93

What percentage of women with POF are found to have a premutation in FMR1 when tested?

Answer 93

6.5% of women with POF are found to have a premutation in FMR1 when tested.

13% of women with a family history of POF will have a premutation in FMR1, compared to 3% of women who have an individual history of POF but no family history.

Question 94

What other causes may explain premature ovarian failure (POF) other than Fragile X Syndrome?

Answer 94

1) . Variants of Turner Syndrome and X-chromosome rearrangements that can interrupt the critical region for POF.
2) . Rare Syndromes such as BPES and APECED.
3) . A rare autosomal recessive condition where you have mutations in the FSH receptor gene.
4) . Individuals who have survived childhood cancer and been treated with chemotherapy can find that that has affected their ovarian reserve and may also have an early menopause.

Question 95

What is Primary Ciliary Dyskenesia?

Answer 95

Primary ciliary dyskenesia is a problem with the cilia in the body, which are important for a huge array of processes in the body beginning at embryo development (important for the embryo being able to know which side is right and which is left). Lack of cilia during embryo development can lead to Situs inversus (heart ends up on the wrong side of the chest, other organs on wrong side).

In normal cilia you have dyenin arms, but in individuals affected with primary ciliary dyskenesia the dyenin arms are absent and so essentially the cilia don’t work as well as they should. This is diagnosed by performing a biopsy of the respiratory epithelium, usually by nasal brushings and then looking at the cilia structure down the microscope.

Primary ciliary dyskenesia may also be known as immotile cilia syndrome, or Kartageners syndrome.

Primary ciliary dyskenesia also has other features that are clinically important. The presentation of the condition is slightly like Cystic Fibrosis because people who do not have cilia going through their respiratory tract are not able to cough as effectively and clear the mucus from their lungs. They therefore end up with chronic pulmonary infections and bronchiectasis (large pools of infections in the lungs). Ear infections and sinusitis are also very common with primary ciliary dyskenesia.

Primary ciliary dyskenesia is an autosomal recessive condition. It is associated with 8-12 genes currently, but we still only identify mutations in about 40% of individuals with the condition tested. Must be other associated genes yet to be identified.

The reason primary ciliary dyskenesia is relevant in terms of infertility is because the flagella, the tail of the sperm, is effectively a cilia. Therefore in individuals affected by primary ciliary dyskenesia the sperm are not able to move as well as they should. Approximately 50% of males with primary ciliary dyskenesia are infertile. Females with this condition can also be infertile due to impaired ciliary function of the oviduct. However, the infertility is less of an issue with females.

Question 96

What is wrong with the cilia in primary ciliary dyskenesia?

Answer 96

In normal cilia you have dyenin arms, but in individuals affected with primary ciliary dyskenesia the dyenin arms are absent and so essentially the cilia don’t work as well as they should. This is diagnosed by performing a biopsy of the respiratory epithelium, usually by nasal brushings and then looking at the cilia structure down the microscope.

Question 97

By what other names is primary ciliary dyskenesia known?

Answer 97

Primary ciliary dyskenesia may also be known as immotile cilia syndrome, or Kartageners syndrome.

Question 98

What are the main clinically important features of primary ciliary dyskenesia?

Answer 98

Primary ciliary dyskenesia also has other features that are clinically important. The presentation of the condition is slightly like Cystic Fibrosis because people who do not have cilia going through their respiratory tract are not able to cough as effectively and clear the mucus from their lungs. They therefore end up with chronic pulmonary infections and bronchiectasis (large pools of infections in the lungs). Ear infections and sinusitis are also very common with primary ciliary dyskenesia.

Question 99

What mode of inheritance does primary ciliary dyskenesia follow?

Answer 99

Primary ciliary dyskenesia is an autosomal recessive condition. It is associated with 8-12 genes currently, but we still only identify mutations in about 40% of individuals with the condition tested. Must be other associated genes yet to be identified.

Question 100

How can primary ciliary dyskenesia lead to infertility?

Answer 100

The reason primary ciliary dyskenesia is relevant in terms of infertility is because the flagella, the tail of the sperm, is effectively a cilia. Therefore in individuals affected by primary ciliary dyskenesia the sperm are not able to move as well as they should. Approximately 50% of males with primary ciliary dyskenesia are infertile. Females with this condition can also be infertile due to impaired ciliary function of the oviduct. However, the infertility is less of an issue with females.

Question 101

What is Autosomal Dominant Polycystic Kidney Disease (ADPKD)?

Answer 101

A condition where the individual develops numerous cysts on their kidney. It is the kidneys that cause the main problems with this condition, but they can also get cysts in the liver and the pancreas also.

We also know that ADPKD can affect fertility in males. Males can present with seminal vesicle cysts, however, these cysts are no longer thought to be the actual cause of the infertility. It is no thought that the problem is more likely due to defects in sperm motility.

Question 102

How does Autosomal Dominant Polycystic Kidney Disease (ADPKD) affect fertility in males?

Answer 102

ADPKD can affect fertility in males. Males can present with seminal vesicle cysts, however, these cysts are no longer thought to be the actual cause of the infertility. It is no thought that the problem is more likely due to defects in sperm motility.

Question 103

List some single gene causes of infertility.

Answer 103

CF,
Fragile X,
Myotonic dystrophy,
Kalmann syndrome,
Primary ciliary dyskinesia,
Autosomal dominant polycystic ovary disease.