Sex Chromosome Syndromes

Question 1

What is the incidence of Turner Syndrome?

Answer 1

The incidence of Turner syndrome is 1:2000-1:5000 liveborn girls.

95% of Turner conceptuses fail to reach term.

Question 2

What parental factor is Turner syndrome associated with?

Answer 2

Turner syndrome is associated with advanced paternal age and the majority of Turner patients lack the paternal sex chromosome.

Question 3

Is there usually a high recurrence risk with Turner syndrome?

Answer 3

Not usually. Turner syndrome is generally sporadic. However, there are some maternal mosaic individuals or individuals with balanced structural abnormalities that have an increased risk of producing Turner offspring.

Question 4

What individuals will be at risk of a high recurrence risk of having offspring with Turner syndrome?

Answer 4

• Mothers who are mosaic for Turner syndrome

- Individuals with balanced structural abnormalities

Question 5

How does the Turner syndrome phenotype present in the fetus?

Answer 5

• Growth restriction (Interuterine growth retardation (IUGR))
• Excess of fluid gathers at the nape of the neck (cystic hygroma) which can be identified on USS
• Massive lymphadema due to failure of lymphatic drainage. This is usually partially resolved if the fetus survives to term.

Question 6

How does Turner Syndrome present in newborns?

Answer 6

• Small for dates
• Residual lymphadema (excess fluid beneath the skin) of hands and feet. This is residue of the in utero condition
• Nail Hypoplasia (as a result of lymphadema)
• Excess skin at nape of neck

Question 7

How does Tuner syndrome present in childhood?

Answer 7

• Short stature (92%)
• High arched palate (82%)
• Short neck/low hairline (80%)
• Hypoplastic widely spaced nipples (78%)
• Broad chest, cubitus valgus, nail hypoplasia, lymphedema, prominent ears, excess nevi

Question 8

How would Turner syndrome present in a untreated adolescent?

Answer 8

• Short stature (98%)
• Primary amenhorrhea
• Delayed puberty with no secondary sex characteristics

Question 9

Describe the cytogenetics of Turner syndrome. What different chromosomal problems can lead to Turner syndrome?

Answer 9

• 55% of Turner syndrome cases have the classical 45,X karyotype.
• 25% carry 46 chromosomes with 1 normal X chromosome and 1 structurally abnormal X chromosome (about 12-20% of these cases will be 46,X,i(X)(q10) where the second X chromosome is and X chromosome made up of only the long arm of the X.
• At least 15% of cases are Mosaic (if 95% of Turner conceptuses don’t survive to term then it is thought probable that a proportion of those that do survive to term are likely to be undiscovered mosaics). A large proportion of the mosaics carry a numberical mosaicism. They have a 45,X cell line along with a 46,XX cell line and often a 47,XXX cell line. You will also have Tuner syndrome presenting where the second cell line is a 46,XY cell line. The mosaics may also present as structural mosaics such as 45,X in combination with 46,X,i(X)(q10) or incombination with 46,X,+marker.

Question 10

Decribe the types of mosaicism you are likely to see in Turner syndrome.

Answer 10

At least 15% of cases are Mosaic (if 95% of Turner conceptuses don’t survive to term then it is thought probable that a proportion of those that do survive to term are likely to be undiscovered mosaics).

• 45,X/46,XX/47,XXX OR 45,X/46,XY:

A large proportion of the mosaics carry a numberical mosaicism. They have a 45,X cell line along with a 46,XX cell line and often a 47,XXX cell line. You will also have Tuner syndrome presenting where the second cell line is a 46,XY cell line.

• 45,X/46,X,i(X)(q10) OR 45,X/46,X,+mar:

The mosaics may also present as structural mosaics such as 45,X in combination with 46,X,i(X)(q10) or incombination with 46,X,+marker.

Question 11

Describe the features of classic Turner syndrome (the 45,X Karyotype).

Answer 11

• 20-30% have congenital heart malformations
• 33-60% have structural anomalies of the kidneys (single ‘horseshoe’ fused kidney)
• Untreated adult mean height is 4’10”
• Streak ovaries
• Infertile
• No secondary sexual development if left untreated

Question 12

Describe the features that are likely to be found in Turner patients that are numerical mosaics (45,X/46,XX).

Answer 12

• May have a milder phenotype
• May be taller
• May enter puberty spontaneously
• Likely to have secondary amenorrhea/premature menopause rather than primary amenorrhea
• May be fertile/subfertile
• Sometimes with 47,XXX cell line

Question 13

Describe the features that are likely to be found in Turner patients that have a structural mosaicism.

Answer 13

• Patients with a structural mosaicism will always have a 45,X cell line combined with either 46,X,i(X)(q10) OR 46,X,r(X) OR 46,X,del(Xq).
• They may show fewer of the classical Turner features perhaps only with displaying short stature and gonadal dysgenesis.
• The presence of a mitotically unstable abnormality of the X such as an isochromosome or a ring, results in post zygotic generation of the 45,X cell line.

Question 14

What further investigations should be undertaken in cases where a Turner syndrome patient presents with 45,X/46,X,+mar?

Answer 14

Where a Turner syndrome patient presents with a 45,X/46,X,+mar or ring karyotype then the marker or ring should always be investigated to determine whether it is derived from the X or the Y chromosome.

If Y material is present in a phenotypic female patient then there is an elevated risk of gonadoblastoma.

It is currently thought that the gonadoblastoma critical region is located in the proximal Yq. There is a candidate gonadoblastoma gene which is called TSPY.

Mosaics with X-derived rings generally have classical features of Turner syndrome. If XIST is absent on the X-derived marker then they may have a more sever genotype due to failure of X inactivation resulting in funcitonal disomy. Severity of phenotype will be dependent on the genes present. Small markers without XIST may not necessarily effect phenotype.

Question 15

What problems might present if a Turner syndrome patient has a structural mosaicism involving a Y-derived marker or ring chromosome?

Answer 15

If Y material is present in a phenotypic female patient then there is an elevated risk of gonadoblastoma.

It is currently thought that the gonadoblastoma critical region is located in the proximal Yq. There is a candidate gonadoblastoma gene which is called TSPY.

Question 16

In what region of the Y chromosome is the gonadoblastoma critical region thought to be located?

Answer 16

It is currently thought that the gonadoblastoma critical region is located in the proximal Yq. There is a candidate gonadoblastoma gene which is called TSPY.

Question 17

What is the candidate gonadoblastoma gene called?

Answer 17

There is a candidate gonadoblastoma gene which is called TSPY.

Question 18

What problems might present if a Turner syndrome patient has a structural mosaicism involving a X-derived marker or ring chromosome?

Answer 18

Mosaics with X-derived rings generally have classical features of Turner syndrome. If XIST is absent on the X-derived marker then they may have a more sever genotype due to failure of X inactivation resulting in funcitonal disomy. Severity of phenotype will be dependent on the genes present. Small markers without XIST may not necessarily effect phenotype.

Question 19

How is Turner syndrome treated?

Answer 19

• Growth - treatment with growth hormone can give patients an improved final height. The earlier the treatment is started the better the outcome which is one reason it is important to diagnose Turner syndrome as early as possible.
• Puberty can be induced and they can have secondary sex characteristics if they are treated with oestrogen and progesterone at an appropriate age.
• Fertility - Turner syndrome patients are able to carry a pregnancy if they are given appropriate hormone treatment and oocyte donation, gamete or embryo transplant.
• If Y material is present then surgery can be performed to remove streak ovaries because of elevated gonadoblastoma risk

Question 20

What is the incidence of Klinefelter Syndrome?

Answer 20

The incidence of Klinefelter syndrome is about 1 in 500 to 1 in 1000 men.

Question 21

What are the most common karyotypes for Klinefelter syndrome?

Answer 21

The karyotype is usually 47,XXY (the second X is inactivated).

Klinefelter syndrome is often mosaic with 46,XY. Although classical klinefelter patients are usually infertile, mosaic patients may be sub-fertile.

Question 22

What is the common phenotype of Klinfelter patients?

Answer 22

Klinefelyer patients are usually tall with occasional gynaecomastia.

Question 23

Describe the most common clinical presentation of Klinefelter Syndrome (what situations usually lead to Klinefelter syndrome being detected?)

Answer 23

Klinefelter patients usually present to a cytogenetics department as males with fertility problems.

Klinefelter syndrome is occasionally detected in childhood in referrals with mild developmental delay / mild learning difficulties or by chance.

Question 24

What are the clinical features of Klinefelter syndrome?

Answer 24

• Usually taller than average
• Disproportionally long limbs
• 30-50% have gynaecomastia - increased risk of breast carcinoma
• Infertility / Azoospermia (do not produce any sperm)
• I.Q may be reduced relative to sibs (usually still falls within normal range)

In reality most Klinefelter patients have a fairly normal appearance. Gynaecomastia where present is usually not particularly severe. Limbs tend to be long and tall stature is very common. Most Klinefelter individuals are undetected until they present with infertility.

Question 25

What chromosome findings other than Klinefelter syndrome are you likely to find in infertile men?

Answer 25

In patients referred with primary infertility it is always useful to check for sex chromosome mosaicism. Mosaicism for a 45,X cell line with a 46,XY cell line may be detected and in these cases it is important to check the Y chromosome closely for structural abnormalities.

Structural abnormalities of the Y chromosome such as an isodicentric Y chromosome or a ring Y chromosome may be mitotically unstable, which will explain the disappearance of the Y chromosome and the resulting 45,X cell line.

Deletion or disruption of the proximal Yq will disrupt the infertility loci and result in infertility.

Another possible finding in a patient presenting with primary infertility would be a Robertsonian translocation (or other structural chromosome abnormalities, especially involving acrocentrics).

Question 26

In cases where a patient presenting with infertility is detected to be 45,X/46,XY why is it particularly important to check the Y chromosome closely for structural abnormalities?

Answer 26

In patients referred with primary infertility it is always useful to check for sex chromosome mosaicism. Mosaicism for a 45,X cell line with a 46,XY cell line may be detected and in these cases it is important to check the Y chromosome closely for structural abnormalities.

Structural abnormalities of the Y chromosome such as an isodicentric Y chromosome or a ring Y chromosome may be mitotically unstable, which will explain the disappearance of the Y chromosome and the resulting 45,X cell line.

Deletion or disruption of the proximal Yq will disrupt the infertility loci and result in infertility.

Question 27

What is likely to occur if the proximal Yq is disrupted or deleted?

Answer 27

Deletion or disruption of the proximal Yq will disrupt the infertility loci and result in infertility.

Question 28

Describe the 47,XYY chromosome aneuploidy syndrome.

Answer 28

Generally speaking has a very mild clinical manifestation. Incidence is is about 1 in 840 newborns. May be quite tall with prominent glabella (forehead). IQ may be lower than sibs. Speech delay is common.

47,XYY was originally thought to be strongly associated with behavioural problems. These individuals do seem to suffer with hyperactivity and temper tantrums in childhood but for the majority this is not a problem as adults.

47,XYY individuals display normal fertility and no increased risk of chromosome imbalance is observed in offspring.

Question 29

What is the incidence of 47,XYY?

Answer 29

Incidence is is about 1 in 840 newborns.

Question 30

What level of fertility would be expected in a 47,XYY individual?

Answer 30

47,XYY individuals display normal fertility.

Question 31

Would a 47,XYY individual have a greater risk of chromosome imbalance in offspring?

Answer 31

No increased risk of chromosome imbalance is observed in offspring.

Question 32

What is the incidence of 47,XXX?

Answer 32

47,XXX is found in about 1 in 1000 females.

Question 33

Describe the features of 47,XXX individuals.

Answer 33

47,XXX affects about 1 in 1000 females. These individuals essentially have a normal phenotype. They may exhibit mild developmental and motor delay but there is wide variation. There are some reports of there being an increased risk of having XXX daughters and XXY sons.

Question 34

Describe the features associated with the 48,XXXX karyotype.

Answer 34

• The I.Q. is affected as more X chromosomes are added. These females will have mild to moderate mental retardation (I.Q. 30-80).
• They have a normal to tall stature.
• Speech delay
• Downs-like features including upward slanting palpebral fissures, microcephaly, epicanthic folds, midface hypoplasia.
• Menstrual disorders are common.
• May have reduced fertility but when they are fertile their offspring are usually normal.
• Normal survival.
• Additional X chromosomes are maternally derived.

Question 35

In what chromosomal aneuploidy might you observe Downs-like features?

Answer 35

48,XXXX, 49,XXXXX

Question 36

What features are likely to present in individuals with a 49,XXXXX karyotype?

Answer 36

• Moderate to severe mental retardation
• Prenatal onset of growth deficiency
• Microcephaly
• Downs-like features including upward slanting palpebral fissures, low nasal bridge, short neck, congenital hear defects

Question 37

Describe the features you are likely to observe in male patients with 2 extra copies of the X chromosome (48,XXXY).

Answer 37

• They have an I.Q or around 50 (mild to moderate mental retardation)
• Genital hypoplasia (reduced genital size)
• Mild dysmorphisms including coarse facies, flat nose, epicanthic folds, prognathia (enlarged chin)
• Normal height
• Usually additoinal maternal X chromosomes

Question 38

Describe the features you are likely to observe in male patients with 3 extra copies of the X chromosome (49,XXXXY).

Answer 38

• Mean I.Q of about 35 (moderate to severe mental retardation)
• Low birth weight, short stature
• Hypogonadism
• Downs-like features including broad nose, hypertelorism, upward slanting palpebral fissures, epicanthic folds, prognathism

Question 39

True or false? As the number of sex chromosomes increases the severity of the clinical phenotype increases.

Answer 39

True.

Question 40

True or false? If there are two or more X chromosomes all but one will be inactivated.

Answer 40

True.

Question 41

What is the full name of the SHOX gene?

Answer 41

The Short stature homeobox gene.

Question 42

Where is the SHOX gene located?

Answer 42

The SHOX gene is located in the pseudoautosomal region of Xp/Yp.

Question 43

What proof is there that the SHOX gene is associated with short stature?

Answer 43

Complete SHOX gene deletions were detected in patients with idiopathic short stature.

Question 44

The loss of which gene is responsible for the short stature and skeletal abnormalities in Turner syndrome?

Answer 44

It is the loss of the SHOX gene that is thought to be associated with the short stature and skeletal abnormalities displayed in Turner syndrome.

Question 45

Mutations in which gene are associated with Leri-Weill dyschondrosteosis (LWD)?

Answer 45

Mutations in the SHOX gene are associated with Leri-Weill dyschondrosteosis.

Question 46

Describe the features of Leri-Weill dyschondrosteosis.

Answer 46

LWD is a pseudoautosomal dominant disorder and is characterised by disproportionate short stature and characteristic curving of the radius in the arms, known as ‘Madelung deformity’.

Homozygous loss of SHOX results in more severe Langer mesomelic dysplasia (LMD).

Question 47

What does homozygous loss of the SHOX gene result in?

Answer 47

Homozygous loss of SHOX results in more severe Langer mesomelic dysplasia (LMD).

Question 48

Describe the features of Kallmann syndrome.

Answer 48

• Anosmia due to agenesis of the olfactory lobes (transmitting females have partial or complete anosmia).
• Hypogonadism secondary to deficiency of hypothalmic GnRH.
• Mild mental retardation.
• Colour blindness.

Question 49

What are the 2 forms of Kallmann syndrome?

Answer 49

There are 2 forms of Kallmann syndrome:

1) . Autosomal dominant form resulting from loss-of-function mutations in fibroblast growth factor receptor-1 (FGFR1) gene.
2) . Sex linked form due to mutation or deletion of the KAL1 gene - close to the PAR. There is a higher prevalence of the disease in males because KAL1 partially escapes X inactivation.

Question 50

Why is there a higher prevalence of the sex linked form of Kallmann syndrome in males?

Answer 50

There is a higher prevalence of the disease in males because KAL1 partially escapes X inactivation.

Question 51

What gene is associated with the autosomal dominant form of Kallmann syndrome?

Answer 51

Autosomal dominant form results from loss-of-function mutations in fibroblast growth factor receptor-1 (FGFR1) gene.

Question 52

What gene is associated with the sex linked form of Kallmann syndrome?

Answer 52

The sex linked form of Kallmann syndrome results from mutation or deletion of the KAL1 gene - close to the PAR. There is a higher prevalence of the disease in males because KAL1 partially escapes X inactivation.

Question 53

What is the incidence of X linked Icthyosis?

Answer 53

X linked Icthyosis affects about 1 in 2000 to 1 in 6000 male births.

Question 54

Describe the features of X linked Icthyosis

Answer 54

X linked Icthyosis affects about 1 in 2000 to 1 in 6000 male births.

It is characterised by a general scaling of the skin with dark polygonal dark brown scales on the extensor aspects of the limbs.

It is associated with placental steroid sulfatase (STS) deficiency and is a result of the complete or partial deletion of the STS gene mapped to Xp22.3.

Question 55

Where has the STS gene been mapped to?

Answer 55

The STS gene has been mapped to Xp22.3.