Difference between revisions of "2011 Group Project 3"

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One of the most common disorders of sex chromosomes in humans is Klinefelter’s Syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies. Thee chromosomal vbariations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s Syndrome often go through life without being karyotyped, meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. Males born with Klinefelter Syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes. They have increased susceptibility to diabetes, cardiovascular disease and cancer, although it is still unclear why. In around 80% of cases, the karyotype for Klinefelter’s Syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition. The appearance or phenotype of Klinefelter Syndrome often becomes evident after puberty. Prior to puberty, the pituitary gland and gonad function is relatively normal in sufferers<ref><pubmed>21397196</pubmed></ref>. Males with Klinefelter’s syndrome generally have IQs which are 10-15 points lower than the general population. Interestingly, these differences in IQ levels were only minor. There is also a decreased head circumference found in XXY males as opposed to normal karyotype males. As well, males with Klinefelter’s Syndrome generally have delayed speech development<ref><pubmed>7065696</pubmed></ref>. There is also a higher chance that those affected will experience behavioural problems, possibly due to lower IQ levels. The vast majority of males are not diagnosed prenatally with Klinefelter’s Syndrome. In Denmark in particular, only around a quarter of all people are diagnosed with Klinefelter’s Syndrome. A typical male suffering from Klinefelter’s is characterized by abnormally long legs and arm span, feminine-like distribution of adipose tissue including a condition known as gynecomastia, absent or decreased facial and pubic hair as well as small hyalinized testes and a small penis <ref><pubmed>12574191</pubmed></ref>. There has also been an association hypothesized between tooth size and Klinefelter's Syndrome<ref><pubmed>1686171</pubmed></ref>. This could be attributed to a growth gene which may be found in the Y chromosome, as opposed to the X chromosome since females have a smaller crown size than males. Since 47,XXY males have a taller body stature than normal males, it is not a surprise that Klinefelter sufferers have larger tooth sizes. Seizures can typically occur, and when seizures occur in males with Klinefelter's Syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's Syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Below are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's Syndrome, and the incidence of Klinefelter's Syndrome amongst the Danish population.
 
One of the most common disorders of sex chromosomes in humans is Klinefelter’s Syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies. Thee chromosomal vbariations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s Syndrome often go through life without being karyotyped, meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. Males born with Klinefelter Syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes. They have increased susceptibility to diabetes, cardiovascular disease and cancer, although it is still unclear why. In around 80% of cases, the karyotype for Klinefelter’s Syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition. The appearance or phenotype of Klinefelter Syndrome often becomes evident after puberty. Prior to puberty, the pituitary gland and gonad function is relatively normal in sufferers<ref><pubmed>21397196</pubmed></ref>. Males with Klinefelter’s syndrome generally have IQs which are 10-15 points lower than the general population. Interestingly, these differences in IQ levels were only minor. There is also a decreased head circumference found in XXY males as opposed to normal karyotype males. As well, males with Klinefelter’s Syndrome generally have delayed speech development<ref><pubmed>7065696</pubmed></ref>. There is also a higher chance that those affected will experience behavioural problems, possibly due to lower IQ levels. The vast majority of males are not diagnosed prenatally with Klinefelter’s Syndrome. In Denmark in particular, only around a quarter of all people are diagnosed with Klinefelter’s Syndrome. A typical male suffering from Klinefelter’s is characterized by abnormally long legs and arm span, feminine-like distribution of adipose tissue including a condition known as gynecomastia, absent or decreased facial and pubic hair as well as small hyalinized testes and a small penis <ref><pubmed>12574191</pubmed></ref>. There has also been an association hypothesized between tooth size and Klinefelter's Syndrome<ref><pubmed>1686171</pubmed></ref>. This could be attributed to a growth gene which may be found in the Y chromosome, as opposed to the X chromosome since females have a smaller crown size than males. Since 47,XXY males have a taller body stature than normal males, it is not a surprise that Klinefelter sufferers have larger tooth sizes. Seizures can typically occur, and when seizures occur in males with Klinefelter's Syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's Syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Below are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's Syndrome, and the incidence of Klinefelter's Syndrome amongst the Danish population.
 
[[File:Emotional Response to 'cartoon' test Klinefelter Syndrome.png|thumb|center|The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]
 
[[File:Emotional Response to 'cartoon' test Klinefelter Syndrome.png|thumb|center|The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]
[[File:Incidence of Klinefelter Syndrome amongst the Danish population from 1970-2008.png|thumb|center|Danish statistics of Klinefelter Syndrome]]
 
  
 
==Signs and Symptoms==
 
==Signs and Symptoms==

Revision as of 13:37, 9 September 2011

Note - This page is an undergraduate science embryology student group project 2011.
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip


Klinefelter's Syndrome

--Mark Hill 14:36, 8 September 2011 (EST) Good sub-heading structure and overall draft text layout. Some sections very content poor, who was working on Diagnosis and Current Research? In particular where are all the figures???

  • Introduction- you have the content there, but it reads very poorly in structure. You should try and fix this. Remember the introduction is the first thing that people will read. Also good to have some figure to interest the reader. There are also lots of clinical terms that may not be understood by the average undergraduate student.
  • History - There are only 3 worthy features in the history of this disease? You have not done the work here. This should perhaps also be structured as a timeline, bullets date first in bold.
  • Epidemiology - read the first sentence, its not English. The next section also is not very clear. I think this whole section should be looked at again in terms of structure and clarity.
  • Signs and Symptoms - this should illustrate some of these Signs and Symptoms, not the genital features please.
  • Diagnosis - OK this is sort of a description for Karyotyping, but it is not complete or accurate description of the method. Look it up please and fix this.
  • Etiology - this is not a description of non-disjunction, which is what this section should be about.
  • Pathogenesis - first sentence is repetition of previous sections, this should have been fixed by now so that the same content does not appear in multiple sub-headings.
  • Case Study- I don't think you need this section.
  • Other Similar Defects -first identify why they are similar, then explain how you will describe in a table.
  • Current Research - very poor. Who in the group should have done this section?


Introduction

Klinefelter's syndrome is a condition wherein a male has an extra X chromosome. Typically, men and women have two sex chromosomes, women have two X chromosomes (46,XX), while men have an X and Y chromosome (46,XY). '46' refers to the total number of chromosomes present including both autosomes and sex chromosomes. However, men with Klinefelter's syndrome have three sex chromosomes (47,XXY) due to a process known as non-disjunction[1].

In some very rare cases there are two or more extra copies of the X chromosome present (48,XXXY, or 49,XXXXY). This generally results in more prominent clinical features. In approximately 20% of cases, 46,XY/47,XXY mosaicism can occur[2]. This refers to the situation where the extra chromosome is only present in some cells, this is due to errors occurring during mitosis.


Klinefelter's syndrome usually presents with a few standard clinical abnormalities. Affected men can have reduced fertility and hypogonadism. However, a high proportion of affected men may not show any symptoms and the severity of the disorder differs greatly from person to person. It is thought to be one of the most common conditions caused by non-disjunction[3].

This disorder was first described by Harry F. Klinefelter in 1942 [4]. He describes a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis.

History

Klinefelter syndrome was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; gynecomastia (breast development), azoospermia, hyalinised and small testes, absent spermatogenesis, elevated levels of follicle-stimulating hormone (FSH) and hypogonadism. [5] [6]


In 1949, Murray L. Barr and Ewart G. Bertram discovered that patients with Klinefelter’s syndrome had positive sex chromatin material in their epithelial cells, this is normal for females but not in males. [7] It was a dense chromatin mass which they later termed, Barr body. This discovery led to the use of smears of stained buccal mucosal cells which determined whether the infant’s genetic sex matched the phenotypic sex.


The late 1950’s led to a breakthrough in understanding Klinefelter’s syndrome. In 1956, investigations described 7 patients with Klinefelter’s syndrome as a result of the buccal smears that demonstrated Barr bodies (2). However, the cause of the syndrome remained unknown until 1959, when a discovery that a patient with KS had 47 chromosomes, including an extra X chromosome established that the Barr body seen in patients with KS corresponds to an extra X chromosome. [8]


Epidemiology

One of the most common disorders of sex chromosomes in humans is Klinefelter’s Syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males[9]. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies. Thee chromosomal vbariations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s Syndrome often go through life without being karyotyped, meaning that they are left undiagnosed[10]. Males born with Klinefelter Syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes. They have increased susceptibility to diabetes, cardiovascular disease and cancer, although it is still unclear why. In around 80% of cases, the karyotype for Klinefelter’s Syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition. The appearance or phenotype of Klinefelter Syndrome often becomes evident after puberty. Prior to puberty, the pituitary gland and gonad function is relatively normal in sufferers[11]. Males with Klinefelter’s syndrome generally have IQs which are 10-15 points lower than the general population. Interestingly, these differences in IQ levels were only minor. There is also a decreased head circumference found in XXY males as opposed to normal karyotype males. As well, males with Klinefelter’s Syndrome generally have delayed speech development[12]. There is also a higher chance that those affected will experience behavioural problems, possibly due to lower IQ levels. The vast majority of males are not diagnosed prenatally with Klinefelter’s Syndrome. In Denmark in particular, only around a quarter of all people are diagnosed with Klinefelter’s Syndrome. A typical male suffering from Klinefelter’s is characterized by abnormally long legs and arm span, feminine-like distribution of adipose tissue including a condition known as gynecomastia, absent or decreased facial and pubic hair as well as small hyalinized testes and a small penis [13]. There has also been an association hypothesized between tooth size and Klinefelter's Syndrome[14]. This could be attributed to a growth gene which may be found in the Y chromosome, as opposed to the X chromosome since females have a smaller crown size than males. Since 47,XXY males have a taller body stature than normal males, it is not a surprise that Klinefelter sufferers have larger tooth sizes. Seizures can typically occur, and when seizures occur in males with Klinefelter's Syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures[15]. It is very difficult to diagnose a child with Klinefelter's Syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Below are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's Syndrome, and the incidence of Klinefelter's Syndrome amongst the Danish population.

The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men

Signs and Symptoms

Screening is recommended when the following signs of Klinefelter syndrome are observed.

• Infertility

• Delayed speech and language development

• Accelerated growth in height

• Subnormal intelligence or mental retardation (Severity is proportional to the number of extra X chromosomes)

• Behavioral problems or psychological distress


These are the symptoms.

• Small, Firm testes

• Small penis

• Decreased pubic, facial and armpit hair

• Enlarged breast

• Tall physique

• Abnormal body proportions (long limbs and short trunk)


[16] [17]

Diagnosis

Karyotype of leukocytes can be done to diagnosis this condition. Karyotype is a procedure where a sample of blood taken. Leukocytes (white blood cells) are separated from the sample and cultured onto a tissue medium. The chromosomes of these cells are then analyzed for aberrations, additional X chromosomes.

[18]

Etiology

The additional sex chromosome in men with Klinefelter syndrome results from non-disjunction and may result from either a paternal or maternal origin. Klinefelter syndrome usually encompasses the clinical consequences of an XXY karotype. There are other variant karotypes which can occur that can include an additional X chromosome or an additional X and Y chromosome. Men with these karotypes often have often more severe phenotypes with those of the XXY karotype. (1) The additional X chromosome in 47, XXY results sporadically from either meiotic or mitotic non-disjunction in the developing zygote. The possibility of X chromosome non-disjunction increases with advancing maternal age. Each additional X chromosome is associated with an IQ decrease of 15-16 points (2). The physical manifestations of Klinefelter syndrome are predominantly moderate, as the additional X chromosome is usually inactivated. However, the X chromosome is not completely inactivated. As the number of X chromosome increases the phenotypes are more severe (1). 48, XXYY are thought to result from the fertilisation of a normal female oocyte with an aneuploid sperm produced through nondisjunction events in both meiosis 1 and 2 spermatogenesis. With 47, XXY postzygotic nondisjunction may occur in mitosis in 8% of individuals with XXY and 14% with XXX. - Mosaicism occurs in generally 15% of men, with an additional X chromosome. - Developmental and behavioural phenotypes


Pathogenesis

An additional X chromosome in a Klinefelter syndrome patient is acquired through abnormal cellular division. More often the aberrant cell division results when the event of nondisjunction takes place during parental gametogenesis. This is where the homologous chromosome or sister chromatid has failed to separate normally thus making the distribution of genetic content amongst the daughter cell uneven. So the sperm or the egg not only has the normal single sex chromosome but also an extra X chromosome. Apart from nondisjunction, uneven separation during mitosis in the zygote can lead to an extra X chromosome.

As a result of this genetic mutation, the characteristic shrunken testes and the absence of motile sperm of the Klinefelter syndrome can be observed. These symptoms indicate that the seminiferous tubule and sertoli cells have lost its function. This has many consequences, one of which is the decreased inhibin hormone level. This in turn results in the elevation of gonadotropin level, which is the hallmark of Klinefelter syndrome.


Gonadotropin levels increases as a result of low levels of inhibin because it act as a feedback inhibitor on the pituitary gland. However, the elevated gonadotropin level can only be observed during and after puberty. This is shown in a study with prepubertal boys. One group of subjects have an additional X chromosome while the control group did not. By comparing the two groups a difference in the gonadotropin level was not observed.

[19]

Case Study

Management

Androgen Therapy

Androgen therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass[20].

However, this has been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period[21]. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment[22].

Fertility

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate spermatogenesis[23]. There are two main methods used to treat non-obstructive azoospermia, microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in in vitro fertilisation (IVF). It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage[24], and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed[25]. Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present[26][27]

Other Similar Defects

Turner Syndrome 47, XYY 48,XXYY
Turner Syndrome is similar to Klinefelter Syndrome due to the patient having an abnormal karyotype. Women are affected by this condition, as they are only given one X chromosome when affected. It differs from Klinefelter’s, since the men are given an extra X chromosome in Klinefelter’s Syndrome. Girls with Turner Syndrome can lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy[28]. Like Klinefelter’s Syndrome sufferers, the patient is infertile. The phenotype of Turner Syndrome is very variable, in the sense that girls can have the standard symptoms from it as aforementioned, or they can be asymptomatic and blend in with the rest of the population. In embryology, however, the embryo can have a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There can also be puberty delay because of gonadal dysgenesis. As well as all this, there can also be congenital defects of the heart, kidney and autoimmune system [29]. Many women with Turner’s Syndrome have normal intelligence, whereas boys with Klinefelter’s Syndrome have slightly below average intelligence. Some of the symptoms of Klinefelter’s Syndrome and Turner Syndrome are similar, since sufferers of both conditions may have learning difficulties and difficulty with social interaction[30].
Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)
In terms of 47, XYY Syndrome, this is the only chromosomal aneuploidy which is not selected against before birth. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during gametogenesis[31]. A study was conducted into the prolonged P-R intervals of the PQR cycle of the heart. It was found that males with 47, XYY Syndrome had extremely prolonged P-R intervals and there was little other cardiac abnormalities detected, as seen in a male patient. More studies are currently being done to see if this phenomenon is just a coincidence or if it is a symptom of the syndrome[32].
Karyogram of male with 47,XYY Syndrome
48,XXYY was frequently known as another variant of Klinefelter’s Syndrome. Individuals who are afflicted are very aggressive and uncooperative with others around them [33]. Clinically, the signs and symptoms of 48,XXYY are non-specific. Therefore, various symptoms such as tall stature, truncal obesity and skin ulcers can be seen. In some cases, signs of acromegaly have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan[34]. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance[35].
Male with 48,XXYY Syndrome

Current Research

Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI

  • Significance of additional X chromosome on neural systems

Glossary

X and Y chromosomes- X chromosomes come from the female and code for some female characteristics. Y chromosomes come from the male and code for male characteristics. XX is for a female and XY is for a male.

Hypogonadism- Occurs when the sex glands produce little to no hormones.

Gynecomastia- Is the abnormal development of large mammary glands in males which give large breasts.

Spermatogenesis- Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

Azoospermia-Occurs when males have little to no sperm in the semen

Hyalinised-The state of something being hyaline (clear and translucent)

Chromatin-Composed of genetic material that forms chromosomes and is com posed of DNA

buccal mucosal cells- Cells that secrete mucus

Barr bodies-Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

Aneuploidies-Abnormal number of chromosomes

pituitary gland-Endocrine gland that secretes hormones that regulate homeostasis

Karyotype-Number and/or appearances of chromosomes in a eukaryotic cell nucleus

Leukocytes-White blood cells which are cells of the immune system

Gametogenesis- Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

seminiferous tubule- Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

sertoli cells- Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

Gonadotropin- Protein hormones secreted by gonadotrope cells of the pituitary gland.

Dysgenesis- Defective or abnormal development of an organ, especially of the gonads

PQR cycle- Cycle of the heart, the heartbeat is measured as the PQR interval, so it is split into three parts of P, Q and R

P-R intervals- The cycle from P-R of the heartbeat

References

  1. <pubmed>17062147</pubmed>
  2. <pubmed>21397196</pubmed>
  3. <pubmed>17062147</pubmed>
  4. Klinefelter HF, Reifenstein EC & Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone. American Journal of Clinical Dermatology 1942; 2: 615–627.
  5. <pubmed> 17415352 </pubmed>
  6. <pubmed> 21397196 </pubmed>
  7. <pubmed> 15729733</pubmed>
  8. <pubmed> 13632697</pubmed>
  9. <pubmed>17062147</pubmed>
  10. <pubmed>9160389</pubmed>
  11. <pubmed>21397196</pubmed>
  12. <pubmed>7065696</pubmed>
  13. <pubmed>12574191</pubmed>
  14. <pubmed>1686171</pubmed>
  15. <pubmed>20438626</pubmed>
  16. http://www.genome.gov/19519068
  17. http://emedicine.medscape.com/article/945649-clinical#a0217
  18. http://www.genome.gov/19519068
  19. Cynthia M. Smyth, MD; William J. Bremner, MD, PhD Klinefelter Syndrome. Arch Intern Med. 1998;158:1309-1314
  20. <pubmed>20482304</pubmed>
  21. <pubmed>18832949</pubmed>
  22. <pubmed>18832949</pubmed>
  23. <pubmed>11792932</pubmed>
  24. <pubmed>21811543</pubmed>
  25. <pubmed>21716935</pubmed>
  26. <pubmed>11792932</pubmed>
  27. <pubmed>19616796</pubmed>
  28. <pubmed>21454226</pubmed>
  29. <pubmed>21271130</pubmed>
  30. <pubmed>21818630</pubmed>
  31. <pubmed>10545600</pubmed>
  32. <pubmed>537021</pubmed>
  33. <pubmed>15994727</pubmed>
  34. <pubmed>8389624</pubmed>
  35. <pubmed>3714610</pubmed>

2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip