2011 Group Project 1

From Embryology
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


Turner Syndrome

Introduction

Figure 1: The arrow indicates the presence of only one X chromosome in Karyotype [1].

Turner Syndrome (TS), named after Henry Hubert Turner who first described the syndrome in his paper in 1938,[2] is one of the most commonly occuring chromosomal disorders. It is caused by a complete or partial X monosomy in some or all cells and occurs in approximately 1 in 2000 live births in females only. The morbidity rate of spontaneous abortions is 10% and only about 1% of fetuses survive to term.

During normal fetal development, each ovary contain as many as 7 million oocytes. The oocytes gradually reduce to 400,000 during menarche, and during menopause fewer than 10,000 remain. However in TS, the ovaries develop normally during embryogenesis but the absence of the second X chromosome leads to an accelerated loss of oocytes, which is complete by the time the infant reaches 2 years of age. Genetically, menopause occurs before menarche and the ovaries are reduced to atrophic fibrous strands, devoid of ova and follicles (streak ovaries). Development of somatic (nongonadal) tissues that gentically resides on the missing or abnormal X chromosome are also severely affected. For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction [3].

The most frequent clinical features of TS are short stature and gonadal dysgenesis. Other features may include coarctation of the aorta, renal anomalies, neck webbing and lymphoedema. People who have TS all vary in their clinical phenotype. In recent years there has been increased interest in TS due to the introduction of growth hormone treatment and there has been marked improvement in the understanding of this condition as advances in molecular genetic techniques occur. However, there is still need for further research as a multidisciplinary approach to treatment is vital in improving the quality of life of girls with Turner Syndrome [4].

Epidemiology

Figure 2: The arrow indicates the presence of only one X chromosome in the karyotype [1].

TS affects about 1 in 2000 live-born females. There are three types of karyotypic abnormalities but the most frequently observed is the entire X chromosome deletion resulting in 45 X karyotype. The remaining third have structural abnormalities of the X chromosomes and two thirds are mosaics, whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder.

The phenotype of TS varies but involves anomalies of the sex chromosome. It could be caused by the limited amount of genetic material in these abnormal chromosomes. TS can be transmitted from mother to daughter, and thus could be described as a heredity linked syndrome [4].

The loss of one of the sex chromosomes in TS, occurs after the zygote has formed or just after the fusion of the gametes. In 70-80% of cases the retained X chromosome is inherited from the mother. In such circumstances it has led to the different phenotypic expression of the genes present on the X chromosome depending if inherited from the maternally or paternally. The morphological differences from those retaining the maternal, compared to retaining the paternal X chromosome, have shown to have a greater incidence of cardiovascular anomalies and neck webbing.

The missing sex chromosome could be either an X or a Y. This has clinical implications because if the Y material is present there is a risk of up to 30% of gonadoblastoma developing in the dysgenetic gonads. This is because the 'gonadoblastoma locus' is located on the Y chromosome which is situated just below the centromere. The inactivation of the abnormal X chromosomes is another cause that primarily affects hypogonadism phenotypically in females. [5].

Etiology

Figure 3: This figure shows the progeny created from normal disjunction (A), and non-disjunction during both Meiosis I (B) and Meiosis II (C).
Causation of TS can be traced back to the stages of sex-cell development. When sex cells divide through a process called meiosis to create gametes, either a haploid egg (for females) or sperm (for males) two divisions occur, Meiosis I and Meiosis II. Meiosis is the main process which helps create the vast genetic diversity within all populations by allowing recombination and random assortment. During Meiosis I homologous chromosomes are separated; following Meiosis I, sister chromatids separate during Meiosis II.[6] If during either stage of Meiosis I or II the homologous chromosomes or sister chromatids, respectively, do not fully separate, a phenomenon can occur called nondisjunction. Nondisjunction causes an uneven distribution of genetic material to each daughter nuclei.[6]
Figure 4: 22 chromosomal egg + 23 chromosomal sperm = 45 chromsomes in zygote instead of normal 46.
When an uneven distribution is such that one of the gametes does not have any of a chromosome, it can combine with another normal gamete to create a fertilized egg with only one chromosome as opposed to the normal two that are found in human cells; this is called a monosomy. When this occurs in the sex chromosomes leaving only a single X chromosome (X0 genotype) TS is created, leaving only 45 chromosomes in the zygote rather than the normal 46.

TS can also be created by partial monosomy or disjunctions, meaning that although a whole X chromosome is not missing, portions of it are not present or are non-functional, rendering the chromosome useless. Any disjunction seems to be completely sporadic and have yet to be attributed to any genetic link. The only thing known for sure is that during conception a portion of or the whole second sex chromosome is not conveyed to the zygote.[7] Because at least one X chromosome is necessary for vital functions, this condition can only be found in females.

Clinical Manifestations

The following are a list of characteristics and diseases which tend to accompany, be caused by, or be related to TS.

Clinical Manifestations Related Image
Physical Attributes
  • congenital malformations (heart, urinary system, face, neck, ears) [8]
  • gonadal dysgenesis (causes oestrogen deficiencies, which can cause infertility) [4]
  • increased risk of fractures [9]
  • low cortical bone mineral density (BMD) [9]
  • middle ear infections [8]
  • premature ovarian failure [4]
  • short/reduced stature [4]
  • webbed neck [10]
Figure 5: An example of neck webbing.
Prone to Develop Autoimmune Conditions
  • alopecia areata [11]
  • coeliac disease (CD) [12]
  • psoriasis [11]
  • thyroiditis [4]
  • type 1 diabetes [4]
Figure 6: An example of a patient with psoriasis on their arm.
Decreased Cognition
  • emotion processing difficulties [13]
  • increased impulsivity [14]
  • low IQ score [14]
  • nonverbal learning disability (slow math calculations)[13]
  • social cognition difficulties [13]
  • visuoperception/visuoconstruction deficit (identifying and locating is difficult due to poor visual working memory) [14]
Increased Risk of
  • cirrhosis of the liver [8]
  • colon and rectal cancers [8]
  • hypothyroidism [15]
  • inflammatory bowel disease [15]
  • morbidity and mortality [4]
  • neurovascular disease [8]
  • osteoporosis [8]
  • ovarian failure [10]
  • renal and gastrointestinal disease [15]
Cardiac Abnormalities (most serious/life threatening medical problems created by TS)
  • absence of portal vein [16]
  • aortic dilatation and dissection [8]
  • arrhythmias [17]
  • arteriosclerosis [10]
  • biscuspid aortic valves [10]
  • coarctation of the aorta [10]
  • hypertension [10]
  • ischemic heart disease [8]
  • prolapsed mitral valve [10]

Diagnostic Procedures

Diagnostic Definition

Figure 7: Variations of the Second X Chromosome in Turner Syndrome

TS is diagnosed through both an evaluation of physical features and by analysis of the second sex chromosome. The two criteria must be met for classification of TS, an abnormality in the second sex chromosome must be found and the abnormality must be found to be expressed somehow in the individual's traits. Hence if physical characteristics are not present even when the cytogenetic criterion is met the patient is not diagnosed as having TS.[18] In TS the second sex chromosome is either:

  • Completely absent (45,X)[19][20]
  • Partially absent[19][20]
  • Forms an isochromosome (isoXq), possessing a long arm duplication (q) and being devoid of a short arm (p)[19]
  • In a ring formation (rX)[19][20]
  • Is devoid of the homeobox gene, SHOX (short stature homeobox), the deletion being prior to the junction between Xp22.2 and Xp22.3[21][18]

Any of these variations of the second sex chromosome may occur with or without cell line mosaicism. TS may be diagnosed prenatally or postnatally, using this genetic diagnostic definition coupled with an appropriate phenotypic evaluation of the individual, as outlined below.[18]

Prenatal Diagnosis

The prenatal diagnostic tool for TS is karyotype screening and testing for phenotype abnormalities. If TS is diagnosed prenatally, karyotype screening and an evaluation of the individual's traits should be conducted again postnatally for confirmation of this diagnosis. TS is frequently diagnosed after karyotype screening during chorionic villous sampling or amniocentesis.[18] The table below outlines various prenatal tests conducted and the indications that may be present in babies with TS. Although these techniques and the indications they reveal may highlight TS signs, they should not be used as sole diagnostic tools.[18]

Technique Turner syndrome indications Image
Ultrasound
Figure 8: Ultrasound Test Showing Nuchal Translucency.
Figure 9: Ultrasound Test Showing Cystic Hygroma.
Maternal serum screening
Figure 10: Maternal Serum Sampling.

Postnatal Diagnosis

In postnatal diagnosis, karyotype investigation is undertaken for the individual. When a female presents with the following clinical findings, explained in table below, it is recommended that chromosomal analysis is undertaken, so that TS may be eliminated[18]:

Age Phenotypic manifestations/indications Image
Baby/infant
  • Oedema of the hands or feet [24]
  • Nuchal folds [24]
  • Cardiac abnormalities for example aortic dilation, bicuspid aortic valve and aortic coarctation [22]
  • Low hairline [24]
  • Low set ears [24]
  • Small mandible [24]
  • Gonadal dysgenesis [22]
Child
  • Short stature with low growth velocity [19]
  • Markedly elevated levels of follicle-stimulating hormone [18]
  • Turned in elbows [18]
  • Nail hypoplasia [18]
  • Hyperconvex uplifted nails [19]
  • Multiple pigmented benign birthmarks/moles [18]
  • Characteristic faecies [24]
  • Short fourth metacarpal [18]
  • High arched palate [18]
  • Extensive and chronic inflammation/infection of the ear [19]
  • Hearing loss [18]
Figure 11: Four-year-old girl with Turner syndrome. Note somewhat broad chest, prominent ears and ptosis, but otherwise normal proportion. There is no pronounced neck webbing or edema.
Adolescent/Adult
  • Absence of breast development by 13 yr of age [18]
  • Pubertal arrest [22]
  • Primary or secondary amenorrhoea[24]
  • Markedly elevated levels of follicle-stimulating hormone [18]
  • Unexplained short stature [22]
  • Renal abnormalities [19]
  • Immune disorders [19]
Figure 12: A Thirty-five-year-old woman with Turner syndrome. Note increased carrying angle of arms, broad flat chest and sexual infantilism, but the lack of pronounced neck webbing or peripheral edema.

Since an absence of the physical signs of puberty and/or growth failure are often seen as normal variations in the population, these possible indications/symptoms of TS may not be further investigated by many clinicians.[25] When karyotyping in order to exclude natural cell variation, a sufficient number of cells should be assessed. Whilst a sample of blood will often reveal TS, an evaluation of a second tissue sample like the skin is recommend.[20] DNA hybridisation or fluorescent in situ hybridisation should be conducted using a Y centromeric or short arm probe to detect for any additional Y or X chromosomal material. If there is any of the Y chromosome present, this may initiate gonadoblastoma development, another primary indicator of TS. Hence the individual should have both a vaginal ultrasonograph and colour Doppler sonograph of their gonads to detect whether any Y chromosome fragments are present. These tests should be repeated regularly to monitor the patient for any malignancy, if a gonadectomy is not undertaken.[19][18]

Treatment

Cardiac Treatment

When patients are confirmed with TS, it is necessary to have a full cardiac evaulation including a physical exam and a echocardiogram. If cardiac abnormalities are found, monitoring by a cardiologist is recommended including regular blood pressure checks [18]. If no abnormalities are found, blood pressure in TS patients is still routinely checked and a follow up cardiac evaulation is recommended for girls around the age of puberty (12-15) [18]. Coarctation of the aorta and hypoplastic left heart are quite often very serious issues which present in infancy[19] which need to be dealt with surgically [24]. Aortic valves which are bicuspid rather than tricuspid are monitored regularly to ensure complications are found before they seriously effect the health of the patient. [19]

Renal care

Renal anomalies such as posteriorly rotated or horseshoe kidneys are assessed via an ultrasound to determine if any further treatment such as surgery or drug treatment is needed. This renal ultrasound is repeated again at the time the patient is handed over from the pediatic doctor to the adult specialist. [19]

Liver function

As abnormal liver function is highly prevelant in the TS community, liver function tests are performed when regular blood tests are performed. This is particularlly important test at the begining of puberty and when patients are transfered from their pediatrican to adult specialist to pick up any changes in liver enzymes, as raised levels may indicate the onset of cirrhosis of the liver[19].

Speech and Feeding difficulties

Many TS patients have trouble with their speech. It is necessary for them to be refered to an Ear, Nose and Throat (ENT) specialist and to a speech therapist to work on improve any speech problems [18]. TS infants also often suffer from feeding difficulties due to dysfunctional tongue movemnts, poor chewing skills and a highly arched palate. The ENT specialist and speech therapist may be able to help with improving chewing skills and settling down any difficulties [19].

Progression of scoliosis on growth hormone treatment

Management of Puberty and Growth

The main treatment for growth and pubertal development is Hormone Replacement Therapy. Growth Hormone is administered to girls with abnormal growth, resulting in postive growth that is consistent with the expected height of the patient. It is administered as early as 2 years of age, but more often in the age group of 9-12 which is in line with the growth spurt that occurs during puberty [18].

Natural oestrogen and progesterone are administered to girls when they reach the age of puberty in early adolescence. The age at which this treatment commences varies between individuals, as does the dosage. The administration of oestrogen will begin the process of puberty in girls affected by TS and it is important that this begins around the same time as her peers [24].The use of oestrogen is often held off if the patient is also undergoing GH treatment so that maximum growth can be achieved, as oestrogen will induce the fusion of the epiphyses and limit longitudinal bone growth [18]. Around 10% of nonmosaic and 20% of mosaic women with TS will have spontaneous menses (periods) and may not need to undergo Hormone Replacement to initiate puberty. Around 2-5% of these women will have the potential to fall pregnant naturally [24].

Appearance

Extreme neck webbing maybe worrying or uncomfortable to women with TS and in some cases plastic surgery such as Z-Plasty is undertaken to fix this problem. Surgery can however, leave scars which may further trouble patients and often advice is given to wear their hair long[19].

Foot problems are common in young girls with TS with short broad feet making it hard to buy and wear convential shoes[19].Also if convex growth of toenails occurs, surgery is conducted so that the woman can wear normal shoes [24]. Referal to a podiatrist is necessary for correct up to date advice on foot care and for shoe fittings[19].

Ongoing Adult Treatment

Closely monitoring the health of TS adults is vital in the reduction of morbidity and mortality. An annual physical evalution should be undertaken which includes, blood pressure, heart auscultation, thyroid function, breast exam, and pap smear[18]. Particular attention needs to be taken in the area of weight and obesity in TS women due to their high risk of developing diabetes, osteoporosis and hypertension. Patients are to be encouraged to have a healthy lifestyle including healthy eating and exercise[18]. Many TS women will need to undergo fertility treatment and in many cases need the assistance of an egg donation to fall pregnant. Counselling throughout this process is recommended as is the referal to a reproductive specialist with the patient feels ready to start a family [19].

Research

Current research

Since there is no preventative or cure, currently mainly research is being conducted into the areas of symptoms, possible treatments and risks involved with TS.

Growth hormone therapy in Turner syndrome: its affect on height, weight and stature.

  • Growth hormone effect on body composition in Turner syndrome.(2011)[26]: The research findings from this paper conclude that people with TS have lower height, higher BMI and higher proportional sitting height and leg length than that of the normal population, no matter whether they undergo hormone replacement therapy or not.
  • Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone.(2011)[27]: This study has concluded that all adults with TS had a similar quality of life regardless of whether they have a higher stature due to undergoing growth hormone replacement therapy or not. It was hypothesised that height differences did not affect quality of life as the individuals seemed to adapt to their own life challenges.
  • Growth hormone treatment for Turner syndrome in Australia reveals that younger age and increased dose interact to improve response.(2011)[28]: The research from this study found that growth hormone therapy works most optimally if given earlier in life and at a high dose in the first year of treatment.
  • Growth hormone treatment before the age of 4 years prevents short stature in young girls with Turner syndrome.(2011)[29]: Another study which confers that the early introduction of growth hormone therapy is most efficacious. However the individual's glucose metabolism should be monitored as the hormones may affect glucose tolerance transiently.

Oestrogen hormone replacement therapy in Turner syndrome: the adequate dosage and its effect on uterine development, breast development, bone mineral density and sexual characteristics.

  • Growth hormone plus childhood low-dose oestrogen in Turner syndrome.(2011)[30]: This study indicates that undergoing both growth hormone and oestrogen therapy together may help increase the efficacy of each (increasing growth in height and pubertal development) more than when they act alone.
  • Oestrogen requirements in girls with Turner syndrome; how low is enough for initiating puberty and uterine development?(2011)[31]: This study assessed the minimal dosage of oestrogen that is required to bring about desired pubertal development in girls with TS.
  • Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels.(2009)[32]: It was found that uterus of women with TS who had undergone oestrogen was underdeveloped, however the exact cause of this needs to be further researched.

Pregnancy and Turner syndrome: evaluation and treatment of risks involved with pregnancy for: the mothers of Turner syndrome babies, for individuals with Turner syndrome and for the babies of individuals with Turner syndrome.

  • Familial occurrence of Turner syndrome: casual event or increased risk?(2011)[33]: This research examined whether there is a higher probability of having a second child with Turner syndrome and concluded that there is evidence in the small cohort that they used of a greater probability. It is suggested that a larger study be conducted to look further into these findings.that
  • Obstetric Outcomes in Women with Turner Karyotype.(2011)[34]: In this study it was found that women with TS had shorter pregnancies than that of a control group, but no other marked difference was observed between the groups.
  • Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of Health experience.(2011)[35]: This paper examined a number of pregnant women with TS, some who incidentally went through puberty even though they had no hormone replacement therapy and another group that had undertaken hormone replacement therapy. Though there were not many complications in either group, the groups were small in number and one mother did have cardiovascular difficulties later on in life. Hence a thorough examination of pregnant TS women should be conducted prior to conception.
  • Turner's syndrome and pregnancy: has the 45,X/47,XXX mosaicism a different prognosis? Own clinical experience and literature review.(2011)[36]: This article assessed the prognosis of pregnant women with TS. They concluded that spontaneous pregnancy increases the risk of the baby having phenotypic and chromosomal abnormalities compared with women having assisted reproductive therapies.

Future research

Future research needs to be conducted in the following areas: to follow up on the suggestions given in the conclusions of current research papers as outlined in the prior section and also into how the care system is functioning for TS individuals as outlined below.

  • Medical Care of Girls with Turner Syndrome: Where are we Lacking?(2011)[37]: This research found that a large proportion (>50%) of people with TS are not given adequate information upon diagnosis or screenings for complications and symptoms. Therefore it is suggested in order to rectify this issue that more education should be given to physicians on the syndrome
  • Standardized multidisciplinary evaluation yields significant previously undiagnosed morbidity in adult women with Turner syndrome.(2011)[38] and Turner's syndrome requires multidisciplinary approach.(2009)[39]: These article evaluate the need for a multidisciplinary approach to treatment of TS. Since the symptoms can be wide ranging and severe, it is difficult but necessary for all of them to be examined in each individual. Hence a greater care plan for individuals should be implemented upon diagnosis.

Related Pages

  • X Chromosome : A more in depth description of the structure and role of the X chromosome.
  • Cell Division - Meiosis & Oocyte Development  : Examination of the process of meiosis and the developing oocyte, will assist in the comprehension of why and how there is and abnormality or absence of the X chromosome.
  • Menstrual Cycle : An abnormal menstrual cycle can often be an indicator of TS, hence this information on the normal menstrual pattern is helpful in understanding more about the symptoms and diagnosis of TS.

Glossary

Alpha-fetoprotein is a protein with an unknown function. It makes up, up to one third of the protein serum levels found in the second trimester of pregnancy and in neural tube defects, these alpha-fetoprotein levels are elevated. [40]
Amniocentesis is a prenatal diagnostic tool. The procedure involves the sampling of amniotic fluid from the amniotic sac using a syringe, that is then tested for a number of abnormalities. [41]
Brachycephaly is a condition where the coronal suture of the skull fuses prematurely. Since the skull is unable to expand any further in the anterior-posterior directions due to this closure, it grows to an abnormal size in in the lateral dimension.[42]
Coarctation of the aorta is an abnormality where the aorta is constricted at one or various sections. This can be caused by genetic and/or environmental factors.[41]
Chorionic villous sampling is a prenatal diagnostic tool which can be used from 7 weeks after fertilisation. It is used to test for a number of chromosomal abnormalities including X-linked and metabolic disorders.[41]
Cystic hygroma is a prenatal abnormality where fluid builds up in the posterior portion of the neck. The body may or may not relieve itself naturally of this accumulation of fluid after birth. [43]
DNA-DNA hybridisation is a technique used to compare the similarities and differences between two sets of genes.[44]
Doppler sonography uses the doppler effect to help image and measure blood flow pattern in the patient.[45]
Estriol is a hormone that is produced in greater amounts during pregnancy especially in the second and third trimester. One of its main functions is to assist with blood flow in the placenta and uterus.[40]
Gametes are reproductive (sex) cells (ie: eggs and sperm) that can unite to form a new cell called a zygote. [6]
Gonadoblastoma is an abnormal proliferation of gonadal cells, that may or may not be malignant.[46]
Haploid is the status of a cell having only a single set of unpaired chromosomes, or half the number of chromosomes contained in typical body cells. [6]
hCG is the abbreviation for human chorionic gonadotropin. It is a hormone that functions in the early stage of pregnancy to maintain the blood supply to the corpus luteum.[40]
Homologous chromosomes are pairs of chromosomes, one each obtained from maternal and paternal gametes. 46 total chromosome complements are within an organism, 22 pairs of which are homologous chromosomes (called autosomes); the other 2 chromosomes are the sex chromosomes. [6]
Hypoplasia is when an organ or tissue is not completely developed.[46]
Inhibin A is a peptide produced by the ovaries and acts to restrain the production of follicle-stimulating hormone.[47]
Karyotype is an individual's set of chromosomes, both their number and appearance.[40]
Meiosis is the specific process of cell division within sex cells which halves the number of chromosomes in the cells through via two cell divisions; this is specific to germ cells only, creating haploid gametes (sex cells) from diploid cells. [48]
Monosomy is a condition wherein a specific chromosome is completely missing within one gamete that combines with a normal gamete to form a zygote; a chromosome has no homologue, or matching chromosome, to pair with. [6]
Mosaicism is when a particular type or all cells of an individual do not have the same genetic makeup. This is caused by a mutation during embryonic cell division.[18]
Nondisjunction is the failure of chromosome pairs to separate entirely during either stage of Meiosis. [48]
Oligohydramnios is a prenatal condition, where there is an insufficient amount of amniotic fluid.[41]
Polyhydramnios is a prenatal condition, where there is an excessive amount of amniotic fluid.[41]
Random assortment is the idea first proposed by Gregor Mendel which states that pairs of alleles independently separate during the formation of gametes. [40]
Recombination is the process which by genetic material is crossed over and switched between two segments of DNA which adds to the genetic diversity of the genome.
SHOX gene is the short stature homeobox gene, that when deficient frequently results in short stature.[21]
Sister chromatids are 2 identical copies of a chromatin that are connected at a position in their center called a centromere. [6]
Ultrasonography is a medical technique that employs ultrasound frequencies to visualise a patient's internal bodily structure.[45]

References

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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