chromosomal disorders
TRANSCRIPT
CHROMOSOMAL DISORDERS
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Chromosome abnormality
Chromosome abnormality◦ A chromosome anomaly, abnormality, aberration, or mutation is a missing,
extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes.
◦ A karyotype refers to a full set of chromosomes from an individual which can be compared to a "normal" karyotype for the species via genetic testing.
◦ A chromosome anomaly may be detected or confirmed in this manner. Chromosome anomalies usually occur when there is an error in celldivision following meiosis or mitosis.
◦ There are many types of chromosome anomalies. They can be organized into two basic groups, numerical and structural anomalies
Numerical disorders
◦ This is called aneuploidy (an abnormal number of chromosomes), and occurs when an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy, tetrasomy, etc.).
◦ In humans an example of a condition caused by a numerical anomaly is Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). Trisomy has been determined to be a function of maternal age.
◦ An example of monosomy is Turner Syndrome, where the individual is born with only one sex chromosome, an X.
Structural abnormalities
◦Deletions: A portion of the chromosome is missing or deleted. Known disorders in humans include Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q deletion disorder.
◦Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Known human disorders include Charcot-Marie-Tooth disease type 1A which may be caused by duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17.
Structural abnormalities◦ Translocations: A portion of one chromosome is transferred to another chromosome.
There are two main types of translocations:◦ Reciprocal translocation: Segments from two different chromosomes have been exchanged.◦ Robertsonian translocation: An entire chromosome has attached to another at the
centromere - in humans these only occur with chromosomes 13, 14, 15, 21 and 22.
◦ Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted.
◦ Insertions: A portion of one chromosome has been deleted from its normal place and inserted into another chromosome.
Structural abnormalities
◦ Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.
◦ Isochromosome: Formed by the mirror image copy of a chromosome segment including the centromere.
◦ Chromosome instability syndromes are a group of disorders characterized by chromosomal instability and breakage. They often lead to an increased tendency to develop certain types of malignancies.
Inheritance
◦Most chromosome abnormalities occur as an accident in the egg or sperm, and therefore the anomaly is present in every cell of the body. Some anomalies, however, can happen after conception, resulting in Mosaicism (where some cells have the anomaly and some do not).
◦ Chromosome anomalies can be inherited from a parent or be "de novo". This is why chromosome studies are often performed on parents when a child is found to have an anomaly.
◦ If the parents do not possess the abnormality it was not initially inherited; however it may be transmitted to subsequent generations.
Cri du chat
Cri du chat
◦Cri du chat syndrome, also known as chromosome 5p deletion syndrome, 5p- (said minus) syndrome or Lejeune’s syndrome, is a rare genetic disorder due to a missing part (deletion) of chromosome 5.
◦ Its name is a French term (cat-cry or call of the cat) referring to the characteristic cat-like cry of affected children. It was first described by Jérôme Lejeune in 1963.
◦ The condition affects an estimated 1 in 50,000 live births, strikes all ethnicities, and is more common in females by a 4:3 ratio.
Signs and symptoms
◦ The syndrome gets its name from the characteristic cry of affected infants, which is similar to that of a meowing kitten, due to problems with the larynx and nervous system. About 1/3 of children lose the cry by age 2. Other symptoms of cri du chat syndrome may include:
Signs and symptoms◦ feeding problems because of difficulty swallowing and sucking;
◦ low birth weight and poor growth;
◦ severe cognitive, speech, and motor delays;
◦ behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements;
◦ unusual facial features which may change over time;
Signs and symptoms◦ excessive drooling;
◦ small head and jaw;
◦wide eyes;
◦ skin tags in front of eyes.
Genetics
◦ Cri du chat syndrome is due to a partial deletion of the short arm of chromosome number 5, also called "5p monosomy".
◦ Approximately 90% of cases result from a sporadic, or randomly occurring, de novo deletion. The remaining 10-15% are due to unequal segregation of a parental balanced translocation where the 5p monosomy is often accompanied by a trisomic portion of the genome.
◦ These individuals may have more severe disease than those with isolated monosomy of 5p. A recent study suggests this may not be the case where a trisomy of chromosome 4q is involved.
Genetics◦Most cases involve total loss of the most distant 10-20% of the material on the
short arm. Fewer than 10% of cases have other rare cytogenetic aberrations (e.g., interstitial deletions,mosaicisms, rings and de novo translocations). The deleted chromosome 5 is paternal in origin in about 80% of de novo cases.
◦ Loss of a small region in band 5p15.2 (cri du chat critical region) correlates with all the clinical features of the syndrome with the exception of the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition's etiology. Two genes in these regions, Semaphorine F (SEMA5A) and delta catenin (CTNND2), are potentially involved in cerebral development.
◦ The deletion of the telomerase reverse transcriptase (hTERT) gene localized in 5p15.33 may contribute to the phenotypic changes in cri du chat syndrome as well.
Diagnosis and management
◦Diagnosis is based on the distinctive cry and accompanying physical problems. Seeing as these symptoms are quite easily observable, affected children are typically diagnosed by a doctor or nurse at birth.
◦Genetic counseling and genetic testing may be offered to families with individuals who have cri du chat syndrome. Prenatally the deletion of the cri du chat related region in the p arm of chromosome 5 can be detected from amniotic fluid or chorionic villi samples with BACs-on-Beads technology.G-banded karyotype of a carrier is also useful.
◦ Children may be treated by speech, sound, and occupational therapists. Cardiac abnormalities often require surgical correction.
Down syndrome
◦Down syndrome (DS) or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy ofchromosome 21.
◦ It is typically associated with physical growth delays, characteristic facial features and mild to moderate intellectual disability.
◦ The average IQ of a young adult with Down syndrome is around 50, similar to the mental age of an 8 or 9 year old child.[3]
Down syndrome◦Down syndrome can be identified during pregnancy by prenatal screening or after
birth by direct observation and genetic testing. Since the introduction of screening, pregnancies with the diagnosis are often terminated.[4][5] Regular screening for health problems common in Down syndrome is recommended throughout the person's life.
Down syndrome◦ Education and proper care has been shown to improve quality of life.
◦ Some children with Down syndrome are educated in regular school classes while others require more specialized education.
◦ Some children with Down syndrome graduate from high school and in adulthood some individuals work in the community.
◦ The degree of independence possible for an affected individual varies, and some require a more sheltered work environment.
◦ Support in financial and legal matters is often needed.
◦ Life expectancy is around 50 to 60 years in the developed world with proper health care.
Down syndrome◦Down syndrome is the most common chromosome abnormality in
humans occurring in about 1 per 1000 babies born each year.
◦ It is named afterJohn Langdon Down, the British doctor who fully described the syndrome in 1866.
◦ Some aspects of the condition were described earlier by Jean-Étienne Dominique Esquirol in 1838 and Édouard Séguin in 1844.[11] The genetic cause of Down syndrome, an extra copy of chromosome 21, was identified by Dr. Jérôme Lejeune in 1959.[10]
Signs and symptoms
◦ Those with Down syndrome nearly always have physical and mental disabilities.
◦ As adults their mental abilities are typically similar to that of an 8 or 9 year old.
◦ They also typically have poor immune function and developmental milestones generally are reached at a later age.
◦ There is an increased risk of a number of other health problems including: congenital heart disease, leukemia, thyroid disorders, and mental illness, among others.
Signs and symptomsCharacteristics Percentage Characteristics Percentage
Stunted growth 90%[14] Flattened nose 68%[13]
Mental impairment 99%[15] Abnormal teeth 60%[16]
Increased skin back of neck 80%[10] Bent fifth finger tip 57%[13]
Signs and symptoms
Separation of 1st and 2nd toes 68%[16] Umbilical hernia 90%[17]
Flexible ligaments 75%[13] Short neck 60%[16]
Low muscle tone 80%[18] Shortened hands 60%[16]
Flat head 75%[13] Congenital heart disease 40%[16]
Signs and symptoms
Undescended testicles 20%[19] Single transverse palmar crease 53%[13]
Eyelid fold 60%[16] Protruding tongue 47%[16]
Shortened arms and legs 70% Epicanthic fold 59%[13]
Narrow roof of mouth 76%[16] Strabismus ~35%[2]
Abnormal outer ears 70%[10] Brushfield spots in the iris 56%[13]
Physical
◦ They may have some or all of the following physical characteristics: abnormally small chin, slanted eyes, poor muscle tone, a flat nasal bridge, a single crease of the palm, a protruding tongue due to small mouth, and an enlarged tongue.
◦Other common features include: a flat and wide face,there is a short neck, excessive joint flexibility, extra space between big toe and second toe, an abnormal patterns on the fingertops and short fingers.
◦ Instability of the atlanto-axial joint occurs in approximately 20% and may lead to spinal cord injury in 1-2%.
◦ Around half of those with DS haveobstructive sleep apnea.[10] Hip dislocations occur without trauma in an up to a third.
Physical◦Growth in height is slower resulting in adults tending to have short stature—the
average height for men is 154 cm (5 feet 1 inch) and for women is 142 cm (4 feet 8 inches).[20] Individuals with DS are at increased risk for obesity as they age.[10]
There are growth charts specifically for those with Down syndrome.[10]
Neurological
◦Most individuals with Down syndrome have mild (IQ: 50–70) or moderate intellectual disability (IQ: 35–50) with some cases having severe (IQ: 20–35) difficulties.
◦ As they age they typically perform less well compared to their same aged peers.
◦ Some after 30 years of age may lose their ability to speak.
◦ Those with mosaic Down syndrome typically have scores 10–30 points higher. This syndrome causes about a third of cases of intellectual disability.
Neurological◦ Fine motor skills[24] and large scale motor skills are often delayed which can interfere with
cognitive development. Effects of the condition gross motor skills is variable. Some children will begin walking at around 2 years of age, while others will not walk until age four.
◦ Commonly individuals with Down syndrome have some difficulty speaking with better language understanding.]
◦ 10 to 45% have either stuttering or rapid and irregular speech making them difficult to understand.
◦ They typically do fairly well with social skills.
◦ Behavior problems are not geerally as great as an issue as in other syndromes associated with intellectual disability.[
◦ In children with Down syndrome mental illness occurs in nearly 30% with autism occurring in 5-10%.
◦ While generally happy, symptoms of depression and anxiety may develop in early adulthood.
Neurological◦ Commonly individuals with Down syndrome have some difficulty speaking with
better language understanding.10 to 45% have either stuttering or rapid and irregular speech making them difficult to understand.
◦ They typically do fairly well with social skills.
◦ Behavior problems are not generally as great as an issue as in other syndromes associated with intellectual disability.
◦ In children with Down syndrome mental illness occurs in nearly 30% with autism occurring in 5-10%.[9] While generally happy, symptoms of depression and anxiety may develop in early adulthood.[3]
Neurological◦ Children and adults with DS are at increased risk of epileptic seizures which occur in
5-10% of children and up to 50% of adults.
◦ This includes an increased risk of a specific type of seizure called infantile spasms.
◦Many (15%) who live past 40s develop dementia of the Alzheimer's disease type.[Of those who reach 60 years, 50-70% have the disease.[3]
Senses
Brushfield spots, visible in the irises of a baby with Down Syndrome.
Senses◦Hearing and vision disorders occur in more than half of people with DS.
◦ Vision problems occur in 38 to 80%. Between 20 and 50% have strabismus, in which the two eyes do not move in tandem.
◦ Refractive errors requiring glasses or contacts are also common.
◦ Cataracts (opacity of the lens) occur in 15%, and may be present at birth.
◦ Keratoconus (thin, cone-shaped corneas), and glaucoma (increased eye pressures) are also more common.
◦ Brushfield spots (small white or grayish/brown spots on the periphery of the iris) are present in 38 to 85%.
Senses◦Hearing problems are found in 38-78% of children with Down syndrome compared
to 2.5% of normal children.
◦ Diagnosis and aggressive treatment of chronic ear disease (e.g.otitis media) in children with Down syndrome can bring many of the children up to normal hearing levels.
◦ Age related hearing loss of the sensorineural type occurs at a much earlier age affected 10-70%.[3]
Senses◦Otitis media with effusion is the most common cause of hearing loss in children with
Down's occurring in 50-70%.
◦ Ear infections often start at birth and continue throughout the children's life.[28]The ear infections are mainly due to poor eustachian tube function.
◦ However, excessive wax can also cause obstruction of the outer ear canal and hearing problems. Middle ear problems account for 83% of hearing loss in children with Down syndrome.
◦ The degree of hearing loss varies but even a mild degree can have major consequences for speech understanding, language learning, and academics[2] if not detected in time and corrected.
◦ It is important to rule out hearing loss as a contributing factor in social and mental deterioration.
Heart
◦ The rate of congenital heart disease in newborns with Down syndrome is around 40%.
◦ An atrioventricular septal defect also known as endocardial cushion defect is the most common form with up to 40% affected. This is closely followed by ventricular septal defect that affects approximately 35%
◦Mitral valve problems become common as people age, even in those without heart problems at birth.
◦Other problems that may occur include: tetralogy of Fallot and patent ductus arteriosus.
◦ People with Down syndrome have a lower risk of hardening of the arteries.
Cancer
◦ Although the general incidence of cancer amongst individuals with Down syndrome is the same as in the general population,there is a reduced risk of solid cancers and an increased risk of leukemia and testicular cancer. Solid cancers are believed to be less common due to the tumor suppressor genes present on chromosome 21.
Cancer
◦ Cancers of the blood are 10 to 15 times more common in children with DS.
◦ In particular, acute lymphoblastic leukemia is 20 times more common and the megakaryoblastic form of acute myelogenous leukemia is 500 times more common.
◦ Transient myeloproliferative disease, a disorder of blood cell production that does not occur outside of Down syndrome, affects 3-10% of infants.The disorder is typically not serious but occasionally can be.
◦ It resolves most times without treatment; however, in those who have had it there is a 20 to 30 percent risk of developing acute lymphoblastic leukemia at a latter time
Endocrine
◦ Problems of the thyroid gland occur in 20-50%.
◦ Low thyroid is the most common, occurring in almost half of those with DS. Thyroid problems can be due to a poorly or non functioning thyroid at birth (known as congenital hypothyroidism) which occurs in 1%or can develop latter due to an attack on the thyroid by the immune system resulting in Graves disease or autoimmune hypothyroidism.
◦ Type 1 diabetes mellitus is also more common.
Gastrointestinal
◦ Constipation occurs in nearly half of people with DS and may result in changes in behavior.
◦ One potential cause is Hirschsprung's disease, which is due to a lack of nerve cells controlling thecolon, which occurs in 2 to 15%.
◦Other frequent congenital problems include: duodenal atresia, pyloric stenosis, Meckel diverticulum and imperforate anus.
◦ Celiac disease affects about 7-20% and gastroesophageal reflux disease is also more common
Fertility
◦Males with Down syndrome usually do not father children, while females have lower rates of fertility relative those who are unaffected.
◦ Fertility is estimated to be present in 30-50% of women and they often have difficulties with miscarriages, premature births, and labor.
◦Menopause typically occurs at an earlier age.[3] The poor fertility in men is thought to be due to problems with sperm development; however, it may also be related to not being sexually active.
◦ As of 2006 there have been three recorded instances of males with DS fathering children and 26 cases of women having children.Without assisted reproductive technologies, approximately half of the pregnancies of someone with Down syndrome will also have the syndrome.
Genetics
◦Down syndrome is caused by having three copies of the genes on chromosome 21, rather than the usual two.
◦ The parents of the affected individual are typically genetically normal.[ Those who have one child with Down syndrome have about a 1% risk of having a second child with the syndrome, if both parents are found to have normal karyotypes.
Genetics◦ The extra chromosome content can arise through several different mechanisms.
The most common cause (approximately 92-95% of cases) is a complete extra copy of chromosome 21, resulting in trisomy 21.
◦ In 1 to 2.5%, some of the cells in the body are normal and others have trisomy 21, known as mosaic Down syndrome.[41][45] The other common mechanisms that can give rise to Down syndrome include Robertsonian translocation, isochromosomes, ring chromosomee, which contain additional material from chromosome 21. These findings occurs in approximately 2.5% of cases.
◦ Isochromosomes result when the two long arms separate together on one chromosome.
Karyotype◦ Trisomy 21 (also known by the karyotype 47,XX,+21 for males and 47,XY,+21 for
females) is caused by a failure of the chromosomes to separate during egg or sperm development.
◦ As a result, a sperm or egg cell is produced with an extra copy of chromosome 21; this cell thus has 24 chromosomes.
◦When combined with a normal cell from the other parent, the embryo and baby has 47 chromosomes, with three copies of chromosome 21. Trisomy 21 is the cause of approximately 92 to 95% of cases of Down syndrome, with 88% of cases resulting from non separation of the chromosomes in the mother and 8% coming from non separation in the father.
Translocation
◦ The extra chromosome 21 material may also occur due to a Robertsonian translocation in 2-4% cases.This may be a new mutation or previously present in one of the parents.
◦ In this case, the long arm of chromosome 21 is attached to another chromosome, often chromosome 14 known as 45XY,t(14q21q) in males. The risk of this type of Down syndrome is not related to the mothers age.The parent with such a translocation is usually normal physically and mentally
◦ however, during production of egg or sperm cells there is a higher chance of creating reproductive cells with extra chromosome 21 material.This results in a 15% chance of having a child with DS when the mother is affected and a less than 5% risk if the father is affected.[
◦ Additionally some children may inherit this translocation while not have DS but are subsequently at higher risk of having children with DS themselves.
◦ In this case it is sometimes known as familial Down syndrome.
Mechanism
◦ In general, extra chromosome 21 DNA leads to an over-expression of certain genes. This over expression is about 50%.
◦ It is estimated that chromosome 21 contains around 310 genes.]\
◦ Some research has shown that the parts of the chromosome which are of greatest importance are bands 21q22.1-q22.3.
◦ This area includes genes for amyloid, superoxide dismutase, and likely the ETS-2 proto oncogene.
◦Other research has not confirmed these findings.
Mechanism◦ The dementia which occurs in Down syndrome is due to too much
amyloid beta peptides being produced in the brain.
◦ Senile plaques and neurofibrillary tangles are present in nearly all by 35 years of age even though dementia may not be present.
◦ Those with DS lack a normal number of lymphocytes and produce less antibodies which contributes to there increased risk of infection.[10]
Screening
◦Guidelines recommend that screening for Down syndrome be offered to all pregnant women, regardless of age. A number of tests can be used, with varying levels of accuracy. They are usually used in combination to increase their detection rate, while maintaining a low false positive rate, but are not definitive.[10]
◦ If screening is positive either amniocentesis or chorionic villous sampling is required to confirm the diagnosis.
◦ Screening in both the first and second trimesters is better than just screening in the first trimester.
◦ The different screening techniques in use are able to pick up 90 to 95% of cases with a false positive rate of between 2 and 5%.
Ultrasound◦ Enlarged NT and absent nasal bone in a fetus at 11 weeks with Down syndrome
◦Ultrasound imaging can be used to screen for Down syndrome. Finding that increase the risk, when seen at 14 to 24 weeks of gestation include: a small or no nasal bone, large ventricles, nuchal fold thickness, and an abnormal right subclavian artery among others. The presence or absence of many markers is more accurate.
◦ Increased fetal nuchal translucency (NT) indicates an increased risk of Down syndrome picking up 75-80% of cases and being falsely positive in 6%.
Blood tests
◦ Several blood markers can be measured that to predict the risk of Down syndrome during the second trimester.[61] Often two or three or used in combination with two or three of: α-fetoprotein, unconjugated estriol, total hCG, and free βhCG detecting about 60-70% of cases.[61] First trimester screening with markers is not as accurate and thus is not generally recommended by itself.
◦ Testing of the mother's blood for fetal DNA is being studied and appears promising in the first trimester.
Blood tests◦ The International Society for Prenatal Diagnosis considers it a reasonable screening
option for those women whose pregnancies are at a high risk for trisomy 21.
◦ Accuracy has been reported at 98.6% in the first trimester of pregnancy.
◦ Confirmatory testing by invasive techniques (amniocentesis, CVS) is still required to confirm the screening result.
Diagnosis
◦When screening tests predict a high risk of Down syndrome, a more invasive diagnostic test (amniocentesis or chorionic villus sampling) is needed to confirm the diagnosis.[56] If Down syndrome occurs in 1 in 500 pregnancies and the test used has a 5% false positive rate, this means that of 28 women who test positive on screening only 1 will have Down syndrome confirmed.
◦ If the screening test has a 2% false positive rate this improves to 1 out of 10 who test positive on screening having a fetus with DS.
◦ Amniocentesis and chorionic villus sampling are more reliable; however, carry an increased risk of miscarriage of between 0.5 and 1%.
◦ There is also an increased risk of limb problems in the offspring due to the procedure.
◦ The risk from the procedure is greater the earlier it is preformed and thus amniocentesis is not recommended before 15 weeks gestational age and chorionic villus sampling before 10 weeks gestational age]
Abortion rates
◦ About 92% of pregnancies in the United Kingdom and Europe with a diagnosis of Down syndrome are terminated.
◦ In the United States termination rates are around 67%; however this varies significantly depending upon the population looked at.
◦When non pregnant people are asked if they would have a termination if their fetus tested positive 23-33% said yes, when high risk pregnant women were asked 46-86% said yes, and when women who screen positive are asked 89-97% say yes.[
After birth
◦ The diagnosis can typically be made based on the appearance of the child at birth.
◦ An analysis of the child's chromosomes is recommended to confirm the diagnosis and determine if a translocation is present as if it this may help determine the risk of the child's parents having further children with DS.
◦ Parents generally wish to know the possible diagnosis once it is suspected and do not wish pity.
Management
◦ Efforts such as early childhood intervention, screening for common problems, medical treatment where indicated, a good family environment, and work related training can improve the development of children with Down syndrome.
◦ Education and proper care can improve quality of life.
◦ Typical vaccinations are recommended.
Medications
◦ Efforts to prevent respiratory syncytial virus (RSV) with human monoclonal antibodies should be considered, especially in those with heart problems.[2] In those who develop dementia there is no evidence for memantine, donepezil, rivastigmine, or galantamine.
Edwards syndrome◦ Edwards syndrome (also known as Trisomy 18 [T18]) is a genetic disorder
caused by the presence of all or part of an extra 18th chromosome. This genetic condition almost always results from nondisjunction during meiosis. It is named after John Hilton Edwards, who first described the syndrome in 1960.
◦ It is the second most common autosomal trisomy, after Down syndrome, that carries to term.
Edwards syndrome◦ Edwards syndrome occurs in around one in 6,000 live births and around 80 percent
of those affected are female. The majority of fetuses with the syndrome die before birth.
◦ The incidence increases as the mother's age increases. The syndrome has a very low rate of survival, resulting from heart abnormalities, kidney malformations, and other internal organ disorders.
Signs and symptoms ◦ Children born with Edwards syndrome may have some or all of the following
characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, intellectual disability, developmental delays, growth deficiency, feeding difficulties,breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).
Signs and symptoms
◦ Some physical malformations associated with Edwards syndrome include small head (microcephaly) accompanied by a prominent back portion of the head (occiput); low-set, malformed ears; abnormally small jaw (micrognathia); cleft lip/cleft palate; upturned nose; narrow eyelid folds (palpebral fissures); widely spaced eyes (ocular hypertelorism); drooping of the upper eyelids (ptosis); a short breast bone; clenched hands; choroid plexus cysts; underdeveloped thumbs and or nails, absent radius, webbing of the second and third toes; clubfoot or Rocker bottom feet; and inmales, undescended testicles.[3][4]
Genetics
◦ Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or in part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations but is more prevalent in female offspring.[7]
Genetics◦ A healthy egg and/or sperm cell contains individual chromosomes, each of which
contributes to the 23 pairs of chromosomes needed to form a normal cell with a typical human karyotype of 46 chromosomes. Numerical errors can arise at either of the two meiotic divisions and cause the failure of a chromosome to segregate into the daughter cells (nondisjunction). This results in an extra chromosome, making the haploid number 24 rather than 23. Fertilization of eggs or insemination by sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.[8]
Genetics◦ Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With
nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo has 47 chromosomes, with three copies of chromosome 18.
Genetics◦ A small percentage of cases occur when only some of the body's cells have an extra
copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes.
◦ Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception.
◦ Affected individuals have two copies of chromosome 18 plus extra material from chromosome 18 attached to another chromosome. With a translocation, a person has a partial trisomy for chromosome 18, and the abnormalities are often less severe than for the typical Edwards syndrome.
Prognosis
◦ In 2008/2009, there were 495 diagnoses of Edwards syndrome (trisomy 18) in England and Wales, 92% of which were made prenatally. There were 339 abortions, 49 stillbirths/miscarriages/fetal deaths, 72 unknown outcomes, and 35 live births.
◦ Because approximately 3% of cases with unknown outcomes are likely to result in a live birth, the total number of live births is estimated to be 37 (2008/09 data are provisional). Major causes of death include apnea and heart abnormalities.
◦ It is impossible to predict an exact prognosis during pregnancy or the neonatal period
Prognosis◦Half of infants with this condition do not survive beyond the first week of life.
◦ The median lifespan is 5–15 days.
◦ About 8% of infants survive longer than 1 year.
◦ One percent of children live to age 10, typically in less severe cases of the mosaic Edwards syndrome.
◦ Parents with surviving children who take part in support groups report that these children enriched their family and their couple irrespective of the length of their lives.
Epidemiology
◦ Edwards syndrome occurs in approximately 1 in 6,000 live births, but more conceptions are affected by the syndrome because the majority of those diagnosed with the condition prenatally will not survive the prenatal period.
◦ Although women in their 20s and early 30s may conceive babies with Edwards syndrome, the risk of conceiving a child with Edwards syndrome increases with a woman's age. The average maternal age for conceiving a child with this disorder is 32½.
Patau syndrome◦Patau syndrome /ˈpætaʊ/ is a syndrome caused by a chromosomal abnormality, in
which some or all of the cells of the body contain extra genetic material from chromosome 13.
Patau syndrome◦ This can occur either because each cell contains a full extra copy of chromosome
13 (a disorder known as trisomy 13or trisomy D), or because each cell contains an extra partial copy of the chromosome (i.e., Robertsonian translocation) or because of mosaic Patau syndrome. Full trisomy 13 is caused by nondisjunction of chromosomes during meiosis (the mosaic form is caused by nondisjunction during mitosis).
Patau syndrome◦ The extra genetic material from chromosome 13 disrupts the normal course of
development, causing multiple and complex organ defects. Like allnondisjunction conditions (such as Down syndrome and Edwards syndrome), the risk of this syndrome in the offspring increases with maternal age at pregnancy, with about 31 years being the average.[1] Patau syndrome affects somewhere between 1 in 10,000 and 1 in 21,700 live births.[2
Causes
◦ Patau's syndrome is the result of trisomy 13, meaning each cell in the body has three copies of chromosome 13 instead of the usual two. A small percentage of cases occur when only some of the body's cells have an extra copy; such cases are called mosaic Patau.
Causes◦ Patau syndrome can also occur when part of chromosome 13 becomes attached to
another chromosome (translocated) before or at conception in aRobertsonian translocation. Affected people have two copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 13 and often the physical signs of the syndrome differ from the typical Patau syndrome.
Causes◦Most cases of Patau syndrome are not inherited, but occur as random events during
the formation of reproductive cells (eggs and sperm). An error in cell division called non-disjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of the chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 13 in each of the body's cells. Mosaic Patau syndrome is also not inherited. It occurs as a random error during cell division early in fetal development.
Causes◦ Patau syndrome due to a translocation can be inherited. An unaffected person can
carry a rearrangement of genetic material between chromosome 13 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 13. Although they do not have signs of Patau syndrome, people who carry this type of balanced translocation are at an increased risk of having children with the condition.
Manifestations and physical findings
◦Of those fetuses that do survive to gestation and subsequent birth, common abnormalities may include:
◦Nervous system◦ Intellectual disability and motor disorder◦ Microcephaly◦ Holoprosencephaly (failure of the forebrain to divide properly).◦ Structural eye defects, including microphthalmia, Peters anomaly (a type of eye
abnormality), cataract, iris and/or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia
◦ Meningomyelocele (a spinal defect)
◦Musculoskeletal and cutaneous◦ Polydactyly (extra digits)◦ Cyclopia◦ Proboscis◦ Low-set ears[3]
◦ Prominent heel◦ Deformed feet known as rocker-bottom feet◦ Omphalocele (abdominal defect)◦ Abnormal palm pattern◦ Overlapping of fingers over thumb◦ Cutis aplasia (missing portion of the skin/hair)◦ Cleft palate
◦Urogenital◦ Abnormal genitalia◦ Kidney defects
◦Other◦ Heart defects (ventricular septal defect) (Patent Ductus Arteriosus)◦ Dextrocardia◦ Single umbilical artery
Diagnosis
◦Diagnosis is usually based on clinical findings, although fetal chromosome testing will show trisomy 13. While many of the physical findings are similar to Edward's syndrome there are a few unique traits, such as polydactyly.
◦ However, unlike Edward's syndrome and Down syndrome, the quad screen does not provide a reliable means of screening for this disorder. This is due to the variability of the results seen in fetuses with Patau.
Treatment
◦Medical management of children with Trisomy 13 is planned on a case-by-case basis and depends on the individual circumstances of the patient. Treatment of Patau syndrome focuses on the particular physical problems with which each child is born. Many infants have difficulty surviving the first few days or weeks due to severe neurological problems or complex heart defects. Surgery may be necessary to repair heart defects or cleft lip and cleft palate.
Treatment◦ Physical, occupational, and speech therapy will help individuals with Patau
syndrome reach their full developmental potential. Surviving children are described as happy and parents report that they enrich their lives.
◦ The cited study grouped Edwards syndrome, which is sometimes survivable beyond toddlerhood, along with Patau, hence the median age of 4 at the time of data collection
Prognosis
◦More than 80% of children with Patau syndrome die within the first year of life.
Trisomy 8
◦ Trisomy 8, also known as Warkany syndrome 2, is a human chromosomal disorder caused by having three copies (trisomy) of chromosome 8. It can appear with or without mosaicism.
Characteristics
◦Complete trisomy 8 causes severe effects on the developing fetus and can be a cause of miscarriage.
◦ Complete trisomy 8 is usually an early lethal condition, whereas trisomy 8 mosaicism is less severe and individuals with a low proportion of affected cells may exhibit a comparatively mild range of physical abnormalities and developmental delay.
◦ Individuals with trisomy 8 mosaicism are more likely to survive into childhood and adulthood, and exhibit a characteristic and recognizable pattern of developmental abnormalities.
Characteristics◦ Common findings include retarded psychomotor development, moderate to severe
mental retardation, variable growth patterns which can result in either abnormally short or tall stature, an expressionless face, and many musculoskeletal, visceral, and eye abnormalities, as well as other anomalies.[5] A deep plantar furrow is considered to be pathognomonic of this condition, especially when seen in combination with other associated features.[6] The type and severity of symptoms are dependent upon the location and proportion of trisomy 8 cells compared to normal cells.
Other conditions
◦ Trisomy 8 mosaicism affects wide areas of chromosome 8 containing many genes, and can thus be associated with a range of symptoms.
◦Mosaic trisomy 8 has been reported in rare cases of Rothmund-Thomson syndrome, a genetic disorder associated with the DNA helicase RECQL4 on chromosome 8q24.3. The syndrome is "characterized by skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, short stature, premature aging, and increased risk of malignant disease".[7]
Other conditions◦ Some individuals trisomic for chromosome 8 were deficient in production of
coagulation factor VII due to a factor 7 regulation gene (F7R) mapped to 8p23.3-p23.1
◦ Trisomy and other rearrangements of chromosome 8 have also been found in tricho–rhino–phalangeal syndrome
◦ Small regions of chromosome 8 trisomy and monosomy are also created by recombinant chromosome 8 syndrome (San Luis Valley syndrome), causing anomalies associated with tetralogy of Fallot, which results from recombination between a typical chromosome 8 and one carrying a parental paracentric inversion.
◦ Trisomy is also found in some cases of chronic myeloid leukaemia, potentially as a result of karyotypic instability caused by the bcr:abl fusion gene.
Trisomy 22
◦ Trisomy 22 is a chromosomal disorder in which there are three copies of chromosome 22 rather than two. It is a frequent cause of spontaneous abortion during the first trimester of pregnancy. Progression to the second trimester and livebirth are rare. This disorder is found in individuals with an extra copy or a variation of chromosome 22 in some or all cells of their body. There are many kinds of disorders associated with Trisomy 22:
Emanuel Syndrome◦ Emanuel Syndrome is named after the genetic contributions made by researcher
Dr. Beverly Emanuel. This condition is assigned to individuals born with an unbalanced 11/22 translocation. That is, when a fragment of chromosome 11 is moved, or translocated to chromosome 22.
◦ 22q11 Deletion Syndrome [2] is a rare condition which occurs in approximately 1 in 4000 births. This condition is identified when a band in the q11.2 section of the arm of chromosome 22 is missing or deleted. This condition has several different names, The 22q11.2 Deletion Sydrome, Velocardiofacial syndrome, DiGeorge Syndrome, Conotruncal Anomaly Face syndrome, Opitz G/BBB Syndrome, Cayler Cardiofacial Syndrome.The effects of this disorder are different in each individual but similarities exist such as heart defects, immune system problems, a distinctive facial appearance, learning challenges, cleft palate, hearing loss, kidney problems, hypocalcemia, and sometimes psychiatric issues.
22q11 microduplication syndrome◦ 22q11 microduplication syndrome is the opposite of the 22q11 deletion
syndrome, in this condition, a band of q.11.2 section of chromosome 22 is duplicated. Individuals carrying this deficiency are relatively “normal” as in they don’t possess any major birth defects or major medical illnesses.
◦ This microduplication is more common than the deletion; this might be due to the milder phenotype of the individuals.
Phelan-McDermid Syndrome◦Phelan-McDermid Syndrome / 22q13 Deletion Syndrome is a condition
caused by the deletion of the tip of the q arm on chromosome 22. Most individuals with this disorder experience cognitive delays as well as low muscle tone and sleeping, eating and behavioural issues.
Chromosome Ring 22 ◦Chromosome Ring 22 is a rare disorder caused by the break and re-join of both
ends of chromosome 22, forming a ring. The effects on the individual with this disorder are dependent on the amount of genetic information lost during the break/re-join. Major characteristics for this disorder are mental retardation, muscle weakness and lack of coordination
Cat Eye Syndrome◦Cat Eye Syndrome / Schmid Fraccaro Syndrome is a condition caused by a
partial trisomy or tetrasomy in chromosome 22. A small extra chromosome is found, made up of the top half of chromosome 22 and a portion of the q arm at the q11.2 break. This chromosome can be found three or four times.
◦ This syndrome is referred as “Cat Eye” due to the eye appearance of reported affected individuals who have coloboma of the iris ; however, this feature is only seen in about half of the cases.
◦Mosaic trisomy 22 is a disorder in which an extra chromosome 22 is found only in some cells of the body. The severity of each case is determined by the number of cells with this extra copy. Some characteristics of individuals with this condition are cardiac abnormalities, growth retardation, mental delay, etc..
◦Complete Trisomy 22[8] is in contrast with Mosaic trisomy 22; this disorder is characterized by an extra copy of chromosome 22 which is found in each cell of the body of the affected individual. These cases are very rare, and most of the affected individuals die before birth or shortly after
Klinefelter syndrome◦Klinefelter syndrome or Klinefelter's syndrome is the set of symptoms
resulting from additional X genetic material in males. Also known as47,XXY or XXY, Klinefelter syndrome is a genetic disorder in which there is at least one extra X chromosome to a standard human male karyotype, for a total of 47 chromosomes rather than the 46 found in genetically typical humans.
◦While females have an XX chromosomal makeup, and males an XY, individuals with Klinefelter syndrome have at least two X chromosomes and at least one Y chromosome.
◦ Because of the extra chromosome, individuals with the condition are usually referred to as "XXY males", or "47,XXY males".
◦ This chromosome constitution (karyotype) exists in roughly between 1:500 to 1:1000 live male births but many of these people may not show symptoms. If the physical traits associated with the syndrome become apparent, they normally appear after the onset of puberty.
◦ In humans, 47,XXY is the most common sex chromosome aneuploidy in males and the second most common condition caused by the presence of extra chromosomes. Other mammals also have the XXY syndrome, including mice.
◦ Principal effects include hypogonadism and sterility. A variety of other physical and behavioural differences and problems are common, though severity varies and many XXY boys have few detectable symptoms.
Signs and symptoms
◦ There are many variances within the XXY population, just as within the 46,XY population. While it is possible to characterise XXY males with certain body types and physical characteristics, that in itself should not be the method of identification as to whether or not someone has XXY. The only reliable method of identification is karyotype testing. The degree to which XXY males are affected, both physically and developmentally, differs widely from person to person.
Signs and symptoms◦Physical
◦ As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys their age.
◦During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may have larger breasts, weaker bones, and a lower energy level than other boys.
Signs and symptoms◦ As babies and children, XXY males may have weaker muscles and reduced strength.
As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys their age.
◦During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may have larger breasts, weaker bones, and a lower energy level than other boys.
Signs and symptoms◦ By adulthood, XXY males look similar to males without the condition, although they
are often taller. In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).
◦ Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population.
◦ About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.
Signs and symptoms◦ Affected males are often infertile, or may have reduced fertility. Advanced
reproductive assistance is sometimes possible.
◦ The term hypogonadism in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this (primary) hypogonadism, individuals will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.
◦ Despite this misunderstanding of the term, however, it is true that XXY men may also have microorchidism (i.e., small testicles).
Signs and symptoms◦ XXY males are also more likely than other men to have certain health problems,
which typically affect females, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis.
◦ In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.
Cause
◦ The extra X chromosome is retained because of a nondisjunction event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in this case the X and Y sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY offspring. The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births.
Cause◦ Another mechanism for retaining the extra X chromosome is through a
nondisjunction event during meiosis II in the female. Nondisjunction will occur when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. (meiosis) An XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring.
Treatment
◦ The genetic variation is irreversible. Often individuals that have noticeable breast tissue or hypogonadism experience depression and/or social anxiety because they are outside of social norms. This is academically referred to as psychosocial morbidity. At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome to ameliorate current poor psychosocial outcomes.
◦ By 2010 over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with Klinefelter syndrome.
Prognosis
◦ There is research suggesting Klinefelter syndrome substantially decreases life expectancy among affected individuals, though the evidence is not definitive. A 1985 publication identified a greater mortality mainly due to diseases of the aortic valve, development of tumors and possible subarachnoid hemorrhages, reducing life expectancy by about 5 years. Later studies have reduced this estimated reduction to an average of 2.1 years. These results are still questioned data, are not absolute, and will need further testing.
History
◦ The syndrome was named after Harry Klinefelter, who, in 1942, worked with Fuller Albright at Massachusetts General Hospital in Boston, Massachusetts and first described it in the same year.[13][29] The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used.
Turner syndrome
◦ Turner syndrome or Ullrich–Turner syndrome (also known as "Gonadal dysgenesis"[1]:550), 45,X, encompasses several conditions in humanfemales, of which monosomy X (absence of an entire sex chromosome, the Barr body) is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent or has other abnormalities (unaffected humans have 46 chromosomes, of which two are sex chromosomes). In some cases, the chromosome is missing in some cells but not others, a condition referred to as mosaicism or "Turner mosaicism".
Turner syndrome◦Occurring in 1 in 2000[3] – 1 in 5000 phenotypic females, the syndrome manifests
itself in a number of ways. There are characteristic physical abnormalities which affect many but not all people with Turner syndrome, such as short stature, swelling, broad chest, low hairline, low-set ears, andwebbed necks. Girls with Turner syndrome typically experience gonadal dysfunction (non-working ovaries), which results in amenorrhea (absence of menstrual cycle) and sterility. Concurrent health concerns may also be present, including congenital heart disease, hypothyroidism (reducedhormone secretion by the thyroid), diabetes, vision problems, hearing concerns, and many autoimmune diseases.[6] Finally, a specific pattern of cognitive deficits is often observed, with particular difficulties in visuospatial, mathematical, and memory areas.
Turner syndrome◦ Short stature
◦ Lymphedema (swelling) of the hands and feet
◦ Broad chest (shield chest) and widely spaced nipples
◦ Low hairline
◦ Low-set ears
◦ Reproductive sterility
◦ Rudimentary ovaries gonadal streak (underdeveloped gonadal structures that later become fibrosed)
◦ Amenorrhoea, or the absence of a menstrual period
◦ Increased weight, obesity
◦ Shield shaped thorax of heart
◦ Shortened metacarpal IV
◦ Small fingernails
◦ Characteristic facial features
◦Webbed neck from cystic hygroma in infancy
◦ Aortic valve stenosis
◦ Coarctation of the aorta
◦ Bicuspid aortic valve
◦Horseshoe kidney
◦ Visual impairments sclera, cornea, glaucoma, etc.
◦ Ear infections and hearing loss
◦High waist-to-hip ratio (the hips are not much bigger than the waist)
◦ Attention Deficit/Hyperactivity Disorder or ADHD (problems with concentration, memory, attention with hyperactivity seen mostly in childhood and adolescence)
◦Nonverbal Learning Disability (problems with math, social skills and spatial relations)
◦Other features may include a small lower jaw (micrognathia), cubitus valgus,[8] soft upturned nails, palmar crease, and drooping eyelids. Less common are pigmented moles, hearing loss, and a high-arch palate (narrow maxilla). Turner syndrome manifests itself differently in each female affected by the condition, therefore, no two individuals will share the same features.
Cause
◦ Turner syndrome is caused by the absence of two complete copies of the X chromosome in some or all the cells. The abnormal cells may have only one X (monosomy) (45,X) or they may be affected by one of several types of partial monosomy like a deletion of the short p arm of one X chromosome (46,XdelXp) or the presence of an isochromosome with two q arms (46XiXq. In mosaic individuals, cells with X monosomy (45,X) may occur along with cells that are normal (46,XX), cells that have partial monosomies, or cells that have a Y chromosome (46,XY). The presence of mosaicism is estimated to be relatively common in affected individuals (67-90%).
Inheritance
◦ In the majority of cases where monosomy occurs, the X chromosome comes from the mother. This may be due to a nondisjunction in the father. Meiotic errors that lead to the production of X with p arm deletions or abnormal Y chromosomes are also mostly found in the father. Isochromosome X or ring chromosome X on the other hand are formed equally often by both parents. Overall, the functional X chromosome mostly comes from the mother.
◦ In most cases, Turner syndrome is a sporadic event, and for the parents of an individual with Turner syndrome the risk of recurrence is not increased for subsequent pregnancies. Rare exceptions may include the presence of a balanced translocation of the X chromosome in a parent, or where the mother has XO mosaicism restricted to her germ cells.
Diagnosis
45,X karyotype, showing an unpaired X at the lower right
Diagnosis◦ Turner syndrome may be diagnosed by amniocentesis or chorionic villus sampling
during pregnancy.
Prognosis
◦While most of the physical findings are harmless, there can be significant medical problems associated with the syndrome.
◦Prenatal
◦Despite the excellent postnatal prognosis, 99% of Turner-syndrome conceptions are thought to end in spontaneous abortion or stillbirth, and as many as 15% of all spontaneous abortions have the XO karyotype. Among cases that are detected by routine amniocentesis or chorionic villus sampling, one study found that the prevalence of Turner syndrome among tested pregnancies was 5.58 and 13.3 times higher respectively than among live neonates in a similar population.
Epidemiology◦ Approximately 99 percent of all fetuses with Turner syndrome result in spontaneous
termination during the first trimester. Turner syndrome accounts for about 10 percent of the total number of spontaneous abortions in the United States. The incidence of Turner syndrome in live female births is believed to be around 1 in 2000.
