גנטיקה קלינית 130279 (סיכום שיעור 7)
מיגל מורלס 328719059
Aneuploidy is the most common and clinically significant type of human chromosome disorder, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid patients have either trisomy(three instead of the normal pair of a particular chromosome) or, less often, monosomy (only one representative of a particular chromosome). Either trisomy or monosomy can have severe phenotypic consequences.
Trisomy can exist for any part of the genome, but trisomy for a whole chromosome is only occasionally compatible with life. By far the most common type of trisomy in liveborn infants is trisomy 21, the chromosome constitution seen in 95% of patients with Down syndrome (karyotype 47,XX,+21 or 47,XY,+21). Other trisomies observed in liveborns include trisomy 18 and trisomy 13. It is notable that these autosomes (13, 18, and 21) are the three with the lowest number of genes located on them; presumably, trisomy for autosomes with a greater number of genes is lethal in most instances. Monosomy for an entire chromosome is almost always lethal; an important exception is monosomy for the X chromosome, as seen in Turner syndrome
These autosomal trisomies is associated with growth retardation, intellectual disability, and multiple congenital anomalies. Nevertheless, each has a fairly distinctive phenotype that is immediately recognizable to an astute clinician in the newborn nursery. Trisomy 18 and trisomy 13 are both less common than trisomy 21; survival beyond the first year is rare, in contrast to Down syndrome, in which average life expectancy is over 50 years of age.
CNS, Central nervous system
The developmental abnormalities characteristic of any one trisomic state must be determined by the extra dosage of the particular genes on the additional chromosome. Knowledge of the specific relationship between the extra chromosome and the consequent developmental abnormality has been limited to date. Current research, however, is beginning to localize specific genes on the extra chromosome that are responsible for specific aspects of the abnormal phenotype, through direct or indirect modulation of patterning events during early development. The principles of gene dosage and the likely role of imbalance for individual genes that underlie specific developmental aspects of the phenotype apply to all aneuploid condition-
A trisomy of chromosome 21, is the most common anomaly of chromosome number in humans. The majority of cases result from nondisjunction during maternal meiosis I. Trisomy occurs in at least 0.3% of newborns and in nearly 25% of spontaneous abortions. It is the leading cause of pregnancy wastage and is the most common known cause of mental retardation. It is well documented that advanced maternal age is associated with greater risk of meiotic nondisjunction leading to Down syndrome. This may be associated with the prolonged meiotic arrest of human oocytes potentially lasting for more than four decades.
Down syndrome is by far the most common and best known of the chromosome disorders and is the single most common genetic cause of moderate intellectual disability. Approximately 1 child in 850 is born with Down syndrome, and among liveborn children or fetuses of mothers 35 years of age or older, the incidence of trisomy 21 is far higher.
Down syndrome can usually be diagnosed at birth or shortly thereafter by its dysmorphic features, which vary among patients but nevertheless produce a distinctive phenotype. Hypotonia may be the first abnormality noticed in the newborn. In addition to characteristic dysmorphic facial features, the patients are short in stature and have brachycephaly with a flat occiput. The neck is short, with loose skin on the nape. The hands are short and broad, often with a single transverse palmar crease (“simian crease”) and incurved fifth digits (termed clinodactyly).
A major cause for concern in Down syndrome is intellectual disability. Even though in early infancy the child may not seem delayed in development, the delay is usually obvious by the end of the first year. Although the extent of intellectual disability varies among patients from moderate to mild, many children with Down syndrome develop into interactive and even self-reliant persons, and many attend local schools.
There is a high degree of variability in the phenotype of Down syndrome individuals; specific abnormalities are detected in almost all patients, but others are seen only in a subset of cases. Congenital heart disease is present in at least one third of all liveborn Down syndrome infants. Certain malformations, such as duodenal atresia and tracheoesophageal fistula, are much more common in Down syndrome than in other disorders.
Only approximately 20% to 25% of trisomy 21 conceptuses survive to birth. Among Down syndrome conceptuses, those least likely to survive are those with congenital heart disease; approximately one fourth of the liveborn infants with heart defects die before their first birthday. There is a fifteen fold increase in the risk for leukemia among Down syndrome patients who survive the neonatal period. Premature dementia, associated with the neuropathological findings characteristic of Alzheimer disease (cortical atrophy, ventricular dilatation, and neurofibrillar tangles), affects nearly all Down syndrome patients, several decades earlier than the typical age at onset of Alzheimer disease in the general population.
The Chromosomes in Down Syndrome
In at least 95% of all patients, the Down syndrome karyotype has 47 chromosomes, with an extra copy of chromosome 21. This trisomy results from meiotic nondisjunction of the chromosome 21 pair. As noted earlier, the risk for having a child with trisomy 21 increases with maternal age, especially after the age of 30 years. The meiotic error responsible for the trisomy usually occurs during maternal meiosis (approximately 90% of cases), predominantly in meiosis I, but approximately 10% of cases occur in paternal meiosis, often in meiosis II. Typical trisomy 21 is a sporadic event, and thus recurrences are infrequent, as will be discussed further later.
Approximately 2% of Down syndrome patients are mosaic for two cell populations—one with a normal karyotype and one with a trisomy 21 karyotype. The phenotype may be milder than that of typical trisomy 21, but there is wide variability in phenotypes among mosaic patients, presumably reflecting the variable proportion of trisomy 21 cells in the embryo during early development.
Approximately 4% of Down syndrome patients have 46 chromosomes, one of which is a Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22). The translocation chromosome replaces one of the normal acrocentric chromosomes, and the karyotype of a Down syndrome patient with a Robertsonian translocation between chromosomes 14 and 21 is therefore 46,XX or XY,rob(14;21)(q10;q10),+21. Despite having 46 chromosomes, patients with a Robertsonian translocation involving chromosome 21 are trisomic for genes on the entirety of 21q.
A carrier of a Robertsonian translocation, involving, for example, chromosomes 14 and 21, has only 45 chromosomes; one chromosome 14 and one chromosome 21 are missing and are replaced by the translocation chromosome
Trisomy 13 (Patau Syndrome)
Trisomy 13, also referred to as Patau syndrome, is the fourth most common autosomal disorder in humans and has a prevalence of about 1/10,000 to 1/15,000 live births.10 The pattern of malformations observed in children with trisomy 13 is the combination of an orofacial cleft, microphthalmia, and posterior polydactyly of the limbs. The entire spectrum of the facial characteristics associated with holoprosencephaly, ranging from cyclopia to premaxillary agenesis, can be seen in infants with trisomy 13. Similar to trisomies 18 and 21, congenital heart malformations are common in infants with trisomy 13 and occur in about 80% of affected infants. The prognosis for both survival and development is similar to that of children with trisomy 18. However, for infants with trisomy 13, the presence of holoprosencephaly is probably the single most important finding that predicts survival. To this end, it should be noted that most children with trisomy 13 who survive early infancy usually do not have holoprosencephaly. Approximately 80% of children with trisomy 13 have three complete copies of chromosome 13, and most of the remaining cases have three copies of the long arm of chromosome 13 caused by an unbalanced robertsonian translocation. Only a few percent of children with trisomy 13 are mosaic. The recurrence risk for trisomy 13 is similar to that for trisomy 18. SOFT is also a resource for families of children with trisomy 13.
Trisomy 18 (Edward Syndrome)
The distinct pattern of malformation known as Edward syndrome caused by trisomy 18 is the third most common autosomal disorder and occurs in about 1 in 5000 to 6000 live-born infants. Trisomy 18 is also a common and important recognizable chromosomal cause of stillbirth, and among live-born cases, females comprise four times the number of cases as males. Similar to trisomy 21, trisomy 18 occurs with increased frequency as a woman ages. Infants with trisomy 18 have a recognized pattern of multiple congenital anomalies and an increased neonatal and infant mortality rate. The constellation of findings is as recognizable to the experienced clinician as Down syndrome.
The pattern of abnormalities observed in infants with trisomy 18 consists of prenatal growth deficiency of length and weight, a distinctive face characterized by a high forehead, small facial structure and mouth, short sternum, and a characteristic set of hand findings consisting of overlapping fingers and hypoplastic nails. Ninety percent of children with trisomy 18 have structural heart malformations, usually consisting of a ventricular septal defect with a polyvalvular dysplasia; some children will have more serious malformations such as hypoplastic left heart or a double outlet right ventricle.
Neonatal and infant mortality are increased; 50% of children with trisomy 18 syndrome die in the first week of life, and about 90% have died by age 1. The cause of most infant deaths is probably central apnea. The common heart malformations observed in infants with trisomy 18 are rarely the sole cause of death but may contribute to early death of some children. Individuals who survive into later infancy and childhood consistently have a significant developmental disability. The degree of disability is marked enough that children with trisomy 18 do not usually walk unsupported or develop expressive language. However, all children progress slowly in attaining milestones, recognize their families, and demonstrate skills that are usually age-appropriate for a 6- to 12-month-old child. Some older children develop skills such as feeding themselves and understanding cause and effect comparable to the developmental age of a 2 year old.11 The plight of families who have an infant with trisomy 18 is obviously overwhelming. Decisions to be made about management during newborn and early infancy are complex, and practitioners who care for families of children with trisomy 18 have both the challenge and the opportunity to support the parents in a memorable and significant manner. Carey has outlined these challenges and opportunities in a comprehensive review.
Ninety-five percent of infants with Edward syndrome have three copies of the entire chromosome 18. The remaining 5% have either mosaicism or partial trisomy of most of the long arm of chromosome 18. The chance for recurrence in future pregnancies is about 1% in families in which the mother is less than 35 years old, and it is most likely the age-specific risk for the older mothers. As in Down syndrome and all other chromosome syndromes, parents should be referred to a parents’ support group. The Support Organization for Trisomy 18, 13, and Related Disorders (SOFT) (http://www.trisomy.org) is a helpful resource for families of children with trisomy 18 and 13 and other chromosome syndromes that involve similar medical difficulties.
Sex Chr. Abnormalities
About 1 in 500 live-born infants has an abnormality of the X or Y chromosomes. Three conditions-47, XXY (Klinefelter syndrome), 47, XYY, and 47, XXX-comprise over 80% of this group of disorders. The phenotypic characteristics of these conditions are more subtle typically than those caused by abnormalities of the autosomes. Therefore, the diagnosis is not entertained unless there is a high index of suspicion. The phenotypes of children with Turner syndrome, 49, XXXXY, and 49, XXXXX, are more distinct.
Turner syndrome was described in 1938 by Henry Turner in females with proportionate short stature, a lack of secondary sexual characteristics, and gonadal dysgenesis leading to infertility.16 Many patients with Turner syndrome also have congenital heart defects, most commonly obstructive lesions of the left side of the heart (bicuspid aortic valve in 50% and coarctation of the aorta in 15–20%). These abnormalities are the cause of the most significant medical problems in girls with Turner syndrome. However, affected individuals also have a characteristic physical appearance consisting of a triangular shaped face, posteriorly rotated ears, a broad neck, and lymphedema of the hands and feet at birth.
The prevalence of Turner syndrome is low compared with other sex chromosome abnormalities, with about 1/2500 to 1/5000 live-born females having the condition. If no heart abnormalities are present, the primary medical impact of the syndrome is the short stature and the associated infertility and lack of secondary sexual development. In many cases of newborn females with Turner syndrome, the phenotype is easily recognizable and diagnosed on clinical features alone. However, the range of abnormalities observed in children with Turner syndrome is much wider than many of the chromosome syndromes. Clues such as dorsal lymphedema, the presence of a left-sided obstructive cardiac lesion, or a webbed neck suggest ordering a karyotype. Guidelines for the routine medical care and health supervision of girls with Turner syndrome have been developed by the American Academy of Pediatrics.17 Various support groups for families have been established (www.turner-syndrome-us.org/).
About half of all females with the Turner syndrome phenotype will have the 45, X chromosome constitution. The remaining cases will have either 45,X/46,XX mosaicism or some degree of monosomy of the X short arm. There is a long listing of various karyotypic findings associated with the Turner syndrome phenotype.
In addition to the clinical settings mentioned above, the 45,X karyotype will also be seen in the evaluation of fetal loss; more than 90% of all conceptions with 45,X die before birth. The characteristic fetal loss occurs in the second trimester with massive hydrops and a nuchal bleb (cystic hygroma). The hy-drops and nuchal bleb are related to a malformation of lymph channel development that is probably also responsible for the web neck in live-born females with Turner syndrome.
Mosaicism for Chromosome Abnormalities
When a person has a chromosome abnormality, whether numerical or structural, the abnormality is usually present in all of his or her cells. Sometimes, however, two or more different chromosome complements are present in an individual; this situation is called mosaicism. Mosaicism is typically detected by conventional karyotyping but can also be suspected on the basis of interphase FISH analysis or chromosomal microarrays.
A common cause of mosaicism is nondisjunction in an early postzygotic mitotic division. For example, a zygote with an additional chromosome 21 might lose the extra chromosome in a mitotic division and continue to develop as a 46/47,+21 mosaic. The effects of mosaicism on development vary with the timing of the nondisjunction event, the nature of the chromosome abnormality, the proportions of the different chromosome complements present, and the tissues affected. It is often believed that individuals who are mosaic for a given trisomy, such as mosaic Down syndrome or mosaic Turner syndrome, are less severely affected than nonmosaic individuals.
Common Deletions Syndromes
The first deletion or partial trisomy described in humans was 4p in 1961 and reports of children with 5p and 18p followed in 1963.1 Deletions of the distal portions of chromosomes 4p, 5p, and 18q have well-characterized patterns of malformation. The chromosome syndrome catalog and the database of Schinzel1 provide further details. Unlike the classical autosomal trisomy syndromes, the phenotypic spectrum of these and other partial monosomy and trisomy conditions varies substantially, contingent on the size of the extra or missing chromosomal segments and whether there is duplicated material from another chromosome present (eg, unbalanced translocation). Moreover, determination of natural history of these conditions is often complex because of the selection bias of case reports that tend to report the more unusual manifestations and findings from infants and young children.
Wolf-Hirschhorn syndrome (WHS) was first described in the early 1960s and is related to partial loss of material from the distal short arm of chromosome 4. The frequency is estimated to be about 1/50,000 births with a female predominance. Early case reports suggested that about one third of these children died in infancy, but there are now many adolescents and adults with WHS. A recent investigation from the United Kingdom indicates that more than 80% of infants with WHS survive the early years of life and stress the overstated mortality of the early work.
The phenotype of WHS is quite characteristic and consists of pre- and postnatal growth deficiency, microcephaly, a characteristic appearance of the nose, hypertelorism, a short philtrum, and hypotonia. Congenital heart malformations are observed in about one half of cases. Problems in infancy consist primarily of severe feeding difficulties and a marked increased incidence of seizures, which occur in almost 90% of children with WHS. The severity of the seizures seems to diminish after the first few years of life, and they cease by age 10. The developmental disability of children with WHS is significant, but there are a number of older children who are able to walk unsupported and gain toilet control. A few children speak in phrases or sentences. Children with WHS should be monitored for visual and hearing problems when young and scoliosis as older children and adolescents. Similar to the autosomal trisomies, guidelines for routine supervision have been proposed, and there exists a support group for families of children with WHS.
Cri-du-chat syndrome is caused by a deletion of the short arm of chromosome 5p and is one of the most well-known chromosome disorders because of the famous and distinctive cry.1,3 Other than the cry, which is said to resemble the sound of a cat and is caused by an anatomic alteration of the larynx, none of the phenotypic abnormalities is specific. However, the facial characteristics are quite similar in early childhood, including a round face with telecanthus and mild down-slanting of the palpebral fissures. Major malformations are less common in 5p deletion syndrome than in the autosomal trisomes, although about 30% of children will have a heart defect. The degree of developmental disability is also significant, but similar to WHS, the original case reports probably reflected only the most severely affected children. The 5p- support group (http://wwwfivepminus.org) provides resources and support for families of individuals with the syndrome.
The 18q deletion syndrome, sometimes referred to as De Grouchy syndrome, is characterized by variable microcephaly and developmental disabilities.1,3 Growth deficiency is also observed, although it is less frequent than in the other autosomal syndromes. The severity of abnormalities appears to be related to the size of the monosomic region (ie, a larger deletion is associated with more problems than is a smaller deletion). Craniofacial features include deep-set eyes and a notable mid-facial hypoplasia, producing a facial gestalt that is characteristic. The fingers are thin, and there are often prominent dimples at the elbow and shoulder joints. Major malformations are less common than in the autosomal trisomy syndromes, but narrowed or atretic ear canals are a hallmark of the condition, and the presence of this finding in a child with multiple minor anomalies should raise the suspicion of 18q deletion syndrome.
Balanced Translocations with Developmental Phenotypes
Reciprocal translocations are relatively common. Most are balanced and involve the precise exchange of chromosomal material between nonhomologous chromosomes; as such, they usually do not have an obvious phenotypic effect. However, among the approximately 1 in 2000 newborns who has a de novo balanced translocation, the risk for a congenital abnormality is empirically elevated several-fold, leading to the suggestion that some balanced translocations involve direct disruption of a gene or genes by one or both of the translocation breakpoints.
Detailed analysis of a number of such cases by FISH, microarrays, and targeted or whole-genome sequencing has identified defects in protein-coding or noncoding RNA genes in patients with various phenotypes, ranging from developmental delay to congenital heart defects to autism spectrum disorders. Although the clinical abnormalities in these cases can be ascribed to mutations in individual genes located at the site of the translocations, the underlying mechanism in each case is the chromosomal rearrangement itself.
Maternal Serum Screening
Maternal serum screening (MSS) utilizing feto-placental proteins was developed in an attempt to provide more pregnancy specific risk assessment. While studying increased maternal serum alpha-fetoprotein for the detection of open neural tube defects it was also noted that this marker was decreased in pregnancies with Down syndrome. Other markers including, human chorionic gonadotropin, unconjugated estriol, and dimeric inhibin A, were then also found to display a characteristic pattern in pregnancies with Down syndrome leading to the development of second-trimester double, triple, and quadruple screening, respectively. The accuracy of these maternal serum screens is heavily dependent on the clinical information entered into the algorithm. Incorporation of just one incorrect parameter (i.e., gestational age) can provide a false-positive or false-negative result. An additional drawback to these screens is the delay in performance until the second trimester, excluding the option for early termination in the case of an affected pregnancy.
First-trimester screening including incorporation of fetal nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A), and the beta subunit of human chorionic gonadotropin (β-hCG), soon emerged as a superior screening method. This approach eliminates the error due to inaccurate gestational dating, since ultrasound measurement of the fetal crown-rump length is part of the algorithm. First-trimester screening achieves a high detection rate for Down syndrome (85 %–90 %) and trisomy 18 (90 %–95 %) with a 5 % false-positive rate, and provides earlier prenatal diagnosis and the option of termination in the case of an affected pregnancy.
Several screening modalities that incorporate elements in both the first and second trimesters were then created to further increase the detection rate and decrease the false-positive rate. There are various strategies to performing this type of combined screening, including those which incorporate only serum feto-placental protein markers (i.e., serum integrated) as well as those incorporating ultrasound and serum markers (i.e., integrated, sequential, and contingent). The type of strategy utilized depends on patient preference as well as availability of certified NT providers.
Second-trimester ultrasound for evaluation of structural malformations and “soft markers” is also utilized as a screening for fetal aneuploidy. Some centers will perform “genetic sonograms” by incorporating likelihood ratios for various ultrasound markers to produce a risk for aneuploidy, mainly Down syndrome. This information is often interpreted in the context of the patient’s other risk factors, including age and MSS results. There is a wealth of literature regarding the utility of second-trimester ultrasound screening for aneuploidy