Week 3 2024 Constitutional Aneuploidies.pdf

Constitutional Aneuploidies Terra-Cotta Figurine from the Tolteca culture of Mexicodated to around 500 A.D. Martinez-Frias (2005:231) Human chromosomes ⚫ ⚫ In the “normal” state the average human being has 46 chromosomes consisting of 23 pairs − 22 pairs of autosomes − One pair of sex chromosomes...

Constitutional Aneuploidies Terra-Cotta Figurine from the Tolteca culture of Mexicodated to around 500 A.D. Martinez-Frias (2005:231) Human chromosomes ⚫ ⚫ In the “normal” state the average human being has 46 chromosomes consisting of 23 pairs − 22 pairs of autosomes − One pair of sex chromosomes ⚫ XX ⚫ XY Cytogenetics is used to determine deviations from this “normal” state Definitions ⚫ ⚫ Constitutional: what the individual is born with. Aneuploid: a numerical change from the normal diploid (46) state. Hypodiploid- less than 46 chromosomes ⚫ Hyperdiploid- more than 46 chromosomes ⚫ Types of Abnormalities ⚫ Autosomal ⚫ Sex Chromosome ⚫ Trisomy ⚫ Monosomy ⚫ Triploidy ⚫ Combined with structural abnormalities Range of Presentation ⚫ Compatible with life ⚫ Not compatible with life ⚫ Present in all cells ⚫ Present as mosaic cell lines ⚫ In all tissues or restricted to specific tissues Numerical Changes ⚫ Autosomes – mental and physical defect -Trisomy 13 Patau syndrome -Trisomy 18 Edwards syndrome -Trisomy 21 Down syndrome Sex chromosomes – mainly infertility, some mental and physical defect ⚫ -45,X Turner syndrome -47,XXY Klinefelter syndrome -47,XXX -47,XYY Robertsonian Translocations A special structural alteration which changes the number of chromosomes (numerical) ⚫ Form when 2 long (q) arms of any acrocentric chromosomes join at the centromere to produce a single metacentric chromosome − “Balanced” carriers therefore have 45 chromosomes ⚫ ⚫ 95% are nonhomologous ⚫ rob(13;14) is most common ⚫ rob(14;21) Robertsonian Translocation 14 13 Robertsonian translocation (Jorde et al, 2006) 45,XY,der(13;14)(q10;q10) Robertsonian Translocation Aneuploidy ⚫ Most common chromosomal anomaly in abnormal births Approx. 50% of miscarriages show aneuploidy (Trisomies account for 60% of these aneuploidies) ⚫ ⚫ Approx. 25% pregnancies miscarry ⚫ Estimate 20% of conceptions aneuploid (ref: Burgoyne et al 1991) Trisomy 1 and autosomal monosomies lost before pregnancy is recognised (monosomy 21 excepted) ⚫ ⚫ Trisomy for every other chromosome well recognised ⚫ Trisomy 16, Trisomy 22 and Monosomy X common in M/C Autosomal alterations compatible with life:- abnormal outcome ⚫ Trisomy 13 - Patau syndrome ⚫ Trisomy 18 - Edwards syndrome ⚫ Trisomy 21 - Down syndrome ⚫ Derivative chromosomes ⚫ Isochromosomes ⚫ 12p Pallister-Killian syndrome ⚫ 18p ⚫ 22q cat-eye syndrome Maternal Age Effect ⚫ ⚫ ⚫ ⚫ An increase in maternal age has been shown to be directly proportional to an increased risk of having a pregnancy effected by the major trisomies. Aneuploidy results from nondisjunction, being an error occurring in meiosis I, meiosis II or mitosis − MI- failure of homologous chromosomes to separate − MII- failure of sister chromatids to separate − Mitotic errors occur post zygotically and usually result in mosaic aneuploidy. Age factor is thought to be related to a decline in the functional competence of the meiotic spindle. Nondisjunction occurs in 3-4% of sperm and 15-20% in oocytes ⚫ ⚫ Maternal Age Effect (as provided from the NHS) There is an increased risk of chromosome anomalies with advancing maternal age. The observed risk of having a live born baby with Down syndrome (in the absence of a family history) is: ⚫ Age Risk ⚫ 25 1 in 1500 ⚫ 30 1 in 800 ⚫ 35 1 in 350 ⚫ 36 1 in 300 ⚫ 37 1 in 200 ⚫ 38 1 in 170 ⚫ 39 1 in 140 ⚫ 40 1 in 100 ⚫ 45 1 in 30 Am Fam Physician. 2000 Aug 15;62(4):825-832 Meiosis I nondisjunction MI- failure of homologous chromosomes to separate Meiosis II nondisjunction MII- failure of sister chromatids to separate Mitosis nondisjunction Mitotic errors occur post zygotically and usually result in mosaic aneuploidy. 47,N 46,N 45,N Trisomy 13- Patau syndrome ⚫ Prevelence appox. 0.7- 3.0 in 10,000 live births ⚫ Short life expectancy − 90% mortality rate by 1yr, mean survival 10 days ⚫ Severe MR, v.poor prognosis ⚫ CNS defects, inc. microcephaly, small eyes ⚫ Heart (VSD, ASD) and kidney abnormalities ⚫ Cryptorchidism / bicornate uterus ⚫ Sixth finger on ulnar side of hand ⚫ Maternal age effect (90% cases maternal) Patau syndrome Brain defects – holoprosencephaly, cyclopia, proboscis Cleft lip/palate (midline defects) 47,XY,+13 Patau syndrome Trisomy 18- Edwards syndrome ⚫ The second most common autosomal trisomy, occurs approx. 5 in 10,000 live births. ⚫ Females > males ⚫ Mortality rate studies show 3-25% before 1yr ⚫ Growth deficiency (prenatal) ⚫ Severe MR ⚫ Prominent occiput, low-set misshapen ears, small mouth and jaw, choroid plexus cysts, microcephaly ⚫ “Rocker-bottom” feet ⚫ Clenched fists ⚫ Heart defects (VSD most common) ⚫ Maternal age effect (90% cases maternal) Edwards syndrome 47,XY,+18 Edwards syndrome Trisomy 21- Down syndrome ⚫ The most common autosomal trisomy, occurs approx. 1 in 700 live births ⚫ Compatible with full life expectancy ⚫ Heart abnormalities (40-50%) ⚫ ⚫ ⚫ 10-20% increased risk of developing childhood leukaemia (particularly AML) Degree of mental impairment can be highly variable Increased maternal age is the major risk factor for having a child with Down syndrome (90% maternal meiotic error- 75% of these from meiosis I error) Terra-cotta sculpture that was made at the mid-point of the first century (approximately the year 500), which belongs to the “Tolteca” culture of Mexico. In the terra-cotta, it is easy to identify the short palpebral fissures, oblique eyes, midface hypoplasia, and open mouth with macroglossia, findings that clearly define the face of a person with Down syndrome. Martinez-Frias ML,The Real Earliest Historical Evidence of Down Syndrome, Am J Med Genet 132A:231,2005 47,XY,+21 Down syndrome 1 2 3 6 7 8 13 14 15 19 20 9 21 4 5 10 11 12 16 17 18 22 X Y Mosaics Cytogenetic changes can also be observed in mosaic form ⚫ There may be two or more cell lines ⚫ The % of different cell lines may vary between different tissues ⚫ Some mosaic cell lines can only be detected in specific tissues ⚫ Often due to a post-zygotic mitotic error ⚫ Mosaics ⚫ ⚫ Mosaicism: presence in an individual of two or more cell populations arising from a single zygote (mitotic error) Chimerism: presence within an individual of two cell populations arising from 2 separate zygotes (possible fusion of dizygotic twins or fertilisation of a retained polar body) Mosaic Trisomy's ⚫ Trisomy 20 ⚫ Trisomy 8 ⚫ Trisomy 21 Isolated case reports for the other autosomes (inc. 9 and 14) ⚫ ESAC/marker chromosomes including invdup(15), tetrasomy 12p and 22p ⚫ Isochromosome 12p – Pallister-Killian syndrome ⚫ % of mosaicism varies in different tissues ⚫ Results in 4 copies of the 12p (tetrasomy) in affected cells ⚫ Detected in amniotic fluid and fibroblast cells NOT in blood ⚫ Normal to increased birth weight ⚫ Mental delay, heart defects, cataracts, hearing loss ⚫ Prominent forehead, wide-set eyes, short nose, sparse scalp hair ⚫ OMIM# 601803 Isochromosome 12p – Pallister-Killian syndrome Isochromosome 22q – Cat-eye syndrome SCHMID-FRACCARO SYNDROME CHROMOSOME 22 PARTIAL TETRASOMY INV DUP(22)(q11) ⚫ ⚫ ⚫ ⚫ ⚫ ⚫ ⚫ ⚫ rare: 1 in 150,000 Ocular coloboma Results in 4 copies of 22p (tetrasomy) Renal tract abnormalities, anal atresia Borderline normal to mild mental delay Heart defects, hernias, cleft palate, scoliosis/skeletal problems Preauricular tags or dimples OMIM# 115470 Isochromosome 22q – Cat Eye syndrome Image : Park et al. J Genet Med 2017;14:43-47 Coloboma of the eye Observations from Miscarriage ⚫ ⚫ ⚫ ⚫ ⚫ ⚫ Approximately 70% cytogenetically abnormal Most are numerical – mainly trisomy Most trisomic conceptions spontaneously abort in the first trimester Triploidy is often observed – trisomy of all chromosomes ie 69 chromosomes (Tetrasomy is rare but has also been observed) Trisomy of every chromosome recorded, occasionally double trisomy In many cases there is little or no fetal development Triploidy – 69 chromosomes ⚫ Results from 3 sets of haploid gametes Affects around 1%-2% of all conceptions and constitutes up to 10% of chromosomal defects detected in the first-trimester pregnancy losses. ⚫ Not affected by maternal age ⚫ Diandry: two paternal copies – most cases ⚫ Most often a result of di-spermy (>60%) ⚫ Can lead to formation of partial hydatidiform molar pregnancies ⚫ increased risk of maternal complications such as preeclampsia, hyperthyreosis or gestational trophoblastic neoplasia ⚫Digyny: two maternal copies ⚫ Most often a diploid egg fertilised with a haploid sperm ⚫Distinctive ultrasound features of both triploid phenotypes are an evidence of genomic imprinting ⚫ Turner syndrome – 45,X (Monosomy X) ⚫ Affects 50 per 10,000 females (Stochholm et al, 2006, PMID: 16849410) ⚫ Approx. 90% 45,X conceptions miscarry ⚫ Short stature ⚫ Swelling in hands and feet (disappearing after birth) ⚫ Webbed neck, broad chest with widely-spaced nipples ⚫ Infertile - failure to develop secondary sexual characteristics ⚫ Normal IQ In 80% of cases the X is maternal in origin, with the paternal X absent. ⚫ Turner syndrome – 45,X (Monosomy X) Dr. Catherine Ward-Melver, a clinical geneticist at Akron Children's Hospital in Akron, Ohio, has Turner syndrome, a genetic disorder that causes short stature. The 4-foot, 8-inch doctor became president of the Turner Syndrome Society of the United States in January 2007. She is pictured 2007 (left) and 2020 (right), working at the hospital. Constitutional Aneuploidy Summary ⚫ ⚫ ⚫ ⚫ ⚫ ⚫ Most autosomal numerical alterations are lethal – those that result in a live born infant are abnormal Sex chromosome aneuploidies may be associated with normal phenotype with infertility Autosomal trisomy in mosaic form is often milder in clinical presentation Trisomy for every chromosome, reported mostly in spontaneous miscarriage Monosomy is most often lethal. The risk of aneuploidy increases with maternal age. Acquired Aneuploidies Chromosome aneuploidies are also a frequent occurrence in acquired conditions such as leukaemias. Presence of these aneuploidies can also be prognostic indicators ⚫ Monosomy 7 and monosomy 5 − ⚫ Monosomy 17 − ⚫ Linked with the over-expression of RUNX1 Trisomy 8 − ⚫ Results in the loss of the TP53 gene and observed in a variety of blood cancers of multiple lineages and solid tumours Trisomy 21 − ⚫ Frequently observed in myeloid lineage leukaemias May be observed as a primary abnormality and often observed as a secondary abnormality Loss of the Y chromosome − Frequently seen in MDS, however also observed as normally occurring age related loss