Chromosome Abnormality Disorders - PDF Notes

Chromosome abnormality disorders Zsolt Fábián M.D., Ph.D., Dr. Habil. 1 Chromosome abnormality disorders Lesson 1 – Disorders due to numerical chromosomal abnormalities Zsolt Fábián M.D., Ph.D., Dr. Habil....

Chromosome abnormality disorders Zsolt Fábián M.D., Ph.D., Dr. Habil. 1 Chromosome abnormality disorders Lesson 1 – Disorders due to numerical chromosomal abnormalities Zsolt Fábián M.D., Ph.D., Dr. Habil. 2  Chromosome abnormality disorders Disorders due to numerical chromosomal abnormalities New‐born girl Floppy baby (hypotonia) Excess nuchal skin, bilateral single palmer (simian) creases Healthy parents, both aged 33 – No family history of disease – Declined prenatal testing despite relatively advanced maternal age Down Syndrome suspected, karyotype ordered At a maternal age of 35 or older prenatal testing is strongly indicated. Helen's mother was 2 years younger than this at the time of birth so prenatal testing may not have seemed as urgent. While advanced maternal age increases the risk of Down Syndrome, most Down babies are actually born to younger mothers. Two reasons: More extensive prenatal testing in older mothers Younger mothers tend to have babies much more often than older mothers 3  Chromosome abnormality disorders Disorders due to numerical chromosomal abnormalities Karyotype indicates a 47,XX +21 genotype 4  Chromosome abnormality disorders Down syndrome Cytogenetics Clinical presentation 95% are complete trisomy 21 A major cause of intellectual disability – 47,XX +21 or 47,XY +21  ~ 80% of cases have IQ 25‐50 – caused by meiotic nondisjunction 40% congenital heart disease in a parent  septal defects and other defects 4% have Robertsonian translocations of endocardial cushion 1% are mosaic due to mitotic 10‐20x increased risk of leukemia (ALL nondisjunction or AML) – Milder features depending on age After ~40 yrs neuropathological at which nondisjunction occurred changes comparable to those seen in Incidence: 1 in 700‐800 Alzheimer disease develop in almost all Down syndrome patients  The APP gene is on chr. 21 Decreased life expectancy  50% survival past 50 years The endocardial cushions are two thicker areas that develop into the walls (septum) that divide the 4 chambers of the heart. Endocardial cushion defect (ECD) ‐ The walls separating all 4 chambers of the heart are poorly formed or absent. Also, the valves separating the upper and lower chambers of the heart have defects during formation. ALL – Acute lymphocytic leukemia AML – Acute myeloid leukemia Note the early onset of Alzheimer disease. Most common after age 65. 5  Chromosome abnormality disorders Down syndrome Nuchal – back of neck Brachycephaly – uniform flattening, wider head, less depth, with longer head height Flat Occiput – back of head Palpebral fissures – the distance (horizontal and vertical) between the medial and lateral canthi (ie. the opening of the eye) Epicanthal Folds – a skin fold over the inner corner (medial canthus) of the eye Atresia – abnormal narrowing or closure Strabismus – abnormal alignment of the eyes Hirschsprung disease is a blockage of the large intestine 6  Chromosome abnormality disorders Down syndrome upward sloping palpebral fissures dysmorphic facies over‐folded helix single palmar (simian) crease short stature, small head, nose and ears 7  Chromosome abnormality disorders Down syndrome There is a progressively increasing risk of trisomy 21 with increasing maternal age At maternal age 35 the risk of having a child affected by Down Syndrome outweighs the risk of induced miscarriage in prenatal diagnosis by Chorionic Villus Sampling (CVS) A maternal age of 35 has traditionally been used as the cut off for advanced maternal age. It’s important to understand that the increased risk of having a child with Down Syndrome doesn’t being at age 35 but increases progressively with increasing maternal age. Non‐invasive prenatal screening (by ultrasonography and maternal blood testing) can detect most cases of Down Syndrome without risk of inducing miscarriage, and are now used in all pregnancies regardless of the maternal age. 8  Chromosome abnormality disorders Trisomy of chr. 13 – Patau syndrome Clinical Presentation Severe cleft lip/palate Microcephaly Cardiac defects Genito‐urinary & renal defects Polydactyly Mean survival 7 days – 5‐10% survive to 1 year 1 in 5000 live births 9  Chromosome abnormality disorders Trisomy of chr. 18 – Edwards syndrome Clinical Presentation Microcephaly CNS & Cardiac malformations Prominent occiput Micrognathia Low set ears Short neck Overlapping fingers Renal malformations Limited hip abduction Rocker‐bottom feet Median survival 14.5 days – 50% die within 7 days – lethal, miscarriage  Disomic for chromosome 21 (2 copies)  After fertilization results in a trisomic conceptus ‐> Down Syndrome 100% of live‐born offspring of a 21q21q balanced carrier will have Down Syndrome If a child is born with translocation Down Syndrome it's important to karyotype the parents because of the 1/3 chance that one (most likely the mother) is a balanced carrier – and is therefore at risk of having further children with Down Syndrome The balanced parent will carry just a single 21q21q chromosome with no normal copies of chromosome 21. During meiosis I the 21q21q will segregate into one daughter cell and not the other, so gametes will either have 21q21q or no copy of 21 at all. After fertilization the resulting conceptus will be either trisomic (21q21q + a normal 21 from the other normal parent) or monosomic (only 1 normal 21 from the other normal parent) 26  Chromosome abnormality disorders Lesson 4 – Autosomal deletion disorders Zsolt Fábián M.D., Ph.D., Dr. Habil. 27 Chromosome abnormality disorders Structural Chromosomal Aberrations 28  Chromosome abnormality disorders Wolf‐Hirschhorn Syndrome Clinical Presentation Characteristic facies  Broad, flat nasal bridge, high forehead  "Greek Warrior Helmet" Microcephaly Growth retardation (not skeletal dysplasia) Severe mental deficiency Hypotonia, seizures Karyotype: 4p‐ (4p16 critical region) There are numerous mechanisms that can result in Wolf‐Hirschhorn including interstitial deletions and translocations in 4p. All cases involve loss of 4p16 29  Chromosome abnormality disorders Cri‐du‐chat Syndrome Clinical Presentation Clinical Presentation Cat‐like cry Mental deficiency Microcephaly Distinct facies Hypertelorism – wide‐spaced eyes Epicanthal folds Downward sloping palpebral fissures Karyotype: 5p‐, Loss of 10‐20% of distal p arm in most cases 30  Chromosome abnormality disorders Microdeletion Syndromes Microdeletion Syndromes – caused by chromosomal deletions less than 5Mbp Microdeletions are usually only detected by molecular diagnostics using DNA probes Wolf‐Hirschhorn is often also classified as a microdeletion syndrome since it can be caused by only a 4p16 deletion 31  Chromosome abnormality disorders Summary 1. Karyotypes have low resolution and can be used to detect numerical abnormalities and large‐scale autosomal deletion syndromes, but can rarely detect microdeletion syndromes like 22q11 deletion. 2. Trisomy 21 is the most common cause of Down Syndrome. Major presentations are intellectual disability, hypotonia, characteristic facies, single palmar crease, congenital heart defects, leukemia and Alzheimer disease 3. The risk of trisomies increases with increasing maternal age. 4. Trisomy 13 causes Patau Syndrome. Major presentations are severe facial clefting, cardiac, genito‐urinary, and renal defects. Mean survival is 7 days. 5. Triosomy 18 causes Edwards Syndrome. Major presentations are microcephaly, CNS and cardiac malformations, hand clenching with overlapping fingers, rocker bottom feet. Mean survival is 14 days. 6. Monosomy for X (45, X) causes Turner Syndrome. 99% of 45,X embryos are miscarried. Most cases are 45,X/46,XX or 45,X/46,XY mosaics. Mosaics are more likely to survive to birth and may have variable presentations depending on the degree of mosaicism. 7. Major presentations of Turner Syndrome are short stature, delayed puberty, amenorrhea, gonadal dysgenesis, webbing of the neck. Life expectancy and IQ are normal.  Chromosome abnormality disorders Summary II 8. Klinefelter Syndrome is occurs with 47,XXY karyotypes. Major presentations are tall stature and feminization of secondary sex characteristics. Life expectancy and IQ slightly below average. 9. Individuals with balanced translocations are usually phenotypically normal but are at risk of passing an unbalanced compliment of chromosome onto their offspring and having children with congenital anomalies. 10. Carriers of Robertsonian Translocations with 45 chromosomes are balanced but have a high risk of having unbalanced children with congenital anomalies. 11. A live‐born child of a 45,XX (or XY),rob(14q21q) individual has a 33% chance of having translocation Down Syndrome. 12. A live‐born child of a 45,XX (or XY),rob(21q21q) individual has a 100% chance of having translocation Down Syndrome. 13. Deletion of the p arm of chromosome 4 (4p‐) causes Wolf‐Hirschhorn Syndrome. Major clinical presentations are intellectual disability and ‘Greek Warrior Helmet’ facies. 14. Deletion of the p arm of chromosome 5 (5p‐) causes Cri‐du‐Chat syndrome. Major clinical presentations are intellectual disability, microcephaly and a ‘Cat‐like’, mewing cry.  Chromosome abnormality disorders Learning objectives 1. Use a karyotype to diagnose a disorder caused by a numerical chromosome abnormality. 2. Describe the major clinical aspects of the autosomal trisomies, aneuploidies of the sex chromosomes, and autosomal deletion syndromes (4p‐ and 5p‐). 3. Evaluate the risk to parents of having a child affected by Down Syndrome due to Trisomy 21 or Robertsonian translocations. 4. Compare the risk of miscarriage and clinical presentation of 45,X Turner Syndrome with 45,X/46,XX (or XY) mosaics. 5. Explain why a carrier of a balanced translocation is at risk of having unbalanced offspring. 6. Describe a Robertsonian translocation and explain why a carrier of a Robertsonian translocation with 45 chromosomes is balanced but at risk of having a child with a chromosomal imbalance.