Syndromes Trisomy 21 Down Syndrome • Characteristic facial features: –Upward‐slanting palpebral fissures –Epicanthal folds –Flat nasal bridge Brushfield spots • Bridged palmar crease: two transverse palmar creases are connected by a diagonal line • Wide space between first and second toes • Short fifth finger • Small ears • Flat occiput Trisomy 21: Physical Findings Hypotonia Small head Epicanthal folds Flat nasal bridge Upward slanting palpebral fissures • Brushfield spots • • • • • • Small mouth and ears • Extra skin at the nape of neck • Single transverse palmar crease • 5th finger clinodactylyl • Sandal toe gap Trisomy 21: Associated defects • • • • • • • • • Congenital heart defects Mental retardation Leukemia Hearing loss, otitis media Hirschsprung disease, duodenal atresia Cataracts Thyroid disease Hip dislocation Atlantoaxial instability/dislocation Down syndrome • 1 in 700 live births • >60% spontaneously aborted • 20% stillborn • • • • • Facial appearance permits diagnosis Marked muscle hypotonia as baby Learning difficulty (IQ usually <50) Congenital heart malformations (40%) Incidence increases with maternal age Three different patterns of chromosomes can cause Down syndrome • 95% people have three separate copies of chromosome 21 ‐ trisomy 21 –non disjunction • 4% have the extra copy of chromosome 21 because of a Robertsonian translocation Non‐disjunction Non‐disjunction • 1% have mosaicism with normal and trisomy 21 cell lines (and usually have much milder features because of the presence of the normal cells); ‐ occurs postzygotically Meiotic Non‐disjunction (Trisomy 21: 75% meiosis 1) Trisomy Monosomy (lethal) Trisomy 21: 47,XX,+21 three separate copies of chromosome 21 Interphase FISH test for trisomy 21 The chromosome 21 probe is labelled with a red fluorochrome and a control probe (for chromosome 18) is labelled in green. The two green dots show that the hybridization has worked for this cell, and the three red dots show that there are three copies of chromosome 21. The clinical report is based on examining a large number of cells. For prenatal diagnosis a mix of differently coloured probes from chromosomes 13, 18, 21, X and Y is often used. Incidence of trisomy 21 at the time of chorionic villus sampling (10‐11 weeks), amniocentesis (16 weeks) and term. The incidence of trisomy 21 increases with increasing maternal age. Trisomy 21 amniocyte The trisomy 21 type of Down syndrome is the result of an error in meiosis, and has a recurrence risk of about 1 in 100. Neonatal features • Flat facial profile • Poor Moro reflex • Excessive skin at the nape of neck • Slanted palpebral fissures • Hypotonia • Hyper flexibility of joints • Dysplasia of pelvis • Anomalous ears • Dysplasia of midphalanx of fifth finger • Transverse palmer crease Mental Retardation Almost all DS babies have MR. Mildly to moderately retarded . Starts in the first year of life. Average age of sitting (11 mon), and walking (26 mon) is twice the typical age. • First words at 18 months. • IQ declines through the first 10 years of age, reaching a plateau in adolescence that continues into adulthood. • • • • Heart Disease • • • • • • • 50 % of Down Syndrome pts have heart disease Atrioventricular septal defect VSD / ASD PDA Tetralogy of Fallot Mitral valve prolapse Note: all the anomalies are the common malformations observed in the population, none of them is observed exclusively in DS GI abnormalities • 5% of cases • Duodenal atresia or stenosis, sometimes association with annular pancreas in 2.5 % of cases • Imperforate anus • Esophageal atresia with TE fistula is less common • Hirschsprung’s disease • Strong association with celiac disease 5 – 16 % , 5 – 16 fold increase as compared to general population Growth • • • • BW, length and HC are less in DS Reduced growth rate Prevalence of obesity is greater in DS Weight is less than expected for length in infants with DS, and then increases disproportionally so that they are obese by age 3‐4 yrs Eye problems Most common disorders are Refractory error – 35 to 76 percent Strabismus – 25 to 57 percent Nystagmus – 18 to 22 percent Cataract occur in 5 % of newborns. Frequency increases with age. Hematologic disorders • The risk of leukemia is 1 to 1.5 percent. • 65% of newborn have polycythemia resulting in hypoglycemia. • Risk of AML and ALL is also much higher than the general population. • Transient leukemia – exclusively affects NB. ‐ It is asymptomatic with spontaneous resolution in 2‐ 3 months. ‐ Vesiculopustular skin eruptions are common and resolve with disorder. Hearing loss • Unilateral or bilateral • Conductive, sensorineural or mixed • Otitis media is a frequent problem Endocrine disorder • Thyroid disease – Hypothyroidism occurs more frequently than hyperthyroidism. • Diabetes – The risk of type 1 diabetes is three times greater than that of the general population. Mortality Median age of death has increased from 25 yrs in 1983 to 49 yrs in 1997, an average of 1.7 yrs increase per year. Most likely cause of death is CHD, Dementia, Hypothyroidism and Leukemia. Improved survival is because of increased placements of infants in homes and changes in treatment for common causes of death. REPRODUCTION Women with DS are fertile and may become pregnant. REPRODUCTION Nearly all males with DS are infertile. The mechanism is impairment of spermatogenesis Down’s Syndrome Analyzing the origin of extra chromosome 21 ？ p1 p4 p3 p2 Patau Syndrome A picture demonstrating polydactyly, or extra fingers, a common abnormality in Patau syndrome. Description • Patau syndrome ‐ also known as trisomy 13 and trisomy D. • Affects about 1 in 12,000 live births. • More than 80% of infants with Patau syndrome die within their first year of life. The Simian line, or an abnormal palm pattern that is usually a symptom of Patau syndrome. Cayden Phipps: 3A ‐ Abrams 36 History Patau syndrome, or “Trisomy 13”, as it was first called, was first observed by Thomas Bartholin in 1657. However, the actual genetic and chromosomal‐related parts of it were discovered by Dr. Klaus Patau in 1960, hence the name “Patau syndrome”. Cayden Phipps: 3A ‐ Abrams 37 Trisomy 13 Common Problems cont. Muscular and skin problems: • • • • • • Polydactyly, or extra fingers/toes Low‐down ears Prominent heels and deformed feet, called ‘rocker‐bottom’ feet Strange palm patterns, commonly called the Simian line Overlapping of the fingers over thumb Cleft palate Polydactyly The Simian line Cayden Phipps: 3A ‐ Abrams ‘Rocker-bottom’ feet 40 Common Problems, cont. Vascular Problems: • Kidney problems • Heart defects such as ventricular septal defect Kidney Problem The disease shown right is called Polycystic kidney disease (PKD). This is a disorder in which clumps of cysts develop within your kidneys. Cysts are small round sacs containing water-like fluid. Cayden Phipps: 3A ‐ Abrams 41 Common Problems Nervous system problems: • Mental and motor disabilities • Microcephaly, or a less rounded brain resulting in more of an egg‐shaped skull • Eye structure defects: • • • • Microphthalmia, or crossed eyes (may involve one eye or both) Cataracts Sensory Nystagmus, or involuntart “twitching” of the eye Optic nerve hypoplasia, or the underdevelopment of the optic nerve S Cayden Phipps: 3A ‐ Abrams 42 Treatment • There is no treatment to address the condition. However, there are procedures to sustain life for a bit. • Most times, surgery is required to fix defects to allow the child to survive for as long as possible. • Most infants with Patau syndrome die within the first year of life, but many children have trouble surviving the first few days or weeks of life due to severe neurologic and vascular problems. 43 Mosaic Patau A small percentage of cases occur when only some of the body’s cells have an extra copy of chromosome 13, resulting in a mixed population of cells with differing numbers of chromosomes. This is called Mosaic Patau. A baby with a cleft palate, a common abnormality of Patau syndrome. Cayden Phipps: 3A ‐ Abrams 44 Edwards SyndromeTrisomy 18 is a rare genetic disorder caused by an extra copy of chromosome18. Trisomy 18 (Edward) • • • • Incidence 1:4000 live births Males : females 1:3 5‐10% survive first year Death usually due to heart failure or pneumonia • • • • • • • L O L S S C U F • G • S • H •Meckel’s diverticulum, horseshoe kidneys • Dorsiflexed short hallux •Short sternum, mental retardation • Prominent occiput and low‐set, posteriorly rotated malformed auricles • Clenched hand showing typical pattern of overlapping fingers • Rocker‐bottom feet Imprinting: Definition and historical perspectives • Imprinting: an epigenetic modification to DNA that results in “memory of parental origin” • By convention, the inactive allele is said to be “imprinted” • Early evidence: – early embryo nuclear transfer experiments – gynogenetic and androgenetic embryos fail to survive Imprinting: Mechanisms and purpose • Epigenetic modification that is reversible in germ line • DNA methylation and chromatin configuration are important • Imprinting may be a reflection of “parental conflict:” – paternal gene for rapid growth – maternal genes for growth retardation to maximize litter size Experimental and clinical evidence for imprinting • Mouse embryology ‐ opposite phenotypes in cases of uniparental disomy • Human imprinting syndromes: – Prader‐Willi syndrome (inheritance of paternal deletion ‐‐‐> maternal monosomy) – Angelman syndrome (inheritance of maternal deletion ‐‐‐> paternal monosomy) – Beckwith‐Wiedemann syndrome ‐ paternal disomy Map of Imprinted Regions in Human Genome Maternally inherited homolog (left) Paternally inherited homolog (right) Genomic Imprinting Angelman • • • • Seizures Jerky, ataxic movements Abnormal facies Chromosome 15 deletion with maternal imprinting • Maxillary hypoplasia • Large mouth • Prognathism Prader‐Willi • Low tone • Large appetite— obesity • Hypogonadism • Developmental delay/MR • Chromosome 15 deletion, paternal imprinting • Marked obesity • Excess fat over the trunk, buttocks, and proximal extremities • Small hands (and feet) • Hypoplastic penis and scrotum