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
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
Hearing loss, otitis media
Hirschsprung disease, duodenal atresia
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
• 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
(Trisomy 21: 75% meiosis 1)
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
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
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.
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
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
Patau Syndrome
A picture demonstrating
polydactyly, or extra fingers,
a common abnormality in
Patau syndrome.
• 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
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
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
The Simian line
Cayden Phipps: 3A ‐ Abrams
‘Rocker-bottom’ feet
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
Cayden Phipps: 3A ‐ Abrams
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)
Sensory Nystagmus, or involuntart “twitching” of the eye
Optic nerve hypoplasia, or the underdevelopment of the optic nerve
Cayden Phipps: 3A ‐ Abrams
• 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
Cayden Phipps: 3A ‐ Abrams
Edwards SyndromeTrisomy 18
is a rare genetic disorder
caused by an extra copy of
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
• 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
Maternally inherited
homolog (left)
Paternally inherited
homolog (right)
Genomic Imprinting
Jerky, ataxic movements
Abnormal facies
Chromosome 15 deletion with maternal imprinting
• Maxillary hypoplasia
• Large mouth
• Prognathism
• Low tone
• Large appetite—
• 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