Chromosomal Syndromes Flashcards
What is the approximate incidence of Trisomy 21?
1 in 600, 4 times higher if you count first trimester spontaneous abortions
What are the most important clinical signs of Down syndrome?
- Hypotonia
- Single transverse palmar crease (only 5% chance in a normal person)
- Round, flat face with increased distance between eyes
- Clinodactyly - short, curved 5th finger
- Intellectual disability
- Hearing and heart defects
Why do Down’s syndrome patients reach developmental milestones relatively slower?
Decreased muscle tone makes tasks like sitting, walking, talking more difficult, although their muscle tone tends to improve with age
How does fertility in Down’s syndrome differ between men and women?
Women - they often have ovulatory dysfunction, but are fertile
Men - low testosterone levels make fertility unlikely
What congenital heart defects do Down’s syndrome patients have?
Atrial and ventricular septal defects in about ~50% of cases
What types of cancer are Down’s syndrome patients at increased risk for?
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)
What gives Down’s patients the best prognosis for development?
Normal family life in their own home, and maybe even mainstreaming or inclusion in normal schools
What causes the majority of Down syndrome, and what are the other two causes?
- Nondisjunction - 95%, advanced materal age is important
- Mosaicism - 1%
- Translocation - 4% (higher in younger women)
How does the risk of aneuploidy compare to the risk of Down syndrome?
It’s about twice as high, Down syndrome makes up 50% of aneuploidy
Are there more Down syndrome children born from women older or younger than 35 years?
Younger -> since they are having more kids. But advanced maternal age increases Down syndrome risk. Only 5% of nondisjunctions are paternal
What is mosaic trisomy 21 and how is its severity affected?
How does this differ from Edward syndrome?
Trisomy 21 as a result of a mitotic non-disjunction, only part of the body’s cells will be trisomy 21. May have a less severe phenotype but difficult to prove
Edward syndrome mosaicism occurs rarely, but they actually do tend to have a better prognosis
What is translocation trisomy 21? Is maternal age associated?
When all or part of chromosome 21 becomes attached to another chromosome. Unbalanced translocation is inherited.
Maternal age is not associated with transloations
What is the recurrence risk of Down syndrome due to nondisjunction?
Whatever is higher: risk due to maternal age or 1%
What is the chance of translocation trisomy 21 depending on who carries a balanced translocation?
10-15% if mother is a carrier
5% if father is a carrier
100% if it’s a balanced 21:21 translocation
This makes up about 50% of translocation cases
What is Edward syndrome and who does it most commonly affect?
Trisomy 18, affects females to males more often (3:1)
What are the common features of Edward syndrome before birth?
Polyhydramnios, growth retardation, decreased fetal activity, and only 1 umbilical artery
What are the important clinical features of Edward syndrome after birth?
- Hypertonia - increased muscle tone. Leads to clenched fist with overlapping 3rd / 4th finger, rocker-bottom feet (clubbed)
- Hypoplastic sternum with missing 12th ribs
- Microcephaly
Why are translocations rarely the cause of Edward syndrome? How can this possibility be excluded?
Since chromosome 18 is not acrocentric
Can be exclused via chromosomal studies of an infant. If it is a translocation, parental karyotypes need to be tested to see if there is a balanced translocation
What is Trisomy 13? What are its clinical hallmarks?
Patau syndrome
Hallmarks: Midfacial and forebrain developmental abnormalities, including HOLOPROSENCEPHALY, failure of forebrain to differentiate into two hemispheres
What can be seen in utero in Patau syndrome?
Growth retardation, like Edward
What dysmorphologies are associated with Patau syndrome?
- Micrognathia (small jaw) with cleft lip / palate
- Polydactyly
- Scalp defect
- Microcephaly with severe intellectual disability
- Septal defects
- POLYCYSTIC KIDNEY
What is the prognosis for Trisomy 13?
80% die within 1 month, only 5% survive the fist 6 months
What is the common cause for Trisomy 13?
Nondisjunctional events, for some reason translocations are rare even though 13 is acrocentric chromosome
What are chromosome microdeletions and what typically needs to be used to visualize them?
Deletion of multiple genes at closely linked loci. Might be able to be seen via karytotyping, but often visible only by FISH or arrayCGH
Give two other names for Velocardiofacial syndrome
DiGeorge Syndrome, 22q deletion syndrome, CATCH-22
What are the clinical features of DiGeorge syndrome?
It’s a pouch 3 and 4 issue, so it affects the immune system due to small or absent thymus, also hypcalcemia due to poor parathyroid development
Velo: Velopharyngeal incompetence: cleft palate, speech, and feeding problems
Cardio - tetralogy of Fallot, inerrupted aortic arch, ventricular septal defect, truncus arteriosus
Facial - asymmetric crying faces, overfolded ears, long face
What is the most common etiology of DiGeorge syndrome?
95% microdeletion, of these: 94% de novo 22q11 deletion, 6% inherited 22q11
Last 5%: Atypical deletion or rearrangement
What is the highest recurrence risk of DiGeorge?
50% if inherited (one chromosome will be abnormal). De novo is very low
What are the characteristics of XYY syndrome?
1:840 newborns, but majority are normal, fertile males. Hard to detect.
They have tall, thin stature with poor fine motor coordination. A prominent glabella, and some will have intention tremor. Severe acne in adolesence
How is the behavior of XYY different?
They tend to have a dull mentality with explosive behavior. They are 10-15 IQ points below siblings, agressive and distractable.
Not overrepresented in prisons.
What is the most common etiology of XYY?
Nondisjunction during male meiosis II. Passing this from father to son is actually rare though
What is the single most common cause of hypogonadism and infertility in males? Why?
Klinefelter (XXY) syndrome. This syndrome leads to testosterone less than 1/2 of normal, and excess gonadotropin leads to hyalinization and fibrosis of seminiferous tubules, as well as gynecomastia
What is the disposition of Klinefelter patients?
Behavior problems including immaturity, insecurity, and shyness. Also have IQ’s 10-15 points below that of their siblings, with late onset of speech
What are some physical manifestations of XXY? How does this relate to therapy?
Almost half will have moderate intention tremor, as well as obesity if testosterone is not replaced
Typical treatment includes testosterone supplementation when diagnosed in childhood
What are the karyotypes of XXY patients / why are they special?
Up to 22% will have XXY/XY mosiacs, where they have a better prognosis
What can lead to a very bad variant of Klinefelter’s?
Two meiotic nondisjunctions (one from each parent) in the sex chromosomes -> can lead to XXXY and XXYY which are further intellectually challenged / behavior problems
What are the clinical features of Turner’s syndrome?
- Decreased birth weight / short stature
- Gonadal dygenesis
- Transient congenital lymphedema
- Thyroid disease
- Cardiac abnormalities -> coarction of the aorta
- Ovarian degeneration requiring estrogen replacement therapy. Pregnancy is only possible via artificial reproductive technologies
What is transient congenital lymphedema and what physical signs does this relate to?
Overflow of lymph, relates to puffy hands/feet + webbed neck. Even when the edema subsides, the webbing of the neck remains, commonly from cystic hygroma blocking lymph flow
What are two other dysmorphic features of Turner syndrome?
Strabismus, cubitus valgus (outward bending of elbow)
What factor in Turner’s patients increases the risk of gonadoblastoma?
45,X/46,XY mosaicism
What should be done if intellectual disability is found in Turner’s syndrome patients and why?
Chromosomal microarray, as it is likely caused by an X-autosome translocation, since intellectual disability is rarely a finding of 45,X.
What is the most likely chromosome to be missing in Turner’s syndrome?
The paternal contribution, and thus there is no association between occurrence and advanced maternal age.
Most are sporadic cases so recurrence risk is low
