Chromosomal Syndromes

Question 1

What is the approximate incidence of Trisomy 21?

Answer 1

1 in 600, 4 times higher if you count first trimester spontaneous abortions

Question 2

What are the most important clinical signs of Down syndrome?

Answer 2

1. Hypotonia
2. Single transverse palmar crease (only 5% chance in a normal person)
3. Round, flat face with increased distance between eyes
4. Clinodactyly - short, curved 5th finger
5. Intellectual disability
6. Hearing and heart defects

Question 3

Why do Down’s syndrome patients reach developmental milestones relatively slower?

Answer 3

Decreased muscle tone makes tasks like sitting, walking, talking more difficult, although their muscle tone tends to improve with age

Question 4

How does fertility in Down’s syndrome differ between men and women?

Answer 4

Women - they often have ovulatory dysfunction, but are fertile

Men - low testosterone levels make fertility unlikely

Question 5

What congenital heart defects do Down’s syndrome patients have?

Answer 5

Atrial and ventricular septal defects in about ~50% of cases

Question 6

What types of cancer are Down’s syndrome patients at increased risk for?

Answer 6

Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)

Question 7

What gives Down’s patients the best prognosis for development?

Answer 7

Normal family life in their own home, and maybe even mainstreaming or inclusion in normal schools

Question 8

What causes the majority of Down syndrome, and what are the other two causes?

Answer 8

1. Nondisjunction - 95%, advanced materal age is important
2. Mosaicism - 1%
3. Translocation - 4% (higher in younger women)

Question 9

How does the risk of aneuploidy compare to the risk of Down syndrome?

Answer 9

It’s about twice as high, Down syndrome makes up 50% of aneuploidy

Question 10

Are there more Down syndrome children born from women older or younger than 35 years?

Answer 10

Younger -> since they are having more kids. But advanced maternal age increases Down syndrome risk. Only 5% of nondisjunctions are paternal

Question 11

What is mosaic trisomy 21 and how is its severity affected?

How does this differ from Edward syndrome?

Answer 11

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

Question 12

What is translocation trisomy 21? Is maternal age associated?

Answer 12

When all or part of chromosome 21 becomes attached to another chromosome. Unbalanced translocation is inherited.

Maternal age is not associated with transloations

Question 13

What is the recurrence risk of Down syndrome due to nondisjunction?

Answer 13

Whatever is higher: risk due to maternal age or 1%

Question 14

What is the chance of translocation trisomy 21 depending on who carries a balanced translocation?

Answer 14

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

Question 15

What is Edward syndrome and who does it most commonly affect?

Answer 15

Trisomy 18, affects females to males more often (3:1)

Question 16

What are the common features of Edward syndrome before birth?

Answer 16

Polyhydramnios, growth retardation, decreased fetal activity, and only 1 umbilical artery

Question 17

What are the important clinical features of Edward syndrome after birth?

Answer 17

1. Hypertonia - increased muscle tone. Leads to clenched fist with overlapping 3rd / 4th finger, rocker-bottom feet (clubbed)
2. Hypoplastic sternum with missing 12th ribs
3. Microcephaly

Question 18

Why are translocations rarely the cause of Edward syndrome? How can this possibility be excluded?

Answer 18

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

Question 19

What is Trisomy 13? What are its clinical hallmarks?

Answer 19

Patau syndrome

Hallmarks: Midfacial and forebrain developmental abnormalities, including HOLOPROSENCEPHALY, failure of forebrain to differentiate into two hemispheres

Question 20

What can be seen in utero in Patau syndrome?

Answer 20

Growth retardation, like Edward

Question 21

What dysmorphologies are associated with Patau syndrome?

Answer 21

1. Micrognathia (small jaw) with cleft lip / palate
2. Polydactyly
3. Scalp defect
4. Microcephaly with severe intellectual disability
5. Septal defects
6. POLYCYSTIC KIDNEY

Question 22

What is the prognosis for Trisomy 13?

Answer 22

80% die within 1 month, only 5% survive the fist 6 months

Question 23

What is the common cause for Trisomy 13?

Answer 23

Nondisjunctional events, for some reason translocations are rare even though 13 is acrocentric chromosome

Question 24

What are chromosome microdeletions and what typically needs to be used to visualize them?

Answer 24

Deletion of multiple genes at closely linked loci. Might be able to be seen via karytotyping, but often visible only by FISH or arrayCGH

Question 25

Give two other names for Velocardiofacial syndrome

Answer 25

DiGeorge Syndrome, 22q deletion syndrome, CATCH-22

Question 26

What are the clinical features of DiGeorge syndrome?

Answer 26

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

Question 27

What is the most common etiology of DiGeorge syndrome?

Answer 27

95% microdeletion, of these: 94% de novo 22q11 deletion, 6% inherited 22q11
Last 5%: Atypical deletion or rearrangement

Question 28

What is the highest recurrence risk of DiGeorge?

Answer 28

50% if inherited (one chromosome will be abnormal). De novo is very low

Question 29

What are the characteristics of XYY syndrome?

Answer 29

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

Question 30

How is the behavior of XYY different?

Answer 30

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.

Question 31

What is the most common etiology of XYY?

Answer 31

Nondisjunction during male meiosis II. Passing this from father to son is actually rare though

Question 32

What is the single most common cause of hypogonadism and infertility in males? Why?

Answer 32

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

Question 33

What is the disposition of Klinefelter patients?

Answer 33

Behavior problems including immaturity, insecurity, and shyness. Also have IQ’s 10-15 points below that of their siblings, with late onset of speech

Question 34

What are some physical manifestations of XXY? How does this relate to therapy?

Answer 34

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

Question 35

What are the karyotypes of XXY patients / why are they special?

Answer 35

Up to 22% will have XXY/XY mosiacs, where they have a better prognosis

Question 36

What can lead to a very bad variant of Klinefelter’s?

Answer 36

Two meiotic nondisjunctions (one from each parent) in the sex chromosomes -> can lead to XXXY and XXYY which are further intellectually challenged / behavior problems

Question 37

What are the clinical features of Turner’s syndrome?

Answer 37

1. Decreased birth weight / short stature
2. Gonadal dygenesis
3. Transient congenital lymphedema
4. Thyroid disease
5. Cardiac abnormalities -> coarction of the aorta
6. Ovarian degeneration requiring estrogen replacement therapy. Pregnancy is only possible via artificial reproductive technologies

Question 38

What is transient congenital lymphedema and what physical signs does this relate to?

Answer 38

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

Question 39

What are two other dysmorphic features of Turner syndrome?

Answer 39

Strabismus, cubitus valgus (outward bending of elbow)

Question 40

What factor in Turner’s patients increases the risk of gonadoblastoma?

Answer 40

45,X/46,XY mosaicism

Question 41

What should be done if intellectual disability is found in Turner’s syndrome patients and why?

Answer 41

Chromosomal microarray, as it is likely caused by an X-autosome translocation, since intellectual disability is rarely a finding of 45,X.

Question 42

What is the most likely chromosome to be missing in Turner’s syndrome?

Answer 42

The paternal contribution, and thus there is no association between occurrence and advanced maternal age.

Most are sporadic cases so recurrence risk is low