Genetics

Question 1

What is malformation?

Answer 1

Structural defect due to localized error in morphogenesis resulting in the abnormal formation of a tissue or organ

Question 2

Dysplasia?

Answer 2

abnormal organization of cells into tissues

Question 3

Deformation?

Answer 3

alteration in shape or structure of a structure or organ that has developed or differentiated normally

Question 4

Disruption?

Answer 4

defect resulting from the destruction of a structure that had formed normally before the insult

Question 5

Sequence?

Answer 5

Single error in morphogenesis that results in a series of subsequent defects
e.g. Pierre-Robin sequence, in which a small jaw results in glossoptosis and cleft palate

Question 6

Deformation sequence?

Answer 6

Mechanical (uterine) force that alters structure of intrinsically normal tissue
e.g. Oligohydramnios produces deformations by in utero compression of limbs (e.g., dislocated hips, clubfoot), crumpled ears, or small thorax

Question 7

Disruption sequence?

Answer 7

In utero tissue destruction after a period of normal morphogenesis
e.g. Amnionic membrane rupture sequence, leading to amputation of fingers/toes

Question 8

Malformation syndrome?

Answer 8

Multiple malformations in unrelated tissues with a known unifying cause
e.g., Trisomy 21, Teratogens, other syndromes

Question 9

Association?

Answer 9

An association is a pattern of malformations that occurs together too frequently to be due to random chance alone but for which no specific etiology is yet recognized

Question 10

Neural tube defects?

Answer 10

failure of the neural tube to close spontaneously between the 3rd and 4th week of in utero development.

Question 11

Epidemiology of Down syndrome?

Answer 11

• Incidence approximately 1 in 733 live births
• The risk is highest in women who conceive after age 35 year

Question 12

What causes Down syndrome?

Answer 12

1. Approx. 95% have 3 copies of chromosome 21 (error in meosis)
2. Approx. 1% of persons are mosaics
3. Approx 4% have atranslocationinvolving chromosome 21

Question 13

What is meiotic nondisjunction in Trisomy 21?

Answer 13

• the chromosome 21 pair fails to separate so that on gamete has 2 chromosome 21s and one has none
• fertilization of the gamete with 2 chromosome 21s give rise to a zygote with trisomy 21

Question 14

What is the translocation that causes trisomy 21?

Answer 14

when the extra chromosome 21 is joined onto another chromosome (usually 14 but can also be 15, 22, or 21)

Question 15

What is mosaicism in Trisomy 21?

Answer 15

some of the cells are normal and some have trisomy 21

Question 16

Associated congenital cardiac defects in Down syndrome?

Answer 16

1. Atrioventricular septal defects
2. Ventricular septal defects
3. Isolated atrial septal defects
4. Patent ductus arteriosus
5. Tetralogy of Fallot

Question 17

Pulmonary complications with Down syndrome?

Answer 17

1. Recurrent respiratory infections
2. Sleep-disordered breathing
3. Laryngo- and tracheobronchomalacia
4. Pulmonary hypertension
5. Asthma

Question 18

Other anomalies associated with DS?

Answer 18

1. Congenital gastrointestinal anomalies
2. Hypothyroidism
3. Leukemia
4. Immune dysfunction
5. Diabetes mellitus
6. Seizures
7. Alopecia
8. Juvenile idiopathic arthritis
9. Problems with hearing and vision
10. Alzheimer disease–like dementia (4th decade)

Question 19

GI anomalies associated with Down syndrome?

Answer 19

1. Duodenal atresia
2. Hirschsprung disease
3. omphalocele
4. imperforate anus
5. cholelithiasis

Question 20

Clinical features of Down syndrome?

Answer 20

1. Up-slanting palpebral fissures, epicanthal folds, and flat nasal bridge
   - Anepicanthal foldis a skinfoldof the upper eyelid covering the inner corner of the eye
2. Brushfield spots - Small, white or greyish/brownspotson the periphery of theiris
3. Bridged palmar crease - Two transverse palmar creases are connected by a diagonal line
4. Wide space between first and second toes
5. Short fifth finger
6. Small ears
7. flat occiput
8. infants are usually hypotonic

Question 21

Typical craniofacial appearance of Down syndrome?

Answer 21

1. round face and flat nasal bridge
2. upslanted palpebral fissures
3. epicanthic folds
   - a fold of skin running across the inner edge of the palpebral fissure
4. Brushfield spots in iris
   - pigmented spots
5. small mouth and protruding tongue
6. small ears
7. flat occiput and third fontanelle

Question 22

Later medical problems?

Answer 22

1. delayed motor milestones
2. learning difficulties
3. short stature
4. increased susceptibility to infections
5. hearing impairment from secretory otitis media
6. visual impairments from cataracts, squints, myopia
7. increased risk of leukemia and solid tumors
8. acquired hip dislocation and atlantoaxial instability
9. obstructive sleep apnea
10. increased risk of hypothyroidism and coeliac disease
11. epilepsy
12. early onset Alzheimer disease

Question 23

What is Turner syndrome?

Answer 23

Structural or numeric aberrations of the X chromosomes

Question 24

Clinical features of Turner syndrome?

Answer 24

1. Short stature
2. Delayed puberty due to gonadal failure
3. Wide carrying angle (cubitus valgus)
4. Shieldlike chest
5. Webbed neck
6. Aortic valve stenosis, aortic coarctation, aortic dilation and rupture

Question 25

How to determine inheritance?

Question 26

What is hemopilia?

Answer 26

X-linked bleeding disorder

Question 27

Types of Hemophilia?

Answer 27

Hemophila A: Deficiency of factor VIII Hemophilia B: Deficiency of factor IX Hemophilia C: Deficiency of factor XI

Question 28

Epidemiology of hemophilia?

Answer 28

Hemophilia A occurs in roughly 1 per 5000 live male births Hemophilia B affects 1 in 30,000

Question 29

Etiology of hemophilia?

Answer 29

- The genes for factor 8 and factor 9 are on the X chromosome are affected - The lack of factor 8 or factor 9 delays the generation of thrombin, which is crucial to forming a normal, functional fibrin clot and solidifying the platelet plug that has formed in areas of vascular injury - The severity of the disorder is determined by the degree of clotting factor deficiency

Question 30

What is the chance of transmission from a female carrier to her sons?

Answer 30

50% - With only one copy of the X chromosome, males are more likely to manifest these diseases than females. Each son born to a female carrier of an X-linked recessive trait has a 50% chance of inheriting the trait, but none of this woman's daughters would be expected to be affected (each daughter has a 50% chance of being a carrier)

Question 31

What is the risk of transmitting the affected gene from the father to his sons?

Answer 31

0% - An affected father transmits the mutation to all his daughters, who are carriers, but not to his sons; having received their father's Y chromosome, they would not be affected (thus there is no male-to-male transmission.

Question 32

Diagnosis of hemophilia A and B?

Answer 32

1. Suggested by Prolonged aPTT 2. Confirmed by specific assays for either factor VIII or IX

Question 33

What is hypothyroidism?

Answer 33

a condition in which the thyroid gland doesn't produce enough thyroid hormone

Question 34

What are the types of hypothyroidism?

Answer 34

1. primary 2. secondary

Question 35

What is primary hypothyroidism?

Answer 35

when the thyroid gland itself is not able to produce adequate amounts of thyroid hormone

Question 36

What causes primary hypothyroidism?

Answer 36

1. Thyroid dysgenesis (80-85%) e.g., agenesis, hypoplasia, ectopia. 2. Defects in thyrotropin (TSH) responsiveness e.g., TSH receptor-blocking antibodies, Mutation in TSH receptor (TSHR) 3. Defect in thyroid hormone synthesis (dyshormonogenesis) 4. Iodine deficiency e.g. endemic goiter 5. Maternal medications e.g., methimazole, propylthiouracil

Question 37

What is secondary hypothyroidism?

Answer 37

when the thyroid gland itself is normal and the pathology is related to the pituitary gland or hypothalamus

Question 38

Causes of secondary hypothyroidism?

Answer 38

1. Isolated TSH deficiency (e.g., Mutation in TRH receptor) 2. Multiple pituitary hormone deficiencies

Question 39

What is Pendred syndrome?

Answer 39

- is an autosomal recessive disorder composed of sensorineural deafness and goiter - Pendred syndrome is caused by a mutation in the chloride–iodide transport protein pendrin (SLC26A4) that is expressed in the thyroid gland and the cochlea

Question 40

Clinical manifestation of hypothyroidism?

Answer 40

1. Wide anterior and posterior fontanels at birth 2. Prolonged jaundice (indirect hyperbilirubinemia) - delayed maturation of hepatic glucuronide conjugation 3. Cry little, sleep much, have poor appetites, and are generally sluggish 4. Feeding difficulties, sluggishness, lack of interest, somnolence, and choking spells during nursing 5. Respiratory difficulties, partly caused by macroglossia 6. Noisy respirations, and nasal obstruction 7. Constipation that does not usually respond to treatment 8. Large abdomen, umbilical hernia 9. Subnormal temperature 10. Cold skin on the extremities 11. Edema of the genitals and extremities 12. Low pulse