Genetics Flashcards
What is malformation?
Structural defect due to localized error in morphogenesis resulting in the abnormal formation of a tissue or organ
Dysplasia?
abnormal organization of cells into tissues
Deformation?
alteration in shape or structure of a structure or organ that has developed or differentiated normally
Disruption?
defect resulting from the destruction of a structure that had formed normally before the insult
Sequence?
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
Deformation sequence?
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
Disruption sequence?
In utero tissue destruction after a period of normal morphogenesis
e.g. Amnionic membrane rupture sequence, leading to amputation of fingers/toes
Malformation syndrome?
Multiple malformations in unrelated tissues with a known unifying cause
e.g., Trisomy 21, Teratogens, other syndromes
Association?
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
Neural tube defects?
failure of the neural tube to close spontaneously between the 3rd and 4th week of in utero development.
Epidemiology of Down syndrome?
- Incidence approximately 1 in 733 live births
- The risk is highest in women who conceive after age 35 year
What causes Down syndrome?
- Approx. 95% have 3 copies of chromosome 21 (error in meosis)
- Approx. 1% of persons are mosaics
- Approx 4% have atranslocationinvolving chromosome 21
What is meiotic nondisjunction in Trisomy 21?
- 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
What is the translocation that causes trisomy 21?
when the extra chromosome 21 is joined onto another chromosome (usually 14 but can also be 15, 22, or 21)
What is mosaicism in Trisomy 21?
some of the cells are normal and some have trisomy 21
Associated congenital cardiac defects in Down syndrome?
- Atrioventricular septal defects
- Ventricular septal defects
- Isolated atrial septal defects
- Patent ductus arteriosus
- Tetralogy of Fallot
Pulmonary complications with Down syndrome?
- Recurrent respiratory infections
- Sleep-disordered breathing
- Laryngo- and tracheobronchomalacia
- Pulmonary hypertension
- Asthma
Other anomalies associated with DS?
- Congenital gastrointestinal anomalies
- Hypothyroidism
- Leukemia
- Immune dysfunction
- Diabetes mellitus
- Seizures
- Alopecia
- Juvenile idiopathic arthritis
- Problems with hearing and vision
- Alzheimer disease–like dementia (4th decade)
GI anomalies associated with Down syndrome?
- Duodenal atresia
- Hirschsprung disease
- omphalocele
- imperforate anus
- cholelithiasis
Clinical features of Down syndrome?
- Up-slanting palpebral fissures, epicanthal folds, and flat nasal bridge
- Anepicanthal foldis a skinfoldof the upper eyelid covering the inner corner of the eye - Brushfield spots - Small, white or greyish/brownspotson the periphery of theiris
- 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
- infants are usually hypotonic
Typical craniofacial appearance of Down syndrome?
- round face and flat nasal bridge
- upslanted palpebral fissures
- epicanthic folds
- a fold of skin running across the inner edge of the palpebral fissure - Brushfield spots in iris
- pigmented spots - small mouth and protruding tongue
- small ears
- flat occiput and third fontanelle
Later medical problems?
- delayed motor milestones
- learning difficulties
- short stature
- increased susceptibility to infections
- hearing impairment from secretory otitis media
- visual impairments from cataracts, squints, myopia
- increased risk of leukemia and solid tumors
- acquired hip dislocation and atlantoaxial instability
- obstructive sleep apnea
- increased risk of hypothyroidism and coeliac disease
- epilepsy
- early onset Alzheimer disease
What is Turner syndrome?
Structural or numeric aberrations of the X chromosomes
Clinical features of Turner syndrome?
- Short stature
- Delayed puberty due to gonadal failure
- Wide carrying angle (cubitus valgus)
- Shieldlike chest
- Webbed neck
- Aortic valve stenosis, aortic coarctation, aortic dilation and rupture
How to determine inheritance?
What is hemopilia?
X-linked bleeding disorder
Types of Hemophilia?
Hemophila A: Deficiency of factor VIII
Hemophilia B: Deficiency of factor IX
Hemophilia C: Deficiency of factor XI
Epidemiology of hemophilia?
Hemophilia A occurs in roughly 1 per 5000 live male births
Hemophilia B affects 1 in 30,000
Etiology of hemophilia?
- 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
What is the chance of transmission from a female carrier to her sons?
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)
What is the risk of transmitting the affected gene from the father to his sons?
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.
Diagnosis of hemophilia A and B?
- Suggested by Prolonged aPTT
- Confirmed by specific assays for either factor VIII or IX
What is hypothyroidism?
a condition in which the thyroid gland doesn’t produce enough thyroid hormone
What are the types of hypothyroidism?
- primary
- secondary
What is primary hypothyroidism?
when the thyroid gland itself is not able to produce adequate amounts of thyroid hormone
What causes primary hypothyroidism?
- Thyroid dysgenesis (80-85%)
e.g., agenesis, hypoplasia, ectopia. - Defects in thyrotropin (TSH) responsiveness
e.g., TSH receptor-blocking antibodies, Mutation in TSH receptor (TSHR) - Defect in thyroid hormone synthesis (dyshormonogenesis)
- Iodine deficiency
e.g. endemic goiter - Maternal medications
e.g., methimazole, propylthiouracil
What is secondary hypothyroidism?
when the thyroid gland itself is normal and the pathology is related to the pituitary gland or hypothalamus
Causes of secondary hypothyroidism?
- Isolated TSH deficiency (e.g., Mutation in TRH receptor)
- Multiple pituitary hormone deficiencies
What is Pendred syndrome?
- 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
Clinical manifestation of hypothyroidism?
- Wide anterior and posterior fontanels at birth
- Prolonged jaundice (indirect hyperbilirubinemia)
- delayed maturation of hepatic glucuronide conjugation - Cry little, sleep much, have poor appetites, and are generally sluggish
- Feeding difficulties, sluggishness, lack of interest, somnolence, and choking spells during nursing
- Respiratory difficulties, partly caused by macroglossia
- Noisy respirations, and nasal obstruction
- Constipation that does not usually respond to treatment
- Large abdomen, umbilical hernia
- Subnormal temperature
- Cold skin on the extremities
- Edema of the genitals and extremities
- Low pulse
