Genetic disorders - Autosomal, X linked, Chromosomal Flashcards Preview

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Flashcards in Genetic disorders - Autosomal, X linked, Chromosomal Deck (53)
1

Hypotonia
Short stature
Cat-like cry
Microcephaly
MR
Wide and flat nasal bridge

What is it?

Cri du chat syndrome

Deletion of 5p

Other features:
- moonlike face
- hypertelorism
- bilateraly epithcanthal folds
- high arched palate
- VSD

2

"Greek helmet" facies
Ocular hypertelorism
Prominent glabella
Frontal bossing
Dolichocephal
Hypoplasia of eye socket
Ptosis
Strabismus
Beaked nose
MR

What is it?

Wolf Hirschhorn syndrome

Deletion of 4p

Also have:
- microcephaly
- bilateraly epicanthal folds

3

Hypotonia
Frog like legs
Depressed midface
MR
Belligerent personality

18q deletion

4

Microcephaly
Flat wide nasal bridge
Low birth wt
FTT
Ocular malformations
Syndactyly
Hypoplastic or absent thumbs
Micrognathia
Severe MR

13q deletion

5

Hypertonia
Downward slanting palpebral fissures
High palate
Prominent nasal bridge
Low set ears
micrognathia

21q deletion

6

Beckwith-Wiedemann syndrome
- pathogenesis
- PE
- Complications
- Surveillance

Deregulation of imprinted gene expression in chromosome 11

- Fetal macrosomia
- Rapid growth until late childhood
- Omphalocele or umbilical hernia
- Macroglossia
- Hemihyperplasia

MUST MONITOR NEWBORN FOR HYPOGLYCEMIA!

Complications:
- Wilms tumor
- hepatoblastoma
--> Pts with isolated hemihyperplasia are not at risk for Wilms tumor and hepatoblastoma

Surveillancee:
- serum AFP
- Ab/renal US

7

Fragile X syndrome

X linked defect
- affects methylation and expression of FMR1 gene

Trinucleotide repeat disorder! (CGG)

#2 cause of genetic MR
#1 cause MR in boys

Autism + MR

Long narrow face
Prominent jaw
Large ears
Macroorchidism
Macrocephaly

Mitral valve prolapse

Joint hyperlaxity + hypotonia

8

3 yo while girl p/w rectal prolapse

Small for height and weight

Foul smelling bulky stool every day that floats

Repetitive cough

Cystic fibrosis
- AR
- chr 7 (del of Phe 508)
- gene codes for CFTR

CFTR:
- actively secretes Cl- in lungs and GI
- reabsorbs Cl- from sweat

If can't secrete Cl- in lungs --> thick mucus cause water doesn't go there --> plugs lungs and pancreas and liver!

- morbidity and mortality dependent on rate of progression of lung disease

Characteristics:
- chronic airway obstruction and infection
- malabsorb
- FTT
- increased salt content in sweat and other secretions

Presentation:
- meconium ileus
- salty taste on skin
- recurrent resp infections
- malabosprtion
- nasal polyp
- rectal prolapse
- pale stool

Dx:
- increased [ Cl- ] in sweat test via quantitative pilocarpin iontophoresis (will induce sweating so can measure Cl)

Tx:
N acetylcysteine to loosen mucous plugs

9

Clinical features of cystic fibrosis

Respiratory
- Obstructive lung dz -----> bronchiectasis
- Recurrent PNA
- Chronic rhinosinusitis

GI
- Obstruction --> meconium ileus, distal intestinal obstruction syndrome
- Pancreatic dz --> exocrine pancreatic insufficiency, diabetes

Repro
- infertility

MS
- osteopenia --> fx
- kyphoscoliosis
- digital clubbing

10

Freidreich Ataxia

AR or AD

Frataxin gene
- GAA triplet repeats
- chr 9

Frataxin is mt protein in iron hemostasis

Sx < 10 yo
- dysarthric speech and nystagmus
- ataxia
- absent DTRs
- skeletal deformities / feet deformities
- DM

Tx - none

Assoc - HYPERTROPHIC cardiomyopathy!!!!

11

Lesch-Nyhan

X linked

D/o of purine metabolism
- missing hypoxanthine guanine phosphoribosyl transferase (HPRT)

Gives you too much uric acid!

Neuro dysfunction
Motor delay
Self destructive behavior
Choreoathetosis

Dx:
- HPRA enzyme analysis
- presence of dystonia + self mutilation

Tx:
- allopurinol for renal complications
- behavior mod, restraints

12

Wilson disease (Hepatolenticular degeneration)
- genetics
- signs
- dx
- tx

AR

Degeneration of basal ganglia 2/2 increased Cu deposition

Parkinsonism signs + liver failure

Starts between adolescence - 40 yo

Kayser Fleischer rings - at limbus of cornea

Dx:
- Low serum copper
- Low ceruloplasmin
- high urine Cu after give penicillamine
- CT --> hypodense areas in region of basal ganglia
- MRI --> increased T2 signal in caudate and putamen

Tx:
- reduce Cu intake
- D-penicillamine to chelate copper
- triehtylene tetramine dihydrochloride for pts sensitive to penicillamine
- zinc sulfate to reduce Cu absorption

13

Duchenne Muscular Dystrophy

X linked RECESSIVE
- deletion of dystrophin gene (helps anchor muscle fibers)

Presents @ 2-3 yo

Sx:
- poor head control may be 1st sign
- Calf muscle hypertrophy
- Gower's sign, waddling gait
- proximal weakness

Assoc:
- Cardiomyopathy ****
- MR

Dx:
- Increased CPK
- muscle bx (necrosis, fat cells, fibrous tissue)

Prognosis:
- wheelchair bound by age 12
- death by 18 2/2 resp problems

14

Becker Muscular Dystrophy

X linked RECESSIVE

Presents > age 5

Sx:
- like Duchenne but milder
- calf pain w/ exercise

Assoc:
- NO MR
- Cardiomyopathy

Labs:
- Increased CK but less than DMD

Prognosis:
- Pts ok to walk until early adulthood

15

Inheritance pattern of ocular albinism

X linked recessive

16

Werdnig Hoffman inheritance pattern

Autosomal recessive

17

Charcot Marie Tooth inheritance

Autosomal dominant

18

Neurofibromatosis inheritance

Autosomal dominant

Type 1 --> chromosome 17

Type 2 --> chromosome 22

19

Tuberous sclerosis
- core features
- presentation
- PE

Neurocutaneous syndrome

AD
Ch 9 + 16
-- many are new mutations though

Core features:
- MR
- facial fibroangiomas
- hypopigmented spots of skin
- epilepsy

Presentation:
- infantile spasms
- rhabdomyomas of heart --> arrhythmias

PE:
- ash leaf spots (hypopigmentation)
- shagreen patches
- sebaceous adenomas (acne like)
- retinal hamartomas

20

Tuberous sclerosis
- dx
- tx
- complications

Dx
- Tubers are characteristic
- periventricular calcified tubers on CT of head

Tx:
- goal is seizure control

Complications:
- tubers can become malignant astrocytomas

21

Trisomy 21 (Down syndrome)

Usually 2/2 meiotic nondisjunction of homologous chr

Features:
- hypotonia
- small stature
- MR
- flat occiput
- upslanting palpebral fissures
- inner epicanthal folds
- Brushfield spots (in iris)
- hypoplastic teeth
- clinodactyly
- simian creases
- wide gap between 1st and 2nd toes

Cardiac:
- atrioventricular valve defects (endocardial cushion defects)
- VSD
- ASD
- PDA

Skin:
- dry skin
- cutis marmorata (red/blue spiderwebs 2/2 cold)

MS:
- Atlantaxial instability

Higher risk for:
- duodenal atresia
- atlantoaxial instability
- ALL
- alzheimers

Quad screen:
- decreased AFP, estriol
- increased b-HCG, inhibin (HI)

22

Trisomy 18 (Edwards syndrome)

#2 common trisomy

ELection age = 18

Features:
- weak cry
- polyhydramnios
- MR, growth deficiency
- micognathia
- low set ears
- CLENCHED hands
- ROCKER BOTTOM feet

Cardiac:
- VSD (#1)

10% survive to 1 yo

Quad screen:
- decreased AFP, b-HCG, estriol
- normal inhibin A

23

Trisomy 13 (Patau syndrome)

Risks:
- advanced maternal age

Features:
- midline defects - clefts, scalp defects, microcephaly, HOLOPROSENCEPHALY (failure of forebrain to divide properly)
- microphthalmia
- colobomas of iris
- polydactyly

10% survive > 1 yo

Quad screen:
- decreased b-HCG, PAPP-A
- increased nuchal translucency

24

Turner Syndrome

XO

Sporadic

Usually is paternal X chromosome that is missing

Features:
- short stature
- gonadal dysgenesis
- congenital lymphedema (resolves)
- broad chest
- webbed neck
- cubitus valgus ( forearm is angled away from the body to a greater degree than normal when fully extended)
- pigmented nevi

Cardiac:
- bicuspid aortic vavle
- coarctation of aorta

Horseshoe kidneys

Need estrogen replacement

25

Kleinfelter syndrome

#1 single cause of hypogonadism and infertility

47 XXY

Features:
- low IQ
- behavior issues
- tall + slim w/ long limbs
- hypogonadism + small penis
- gynecomastia

Tx:
- testosterone replacement at 11-12 years

26

Achondroplasia inheritance if inherited

AD

Cell signaling defect of Fibroblast growth factor receptor 3

27

LEOPARD syndrome

AD

Lentigines - small pigmented skin spots that are benign

EKG abnormalities - long PR, etc

Ocular hypertelorism

Pulmonic stenosis

Abnormal genitalia (hypogonadism, cryptorchidism)

Retarded growth

Deafness

28

Waardenburg Syndrome

AD
If fresh mutation, assoc w/ older paternal age

- Lateral displacement of inner canthi
- Severe b/l DEAFNESS
- Partial albinism

29

Peutz-Jeghers Syndome

AD
But high rate of spontaneous mutation

- Pigmentation (lips, oral mucous)
- Polyps in jejunum, GI tract
- many have intussusception
- Polyps have low rate of malignancy
- clubbing of fingers seen

30

Ataxia Telangiectasia

Autosomal Recessive

Chromosome 11

Ataxia ---> wheelchair by age 10

Telangiectasia @ 3 yo --> usually on bulbar conjunctiva

Chronic URI

Deficient cellular immunity

Higher risk malignancies

Death 2/2 serious infections or neuro deficit

31

Ehler Danlos syndrome

Autosomal Dominant

Type 4 - autosomal recessive

Qualitative collagen deficiency

Features:
- hyperextensible skin + joints
- poor wound healing
- MVP

32

Marfan syndrome

Autosomal dominant

Fibrillin 1 gene mutation

Features:
- tall
- arachnodactyly (fingers are abnormally long and slender in comparison to the palm of the hand)
- kyophosis
- pectus excavatum

Ocular:
- lens subluxation
- myopia
- RD

Cardiac:
- dissecting aneurysm of ascending aorta
- MVP

Normal intelligence

Vascular complications are chief cause of death

33

Prader Willi syndrome

Deletion on chromosome 15
- paternal allele is not expressed

MR
Hyperphagia
Obesity
Hypogonadism
Hypotonia

34

Angelman's syndrome

Deletion on chromosome 15
- maternal allele is not expressed

MR
Seizures
Ataxia
Inappropriate laughter

35

Uniparental disomy

Offspring gets 2 copies of chromosome from 1 parents, none from the other

Most get normal phenotype

Consider this when a person gets a recessive DO and only 1 parents is carrier

36

Laurence Moon Biedl syndrome

AR

Obesity
Retinits pigmentosa
Polydactyly
Spastic paraplgia
Hypogonadism
MR

37

Variable expressivity

Phenotype varies among ppl w/ same genotype

2 ppl with NF 1 have varying severity

38

Incomplete penetrance

Not all ppl w/ mutant genotype show the phenotype

BRCA1 gene mutations don't always get breast cancer

39

Pleiotropy

1 gene gives many different phenotypic effects

40

Anticipation

Increased severity or earlier onset of dz in next generations

41

Linkage disequlibrium

Tendency for alleles at 2 linked loci to occur together more often than by chance

Measured in population

42

Locus heterogeneity

Mutations at different loci can produce same phenotype

Marfans, MEN 2B , and homocystinuria all cause marfanoid habitus

43

Heteroplasmy

Normal and mutated mt DNA present resulting in variable expression in mt inherited dz

44

Osler Weber Rendu syndrome

Hereditary hemorrhage telangiectasia

AD

Inherited DO of blood vessels

telangiectasia
Recurrent epistaxia
skin discolorations
AVM

45

Von Hippel Lindau disease

AD
Deletion of VHL gene on chromosome 3

Hemangiblastomas of retina/cerebellum/medulla

Usually get b/l RCC

Will activate angiogenic growth factors and constituitive expression of HIF transcription factor

46

Williams syndrome

Deletion of long arm chromosome 7
- has elastin gene on it

- Elfin facies
- Intellectual disability + well developed verbal skills
- HyperCALCEMIA
- VERY friendly

Supravalvular aortic stenosis common

47

22q1 deletion syndromes

CATCH-22

- Cleft palate
- Abnormal facies
- Thymic aplasia --> T cell deficiency
- Cardiac defects
- Hypocalcemia 2/2 parathyroid aplasia

Part of syndromes:
- DiGeorge
- Velocardiofacial syndrome

48

G6PD deficiency

X linked recessive

Need NADPH to get glutathione reduced
- decreased NADPH in RBC --> hemolytic anemia 2/2 poor RBC defense against oxidizing agents

Heinz bodies (Hg precipitated in RBCs)
Bite cells

49

Shwachman-Diamond syndrome

AR

Chromosome 7

Features:
- exocrine pancreatic dysfunction,
- haematologic abnormalities (neutropenia)
- growth retardation

Can look like CF but CF doesn't have neutropenia

50

Waardenburg syndrome

AD

Characteristics for dx;
- sensorineural hearing loss
- iris pigmentary abnormality
- hair hypopigmentation (white forelock or white hairs at other sites on the body)
- dystopia canthorum (lateral displacement of inner canthi)
- first‐degree relative previously diagnosed with Waardenburg syndrome

51

Noonan syndrome

AD

Characteristics:
- pulmonary valve stenosis
- hypertrophic cardiomyopathy
- short stature,
- learning problems,
- webbed neck
- ptosis

52

Myotonic muscular dystrophy

AD

Normal at birth
Develop progressive muscle weakenss and wasting, esp in distal muscles of hands

Characteristic facial feature:
- upper lip in shape of inverted V

Myotonia = delayed muscle relax
- can't release hand after handshake

DM
Testicular atrophy
Frontal baldness
Hypothyroidism

53

Kartegener's syndrome

AR

Triad:
- situs inversus
- recurrent sinusitis
- bronchiectasis

Due to dysmotile cilia (dyenin arms issue in production or attachment)