Genetics Syndrome List 2008

Front 1

Down Syndrome: genetics

Back 1

trisomy 21
increased frequency with advanced maternal age

Front 2

Down Syndrome: phenotype

Back 2

dysmorphic features
congenital heart disease
atlanto-axial instability
duodenal atresia
hypotonia
mental retardation
hypothyroidism
hearing loss
vision concerns
premature senility

Front 3

Trisomy 13: genetics

Back 3

additional chromosome 13
increased frequency with advanced maternal age

Front 4

Trisomy 13: phenotype

Back 4

typically lethal
CNS malformations, CHD
1. Growth retardation and microcephaly (small head).
2. Eye anomalies including microophthalmia and colobomas*.
3. Scalp defects.
4. Congenital cardiac malformations*.
5. Polydactyly.
6. Holoprosencephaly-type cerebral malformations*.
7. Severe Neurologic dysfunction.
8. Cleft lip and palate.

Front 5

Trisomy 18: genetics

Back 5

47 +18
increased frequency with advanced maternal age

Front 6

Trisomy 18: phenotype

Back 6

typically lethal
CNS, CHD
1. Failure to thrive/small for gestational age (low birth weight).
2. Congenital heart disease*.
3. Severe mental retardation
4. Dysmorphic
a. Characteristic hand
b. Rocker bottom feet.

Front 7

Turner Syndrome: Genetics

Back 7

45X
Monosomy X. Common cause of miscarriage.

Front 8

Turner Syndrome: Phenotype

Back 8

1. Congenital Heart defects*.
2. Dysmorphic features.
a. Lymphedema.
b. Wide spaced nipples.
c. Webbed neck.
3. Renal malformations*.
4. Short stature (responds to growth hormone)*.
5. Failure to enter puberty * (provide estrogen treatment.
6. Infertility*.
7. Mild isolated learning disabilities*#.

Front 9

Klinefelter Syndrome: Genetics

Back 9

Chromosomal 47XXY
1/1000 male births

Front 10

Klinefelter Syndrome: Phenotype

Back 10

1. (Tall and thin).
2. Hypogonadism at puberty*.
a. Infertility*.
b. Small testes.
3. Isolated learning disabilities *#.

Front 11

22q11.2 syndrome: genetics

Back 11

AKA DiGeorge and velocardiofacial syndrome
Chromosome microdeletion (contiguous gene) syndrome
93% are de novo

Front 12

22q11.2 syndrome: phenotype

Back 12

1. Congenital heart disease*.
2. Palate abnormalities (cleft palate or velopalatal insufficiency)*.
3. Thymic hypoplasia (immunodeficiency)*.
4. Hypoparathyroidism with hypocalcemia*.
5. Dysmorphic features:
a. Cleft palate.
b. Broad nose.
c. Triphalangeal thumbs.
d. Wide spaced eyes (hypertelorism).
e. Abnormally shaped ears.
6. Developmental Delay*#.
7. Increased frequency of behavioral or psychiatric disorders*.

Front 13

Williams syndrome: genotype

Back 13

1. Chromosome microdeletion (7q11.2).
2. Most are de novo (new mutations).

Front 14

Williams syndrome: phenotype

Back 14

1. Congenital heart disease (esp. Supravalvular aortic stenosis)*.
2. Mild Developmental delay (better language skills)*.
3. Loquacious personality.
4. Dysmorphic facial features.
a. Broad mouth.
b. Prominent ears.
c. Small pointed chin.
5. Hypotonia*#.
6. Hypersensitivity/anxiety.
7. Short stature.
8. Calcium abnormalities*.

Front 15

Marfan syndrome: genotype

Back 15

Autosomal dominant
Variable expressivity

Front 16

Marfan syndrome:phenotype

Back 16

1. Skeletal.
a. Tall stature.
b. Pectus.
c. Scoliosis*.
d. Loose joints*.
e. Dolichostenomelia (long limbs).
f. Hernias*.
g. Pneumothorax (lung collapse)*.
2. Eyes.
a. Myopia (near sighted).
b. Lens dislocation*.
6. Cardiac.
a. Mitral valve prolapse.
b. Aortic root dilatation risk for dissection*.

Front 17

Achondroplasia:genotype

Back 17

1. Autosomal dominant, fully penetrant.
2. Most are de novo mutations.
3. Gain of function mutations.
4. FGFR3 mutations.
5. Homozygous mutations lethal.

Front 18

Achondroplasia:phenotype

Back 18

1. Rhizomelic short stature.
2. Megalencephaly (large head with frontal bossing).
3. Spinal cord compression*.
4. Normal IQ.

Front 19

Neurofibromatosis:genotype

Back 19

1. Autosomal Dominant.
2. Variable expressivity.
3. Tumor suppressor gene.
4. Loss of function mutations.
5. Allelic heterogeneity.

Front 20

Neurofibromatosis:phenotype

Back 20

1. Café au lait spots.
2. Axillary and inguinal freckling.
3. Cutaneous neurofibromas*.
4. Lisch nodules (iris hamartomas).
5. Plexiform neurofibromas*.
6. Optic gliomas*.
7. Bony lesions*.
8. Mild learning disabilities.

Front 21

Familial Adenomatous Polyposis FAP: genotype

Back 21

1. Autosomal dominant.
2. Tumor suppressor gene.

Front 22

Familial Adenomatous Polyposis FAP: phenotype

Back 22

1. Carpet-like presentation of polyps (>100)*.
2. Extremely high risk for colon cancer by age 40.
3. In persons with mutation, prophylactic colectomy recommended.
4. Upper GI polyps also common*.

Front 23

BRACA:genotype

Back 23

1. Automsomal dominant.
2. Two identified genes: locus heterogeneity.
3. Variable penetrance.
4. Tumor suppressor gene.
5. Specific mutations common in individuals of Ashkenazi Jewish ancestry.

Front 24

BRACA:phenotype

Back 24

1. Increased risk for breast and ovarian cancer*.
2. Individuals who have the mutation need increased screening or may elect prophylactic mastecomy and oophorectomy.
3. Male breast cancer with BRCA2 mutations.

Front 25

Li Fraumeni:genotype

Back 25

1. Autosomal dominant.
2. p53 gene.
3. Tumor suppressor gene.

Front 26

Li Fraumeni:phenotype

Back 26

1. High cancer risk.
2. Soft tissue sarcoma/osteosarcomaLeukemia.
3. Melanoma.
4. Cancer of the colon, breast, pancreas, adrenal cortex, and brain.
5. Poor screening/surveillance.

Front 27

Retinoblastoma:genotype

Back 27

1. May be due to germline or somatic mutations.
2. In individuals with germline mutations, it is autosomal dominant.
3. Tumor suppressor gene.
4. Classic example of Knudson’s two-hit hypothesis.
5. 90% penetrant.

Front 28

Retinoblastoma:phenotype

Back 28

1. Tumors may be bilateral or unilateral*.
2. All bilateral cases are due to germline mutations.
3. Unilateral cases may be germline or sporadic.
4. Tumors typically present before the age of 5.
5. Increased risk for non-ocular cancers later in life.

Front 29

Huntington Chorea:genotype

Back 29

1. Triplet repeat expansion of HD Gene (huntington).
2. Autosomal Dominant.
3. CAG, polyglutamine expansion.
4. Anticipation (greater risk for anticipation if paternally inherited).
5. Presymptomatic testing not performed in minors.

Front 30

Huntington Chorea:phenotype

Back 30

1. Adult onset neurodegenerative disease.
2. Motor disturbances.
3. Cognitive deterioration.
4. Behavioral disturbances.
5. No treatment.

Front 31

Cystic Fibrosis:genotype

Back 31

1. Autosomal recessive.
2. Ethnic variation in frequency.
3. Variable expressivity.
4. Monogenic, multi allelic (CFTR gene).

Front 32

Cystic Fibrosis:phenotype

Back 32

1. Onset in infancy to adulthood.
2. Pulmonary disease*.
3. Pancreatic insufficiency*.
4. Elevated sweat chloride.
5. Infertility (obstructive azoospermia).
6. Growth failure.

Front 33

Tay Sachs:genotype

Back 33

1. Lysosomal storage disorder (hexosaminidase A deficiency).
2. Autosomal recessive.
3. Ethnic variation in allele frequency, more common among Ashkenazi Jewish.

Front 34

Tay Sachs:phenotype

Back 34

1. Typically infantile onset.
2. Neurodegeneration.
3. Cherry red spot in retina.
4. Psychosis.
5. Death typically by age 3.

Front 35

PKU (Phenylketonuria):genotype

Back 35

1. Autosomal Recessive.
2. Most common enzyme deficiency.
3. Phenylalanine hydroxylase (PAH) deficiency.

Front 36

PKU (Phenylketonuria):phenotype

Back 36

1. Newborn screening.
2. Asymptomatic until brain damage has been done.
a. Short stature.
b. Mental retardation.
c. Behavioral problems.
3. Well treated with major dietary restriction of Phe.
4. Maternal PKU—high maternal PHE levels affect NORMAL fetus, resulting in an infant with severe mental retardation.

Front 37

Galactosemia:genotype

Back 37

1. Most common disorder of carbohydrate metabolism.
2. Autosomal recessive.
3. Gal-1-P Uridyl transferase.

Front 38

Galactosemia:phenotype

Back 38

1. Newborn screening.
2. Failure to thrive.
3. Liver failure.
4. Developmental delay.
5. Cataracts.

Front 39

Galactosemia:Additional features

Back 39

1. Dietary restriction of lactose improves outcomes.

+ Without treatment, life-threatening illness.

Front 40

Sickle Cell Disease:genotype

Back 40

1. Autosomal recessive.
2. Monogenic, monoallelic Beta hemoglobin.
3. Heterozygote advantage in malarial zones.
4. Ethnic variation in allele frequencies, common among individuals of African descent.

Front 41

Sickle Cell Disease:phenotype

Back 41

1. Anemia.
2. Pain crises.
3. Asplenia (functional asplenia develops).

Front 42

Gaucher Disease:genotype

Back 42

1. Autosomal recessive.
2. Most common Lysosomal storage disorder (glucocerebrosidase deficiency).
3. Ethnic variation in allele frequencies, more common in Ashkenazi Jews.
4. Variable severity.

Front 43

Gaucher Disease:phenotype

Back 43

1. Anemia. Thrombocytopenia*.
2. Hepatosplenomegaly*.
3. Bone involvement*.
4. Poor growth*.
5. Enzyme replacement therapy!!

Front 44

Storage Disorders:genotype

Back 44

1. Most are autosomal recessive except:
a. Fabry (X-linked).
b. Mucopolysaccharidosis Type II (aka Hunter syndrome) (X-linked).
2. Varying enzyme deficiencies.

Front 45

Storage Disorders:phenotype

Back 45

1. Variable presentation depending on disorder and disease severity. Presentation caused by accumulation of material within lysosomes. May involve varying organs. Enzyme replacement of several disorders available.
2. Mucopolysaccharide diseases may have involvement of:
a. Central nervous system.
b. Heart.
c. Skeletal system.
d. Pulmonary system.
e. Liver.
f. Auditory/vision concerns.
g. (Hunter syndrome does not affect vision.)

Front 46

Fragile X Syndrome:genotype

Back 46

1. Triplet repeat expansion disease (FMR1 gene) (CGG repeat).
2. X-linked.
3. Somatic mosaicism.
4. Expansion (seen with maternal inheritance).

Front 47

Fragile X Syndrome:phenotype

Back 47

1. Mental retardation#.
2. ADHD/autistic spectrum behaviors#.
3. Dysmorphic features.
a. Large head.
b. Long face.
c. Large ears.
d. Macroorchidism.
e. Prominent jaw and forehead.

Front 48

Duchenne Muscular Dystrophy:genotype

Back 48

1. X-linked.
2. Monogenic, multiallelic (dystrophin gene).
3. New mutations relatively frequent.
4. Carriers have some clinical features.

Front 49

Duchenne Muscular Dystrophy:phenotype

Back 49

1. Progressive muscle weakness (childhood onset).
2. Calf hypertrophy.
3. Elevated serum Creatine Kinase level.
4. Mild intellectual compromise.

Front 50

Angelman Syndrome:genotype

Back 50

1. Imprinting defect.
2. Absence of maternally derived 15q11-q13.
Microdeletion (70%).
Uniparental disomy (7%).
Mutations in the UBE3A gene (10%).
Imprinting center defect (3%).
3. Abnormal methylation studies will be seen (except those with UBE3A mutations).

Front 51

Angelman Syndrome:phenotype

Back 51

1. Seizures*.
2. Mental retardation.
3. Little to no speech#.
4. “Happy puppet syndrome” (inappropriate smiling /laughing and ataxia).
5. Microcephaly (small head).

Front 52

Prader Willi Syndrome:genotype

Back 52

1. Imprinting defect.
2. Absence of paternally derived 15q11-q13.
a. Microdeletion (70%).
b. Uniparental disomy (30%).
c. Imprinting center defect (rare).
3. Abnormal methylation studies.

Front 53

Prader Willi Syndrome:phenotype

Back 53

1. Morbid obesity.
2. Food seeking behavior#.
3. Hypogonadism.
4. Mental retardation.
5. At risk for obesity-related diseases:
a. Sleep apnea.
b. Cor pulmonale (heart failure due to pulmonary hypertension.
c. Diabetes mellitus.