Pathbio 2 Karyotypic Disorders

Front 1

Trisomy 21

Back 1

most common cause is meiotic non disjunction
95% 47, XX,+21
4% translocation
1% 46,XX/47,XX,21 mosaic(mitotic nondisjunction) 

Incidence: 1/700

Maternal age
 incidence is 1/1500 < 20
 1/25 > 45

Clinical features:
 Mental retardation
 Characteristic facial features
- abundant neck skin
- epicanthic folds & flat facial profile
 Hand anomalies
- simian crease
 Congenital heart defects
 Predisposition to leukemia

Intestinal stenosis, congential heart defects, umbilical hernia, hypotonia, gap btw 1st & 2nd toe, double bubble sign in x-ray, overfolding helix

Diagnosis by: FISH

Front 2

Edwards Syndrome
(Trisomy 18)

Back 2

47, XX,+18 (95%)
46,XX/47,XX, +18

 Incidence: 1/8000
 5-10% survive beyond 1st year

Clinical features:
 Congenital heart defects
 Renal
 Dysmorphisms
 Prominent occiput
 Microcephaly, micrognathia
 Overlapping fingers
 Rocker bottom feet
 CNS defects
 feeding difficulties, apnea
 Mental retardation

Front 3

Patau Syndrome

Back 3

47, XX,+13 most result from non-dysjunction

Incidence: 1/15,000  mental retardation


Clinical features:
 microophthalmia
 Midline facial defects
cleft lip and palate
proboscis (long nose)
 polydactyly, rocker-bottom feet
 congenital heart defects
 renal defects (cysts)
 umbilical hernia
Aplasia cutis congentia (no skin, subq tissue only)

Front 4

Chromosome 22q11.2 deletion syndrome

Back 4

Large region w/ numerous ~1.5 megabases -> clinical heterogeneity

Clinical features:
Encompasses features of velocardial facial syndrome
and DiGeorge syndrome
 congenital heart defects
 cleft palate
 facial dysmorphism
-prominent nose, hypoplastic nares
-Upslanted palpebral fissures
-Small mouth with everted lip
-Small abnormal ears
 developmental delay, psycotic illness
 variable degrees of T-cell immunodeficiency (thymic hypoplasia or agenesis)
 hypocalcemia

Diagnosis by:
FISH

Front 5

Klinefelter Syndrome

Back 5

 Occurs when there are 2 or > X and 1
or > Y
 karyotype
 47, XXY 82%
 46, XY/47,XXY 15%
 48,XXXY and 49 XXXXY rare -> severe phenotype

 one of the most common causes of hypogonadism in the male
 incidence: 1/850 live male births

Clinical features:
 increased length between sole and pubic bone
 small atrophic testes associated small penis
 lack of secondary male characteristics
 gynecomastia
 renal and ureteral abnormalities (renal cysts, hydronephrosis, hydroureter and
ureterocele)

Front 6

Turner Syndrome

Back 6

 monosomy X 45, X0 57%
 Mosaic 29% by conventional karyotype

Clinical features:
 Short stature
 Broad chest with wide spacing of nipples
 Webbed neck
 Ovarian dysgenesis ( streak gonads)
 Many pigmented nevi (birthmark)
 Cardiac defects (coarctation of aorta)
 Congenital lymphedema (hands/feet)

Front 7

Fragile X

Back 7

- FMR 1 gene Xq27.3 codes for FXMR
protein found in cytoplasm of many cells
but is most abundant in neurons and gonads
- Normal: 10-55 repeats
- Transmitting males & carrier females: 55-200
- Full mutation: >200
- Amplification occurs during oogenesis but not during spermatogenesis
- >230 repeats -> abnormal methylation -> extends to promoter region -> transcriptional suppression of the gene

 Incidence 1/1500 M and 1/8000 F
 common genetic cause of mental retardation

Clinical features:
Phenotype full mutation
 Mental impairment (learning
Disabilities-> to mental retardation)
 Abnormal facies
- Elongated face with prominent forehead and jaw
- Large protruding ears
 Macro-orchidism

Front 8

Fragile X-associated tremor/ataxia

Back 8

Occurs in males with premutation

Characterized by late onset cerebellar ataxia
and intention tremor

Diagnosis by:
MRI -> white matter lesions in the middle
cerebellar peduncles and/or brain stem

Front 9

FMR-1 related premature ovarian failure

Back 9

Occurs in ~ 20% of females with FMR1
premutation

Premature menopause (before age of 40 years)

Front 10

Prader-Willi syndrome

Back 10

set of genes located at 15q11-q13 on the
maternal chromosome is imprinted
(silenced)
 functional allele is provided by the paternal
chromosome
 deletion of the paternal allele results in
P-W syndrome
 Both copies of the alleles are from the
mother ie imprinted(uniparental disomy)

Clinical features:
 Poor muscle tone at birth
 Mental retardation
 Short stature, small hands and feet
 hypogonadism
 Obesity
 Face with narrow bifrontal
diameter, almond eyes, full cheeks

Front 11

Angelman syndrome

Back 11

 set of genes located on
chromosome 15q on the paternal chromosome is imprinted(silenced)
 functional allele is provided by
the maternal chromosome
 deletion of the maternal allele
results in Angelman syndrome

Clinical features:
 Mental retardation
 Large mouth and prominent chin
 Ataxic gait and seizures
 Inappropriate laughter (happy
puppets)

"Mom's little angel"

Front 12

Gonadal Mosaicism

Back 12

 Results from mutation that occurs
postzygotically during early embryonic
development
 mutation affects only cells destined for
gonads
 gametes carry the mutation
 somatic cells are normal
 Explains how “normal” patients will have 2
or > children with an autosomal dominant
defect

Front 13

MERRF (myoclonal epilepsy & ragged red fiber disease)

Back 13

-Mitochondrial Gene Mutations
-Mitochondrial encephalomyopathies

Clinical features:
Myoclonus, ataxia, lactic acidosis,
weakness, seizures,progressive
dementia, hearing loss

Diagnosis by:
Succinate dehydrogenase stain (on picture)

Front 14

MELAS (mitochondrial
encephalomyopathy lactic acidosis and
stroke-like episodes)

Back 14

-Mitochondrial Gene Mutations
-Mitochondrial encephalomyopathies