Other Common Chromosome

Anomalies
UY, EARL V.
Trisomy 18: Edwards Syndrome

 1:6,000 incidence
 Prognosis very poor: ~88% die in the 1st year, ~10% survival to 10th year
 Survivors have significant neurologic delay
 There is an increase in incidence based on advanced maternal age
Trisomy 18: Edwards Syndrome

 CV anomalies(90-95%)  Dolicephaly/strawberry skull

 ASD  Low-set ears
 VSD  Hypertelorism
 PDA  Cleft lip and palate
 Dextrocardia  Skeletal abnormalities
 CNS anomalies(70%)  Clenched hands with an overlap of the 2nd and
3rd digits
 Choroid plexus cysts
 Radial ray anomalies
 Agenesis of the corpus calosum
 Absent thumb
 Dandy-Walker continuum
 Rocker-bottom feet(congenital vertical talus)
 NTDs
 11 pairs of ribs
 Abnormal facies
 Single umbilical artery (80%)
 Micrognathia
Trisomy 13: Patau Syndrome

 1:6000 incidence
 Early lethality in most cases, with a median survival of 12 days; ~80% die by 1 year; 10-
year survival ~13%.
 Survivors have significant neurodevelopmental delay
 There may be an increased incidence with advanced maternal age
 Trisomy 13: Patau Syndrome ctd
 CNS HNS malformation(70%)
 holoprosencephaly;
 microcephaly;
 enlarged
 Cleft lip often midline;
 Spina bifida
 Cardiac malformations(50-80%)
 Hypoplastic Left Heart Syndrome
 VSD
 GU anomalies
 Cryptorchidism
 Cystic renal dysplasia
 Abnormal facies (90%)
 Cleft lip and palate
 Microphthalmia
 Micrognathia
 Hypo/hyper-telorism
 Cyclopia with proboscis
 Skeletal abnormalities
 Post-axial polydactyly
 Vertical talus
 Clenched hands w/w/o overlapping digits
Turner Syndrome

 1:5000 incidence
 Only in females
 Important cause of primary amenorrhea, 1/3 of cases
 Characterized by complete or partial monosomy of the x chromosome
 Half have a 45, x chromosome complement(60%), other half will have mosaicism(30%)
and varied structural abnormalities of the x or y chromosome(15%)
 No association with maternal age
 2/3 of cases due to missing paternal sex chromosome
 Turner Syndrome

 MS  GU
 Scoliosis  Streaky uterus
 Short 4th metacarpal and metatarsals  Streak ovary
 Narrowing scapholunate angle  CV
 Madelung deformity  Aortic dissection
 Short stature  GI
 Webbed neck  Pyloric stenosis
 Cubitus valgus
 Pes planus
Turner Syndrome ctd

 45, X/46XY mosaicism can have turner syndrome which can be associated with male
pseudohermaphroditism
 can be defined using FISH method
 The presence of Y chromosome material in a small percentage of Turner Syndrome
sufferers may increase the risk of gonadoblastoma.
Turner Syndrome

 Diagnosis
 Karyotyping
 FISH
 Absence of Barr bodies
 Demonstration of a shortened fourth metatarsals and metacarpals
Turner Syndrome

 GH therapy daily at 5-6 years old onwards until 15-16 years old
 Somatropin daily
 Estrogen started at normal puberty
 Progesterone after or together with Estrogen(NHS, 2021)
Turner Syndrome

 Cardiac evaluation and management

 Evaluation of renal anatomy q3-5y
 Thyroid function evaluation esp of fT4 and TSH q1-2y
 Replacement therapy when necessary
 Hearing evaluation
 Orthodontic exam
 Orthopedic evaluation
 Weight
 Glucose intolerance(Saenger, 2001)
Noonan Syndrome

 Formerly called pseudo-Turner syndrome

 Results from mutations in genes associated with the RAS-MAPK pathway
 PTPN11(50%)
 Most common gene affected
 Encodes a protein-tyrosine phosphatase(shp-2) on chromosome 12q24.1
 Other genes affected are: SOS1(10-13%), RAF1(3-17%), RITI(5%), KRAS(<5%),
BRAF(<2%), MAP2K(<2%), and NRAS(only a few families)
 Affects both sexes
Noonan Syndrome ctd

 Overlapping phenotypes with:

1. LEOPARD syndrome:
1. lentigines,
2. Electrocardiographic abnormalities,
3. ocular hypertelorism,
4. pulmonary stenosis,
5. abnormalities of genitalia,
6. retardation of growth,
7. deafness syndrome,
2. Cardiofaciocutaneous (CFC) syndrome, and
3. Costello syndrome
Noonan Syndrome ctd

 S/Sx

1. short stature,
2. low posterior hairline,
3. shield chest, w/w/o pectus carinatum or pectus excavatum
4. Congenital heart disease
5. short or webbed neck
6. CV: CHD right-side lesions
7. Cryptorchidism
8. Blue/-green eyes
9. Bleeding disorders
Noonan Syndrome

 Chromosomal analysis in tandem with Karyotyping

 IGF-1 and IGF-binding protein 3
Noonan Syndrome

 Cardiac surgery
 Medication and/or transfusions
 GH replacement
 Corrective surgery for cryptorchidism
 Speech therapy
Klinefelter Syndrome

• phenotypically male
• 1:580 births
• most common cause of hypogonadism and infertility in male
• most common sex chromosome aneuploidy in humans
• 80% X47 XXY, 20% multiple sex chromosome aneuploidies
• Mosaicism: 46XY/47XXY
• The greater the aneuploidy, the more severe the mental impairment and dysmorphism
Klinefelter Syndrome

• S/Sx
1. Webbed neck with low hairline
2. Shield chest with widespread nipples
3. Abnormal ears
4. Micrognathia
5. Ears low-set prominent and protruding forward
6. Lymphedema of the hands and feet
7. 50% gynecomastia
8. Small testicles usu 3-4mL in vol
9. Azoospermia 90%; oligoasthenoteratospermia 10%
10. Mosaics have better testicular function
11. Problems with self-esteem in adolescents and adults
• Every additional X chromosome reduces IQ by 10-15 points
Klinefelter Syndrome

 Demonstration of Barr bodies

 Karyotyping
 Serum testosterone, FSH, LH
 Fertility studies
Klinefelter Syndrome

 Testosterone replacement therapy

 Breast tissue removal
 Fertility treatment (ICSI)
Fragile X Syndrome

o CGG repeat expansion silences the gene producing fragile X mental retardation protein
(FMRP)
o The larger the repeat expansion, the more significant the intellectual disability
o FMRP regulates the metabotropic glutamate receptor (mGLUr5) pathway
o FMRP deficiency alters the expression of matrix metalloproteinase(MMP) 9
o MMP9 cleaves ECM and cell surface receptors which allows synaptic and circuit
reorganization
Fragile X Syndrome ctd

 S/Sx
• M
§ Intellectual disability
§ Autistic behavior
§ Post pubertal macroorchidism
§ Hyperextensible finger joints
§ Facial features: long face, large ears, prominent square jaw
§ Fragile X-associated tremor/ataxia syndrome- premutation triple repeat expansions(55-200 repeats)
• F
§ Varying degrees of intellectual disability
§ Premature ovarian failure- Premutation triple repeat expansions

Full mutation (>200 repeats): mean IQ= 42

Fragile X Syndrome

 Diagnosis:
 Fragile X mental retardation (FMR-1) gene test
 Treatment:
 Supportive