Genetics Flashcards
It is a genetic syndrome characterized by midline defect- microphthalmia, cleft lip and palate, associate with VSD and dextrocardia
Patau syndrome- trisomy 13
Routine screen done on 1st TM that combine ultrasound of nuchal translucency and blood test- PAPP-A and B-HCG
Combine screening test
- done at 11-13 wks
- Detect aneuploidies with false positive rate 5%
newborn presenting with macrosomia, macroglossia, abdominal wall defect, hemi hyperplasia
Beckwith-Wiedemann syndrome
Perioperative challenge for children with beckwith-weidemann
Intubation/Airway due to macroglossia
Most common cause of trisomy 21
Non-disjunction (3 copies of chromosome 21)- 94%
others:
translocation- involve chromosome 14 and 21
Physical Features of T21
brachycephaly
flattened occiput
depressed nasal bridge
upslanting palpebral conjunctivae
epicanthal fold large protruding tongue
tranverse palmar crease
sandal gap
hypotonia
Congenital heart anomaly T21
endocardial cushion defect
AV canal, VSD, ASD
-Echo prior to d/c
Congenital GI defect T21
5-10% obstruction
Duodenal atresia
annular pancreas
Hirschsprung
anal atresia
Hematologic abN T21
- 50% polycythemia
- Leukmoid reaction or transient myeloproliferative d/o
- Inc risk 10-18x risk for Acute nonlymphblast leukemia (less 1 y/o), ALL
Common endocrine abN T21
hypothyroid (autoimmune thyroiditis)
DM
obesity
Medical issues of older T21
- Intellectual disability
- Seizure/ infantile spasm
- Dementia like syndrome
- Inc susceptibility to infection
- Strabismus/cataract
- Obstructive apnea
- Hearing loss
Outcome of T18
95% spontaneous abortion
Reocurrence rate 1%
Features T18
- dolichocephaly with prominent occiput
- micrognathia
- short palpebral fissures
- low set ears
- rocker bottom feet
- Over lapping 2nd & 5th digit over 3rd & 4th
Prenataly, gold standard to diagnose chromosomal abN
Amniocentesis
Reoccurence risk of T21
- Nondisjunction 1% above mom-age specific risk
- Unbalance translocation de novo- 1%
- Balanced translocation parent: 10-15% mom, 2-5% dad
No need to test parents if nondisjunction/mosaic
What is the syndrome which presents as:
A neonate presents with:
- short-limbed dwarfism
- fine, sparse hair that is lighter than that of other family members (hypotrichosis)
- immune deficiency.
Cartilage-hair hypoplasia
- mutation of the RMRP gene on chromosome 9p13
- autosomal-recessive
- most common in Old Order Amish and Finnish populations
Infant develops progressive abdominal distention. She does not have a spontaneous bowel movement. A contrast enema shows a narrow-caliber rectum and transition point in the sigmoid colon. A rectal suction biopsy finds no ganglion cells.
What does the baby have?
Hirsprung Disease
- congenital absence of enteric ganglia along a variable length of intestine,
- Incidence in 5,000 births.
- About 70% of HD cases occur in isolation
- Coexisting Down syndrome is present in 2% to 10%
Infant with
- rhabdomyoma
- hypopigmented ashleaf macules
- intracranial tumor
- seizure
- mental deficiency
- One parent has the same condition
Tuberous sclerosis
- autosomal dominant (chromosome 9 and 16)
Newborn presenting with
- pulmonic stenosis (60% incidence)
- hypertrophic cardiomyopathy
- short webbed neck, lymphedema
- hypertelorism, downward eye slanting, low-set ears
- pectus excavatum
- cognitive deficits (35% incidence)
- bleeding diathesis
Noonan syndrome
- autosomal dominant,
- a mutation in the PTPN11 gene
Newborn presenting with:
- omphalocele
- macroglossia
- macrosomia
- hemihyperplasia
- neonatal hypoglycemia
Beckwith-Wiedemann syndrome
Also presents with:
- visceromegaly
- embryonal tumors (eg, Wilms tumor),
- cytomegaly of the fetal adrenal cortex (pathognomonic if present)
genetic defect (most common to least)
- Gene imprinting
- Methylation defects
- paternal uniparental isodisomy
- craniosynostosis
- syndactyl of hands and feet (usually involves 3 digits)
Apert syndrome
- mild to severe intellectual disability
It is the most common of the syndromic craniosynostoses
- no hand/feet abnormalities
- no intellectual disability
- Hydrocephalus
- bilateral choanal atresia
Crouzon syndrome
Craniosynastosis plus
- notable for foot abnormalities
- first toes are short and wide, and bend away from the other toes. T
- syndactyly of the toes.
- the hand is almost never affected
- The lifespan is expected to be normal.
Jackson-Weiss syndrome
Prenatal history associated with Beckwith–Wiedemann syndrome
- female monozygotic twinning, with discordance
- assisted reproductive technology
Most common infantile mitochondrial d/o
Leigh sydrome
- gliosis
- dymyelination
- capillary necrosis
- necrosis of the brain
- Associated with WPW and HCM
Test combination of AFP, B-HCG, unconjugated estriol, inhibin PAPP-A and nuchal translucency
-What does it screen for
Sequential screening
- Trisomy 13, 18, 21, spina bifida
Test that uses fragments of placental DNA in maternal blood stream
NIPS
- identify pregnancies with trisomy 13,18, 21, sex chromosome aneuploidies
- higher sensitivity and specificity than sequential screen
PPV and NPV of NIPS for t21
PPV- 94% for high risk, 50-81% for low risk
NPV- 100%
What is a major anomaly
Has significant medical or cosmetic impact- never considered part of normal variation
What is a minor anomalies
- uncommon in general population
- do not have medical impact
Incidence of anomalies
- 1 minor- 20% of healthy newborn
- 2 minor- 0.8%
- 3 minor- 0.5%; have a 20% chance of a major anomaly
Classification of constellation of anomalies:
It occurs more frequently together but no unified underlying etiology
Association
-ex VACTERL
Classification of constellation of anomalies:
Abnormal formation due to external force
Deformation
Ex: oligohydramnios d/t renal anomaly- flattened face
Classification of constellation of anomalies:
Growth arrest that has been developing normally
Disruption
ex amniotic bands
Classification of constellation of anomalies:
Abnormal fetal structures due to underlying genetic, epigentic, environmental factor
Malformation
Classification of constellation of anomalies:
Group of related anomalies from a single major anomaly that alters (follow) the surrounding or related structures
Sequence
Ex: Pierre Robin- microretrognathia causing tongue to impede closure of embryonal palatal shelves resulting in cleft palate
follow- path- sequence
Classification of constellation of anomalies:
major and minor anomalies that occur in predictable fashion with a single underlying etiology
Syndrome
can be genetic or teratogenic
Newborn presents with:
- macrosomia
- macroglossia
- Abdominal wall defect
- hypoglycemia
What syndrome is this?
Beckwith-Wiedemann Syndrome
- imprint disorder located in chromosome 11p15.5
- Test: Methylation study
- associated with assisted reproductive technique
- most sporadic
- typical features lost during childhood
Complication or outcome for Beckwith-Wiedemann Syndrome
- Wt/ ht >p90
- Normal development
- Embryonal tumors (Wilms, hepatoblastoma)
- Monitor AFP and abdominal ultrasound
- Neonate presents with cholestasis
- PE: triangular facies, broad forehead, deep set eyes, small pointed chin, bulbous nose
- Xray: butterfly vertebrae
- Has renal anomalies
Diagnosis?
Allagille syndrome
Autosomal dominant , develops portal hypertension
True or false: Trisomy 18 is no longer given as a specific example of a lethal condition that would not warrant a trial of neonatal resuscitation
True
As per American Heart Association and AAP
- shared decision-making is encouraged with families.
- Palliative care, a trial of resuscitation, and intensive intervention are all recognized as potential medical approaches for patients with trisomy 18.
Have global developmental delays but also the potential to meet 9- to 12-month milestones
Cardiac surgery may increase quality of life
True or False
All trisomy syndromes are associated with inc maternal age
True
What are the findings in triploidy
Severe growth restriction
syndactyly
clubfeet
No increased risk for reoccurence
It presents with short limbs, ribbon like long bones and mulitple fractures
Osteogenesis imperfecta
- Involves: COL1A1, COL1A2
- Sporadic
- 6% reoccrence rate
- Type II most severe
It presents with
1. large polycystic kidney
2. post axial polydactyl
3. occipital encephalocele
Meckel-Gruber Syndrome
Autosomal recessive
Reoccurence: 25%
Due to ciliary dysfunction
It presents as:
1. Female
2. Fetal edema- excess post nuchal fold or dorsal edema of feet
3. Cardiac: aortic stenosis fr bicupsid valve or CoArc
Turner Syndrome
DX: routine chromsome plus FISH for Y chromosome (could be mosaic)
Add: ECHO, renal US (horseshoe kidney)
No inc risk
Newborn presents with
1. SGA
2. microcephaly with round face
3. hypertelorism with downward palpebral fissure
4. single palmar crease
5. Cat-like cry
6. MR
Cri du chat (5p- Syndrome)
cat-like cry from hypotonia and laryngeal abnormality
Dx: high resolution chromosome, FISH
85% de novo, 15% translocation
-parents offered chromosome analysis
Newborn presents with
Cardiac
AbN facies
Thymic hypoplasia
Cleft lip/palate
Hypocalcemia
Contruncal defect/ Aortic arch abnormality: interrupted aortic arch, truncus, TOF
Broad facies, minor ear anomaly
DiGeorge/Velocardial syndrome
Del 22Q11.2
- Autosomal dominant
- Dx: high resolution chromosome studies, FISH
- Parents offered FISH
- Reoccurence de novo (low), parental deletion (50%)
Newborn presents:
1. growth restriction
2. broad forehead
3. periorbital fullness
4. long philtrum
5. wide mouth
6. supravalvular aortic stenosis
Williams syndrome
Del 7Q11.23
deletion of elastin gene
Dx high reoslution chromosome, FISH
Mostly de novo- no need parental study
Newborn presents with
1. Severe hypotonia
2. feeding diffculty
3. M: undescended testes; F: hypoplastic labia minora
4. almond shaped eyes
5. narrow bifrontal diameter
6. thick saliva
Prader Willi syndrome
secondary to:
1. deletion of paternal 15q11-13
2. Maternal uniparental disomy
3. AbN persistence of imprint paternal chromosome
Dx DNA methylation study, FISH, Karyotype
what is the most common molecular alteration for Beckwith-wiedemann syndrome
involves chromosome 11p15
loss of imprinting/methylation of maternal allele (50%)
A neonate presents with
* brittle, light-colored (white/gray) hair
* thin/absent eyebrows
* hyperelastic skin
* full cheeks
* high-arched palate.
What is the disorder?
Menkes disease
- kinky hair syndrome
- X-linked recessive
- mutation in ATP7A
Newborn presents with
* arachnodactyly with a positive “thumb sign”
* Respiratory distress
* CXR: cardiomegaly and pulmonary vascular congestion
What is the diagnosis
Neonatal Marfans Syndrome
* genetic disorder: mutation in the gene for fibrillin-1 (FBN1)
* occurs de novo
* Affects skeletal, cardiovascular, and pulmonary systems
* Most common presentation: arachnodactyly, , lens subluxation, flexion joint contractures and characteristic facial morphology (crumpled ears, redundant skin)
Cardiac presentation of neonatal marfans syndrome
- pulmonary and aortic root dilation (72%-100%)
- mitral valve prolapse (73%-100%)
- mitral valve regurgitation (89%)
- tricuspid valve regurgitation (67%)
- pulmonary valve regurgitation (22%)
- aortic valve regurgitation (11%)
Most infants with neonatal MFS die of CHF from mitral and tricuspid valve regurgitation
What are the different blots and what it identifies
SNOW
DROP
Southern Blot-DNA
Northern Blot- RNA
Western Blot- Protein
Female newborn presented with seizures difficult to control, absent corpus callosum, occular abnormalities and hemivertebrae,
Diagnosis?
Aicardi syndrome
- Tx: requires mulitple seizure meds
- Usually de novo vs Xlinked dominant
- Buzz words: female patient, agenesis of corpus callosum, intractable seizures, and ocular findings
It is the most common inherited cause of intellectual disability
Fragile X syndrome
- example of anticipation
- Result of result of a loss of function mutation caused by an unstable expansion of a CGG trinucleotide repeats
- Females with CGG expansions between 50-55 and 200 repeats (premutations) : risk of premature ovarian insufficiency and neurocognitive deficits
