Case #5 Translocational Down Syndrome Flashcards
Patient’s mother’s History
Shawana Ubo mother, 23 years old
Bbay girl that was 2500 grams, 30 week gestation
Baby Hx
decreased muscle tone
low birith weight
protential for developing respiratory issues b/c baby is not full term
Facial features
nasal root, flattened maxillary and malar region
produces characteristic appearance fo trisomy 21
Facial profile is flater than normal (middle and right image)
Hands and feet are short and rounded and may have a palmar (plantar) crease.
Hypotonia is present
Floppy Infant Syndrome (FIS)
consider it as a potential Dx
What diseases have infant hypotonia as a symtpom (8)
- Krabbe disease
- Prader-Willi Syndrome
- Aicardi syndrome
- Myasthenia gravis,
- Kernicterus
- Muscular Dystrophy
7, Rett’s Syndrome - Spinal muscular atorphy
- Marfan’s syndrome
Krabbe syndrome
CNS disorder;
globoid cell leukodystorphy
autosomal recessive
Prader-Willi syndrome
Chromosome 15q deletion
exhibits genetic imprinting (differnt phenotype with paternal versus maternal inheritance)
Aicardi syndrome
X-chromosome mutation
ass with absence of corpus callosum
Myasthania Gravis
autoimmunie disease of NMJ
Kernicterus
Bilirubin-induced brain dysfunction
Muscular Dystrophy
X-linked damage to skeletal muscle
Rett’s syndrome
Nuerodevelopmental disorder ass. with microencephaly, small hands and feet
Marfan’s Syndrome
autosomal dominant mutation in CT with mutaiton in FBN1 which assocaites with tumor necrosis factors B-1 (TNF-Beta)
Spinal Muscular Atrophy
Collection of genetic muscle mutations both autosoal and sex-liinked
most of thema re recessive in inheritance pattern
Baby Barika’s symptoms
dysmorphic features including upslanting palpebral fissures, epicanthal folds, poor moro reflex
What was Barika’s cardiac exam
prouces holocystolic murmur
What were Barika’s hands lke
short with wtout and stubby fingers
Prominant palmar crease
What are signs and symptoms caused by FAS (5)
- low birth weight
- small head circumference
- fialture to thrive
- organ dysfunction
- facial abnormalities, inclduing smaller eye openings, flattened cheekbones, and indistinct philtrum (underdeveleoped groove between ose and upper lip)
B/c of FAS, as child maturees, may exihibit
epilepsy
developmental delay
poor coordination/fine otor skills
poor socialization skills, such as difficulty buidlign and maintinta freinsdhips and relatting to groups
lak of imagination or curiosity
learnng difficulties including poor memeroy, inability to understand concepts sucha s time and money, poor language comprehension, poor problem-solicng skills
behavior prolbems including hyperactiivyt, inabiltiy to concentrate, scial withdrawal, subborness, impulsiveness, asnxiety
What is moro relex-
remove body weight of baby from pad, rleease head and allow it to fall back again, normal response is for baby to have startled look, arms shoudl move sideways with palms upa nd thumbs flexed, may cry for a minute, as reflex ends,infatn draws its arms back to body with elbows flexed, then rlexases
Absence moro reflex on both sides uggest
damage to brain or spinal cord
Absene on only one side
suggests ether broken clavicle or injruty to brachial plexus
What is a holosystolic murmur
murmur heard throughout all of systole and can be ass. with a mitral valve or tricupside valve regurgition or ventricular-septal defect
what is a TTE
transthoracic echocardiography (TTE) is a protable and noninvasive and provides rapid sonogram of heart
What is the clinical trial called?
Biology Study of Transient Myeloproliferative Disorder (TMD) in cChildren with Down Syndrome
What is the rationale of clinical trial
Studying the genes expressed in sampels of blood from patients with DS may help doctors ID biomarkers related to cancer
Purpose of clinical trial
to looka t blood samples from newborns with DS.
Necessary to est database of ino of inants iwth gentic disorder only, cancer only, and comorbi presentation of both diseases
How long does genetic testing last
a couple days to proecss
What is incidence of Tirsomy 21
Most common autosomal disorder-
1/700-1000 live births
What is the majority of cases of DS caused by
nondisjuntion
47, XX, +21
47, XY, +21
Who was the disorder named after
John Langdon Down
when dd he discoer it
describedd cohort of children with mental retardation that had very similar morphological characteristics in 186
first named them mongoloids
WHen does trisomy 21 occur (translocation)
error or nondisjunction occurs in teh egg or sperm cell that becomes the zygote and leads to TRISOMY 21,
error is at very beginning of development, every cel that comes from this zygote will hvae an extra chromosome 21
what is Robertsonian Translocation?
rare cause of DS,
unbalanced
occurs beween two ACROCENTRIC chromosomes and fusion of two long arms of each chromosome occurs with loss of short arms (not deleterious)
What kind of “muaiton” did Shawana have?
Balanced translocation
most common between 14 and 21
How did Barika get DS
Mom’s 14,21 + normal 21 from EACH parent (2 21s), then chidl will have DS
What is inheritance pattern>
Chance inheriting 14,21 translocation?
Chance of developing DS
Offspring has 50% chance of inheriting 14.21 translocatino from affected parent
25% chacne offpsring ris for developing DS
Can children be phenoyptially norma?
if mother passes along her nomral 14
if mother passes her 14,21 without passing along an additioanl chromosome 21
What is the mutated gene refereed to
14q21q (two q arms)
what is MOSAIC type of DS
nondisjucntion of 21 occurs very early in MITOTIC division AFTER FERTILIZATION so only one of the two cell lines shows a trisomy for Chromsoome 21
Therefore, peopel with DS have 2 cell lines- one with normal nmber chromosomes, and one iwth extra #21
How is Mosaic DS Dx?
detected by blood test at birth or during AMNIOCENTESIS or CVS duing pregnancy
Typically chromosomes in 20 different cells are counted
If 2+ / 20 cells are normal (have 46 chromosomes) and others have extra #21 (total of 47 chrosomeoms) , bab is said to have mosaic DS
What happens if mosiacism is supected
Cytogenetiist ( chromosome specialist) will suualy count extra cells to confirm Dx
What is a cytogenetecisst
chromosome specialist
How is Mosaicism described? What if there are a total of 50 cells. 10 cells are normal cell lines and 40 have extra number 21 chorosomes
The level of mosaisicm is said to be 80%
or 40/50 !
How accurate is percentage mosaism. Are biopsies usually done
while % is usually determiend by blood cells, % may be different in other tissues or parts of the body! (i.e. 80% can actually have full trisomy in skin or brian cell)
Biopsies are not usually done b/c theya re invasive and usually dont give any inof bout how a eprson with mosaic DS will ultimately funciton
what is the GENE-DOSAGE EFFECT of Trisomy 21 mechanims
DS pehonotype is caused by increased expression of specific genes
What does extra copy f proximal part of 21q.22.3 lead to
gives rise to phenotype of DS including mental retardation, facial features, hand anomalies, and cardiac defects
What is the “DS Critical Region”
theory that only a small protion of the chrosoome actually needed to be triplicated to get effects seen in DS
not a small isolated spot, but likely several ares that are not necesarly side by side
HOw many genes does Chrosome 21 have
200-250 genes
salles chrosome in teh body in ter so number of genes
GEnes that may contribute to variable pheontype in DS include
Superoxide Dismutase (SOD1) COL6A1 ETS2 CAF1A Cytathione BEta Synthase (CBS) DYRK CRYA1 GART IFNAR
APP, GLUR5, S100B, TAM, PFKL
Has any gene been fully linked to any feature ass iwth DS>
NO!
SOD1
overexpresion may cause premature again and dec fucntion of immune system
role in Senile Dementia of Alzheimers type or decresed cogntion is sitll speculative
COL6A1
over expression may be the cause of heart defect
ETS2
over expression may be the cause of Sk abnormalities
CAF1a
overexpression may be detrimental to DNA synthesis
CBS (Cystathione Beta Synthase)
overexpression may disrupt metabolism and DNA repair
DYRK
overexpression may be cause of mental retardation
CRYA1
over expression may be cause of cataracts
GART
overexpression may be cause of cataracts
IFNAR
gene of expression of Interferon, over expressio may interefire with immune system as well as other organ ystems
what are most common cardiac defects
Endocardial Cushion defect
ventricular septal defect
tetralogy of allot
GI defects ass with DS
duodenal atresai (closure or absenec)
annular pancreas
Hirschpung disease
Long term consequence of DS
higher risk of leukemia, hypothyroiism, cervical spine instability
What IQ do they have?
20-35, severe
35-50 moderate
50-70 mild
Is there a cure of DS
no
AAP.org- american acadamey of pediatrics
How to manage if hchld has it
screen children for cardiac defects
GI defects
Hearing and vision loss
hypothyroidsim
What kind of prenatal screenign can be done?
1st trimester with combo of fetal ultrasound to meausre nuchal translucency
Blood tests to measure levels of pregnancy-ass. plams protein A (PAPP-A)
HCG
What kind of creenign can be done at 15-20 week gestation
quad screenign consisting of alpha fetal protein,
estriol
HCG
inhibin A
amniocentesis of CVS can be performed to acheive a definitieve diagnosis
Social implications of having DS or being a caregiver
yep
