Micro Del/Dup Syndromes Flashcards
In most cases, interstitial deletions come about due to?
unequal crossover between homologous regions
What are LCR?
low copy repeat elements
so it is a stretch of duplicated DNA >1kb in size and shares a sequence similarity >90%
What causes Williams Syndrome?
Deletion of 7p11.23
What gene is mainly responsible for Williams Syndrome?
contiguous gene syndrome, Deletion of 7p11.23:
ELN: elastin (connective tissue protein that stores energy + resp for passive recoil)
(cousin WILLIAM is really good at ELa)
What are classic findings in Williams Syndrome at birth?
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
Birth:
- aortic narrowing (AKA supravalvular aortic stenosis) –> scarring process ; can lead to diverticula –> UTI + diverticulitis (in colon) ; also inc risk for peripheral pulm stenosis, hypertension, stroke
- hypercalcemia (irritable + hard to console, kidney stones, poor feeding)
(*hint = bones, stones, abdominal groans)
- facial characteristics –> “Elfin facies” course facial features
^this is like classic triad
Describe the facial features of Williams syndrome in more detail
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
- so due to lack of connective tissue, develop coarse facial features and
- periorbital puffiness/hooded eyes
- Stellate irises (star/flare pattern)
- Epicanthal folds
- Medial eyebrow flare
- Shallow nasal bridge with upturned, square or bulbous nose
- Long, flat philtrum
- Large (patulous) lips, especially lower
- Wide spaced, peg shaped teeth
- “Jowly” appearance
Describe other findings associated with Williams Syndrome aside from classic traid
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
- Dev delay
- ID (75% w IQ <70)
- outgoing personality and want to engage in convo (“cocktail personality”)
- increased verbal skills
- poor visuospacial skills (like if draw house - parts are on dif parts of the page)
- ADHD, OCD, trouble regualting emotions
- short stature
- low tone
- hypothyroidism
- trouble sleeping
- chronic constipation
- progressive hearing loss
- sens to sound
- strabismus, hyperopia
What is the management for Williams Syndrome for infants-toddlers?
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
- serum Ca (sample from urine) every 4-6 mo until 2yo
- thyroid function test annually until 3yo
What is the management for Williams Syndrome for all ages that take place annually?
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
- medical eval
- vision screening - monitor for refractive errors + stabismus
- hearing eval
- monitor BP in both arms
- measure CA/creatine ratio in random spot urine & urinalysis
- cardio eval - annually for 0-5yo, then once every 2-3 years
What is the management for Williams Syndrome for that take place every 2 years?
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
- serum conc of Ca
- thyroid function + TSH level
What is the management for Williams Syndrome that take place every 10 years?
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
- renal + bladder US (looking for kidney stones + diverticulitis)
What is the management for Williams Syndrome for adults?
(contiguous gene syndrome, Deletion of 7p11.23; symp mainly due to ELN)
- oral glucose tolerance test (OGTT) starting at 20y to eval for diab mellitus
- eval for mitral valve prolapse, aortic insufficiency, hypertension, long QT interval, arterial stenosis
- eval for cataracts
What is the cause of Smith Magenis Syndrome?
Deletion of 17p11.2
main effect due to RAI1 (retinoic acid-induced gene 1)
What are the classic findings in Smith Magenis Syndrome?
(Deletion of 17p11.2 – main effect due to RAI1 (retinoic acid-induced gene 1))
- short statue
- dev delay
- congenital anom (heart)
- self-injurious behavior (onychotillomania (pulling fingernails) + polyembolokoilomania (sticking things in orifices))
- *note- they may not register pain well - so they may stick things in places or eat really hot things for sensory seeking behavior)
- reversal of melatonin cycle
What are some additional findings in Smith Magenis Syndrome?
(Deletion of 17p11.2 – main effect due to RAI1 (retinoic acid-induced gene 1))
- 50% have heart defects - screen w Echo
- 20-30% have seizures - clincially observe
- Mod ID
- Autistic char
- short stature (admin GH is not a for this treatment)
- scoliosis
- hearing, vision problems
- renal anomalies - renal US
What causes Potocki-Lupski?
Duplication of 17p11.2
What 2 of these syndromes are reciprocal to one another?
Smith Magenis + Potocki Lupski
What are the classic findings in Potocki Lupski?
(Duplication of 17p11.2)
- even though it is a dup, it can be pretty severe
- hypotonia + FTT
- severe heart defects –> aortic root dilation
- significant behavioral problems + mod ID
- sleep disordered breathing
- swallowing disorders
- speech delay
note - there are cases where parents are affected, and we do not know it bc mild
What are some facial features of Potocki Lupski?
(Duplication of 17p11.2)
- this can really vary pt to pt
- cannot always identify these as new patients
- some may have high arched eyebrows, broad forehead, shorter philtrum
What are management guidelines for Potocki Lupski?
(Duplication of 17p11.2)
- heart anom like aortic root dilation –> Echo every 2-3y
- scoliosis eval
- sleep disordered breathing –> sleep study + maybe swallow study
- PT/OT/ST as needed
- Renal US
- Hearing and vision eval
What is the cause of Rubenstein Taybi?
Deletion of 16p13.3
CREBBP gene most important
- 5-10% –> microdel
- 50-70% –> CREBBP seq
- 5-8% –> EP300 gene (that interacts w CREBBP on chr22)
(The 16yo CRaB’s BP was so high, he was RUBy red)
What are the main physical findings with Rubenstein Taybi?
- ptosis
- prominent nose & flat philtrum
- long columella (hangs over below the nostrils)
- prominent chin
- microcephaly
- short stature
- keloid scars
- hypertrichosis
- wide thumbs, radially deviated (70-97%)
- wide first toes (87-100%)
facial findings can be subtler, but usu the fingers/toes are more noticeable
What are some clinical features (non-physical) associated with Rubenstein Taybi?
- IUGR
- ID (IQ 25 - 79)
- 90% language delay (they are usu non-verbal)
- hypotonia + gross motor delay
- MRI abnorm:
– 74% corpus callosum
– 63% periventricular white matter
– 58% dysmorphic cerebellar vermis
– 32% olfactory bulb hypoplasia - 24-58% heart abnorm
- 24% hearing loss
- feeding problems
- kidney abnorm
- keloid scars
- hypertrichosis
- immune dysfunction (72% recurrent/severe infections, 12% autoimmune)
- neural crest derived tumors (can be all over, like neuroblastoma, oligodendroglioma, meningioma, pheochromocytoma, etc)
What is an important management guideline to keep in mind for Rubenstein Taybi?
- US in newborn in case there is tethered cord
- no cancer or immune sys screening currently
- and also to follow w Neuro, Growth, Opthal, Audio, Pulm, Cardio, GI, GU, Ortho, Dental
What is the cause of Langer Giedion?
deletion of 8p24
What are the two distinct syndromes of Langer Giedion?
- Trichorhinophalangeal Syndrome (Tricho: Hair; Rhino: Nose; Phalangeal: Fingers)
- Hereditary Multiple Osteochondromas
- TRPSII=TRPSI+HMO
- TRPS gene. EXT1 gene
What are the main physical findings of Langer Giedion?
Trichorhinophalangeal Syndrome
- Hair –> sparse, coarse, tendency to baldness bc falls out easily
- Nose –> broad columella (“pear-shaped”), hypoplastic nostrils
- Fingers (and toes) –> brachydactyly, cone shaped epiphyses (think X-ray pic)
- short stature
- IQ usu normal or a little lower
- bone abnorm (in fingers + elsewhere) can lead to pain, hip dysplasia, joint replacement
What are some findings of Langer Giedion aside from TRPS?
- so from the HMO (hered mult osteochondromas) –> multiple exostoses + enchondromata
- think of it as a growth of a bone coming off another bone, and it protrudes out
- ^ lead to disfiguration, joint limitation, some pain
- usu not cancerous
What are management guidelines of Langer Giedion?
(deletion of 8p24; TRPS gene. EXT1 gene)
- manage symptoms –> Ortho for pain or functional issues
- Eval for spinal stenosis as needed (looking for osteochondromas protruding into spinal canal + nerve pain)
- Skel x-rays to eval extent of findings
What is the cause of Miller Dieker?
deletion of 17p13.3
What are the main findings of Miller Dieker + genes assocaited?
(deletion of 17p13.3)
- Lissencephaly (‘smooth brain’ meaning no grooves in cortex bc not enough cortex devleoping) –> PAFAH1B1
- Epilepsy, dysmophism, congenital abnorm (cleft palate, tethered cord) –> YWHAE &/or CRK
- Dev level = 3-5 month old
What are the dysmorphic features associated w Miller Dieker + genes associated?
(deletion of 17p13.3; lissencephaly from PAFAH1B1)
- tall, large, square forehead
- wrinkling forehead
- flattened midface
- low set posteriorly rotated ears
- hypertelorism
- short, upturned nose
- prominent lateral nasal folds
What is the management for Miller Dieker?
(deletion of 17p13.3)
- Dev support
- airway mangement
- feeding support
- constipation meds
- hearing + visual screens
What is the FISH probe to detect 22q11.2 del syndrome?
TUPLE1
How common is 22q11.2 del syndrome?
1/1000
What is the key gene affected in 22q11.2 del syndrome?
TBX1
What percentage of 22q11.2 del syndrome is inherited?
10%
What are the main findings in 22q11.2 del syndrome?
- clinical constellation of findings –> all due to brachial arch derivatives
- micrognathia
- cleft palate
- parathyroid hypoplasia –> low Ca levels
- thymic aplasia –> low T-cell levels
- cardiac defect –> TOF, interrupted aortic arch, transposition of the great arteries
- sim to retinoic acid embryopathy
What are 2 other names for 22q11.2 del syndrome?
- DiGeorge
- VCL - VeloCardioFacial (bc Velo = velopharyngeal insufficiency (nasal speech), Cardio = heart defect, Facial = common facial feat like cleft lip and micrognathia)
- these were both existing terms before the del was found
What are some additional common findings with 22q11.2 del syndrome?
- dysmorphism
- learning disabilities
- hypernasal speech
- hypocalcemia
- thyroid abnormalities
- psych disorders (schiz, anx, dep, etc.)
- cardiovascular malformations
- renal anomalies
- strabismus
- cranial nerve defects (hearing loss, facial palsy)
- recurrent infections
- obesity
What are some notable outcomes with 22q11.2 del syndrome?
- risk of death = 4% dep on cardiac condition
- usu live into adults
- immune defect usu improves, but can sometimes present as Severe Combined Immunodeficiency (SCID)
- hypocalcemia –> can present as seizures or muscle spasms
