Micro Del/Dup Flashcards
How are interstitial deletions caused?
Unequal crossover between homologous regions
When you have a VUS microdup/del what do you do first?
Test the parents.
If inherited you cannot r/o incomplete penetrance and variable expressivity
Determine what genes are within the region and assess if it matches patient’s phenotype.
What is the cause of Williams syndrome?
Deletion of 7q11.23
- Contiguous gene syndrome
- Multiple contributing factors
What is the key gene in Williams syndrome?
- ELN = elastin, a connective tissue protein that stores energy and is responsible for passive recoil
- Arterial narrowing (scarring process)
- Coarse facial features over time
- Tissue laxity—diverticula (outpouchings) of bowel and bladder
What are the classic clinical findings in Williams syndrome at birth/infancy?
- Supravalvular aortic stenosis (aka: Aortic narrowing)
- Hypercalcemia
- Irritable!
- Kidney stones and intrarenal calculi
- Poor feeding
- “Stones, bones, abdominal groans”
- Facial Characteristics
- “Elfin facies”
What are the facial findings in Williams syndrome?
- 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
What are additional findings in Williams syndrome?
- Developmental delay
- Intellectual disability: 75% with IQ <70, remainder are borderline
- Outgoing personality
- “Gregarious” “Cocktail personality”
- Increased verbal skills/fluency (but often empty speech)
- Poor visuospatial skills
- ADHD, obsessive-compulsive, difficulty with emotional regulation
What are complications with Williams syndrome?
- Short stature
- Low tone
- Multiple arterial stenoses:
- Peripheral pulmonic stenosis
- Renal arteryhypertension
- Carotid arterystroke
- Hypothyroidism
- Hypercalcemia
- Low calcium diet
- Sleeping difficulty
- Chronic constipation
- Diverticula (out-pouching of the wall)
- Bladder—UTI
- Colon—Diverticulitis
- Progressive SN hearing loss, ear infections
- Sensitivity to sound
- Strabismus, hyperopia
What is the management in Williams syndrome?
Infants: Serum Calcium q4-6 mos until 2 years
Thyroid function test 1x/yr until 3 years
Vision screening (refractive errors and strabismus)
Hearing eval
Blood pressure (both arms)
Calcium/creatine ratio urine
Cardiology eval
Every 10 years renal & bladder US
Adults: Eval for DM
Mitral valve prolapse, aortic insufficiency, HTN, long QT, arterial stenosis
Cataracts
What is the genetic cause of Smith Magenis syndrome?
Which gene contributes to phenotype?
Deletion of 17p11.2
- Phenotype due to RAI1
- Retinoic acid-induced gene 1
What is the phenotype of Smith Magenis syndrome?
- Short stature, developmental delay, congenital anomalies (heart)
- Self-injurious behavior
- Onychotillomania
- Polyembolokoilomania
- Reversal of melatonin cycle
- Awake at night, sleep during day
What are complications of Smith Magenis syndrome?
- Heart defects in 50% – screen by echocardiogram
- Seizures in 20-30% – clinically observe
- Moderate intellectual disability – evaluate and learning plan
- Autistic characteristics
- Short stature – growth hormone with limited data
- Scoliosis – clinical screening
- Hearing, vision problems – relevant testing
- Renal anomalies – renal ultrasound
What is the genetic cause of Potocki-Lupski syndrome?
Duplication 17p11.2 (reciprocal to Smith Magenis)
What is the phenotype of Potocki-Lupski syndrome?
- Can be severe
- Hypotonia, failure to thrive
- Severe heart defects
- Significant behavioral problems and intellectual disability (mod)
- Can also be mild with diagnosis made in parent after affected child
What are the complications of Potocki-Lupski syndrome?
- Hypotonia
- Poor feeding/FTT
- Heart anomalies (Aortic root dilatation)
- Sleep disordered breathing
- Swallowing disorders
- Speech delay/verbal apraxia
- Moderate ID and autistic spectrum
What are the recommendations in Potocki-Lupski syndrome?
Recommendations
* Echocardiogram every 2-3 years
* Scoliosis eval
* PT/OT/ST Therapies as needed
* Renal ultrasound
* Hearing and vision evaluations
* Sleep study
What is the cause of Rubinstein Taybi syndrome?
Deletion 16p13.3
CREBBP gene most important
From microdeletion to a single gene disorder
* 5-10% caused by microdeletion
* 50-70% are from CREBBP sequencing
* 5-8% caused by EP300 gene (which interacts with CREBBP) located on chr. 22
What are the complications of Rubinstein Taybi syndrome?
- Intrauterine growth retardation (IUGR)
- Intellectual disability (IQ 25 to 79)
- Language delay (90%)
- Hypotonia and gross motor delay
- Short stature and microcephaly
MRI abnormality: - Corpus callosum (73.6%), periventricular white matter (63%), dysmorphic cerebellar vermis (58%), olfactory bulb hypoplasia (32%)
- Congenital heart: 24-58%. Wide range
- Hearing loss 24%
- Feeding problems, reflux, constipation
- Kidney abnormalities
- Keloid scars
- Hypertrichosis
Immune dysfunction (B –cell) - 72% with recurrent/severe infections
- 12% autoimmune issues
Neural crest derived tumors - 132 tumors in 115 individuals
What is the genetic cause of Langer Giedion syndrome?
Deletion 8q24
What are the findings in Langer Giedion syndrome?
- Hair: sparse, coarse, fine, tendency to baldness
- Nose: Broad columella, hypoplastic nasi alae (nostrils)
- Short stature
- IQ generally normal (15% with mild/moderate lower IQ–? bias)
- Short hands and feet, multiple finger anomalies
- Cone shaped epiphyses
- Can affect many other bones
- Complications: Pain, hip dysplasia, joint replacement
What are the skeletal findings in Langer Giedon?
Multiple exostoses and enchondromata
Can cause disfiguration, joint limitation, sometimes pain
Rarely, can lead to cancer
What is the genetic cause of Miller Dieker?
Deletion of 17p13.3
What are the important genes in the deleted region in Miller Dieker?
Lissencephaly (PAFAH1B1
gene)
YWHAE and/or CRK responsible for additional findings
* Epilepsy
* Dysmorphism
* Congenital anomalies
* Cleft palate, tethered cord
What are the facial features in Miller Dieker syndrome?
Dysmorphism:
* tall square forehead
* flattened midface
* low-set posteriorly rotated ear
* short upturned nose
* prominent lateral nasal folds
What is the management in Miller Dieker syndrome?
Symptomatic
* Developmental support
* Airway management/aspiration
* Feeding support
* Constipation medications
* Hearing and vision screens
