Genetic Flashcards
Name 6 medical and 4 developmental characteristics to monitor in 22q11 syndrome
1) Epilepsy
2) Hypothyroid
3) Immune deficency
4) Obesity
5) T2DM
6) Hypocalcemia
7) Congenital heart disease
8) Hypertension
9) Hearing loss
10) scoliosis
1) IDD
2) Anxiety
3) ADHD
4) ASD
3 syndromes on ddx for facial features of FASD?
Prader Willi Syndrome
William syndrome
22q11
Risk of microarray to review with families
1) Incidental findings
2) Variants of uncertain significance
3) Psychosocial consequences (parental guilt, stress related to both positive or negative results)
In Canada, Bill S-201, The Genetic Non-Discrimination Act, passed in 2017, prevents employers and insurance companies from accessing genetic testing results or requesting an individual to undergo genetic testing
CPS Statement
NF1 developmental profile
-normal to low IQ –> 4-8% have ID
-poor visual-spatial perceptive skills
-LD in reading and spelling
-ADHD
- some studies suggest increased ASD
4 developmental and 4 medical characteristics of turners syndrome requring monitoring?
-ADHD
-anxiety
-LD - math
- ID (generally normal)
- spatial awareness/perception challenges
-mood
epilepsy
GI
sleep problems
congenital heart
delayed puberty
2 genetic syndromes in girls with mathematics learning disability
Fragile X
Turner syndrome
Down syndrome, asymptomatic, 3 strategies for management of atlantoaxial instability
parental education on the signs
avoiding contact sports
Importance of c-spine precautions
NF1 criteria and number needed for diagnosis
2/7:
- axillary freckling
- 2 or more neurofibromas or one plexiform neurofibroma
- 2 or more lisch nodules (iris hemartomas)
- optic glioma
- cafe-au-lait macules > or = 6 (>0.5 mm in pre-pubescent, >1.5 mm in post puberty)
- distinct osseos lesion
- family history or genetic mutation
5 features of fragile X premutation
fragile X associated tremor ataxia syntrome
- intention tremor
- cerebellar ataxia
- cognitive impairment (later)
May also have
- parkinsonism
- short term memory impairment
- executive dysfunction
- neuropathy of lower extremities
3 developmental features of T21 that may suggest benefit of using/teaching ASL
receptive > expressive language skills
Strength in visuospatial skills
Impaired pronunciation
Physical features of angelman syndrome
Williams syndrome organ disorder and features associated with ELN gene deletion
Macrocephaly and GI polyps
DDx?
Ix?
Toddler, initially developing appropriately, then lost spoken language, new onset abnormal hand movements, cold hands and feet, what genetic test to do?
MECP2 mutation (Rett Syndrome)
Cognitive profile for Wiliams
mild IDD
Verbal > performance IQ
strength in expressive
visuospatial weakness
ASD symptoms
ADHD
Overly friendly (strength in expressive language and facial expression)
Child with polymicrogyria on MRI and bilateral spasticity. Top 3 differentials.
22q11.2
COL4A1
Congenital ZIka
Congenital CMV
Prenatal alcohol exposure
Child with cafe au lait macules and axillary freckling but has negative NF1 genetic testing. Name 3 DDx
Leigus syndrome (cafe au lait macules, freckling, no other features of NF1) - SPRED1 gene testing
Noonan syndrome
McCune-Albright Sydrome
William’s syndrome: cognitive profile. Name 3 relative strengths and 3 relative weaknesses. Name 3 behavioral challenges.
Strengths
- expressive language
- facial recognition
- short term memory
Weakness
- visuospatial
- motor skills
- cognitive impairment
Behavior
- executive function
- adaptive skills
- sensory processing
- anxiety
- emotional regulation
What is the genetic defect in Turner’s syndrome? What area of functioning on an IQ test would be the weakest? What learning problem is the most common in girls with Turner’s?
Partial or full monosomy of the second sex chromosome (45X0)
· IQ test: Low Performance IQ. Areas of weakness: Visual spatial, executive function, social cognition, processing speed
· Learning disability: NVLD and math
Pediatrics in Review (Loscalzo, 2008)
What are the four first-line plasma investigations from the TIDE protocol?
What are the two first-line urine investigations?
- Plasma amino acids
- Total homocysteine (fasting, minimum 3-4 h)
- Copper
- Ceruloplasmin
What are the two first-line urine investigations? - Organic acids
- Purines/pyrimidines (includes creatine metabolites)
- ?Glycosaminoglycans, oligosaccharides
Likely:
Amino acids
Urine organic acids
homocysteine
microarray
NDDs in NF1
ID
ADHD
SLD
ASD rates unknown but social difficulties common
Language disorders
why should you not do screening xray in trisomy 21 for screening
cervical instability
- not predictive of future symptomatic issues
- falsely reassure
inadequate mineralization prior to 3 years old - no use
2 genetic syndromes associated with math SLD
Turner Syndrome
Fragile X
major features of Rett
midline hand movements (stereotypic hand movements)
Regression in speech
Regression in fine motor
Stereotypic hand movements
Normal early development
cold hands and feet (poor circulation)
Age 1-4 regression, recovery/stabilization by 5 years old
Clinic criteria and exclusion for Rett
All 4 clinical criteria
Atypical Rett 2/4 + 5/11 supportive
Exclusion criteria
- head trauma / severe infection
- metabolic disorder
- grossly abnormal development before 6 months
MECP2 mutation can cause other NDDs that don’t fit with classic Rett (or atypical) = MECP2 related disorder
Neurologic symptoms of premutation of Fragile X
FX- associated tremor/ataxia syndrome
Ataxic
Tremor
Parkinsonism
Neuropathy of lower extremities
Autonomic dysfunction
progressive cogntiive impairments
Executive function issues
Working memory
Strategies to treat aggression in FX - non medication
Decrease overstimulation
Involve psychologist/BT
identify triggers
reduce reinforcing behaviors
Medical and developmental issues to follow in 22q11.2 (Velocardiofacial syndrome)
Cardiac - CHD
Palate abnormalities
Immune deficiency
Calcium
Seizure
GI motility
Growth
cervical spine anomalies
Learning disabilities, developmental delay (70-90%)
25% schizophrenia
language 2’ hearing
ASD 20%
ADHD
Anxiety
Medical complications of NF1
CNS:
Brain tumors
Seizures/Epilepsy
Impairment in coordination/balance/FM
Polyneuropathy
Headaches
MSK:
Dysplasia (long bone, sphenoid wing, vertebral)
Scoliosis
Osteoporosis
Vascular:
Arterial hypertension
Pulmonary hypertension
Stroke
Cardiac
Congenital anomalies
pulmonary valve stenosis
mitral valve anomalies
hypertrophic cardiomyopathy
Pulmonary
Diffuse lung disease
Endo
Delayed puberty
Growth restriction
Cognitive profile in Turner syndrome
Most have normal cognitive abilities
May have decreased non-verbal abilities (compared to their verbal abilities)
Difficulties with visual spatial skills, math
Difficulties with executive functioning, processing speed
Increased rates of ADHD exist in TS
Motor deficits may exist
Social learning may be a challenge - social immaturity, vulnerability
Physical findings of turner
Short stature
Congenital lymphadema of hands/feet
Webbed neck
Nail dysplasia
Narrow/high arched palate
Short forth metacarpal or metatarsals
Shield chest – widely spaced nipples
Low hairline at neck base
Cubitus valgus
Madelung deformity of the forearm and wrist
Clinical features (medical and developmental) of Smith Magenis
DDx for prader willi
chromosomal deletion
Strategies for managing atlantoaxial instability
- Annual surveillance for symptoms (history and neuro exam)
- Caution regarding contact sports and trampoline use (no trampoline use before age 6 and then only supervised)
- Cervical spine precautions during medical interventions
- Counsel regarding warning signs of subluxation
- Will need screening for special olympics (possibly other sport activities as well)
If symptomatic:
Cervical spine XR in neutral position
Referral to pediatric neurosurgeon or orthopedic surgeon
3 reasons why sign language is beneficial for children with Down Syndrome
High risk of developing/worsening hearing loss
Relative strength in visual spatial skills
Relative strength early gesturing
Weakness in expressive language vs. receptive language skills
Two treatable reasons for cognitive impairment in T21
hearing loss
Cataracts/visual impairment
Hypothyroid
Seizures - 5-13%
risk factors for lead exposure in child with T21
developmental delay - at higher risk of putting non-food items in their mouth
sensory seeking (IDD or ASD)
List 4-6 physical features
in Klinefelters
gynecomastia
micro-orchidism and testis
tall stature
wide arm spam
intention tremor
most common genetic abnormality 1/600
Physical Features of Noonan
You are seeing Jack, a 2-year-old boy with global developmental delay. On examination, he has hypotonia, lax joints, soft skin, and a cardiac murmur. He has dysmorphic facial features consisting of a broad forehead, a short nose, and a wide mouth with full lips.
a) What syndrome does he have?
b) What is his expected cognitive profile?
c) What is the typical behavioural phenotype?
d) List two common psychiatric co-morbidities.
Strength in short term verbal memory, visual spatial weakness, mild ID
Executive function/ADHD, overly friendly, non-social anxiety
ADHD, anxiety, mild ID
4 red flags of IEM
regression
seizures
hypotonia
Movement disorders - lip smacking
19-month-old female child initially normal development, says “mama” at one year of age. Then loses all languages. History of seizures and fever. Significant hypotonia, no purposeful hand movements. Profound GDD. Lip smacking and tongue protruding.
Microarray
MECP2
WES
Features of Tuberous sclerosis
Long term consequences of NF1
Hypertension
Stroke (moyamoya)
increase malignancy risk
osteopenia/recurrent fractures
cardiac issues
Klinefelters cognitive profile
IDD (slightly below average)
Low verbal comprehension
Deficit in language production
SLD reading and writing
Low gross and fine motor skills
Difficulty with coordination, speed and dexterity
Unclear profile given historical data bias
2 year old Rafael is referred to you for work of global developmental delay. On history, you find that he has had frequent illnesses requiring antibiotics and he has had a ventricular septal defect repair as well as repair of a bilateral cleft palate. On physical examination, you note posteriorly rotated ears and a slightly small chin. (a) What is the most likely diagnosis? (b) What one test would you order to confirm the diagnosis?
(c) guidance for school entry
(d) risk factor for neuropsychiatric disorders
22q11.2
Microarray
High incidence on learning and behavior challenges
monitor & accommodate
ADHD
ASD
IDD
SLD
Speech
Schizophrenia
Your next patient is Reena, a 3-year-old girl with cognitive impairment, severe speech delay, epilepsy, microcephaly, unusual hand movements, and ataxia.
a) What are the top two genetic conditions on your differential diagnosis?
Angelman - maternal deletion of the UBE3A gene on chromosome 15
- tremulousness of the limbs
MECP2
Sleep problems in Angelman
First line test for PWS
Genetic testing through methylation study
features of PWS by organ system
-Growth - initial FTT, short stature when older, obesity in childhood, hyperphagia
-Head and neck - strabismus, difficulty feeding as infant
-GU - undescended testis, hypogonadism, small phallus in males, hypoplasia of clitoris in females
-MSK - small hands and feet, osteopenia/osteoporosis, scoliosis, kyphosis
-Endo - GH deficiency, thyroid issues, adrenal dysfunction
-Neuro/cognitive - low tone, seizures, IDD (mild), severe SLD
-Sleep - OSA
List 5 behavioural and psychiatric complications in PWS:
Food seeking behavior, hyperphagia, food hoarding, stealing food
Eating non-food items
Rigidity (especially around food)
Skin picking, rectal picking
perseverative behaviors
OCD, psychosis, anxiety, ADHD
4 strategies to help with hyperphagia and food seeking PWS
Putting food away (avoiding commercials, putting food away)
Educating family about food habits and avoiding providing as reward
Routine and structure around food
Locking up foods
Dietician to support balance diet
What is the genetic test for myotonic dystrophy?
What is 2 DSM diagnosis in childhood onset myotonic dystrophy?
DMPK gene (type 1)- DM1
IDD
ADHD
Anxiety
Mood disorders
NF 1. Long term complications
Klinefeltders cognitive profile
mean intelligence slightly below controls (broad range of IQ)
verbal IQ lower than performance IQ
language deficits = lower academic performance and social withdrawal
expressive language more affected than comprehension
neuromaturational delays with reductions in gross and fine motor skills, coordination, speed, dexterity, strength - may effect writing skills, speed on timed activities, athletic activities with peers
features of Smith-Magenis syndrome
Facial features
Mild to moderate infant hypotonia/feeding problems/FTT
Developmental delay, IDD, or speech delays
Stereotypies, maladaptive beahviors
Sleep disturbances
Short stature
obesity
brachydactyly
peripheral neuropathy
optho or otolaryngological abnormalities
You have recently made the diagnosis of ASD in a young boy. His history and clinical evaluation is remarkable for language and intellectual deficits, seizures, hypermotoric and ataxic movements, paroxysms of laughter, and happy disposition. List one genetic syndrome you would consider in this patient. What is the associated gene? What testing would you consider for this patient.
Angelman syndrome (C15q11-13 maternal deletion) – DNA methylation analysis
Characteristics of Cornelia de Lange
ASD
cognitive profile of Williams syndrome?
Cognitive: Usually MID, difficulty with relational vocab and pragmatics, visual spatial/construction (block design); Good at concrete verbal skills, non-verbal reasoning
typical behavioural phenotype: Indiscriminately social, trouble with social cues, making/keeping friends
Physical and medical features angelmans
Physical Exam:
Microcephaly, brachycephaly
Excessive tongue protrusion
Light-coloured eyes and hair
Dark eye lashes
Hypotonia
Hyperreflexia
Tremor
Ataxia
Dysmorphic features - deep set eyes, prominent chin, macrostomia, small and wide-spaced teeth
Seizures
Motor stereotypies
angelmans developmental profile
Developmental & Cognitive Features
GDD/IDD (severe/profound predominates)
ASD
Language disorder
Impaired information processing
Motor deficits
**Visual impairment d/t poorly developed choroid & optic disk; strabismus; hyperopia
Behavioural phenotype
Compulsive laughter
Happy disposition
Hyperactivity
Peculiar communication -
Mouthing objects
Motor stereotypies
Williams syndrome genetic test & 4 physical features
Features of William’s that are due to ELN gene deletion:
Peripheral pulmonary artery stenosis
Supravalvular aortic stenosis
**Blood vessels are thicker and less resilient than normal d/t loss of elastin
Short stature
Hyperflexible joints
Soft skin → premature skin wrinkling
Lung problems
Abnormalities of GI tract
5 clinical features of angelman
GDD/IDD
Language disorder/language delay
Happy disposition
Compulsive bouts of laughter
Ophthalmological problems and visual perception deficits
Hypotonia, ataxia, motor delays
Self injurious behavior
