Pediatric Genetics Flashcards
Common Referrals
- neurologic: autism, ID, DD, seizures, regression, ataxia, muscular
- cardiac: malformation, arrhythmia, sudden death
- sensory: hearing loss, vision loss
- birth defects: limb anomalies, craniosynostosis, CL/P, GU anomalies
- dysmorphic facial features
- tall stature, overgrowth, short stature, FTT
- immunologic disease
- dermatologic disease
- metabolic
- family history of genetic disease
- multiple systems affected in same person (most common)
Dysmorphology
study of structural defect, especially congenital malformations
Key Components of Dysmorphology Evaluation
- history
- pedigree
- physical exam
History
- prenatal history
- postnatal history
- growth and developmental history
Pedigree
- 3 generations
- ask about each pregnancy in chronological order
- note pregnancy losses, neonatal/childhood demises and causes
- presence of similar and dissimilar abnormalities in 1st and 2nd degree relatives
Physical Exam - Head
- head circumference
- examine fontanelles
- examine hair and distribution (aberrant hair whorls can represent aberrant brain development)
Physical Exam - Face
- forehead: hairline to brows (frontal bossing, sloping)
- midface: brows to upper lip, outer canthus to outer canthus (telorism, telecanthus, palpebral fissures, irides, epicanthal folds, nose shape, anteverted nares, philtrum, vermilion border, palate, celfting, open mouth-hypotonia)
- malar regions: upper ear to cheeks (ear symmetry/size/location, preauricular and postauricular differences, pits, tags, cheek symmetry)
- mandible: lower ear, lower lip, jaw (symmetry, prognathism, micrognathia)
Physical Exam - Neck and Trunk
- neck: short, webbed, nuchal folds
- chest: symmetry, pectus, widely spaced/supernumerary nipples
- abdomen: enlargement of any internal organs
Physical Exam - Genitalia
- external: ambiguous, testicular size/volume
Physical Exam - Back
- curvature
- identifiable defects (tufts of hair, sinuses)
Physical Exam - Hands and Feet
- hands: hand length, palm length, middle finger length, poly/syndactyly, pre/postaxial, clenched fists (T18, T13), clinodactyly, dermatoglyphics (arch-T18. whorl-SLOS, loop), palmar crease pattern
- feet: total foot length, poly/syndactyly, pre/postaxail, abnormalities
Physical Exam - Arms and Legs
- acromelia, mesomelia, rhizomelia, micromelia
- defects in epiphyses, metaphyses, diaphyses
- factured vs malformed bones (Halberd appearance - metatropic dysplasia)
Physical Exam - Neurologic
- mental status
- cranial nerves II-XII
- motor exam (strength, tone, symmetry)
- sensory exam
- reflexes (deep tendon, neonatal)
Craniosynostosis
- skull induces brain growth
- anterior fontanelles close 1-3y; posterior fontanelles close 1-3m
- sutures in skull allows for vaginal delivery
- metopic suture is first to close 3-9m and some may not close until adulthood
- craniosynostosis occurs when sutures close prematurely
- 10-20% of primary cases part of malformation syndrome
Scaphocephaly
sagittal synostosis
Trigonocephaly
metopic synostosis
Plagiocephaly
unilateral coronal or unilateral lambdoidal synostosis; positional deformation
Turribrachycephaly
“towering”; bilateral coronal synostosis
Cloverleaf/Kleeblattschadel
bilateral coronal and bilateral lambdoidal synostosis
Craniosynostosis Syndromes
- FGFR2-related isolated coronal synostosis
- Crouzon syndrome
- Pfeiffer syndrome
- Apert syndrome
- Muenke syndrome
Orofacial Clefting
- cleft palate more common in females
- cleft lip more common in males
- recurrence risk of isolated CL/P: 2-4%
- 30% CL/P syndromic
- 50% CP only syndromic
- other causes include maternal exposure to alcohol, cigarettes, valproate, maternal PKU, diabetes
- may be isolated
Genetic Causes of CL/P
- Van der Woude
- 22q11.2, CHARGE, Stickler (Pierre-Robin)
- T13, holoprosencephaly
Hemifacial Microsomia
- not genetic
- facial asymmetry +/- facial nerve palsy, mandibular hypoplasia, macrostomia, hearing loss, radial ray anomalies, cardiac anomalies, renal anomalies
- aka Goldenhar when epibulbar dermoid on eye
ADAM Complex
- asymmetric amputations, disruptions, deformations, adhesions, malformations and mutilations
- caused by entrapment of fetal parts in amniotic bands
- clinical triad: amnion-denuded placenta, amniotic bands, oligohydramnios-related deformation
CL/P Repair
- rule of 10’s for CL: 10lbs, 10wks, Hgb 10g/dL
- nasoalveolar mold helps seal palate and brings flesh of philtrum together
- CP repaired 10 months
CL/P Issues
poor feeding, VPI, poor speech, dental issue, psychological issues
Conductive Hearing Loss
involves structures of outer and middle ear
Sensorineural Hearing Loss
involves structures of inner ear
Causes of Hearing Loss
- 25% idiopathic
- 25% non-genetic: rubella, CMV, retinoic acid, prematurity, gentamicin exposure, trauma, tumor
- 50% genetic: 70% non-syndromic, 30% syndromic
Myopia
near-sightedness
Strabismus
poor coordination between eyes; eyes point in different directions when looking at an object
Exotropia
“wandering eye”
Esotropia
“cross eye”
Ambylopia
“lazy eye”
Nystagmus
eyes wiggle back and forth uncontrollably
Lisch Nodules
benign hamartomas iris; NF1
Stellate Irides
star pattern of irises; Williams
Coloboma
unfused irises; CHARGE
Heterochromia
different colored irises; Waardenburg
Corectopia
displacement of pupil; Axenfeld-Rieger
Cafe Au Lait Macules
- 10-30% have isolated CALM
- consider NF1 (CoC), McCune-Albright (CoM), Legius
ABCDE - Skin
A = asymmetry B = borders (coast of California, coast of Maine) C = color D = diameter E = changes over time
Collodion Membrane
- tight membrane present at birth that does not stretch
- may cause ectropion (eyelids turn out), eclabium (lips turn out)
- cracks and sloughs off over first few weeks
- associated with AR congenital ichthyosis
Lentigenes and Nevi
- caused by problem of migration of melanocytes
- associated with Noonan and congenital melanocytic nevus syndrome
Epidermolysis Bullosa
3 types depending on which skin layer affected
Non-Genetic Skin Findings
- eczema, atopic dermatitis
- Mongolian spot
- baby acne
- cradle cap
Cardiology Issues
- structural: valve malformation, heart malformation, coarctation, stenosis, dilation, dissection
- arrhythmia
- vascular problems
Autism
- complex disorder of brain development characterized by difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors
- present in 1/68 children
- 5-15% have identifiable genetic contribution; 85% no identifiable cause
- preponderance in males
- recurrence risk: 2-18%
- Autism Diagnostic Observation Schedule (ADOS) is gold standard for assessment
- screening at 18m and 24m
- testing includes CMA, autism/ID panels, WES
Normal Age Rolling Over
- gross motor
- 2-6mos
Normal Age Sitting Unassisted
- gross motor
- 5-7mos
Normal Age Walking
- gross motor
- 11-15mos
Normal Age “Mama/Dada”
- language
- 5.5-9mos (nonspecific), 7-13mos (specific)
Normal Age 2 Words
- language
- 10-16mos
Normal Age Combining Words
- language
- 17-24mos
Normal Age Thumb-Finger Grasp
- fine motor, adaptive
- 7-10mos
Normal Age Regard Face
- personal, social
- 0-2mos
Normal Age Feed Self
- personal, social
- 4.5-6.5mos
Normal Age Put on Clothing
- personal, social
- 20-30mos
Common Presentation of Developmental Disorders
- infant/toddler with motor delay
- toddler/preschooler with language delay
- school age child with school failure
Evaluations for Developmental Disorders
- pediatric neurologist
- developmental pediatrician
- audiologist
- psychologist
- speech and language pathologist
- OT
- PT
Developmental Disability
- groups of conditions due to impairment in physical, learning, language, or behavior areas
- conditions begin during developmental period, may impact day-to-day functioning, usually last throughout lifetime
- present in 15% of children
Developmental Delay
- any significant lag in child’s physical, cognitive, emotional, or social maturity
- used for preschool children to determine eligibility services
- not used after 5y
Intellectual Disability
- characterized by broad impairment in cognitive and adaptive functioning
- typically with IQ <70, diagnosed before 18y
- cognitive skill cannot be reliably assessed before age 6y, so may be diagnosed with global developmental delay
Etiology of Developmental Disabilities
- mostly unknown causes
- single gene/Mendelian disorders
- CNVs/cytogenetic causes
First Line Testing Recommendation for GDD/ID/ASD
- CMA
- FMR1 DNA analysis
- WES if other testing uninformative
Pediatric Testing Strategy
- tiered approach beginning with highest yield test and reflexing to other testing if negative
Secondary Findings
- typically adult-onset conditions with medical actionability
- only pathogenic variants reported
- 1-3% of have finding on WES
- ACMG 59
Incidental Findings
- more common in tests not specific to phenotype and likely unrelated to primary reason for testing
- consanguinity
- non-paternity
T/F: To age 18, the parent is the guardian unless other arrangements made
True
Healthcare Proxy
advance medical directive in form of legal document that designates another person to make health care decisions in case person rendered incapable of making own wishes known
Guardianship
determined by a judge and allows another person to have legal rights over individual
