Genetics Flashcards
Dysmorphology
- Aspect of clinical genetics that involves the syndrome diagnosis in children who have unusual facial features, congenital malformations and often have associated cognitive and motor delays.
- >3500 syndromes
- Some are instinctive recognized by past experience
- Others involve pieces of puzzles
Blaschko’s Lines
lines of embryologic ectodermal development
Chromosomal Disorders
- Part or whole chromosome is missing or duplicated
- Example: Down syndrome
- Tested by Karyotype
•Microdeletion or microduplication syndromes
- A very small piece of chromosome is missing or duplicated
- Cannot be seen on karyotype
- Examples: DiGeorge, velocardiofacial; williams syndrome
- Fish/ Array comparative hybridization (ACGH)
Single Gene Disorders
•Dominant (AD), recessive (AR), X-linked
- A mutation in a single gene causing a disorder
- AD: Marfan syndrome, neurofibromatosis, type 1
- AR: cystic fibrosis, sickle cell disease, Tay Sachs disease
- X-linked: Duchenne Muscular dystrophy
- Testing: Mutation analysis, DNA sequencing and or deletion testing
Triple Repeat Disorders
- Trinucleotide repeats in certain genes exceeding the normal, stable threshold which differences for each gene.
- Results may be interference of the normal gene or gene product
- Example: Fragile X, Huntington disease
- DNA tests for number for repeats
Multifactorial Disorder
- A combination of genetics and environment
- Examples: Cleft lip and palate; clubfeet; pyloric stenosis
- No current testing available
Epigenetic Disorder
- Changes are not in the sequencing but in the expression of the DNA
- Examples: Prader Willi; Beckwith-Weidman syndrome
- Testing by Methylation analysis
Receiving a genetic dx helps you to
- Informs reproductive decision
- Preventative strategies
- Explanation of what you can do
- Massive parallel sequencing will explain what is causing the patient’s problem
- Take an 11 year old who has a sudden cardiac arrest.
- Genome would tell the patient’s need for implant
Sequences
•A defect occurs and subsequent development is abnormal
•VACTERLS Association
- V – vertebral anomalies / dysgenesis, vascular anomalies
- A – anal atresia
- C – Cardiac anomalies
- T – trachea-esophageal (T-E) fistula
- E – esophageal atresia
- R – renal anomalies, radial dysplasia
- L – Limb anomalies
- S - Single umbilical artery
CHARGE
- C” for coloboma
- “H” for heart defects
- “A” for atresia choanal
- “R” for retardation of growth and development
- “G” for genitourinary problems
- “E” for ear abnormalities
Complexes
•Abnormalities in adjacent structures
•Goldenhar syndrome
- Affects one side of the face only. :
- Partially formed or totally absent ear (microtia)
- Chin may be closer to the affected ear
- One corner of the mouth may be higher than the other
- Benign growths of the eye
- Missing eye
•Major Anomalies
Easily identified
Involve easily identified malformations
•Congenital abnormalities
- Present at birth
- Does not imply cause
Minor Anomaly
- Physical difference that occur in fewer than 4% of the population
- More commonly in areas that are more variable and complex: face, hand
- 70% in these two area
Normal phenotypic variant
•Present in 4% or more of the population
•Some minor anomalies are markers for occult major malformations
- Sacral tuft of hair or deep sacral dimple: associated with occult spinal dysraphism
- Many genetic syndromes are specific patterns of minor anomalies occurring together
- Specific minor abnormalities of face, hands, feet-Down syndrome
Assess for Major malformation when…
•Three or more minor anomalies increased risk of having major malformation
Most common external anomalies
Face
Auricle
Hands
Feet
Normal Phenotypic Variant (10)
- Saddle (mildly upturned nose)
- Mild to moderate in bowing of lower leg
- Sacral dimple, not deep
- Mild syndactyly of second and third toes
- Toenail hypoplasia in the newborn
- Hydrocele of the testicle
- Epicanthal folds
- Unilateral epicanthal fold is indicative of torticollis
- Slanting of the palpebral fissures
- Brushfield spots (20% of normal newborns)
Frequent newborn findings
Stork bite
•Fine non-elevated pink to red capillary hemangioma at nape of neck, over central forehead and eyelids and in the lumbosacral region
Skull Physical Assessment findings
- Asymmetrical head or face
- Brachycephaly
- Flattened occiput
- Fontanels too large or small
- Overlapping sutures
Facial Proportions
Mandible/Maxilla
- Micrognathism: small mandible
- Retrognathism: Receding
- Prognathism (Projection of jaw beyond that of forehead)
Ocular hypertelorism
•A low nasal bridge will give the appearance of hypertelorism
Telecanthus
consequence of lateral displacement of the inner canthi
Minor abnormalities of the Face
- Synophrys – Fused eyebrows
- Flat bridge of nose
- Hypotelorism
- Anteverted nostrils
- Epicanthal fold
- Iris freckles
- Upward palpebral slant (mongoloid slant)
- Downward palpebral slant (antimongoloid slant)
- Blue sclera
- Epicanthal folds
- Different eye colors
Minor Malformations of the hair
•Circular pattern of hair (cowlick)
Kinky hair, brittle hair including eye brows.
•Hair patterning (4)
- Look for unusual hair pattern
- Low set hair line
- Widow’s peak
- Webbed neck
Asymmetrical Crying Facies
- Higher incidence of congenital heart disease
- Ventriculoseptal defects
- Atrial septal defect
- Patent ductus arteriosus
- Tetralogy of Fallot
- Velocardiofacial syndrome (22q11 deletion syndrome)
Eye Distances
Mean Length in a 5 yr old
- Palpebral fissure length
- Mean length in a five year old is 2.5 cm
- Short palpebral fissures is minor anomaly
Magic Number for Eyes
10 degrees
Slanting of Palpebral fissures
- Normal Horizontal or upward slanting with an angle <10 degrees
- Upward slanting angle >10 degrees
- Downward slanting
- External canthus lower than the internal canthus
Brushfield spots
White spots in Iris
Heterochromia**different colors in one eye – associated with a higher risk of retinal blastoma
Wilson Disease (Hepatolenticular Degeneration )
•Age of onset for Wilson disease
•between 8 years to the mid-50’s
•Presentation of Wilson Disease
- Severe liver cirrhosis.
- Kayser-Fleischer rings
- Deposition of copper in the cornea.
Accompanied by neurological disorder.
Normal distance between eyes
One eye length
Ear Positioning
more than 20 degrees, posteriorly rotated
Minor abnormalities of the auricle region
- Large ears
- Lop ear
- Lack of lobulus
- Lobe crease
- Thick helix or attached to scalp
- Protruding ears (due to lack of development of the posterior auricular ear muscle
- Low set ears
Ears slanted greater than 15 degrees from the perpendicular
Preauricular Tags
- Found anywhere along a line drawn from the tragus to angle of mouth
- 1.7 per 1,000 individuals
- Bilaterally in 6% of affected individuals
- Autosomal dominant inheritance pattern
Preauricular Pits
•Small openings at anterior margin of the helix
Goldenhar syndrome
- Look for facial asymmetry and microtia
- Unilateral or bilateral Hemifacial Microsomia (HFM)
- Microtia - Literally meaning “small ear”,
- Aural Atresia - Absence of the auditory canal
Other Problems: cleft lip/palate, hearing loss, epibulbar dermoids, vertebral anomalies and organ abnormalities including kidney and heart anomalies.
Fetal alcohol lips
Shallow groove
Mouth
Physical Assessment findings
- Small or large tongue (micro or macroglossia)
- Misshapen, missing or extra teeth
- Early loss of teeth
- Late eruption of teeth
- Thin upper lip
- Cleft uvula
- Smooth or abnormal philtrum
Recognition of Abnormalities
- Some minor anomalies run in families as a single variation
- As high as 14% of newborns have at least one minor anomaly.
- If there are three or more minor anomalies, there is approximately a 20% chance of a major anomaly.
Represent deformation due to altered mechanical forces affecting the development of otherwise healthy tissue
Enamel Hypoplasia
•defect in tooth enamel that results in less quantity of enamel than normal
Anodontia
Congenitally missing teeth
•hypodontia
congenital absence of one or a few permanent teeth without any systemic disorders
Hair – May be significant
- Excess body hair
- Hairline and hair distribution
- Large section of white hair in front – Waardenburg Syndrome
- Sparse or brittle hair
5 major diagnostic criteria for WAARDENBURG
- Sensorineural hearing loss
- Iris pigmentary abnormality (two eyes different color or iris bicolor or characteristic brilliant blue iris)
- Hair hypopigmentation (white forelock or white hairs at other sites on the body),
- Dystopia canthorum (lateral displacement of inner canthi
- First-degree relative previously diagnosed with Waardenburg syndrome.
Minor criteria for Waardenburg
- Skin hypopigmentation (congenital leukoderma/white skin patches(Face, trunk, or limbs - 30-36 %)
- Medial eyebrow flare (synophrys)
- Broad nasal root
- Hypoplasia alae nasi
- Premature graying of the hair (before age 30) .
Waardenburg syndrome Diagnosis
Two major or one major plus two minor
Dysmorphology Checklist
hair
- Normal
- Unusual texture
- Sparse/alopecia
- Low posterior hairline
- Low anterior hairline
- Unusual pattern extra whorls
- Unruly, uncombable
- White forelock
Cornelia De Lange
Hairline Low
Hypertrichosis – hair sticks up
Coarse features
Eyebrows are joined
Posterior rotated ears
Developmental delay
Eyelids not right
Postaxial
Ulnar side
Preaxial
Radial side
Brachydactyly
Abnormal digits
Most are autosomal dominant
Minor abnormalities of the Hands
- Clinodactyly (curved fingers)
- Syndactyly (some or all fingers united)
- hypoplastic
- Asymmetric length
- Camptodactyly – contracted
Malportion or disharmony in the length of particular segment of the hand
Nail Hypoplasia
•Incomplete nail development
•Clinodactyly
Curved or bent finger
Palmar Creases
- Formed from second to fifth month
- Once the palmar creases are formed, unchanged throughout life
- Single palmar crease occurs unilaterally in 4 % of general population
- Single palmar crease occurs bilaterally in 1% of the general population
- In Chinese population: normal phenotypic variant 16.8% of Chinese have unilateral crease
- Carefully evaluate for other problems
Palmar Creases
Trisomy 13
- Excess of arches
- Single palmar creases in 60%
Palmar creases
Turner Syndrome
•Predominance of whorls
47, XXY
•Excess of arches
Trisomy 21
- Usually all are ulnar loops
- With single palmar Creases in 50%.
Connective Tissue Disorder
Positive Thumb Sign
Sydney Line
Head line goes completely across palm
Positive wrist sign
If hands are long they overlap
Minor Anomalies of the FEET
- Asymmetric length of toes
- Clinodactyly of second toes with overlapping
- Syndactyl
- Short broad toenail
- Deep crease between hallux and second toe
Wide gap between hallux and second toe
Extremities
- Abnormally positioned feet
- Arachnodactyly
- Extremely long and thin extremities
- Loose joints
- Single Palmar crease
- Polydactyly
- Short or tall stature
Gynecomastia
Enlarged male breast
Widespread nipples
Laterally displaced nipples
Turner** (also see cubitus valgus)
Shield chest
Pectus Excavatum
A condition in which the breastbone sinks into the chest.
Pectus Carinatum
deformity of the chest characterized by a protrusion of the sternum and ribs
Umbilical Anomaly
Single umbilical artery – should have 2
Short umbilical cord
Minor anomalies of Genitalia
- Hypoplasia of the labia majora
- Shawl scrotum
- Condition in which the scrotum surrounds the penis
Abdomen/Back Anomalies
- Normal
- Extra skin/prune belly
- Umbilicus
- Hepatomegaly
- Splenomegaly
- Diastasis recti
- Umbilical Hernia
Evaluate not only height BUT ALSO…
Upper body segment: lower body segment ratio
Ash-leaf spot
white mark on skin
Cafe au lait
brown skin macule
Flammeus Nevis
flat red capillary skin stains
Leopard’s Syndrome (7)
Lentigines (multiple)
Electrocardiographic conduction abnormalities
Ocular hypertelorism
Pulmonary stenosis
Abnormalities of genitalia
Retardation of growth
Deafness
incontinentia pigmenti Whorl of pigment
Swirls on the skin,
swirls on the brain related to seizures and other health problems
Swirls follow lines of Blaschko
Major Anomalies (Head - 5)
•CNS
Anencephaly/Meningomyelocele
Dandy - Walker malformation
•Agenesis of the corpus callosum
•Hydrocephalus, Microcephaly, Macrocephaly
Craniosynostosis
•Occiput/flat or prominent
•Delayed Closure of Fontanel
Anomalies
Anencephaly
Absence of brain development
Absence of dermal covering
Coloboma
Cleft of iris or lid
Hypertelorism
Wide spaced eye
Cherry red spot
Red area of macula of the retina
Ectopia Lentis
- Major criterion
- Ectopia lentis
- Minor criterion
- Abnormal flat cornea
- Increased axial length of globe
- Hypoplastic iris causing decreased miosis
Major eye finding
Coloboma of the Iris
Feet – Major
Rocker bottom feet or curved foot
Abdominal major defects
Abdominal wall defects
Kidney malformation
Anorectal defects
Ambiguous Genitalia
- Hypospadias and bifid scrotum
- Micropenis
- Vaginal atresia
Unusual Growth Patterns
Neural Tube Defects
Neural tube is usually completed by 28th day of development: malformation can result in clubfoot, hydrocephalus, and spinal bifida depending on which part of neural tube is not closed.
Cleft Lip and Palate
Failure of fusion of the frontal process with maxillary process at about 35th day of gestation
BREAST CANCER, OBESITY, ALZHEIMER DISEASE, DIABETES ALCOHOLISM, HEART DISEASE:
Several inheritable traits are consider polygenetic
