Lecture 7 Flashcards
(32 cards)
what is a genetic disease?
o A constellation of physical and developmental findings associated with a genetic change
o Most diseases have a genetic component, but different penetrance = different likelihood of recurrence
o Mendelian genetics = dominant and recessive, sex-linked
Mode of inheritance affects genetic counseling
Risk of being born with the condition is stable, but the presentation is still variable!
modes of inheritance
o If a large amount of material is added or lost, a genetic syndrome will most likely be manifest
o If a single gene is affected, the role of the protein coded by that gene in development/metabolism will determine if the disease is inherited in a dominant or recessive manner
o If the gene is on the X chromosome, the condition is X linked and there will may be differences in penetrance between boys and girls
genetic counseling
o Familial disorder review
Include miscarriages, infant deaths
Pedigree
o Review of pregnancy-related screening
Pregnancy review for teratogens
o Review of newborn metabolic screening
o Developmental review
o Advice regarding current pregnancies
Clearest possible description of possible outcomes in later pregnancies
o Laboratory testing of patient and family when appropriate
o In down syndrome, it is an error in meiosis I phase where you have the wrong number of chromosomes
o Aneuploidies – too many or too few chromosomes
The older your eggs are, the more likely it is that there will be mistakes in this process
Different types of genetic changes
o Aneuploidies (abnormalities in chromosome number) Monosomies, triploidies, elimination or duplication of sex chromosomes
o Duplication or deletions
of a segment of a chromosome
o Uniparental disomy (epigenetic changes)
o Triple repeat expansions
threaten chromosomal stability
Genetic testing
o Karyotype
chromosomes of cultured cells viewed directly
Allows counting and visualization of gross defects
o Fluorescent in-situ hybridization (FISH)
Fluorescent probe seeks out known defects
o Microarray testing
o Whole Exome Sequencing
o Polymerase chain reaction (PCR)
Allows direct analysis of a gene
o Direct enzyme testing (fibroblasts)
aneuploidies
o Down syndrome – Trisomy 21
o Trisomies 18 & 13
These are the three trisomies (18, 13, 21) that are compatible with life
Trisomy 13 is very very serious and typically don’t make it past the first few months of life
o Kleinfelter syndrome (XXY)
o Turner syndrome (X0)
o Increasing incidence with increasing maternal age
But because young women are more likely to be reproducing, most kids with aneuploidies are born to young moms
down syndrome
o An extra copy of the 21st chromosome
Non-disjunction
Unbalanced translocation
Mosaicism
o Each child is different in their phenotype
Many associated conditions
Quite anxiety provoking, especially for new parents
common features of down syndrome
o Small, brachycephalic head o Upslanting palpebral fissures o Epicanthal folds o Flat nasal bridge o Small, folded or dysplastic ears o Midface hypoplasia o Protruding tongue – normal sized tongue but tiny mouth o Short neck o Excessive skin at nape of the neck o Hypotonia o Hyperflexibility of joints o Short broad hands o Transverse palmar crease o Incurved fifth finger o Hypoplastic middle phalanx of fifth finger o Space between the first and second toes o Not all of these characteristics are universal!
associated conditions to down syndrome
o Cardiac – 50 % have congenital heart disease
Endocardial cushion defect, VSD, ASD
Some will need heart surgery
o GI – structural and functional issues Intestinal atresia (most common: duodenal) Hirschsprung Disease GERD Constipation Aspiration of fluids into the lungs Feeding difficulties
o Endocrine – commonly affected system Thyroid dysfunction – thyroid can be congenital or acquired Short stature Diabetes mellitus Celiac disease
associated conditions to down syndrome
o Orthopedic: atlanto-axial instability, flat feet, hyperflexible
o Hematologic: leukemoid reaction, increased incidence of leukemia
o Eye: refractive errors, strabismus, nystagmus, cataracts
o Ears: high incidence of hearing deficits
o Immune: poor chemotaxis
o Neurologic: Low tone, increased risk of seizures
o Metabolic: high incidence of obesity
o Sleep: obstructive sleep apnea
o If you already have learning
management/screening: down syndrome
o Cardiac screen: echo at birth
o Hearing screen: birth, 6 months, at least yearly thereafter
o Eye exam: birth, within the first year, yearly thereafter
o Hematologic screening: birth, yearly, with symptoms
o Thyroid: birth, 6 months, yearly, with symptoms
o Celiac screen: every few years, with symptoms
o Sleep study: everyone by the 4th birthday
Very serious – decreases IQ, affects glycemic index, etc.
o Developmental screening for autism
o Regular dental care
o Nutritional and exercise counseling
o Strengths, potential
o Early intervention services
IFSP (Regional Center)
IEP (school district)
o Total communication
o Local support groups
adulthood and down syndrome
o Intellectual disability (almost universally)
This does not preclude a person with Down syndrome from having an incredibly meaningful and successful life
o Transition to adulthood Guardianship Long term financial planning Vocational training as part of the IEP Living arrangement
o Social network, connectedness
o Psychological and behavioral issues
Increased incidence of Alzheimer’s
o Sexual health
Family planning
Safety
turner syndrome
o Monosomy X (XO, or 45,X)
Loss of part or all of an X-chromosome
females 1:2000 (& ~15% of spont. abortions)
o Physical characteristics Webbed neck, low posterior hairline Edema of hands and feet, often at birth Short stature Shield chest Triangular shape of the face
medical issues associated with turner syndrome
o Congenital heart disease
Coarctation of the aorta
Mitral and aortic valve abnormalities
o Endocrine issues
Amenorrhea & infertility (streak ovaries)
Ovarian failure - absence of secondary sex characteristics
Obesity, diabetes mellitus and hypertension
o About 1/3 have renal anomalies
o Chronic middle ear infections
o Hearing loss
o Autoimmune disorders
Hypothyroidism
Celiac disease
o Learning differences
Deficits in non-verbal communication skills,
Deficits in spatial relationships, such as driving or riding a bike
Executive function
Kleinfelter’s syndrome
o 47 XXY karyotype
Too many X’s!
May have more than 2 copies of X chromosome
o Hypogonadism Small penis and testes Sparse body hair Less muscular body Gynecomastia
o Tall stature
o Fatigue
o Developmental delay or learning difficulties
May present as behavior problems
o Testosterone replacement can be helpful
chromosomal duplications/deletions
o Large portions of a chromosome are duplicated or deleted
o Commonly diagnosed by chromosomal microarray or FISH
o Examples: Williams syndrome – 7q deletion 22q deletion syndromes (Velocardiofacial syndrome, DiGeorge syndrome) Cri du chat syndrome – 5p deletion Miller-Dieker syndrome – 17p deletion Wolf Hirschhorn syndrome – 4p deletion
william syndrome
o Deletion within 7q11.23
o Facial Features Small upturned nose, Long philtrum (upper lip length) Wide mouth Small chin Puffiness around the eyes
clinical features of william syndrome
o Supravalvular aortic stenosis
o Failure to thrive
o Hypercalcemia
May present as terrible colic
o Renal anomalies in some
o Developmental delays and learning difficulties
Low muscle tone at first, then contractures
ADHD
o Friendly, loquacious ‘cocktail party’ personality
o Hypersensitive to sound
management of william syndrome
o Annual cardiac evaluations
o Infancy:
Feeding difficulties
Hypercalcemia
Constipation
o Childhood
Educational support
Support healthy socialization and safety
o Adulthood
Hypertension
Joint limitation
DiGeorge and 22q Deletions
o Incidence 1 in 4000 births
o Part of larger group of syndromes from 22q11.2 deletions called velocardiofacial syndrome
Defective development of 3rd and 4th branchial pouches of the embryo
Includes malformations of parathyroid glands, mediastinum, thymus, heart and great vessels
22q deletion pts physical exam
o Hypertelorism o Short palpebral fissures o Bulbous nose tip o Micrognathia o Ear anomalies o Often: cleft palate/lip o Murmur?
clinical features of 22q deletion
o Congenital heart defects
Aortic arch abnormalities
Tetralogy of Fallot
o Hypocalcemia
o Renal anomalies
o Immunodeficiency due to thymic agenesis or poor thymus development (cellular immunity)
cannot give live viral vaccines until immune status tested
o Hearing problems and speech difficulty
o Learning difficulties
management of 22q deletion
o Immune work-up –T cell and B cell function
o Hypocalcemia – supplementation and monitoring
o Cardiovascular work-up and management
o Monitor hearing, support speech
o Management of cleft palate
o Developmental support and educational support
triple repeat expansions
o Affects the stability of specific chromosomal regions
o Show anticipation – each generation has more and more repeats
Each generation presents early and with more severe symptoms
o Examples: Fragile X disease Huntington disease Myotonic dystrophy Friedreich’s ataxia Spinocerebellar ataxia
