Syndromic Hearing Loss and Deafness Flashcards
What are some things that can reduce the risk of birth defects?
Taking 400 micrograms of folic acid every day, which helps prevents conditions like spina bifida
Stay up-to-date on immunizations
Get regular medical checkups and know the family medical history
Avoid tobacco, including second-hand smoke
Avoid drugs and alcohol
Prevent insect bites
What is the most common sensory deficit in humans?
Hearing loss
Is the prevalence of hearing loss lower in women than men?
Yes
Is hearing loss less prevalent in black people vs white people?
Yes
T/F: A large number of genes essential for normal hearing function have been identified
True
1% of the human genome or ~ 300 genes are associated with normal hearing
How many syndromes are known to include hearing impairment?
Over 400
What is hearing loss caused by?
Both genetic and environmental factors
Acting independently and together
Complex or multifactorial inheritance
What is gene mapping?
Identification of the approximate or exact location of a gene on a chromosome
The street address of the gene on the chromosome
What is gene cloning?
The production of exact copies (clones) of a particular gene or DNA sequence using genetic engineering techniques
DNA extracted from an organism contains all of its thousands of different genes
The genetic engineer must find the one specific gene that encodes the specific protein of interest
How are nonsyndromic loci named?
They are named according to their inheritance patterns
What are modifier genes?
Modifier genes can affect the phenotypic outcome of a given genotype by interacting in the same or in a parallel biological pathway as the disease gene
These modifier genes can modulate expressivity (severity), penetrance, age of onset, progression of a disease, or pleiotropy (two or more seemingly unrelated phenotypic traits) in individuals with Mendelian traits
What is homeostasis?
It is the ability of an organism or a cell to maintain internal equilibrium by adjusting its physiological processes
What is inner ear homeostasis?
The process by which chemical equilibrium of inner ear fluids and tissues is maintained
Is tight control on the ion movement across the cell membrane necessary for proper inner ear function?
Yes
What are the function of the inner ear?
Hair cell functions
Regulation of extracellular endolymph and perilymph
Conduction of nerve impulses
What are the major ions involved in inner ear homeostasis?
Sodium (NA+)
Potassium (K+)
What ions also play a significant role in inner ear homeostasis?
Chloride (Cl-)
Calcium (CA2+)
What is ion homeostasis controlled by?
Numerous ion channels and transporters in the plasma membrane of cells, especially cells lining the scala media
Are the ion channels of the inner ear regulated by various genes?
Yes
Are many disorders of cochlear hearing loss and vestibular dysfunction are caused by disruption of ion homeostasis?
Yes
The disruption of the strial ion transport mechanism is the final pathway common to many of these disorders
Genetic disorders associated with ion transport and pathways are often associated with permanent hearing loss
Disorders from other causes are often transient and may recover without treatment
What is the majority of non-syndromic hearing loss due to?
Alteration of proteins that prevent movement of K+ from the organ of corti to the lateral wall and into the stria
Can hearing loss result from both increased and decreased activity of the strial process?
Yes
What is increased K+ transport in the endolymph or increased endolymph production called?
Endolymphatic hydrops
What is decreased K+ transport in the endolymph or decreased endolymph production called?
Endolymphatic xerosis
Is endolymphatic xerosis caused by various genetic anomalies?
Yes
What is an example of endolymphatic xerosis?
Connexin 26 and KCNE1 and KCNQ1
What is connexin 26?
Gene mutation results in abnormal connexin gap junction proteins
Responsible by itself for 50 to 80% of all AR hearing loss
What is KCNE1 and KCNQ1?
These genes produce proteins that make up K+ channels on the apical stria
Their absence leads to reduced endolymph and associated hearing loss seen in Jervell-Lange-Nielsen syndrome
What are the different classifications for genetic deafness and hearing loss?
Chromosome disorders
External ear changes
Eye disease
Musculoskeletal disease
Renal disease
Cardiac system disease
Neurologic/neuromuscular system disease
Endocrine disorders
Metabolic disorders
Integumentary system disease
No associated physical or mental characteristics
What are additional classifications of deafness?
Congenital genetic group
Delayed onset genetic group
Congenital non-genetic group
Delayed onset non-genetic group
What does congenital mean?
Present at birth
What is cytogenetics?
A branch of genetics that studies structure and function of the cell, especially the chromosomes
Is hearing the lowest man on the totem pole when it comes to individuals with chromosomal abnormalities?
Yes
Often not the primary focus
Primary focus is survival
What trisomy’s can survive to term?
13, 18, 21, and X
What is another name for trisomy 13?
Patau syndrome
Is trisomy 13 rare?
Yes
Of the viable human trisomy’s, does trisomy 13 have the most severe birth defects?
Yes
How many survive with trisomy 13?
The majority of conceptions do not survive to term
Only ~ 5-10% of live births survive past one year
What are some clinical findings with trisomy 13?
Severe intellectual disability due to various brain defects
(Forebrain defects, Agenesis (complete/partial absence) of the corpus callosum Microcephaly)
Bilateral iris, retinal, and optic nerve colobomas resulting in blindness
A coloboma is missing pieces of tissue in structures that form the eye
Cleft lip/palate
Hand and feet polydactyly (supernumerary fingers and toes)
Heart defects such as ventriculo-septal defect
What are some audiologic findings that are associated with trisomy 13?
Abnormal helices
Low-set ear
Most children show a severe to profound bilateral sensorineural hearing loss or deafness
Are there abnormalities with the auditory and vestibular system for trisomy 13?
Yes
Why is hearing not often evaluated with trisomy 13?
Low survival rate
Significant and possibly life-threatening medical, neurological, and cognitive impairments
What is another term for trisomy 18?
Edwards syndrome
Is trisomy 18 more common in males or females?
Females
Possibly due to higher miscarriage of male fetus
What percentage of people with trisomy 18 die within the first week of birth?
50%
What percentage of people with trisomy 18 die within the first year of life?
90%
What are some characteristics of trisomy 18?
Profound intellectual disability with seizures
Small mouth with high arched palate
Clenched hands with overlapping fingers
Heart defects, which are often the cause of death
What are some audiological findings for trisomy 18?
Malformed and low-set pinnae
Temporal bone studies; abnormal middle/inner ear, including failed ossification of ossicles and retarded cochlear development
Based on temporal bone studies, most probably severely HI or deaf; audiometric analysis not reported
What is another term for trisomy 21?
Downs syndrome
What is the most common chromosome defect in humans?
Trisomy 21
How many babies with downs syndrome are born in the US annually?
6,000
Why can trisomy 21 be tolerated during development?
Chromosome 21 is the smallest somatic somatic chromosome with the fewest number of genes
What percentage of babies with trisomy 21 survive to term?
30%
What is the life expectancy for people with trisomy 21?
It went up to 60 years in recent years
Does downs syndrome occur in people of all races and economic levels?
Yes
It’s a democratic condition
Does the incidence of births of children with downs increase with the age of the mother?
Yes
But due to higher fertility rates in younger women, 80% of children with Down syndrome are born to women under 35 years of age
What are some characteristics of downs?
Almost universal intellectual disability and developmental delays; most common cause of intellectual disability
IQ decreases with age
Flattened facial features with furrowed & large tongue (macroglossia)
Short limbs
Short broad hands with transverse palmar crease
Hypotonia in infancy
Upslanted palpebral fissures
Epilepsy is common
Males nearly always infertile; females have reduced fertility
Congenital heart disease is common
40% affected with a potentially life-threatening heart defect
Increased susceptibility to infections including OM
What is a palpebral fissure?
The anatomic name for the separation between the upper and lower eyelids
How does IQ change for someone with downs?
The general IQ for a 2-year-old is 60 while their IQ might be 35 for a 10 year old
What are some audiologic findings for someone with downs?
Low-set pinnae
Stenotic external ear canals, with middle and inner ear defects
Hearing loss in 60% of cases secondary to serous otitis media and impacted cerumen in stenotic ear canals
Hearing loss can be conductive, SNHL, or mixed
Conductive is more commonly observed
What is a robertsonian translocation?
During a Robertsonian translocation, the participating chromosomes break at their centromeres and the long arms fuse to form a single chromosome with a single centromere
The short arms also join to form a reciprocal product, which typically contains nonessential genes and is usually lost within a few cell divisions
How common is a robersonian translocation?
About 1 in 1000 newborns has a Robertsonian translocation
In ~ 4% of cases of Down’s syndrome, the extra 21 is a result of Robertsonian translocation
What are the acrocentric chromosomes?
13, 14, 15, 21, and 22
How is the robertsonian translocation passed down?
In humans, when a Robertsonian translocation joins the long arm of chromosome 21 with the long arm of chromosome 14 (or 15), the heterozygous carrier is phenotypically normal or balanced
There are two copies of all major chromosome arms and hence two copies of all essential genes
However, the progeny of this carrier may inherit an unbalanced (abnormal phenotype) trisomy 21, causing Down Syndrome
Can a robertsonian translocation result in anything other than downs?
Yes
It can result in other syndromes as well
Including trisomy 13
What is mosaicism?
Presence of two or more cell lines (cell populations) that differ genetically in an individual or tissue but that are derived from a single zygote
Can mosaics in single genes be in somatic or germ cells?
Both
Does mosaicism explain the occurrence of rare autosomal dominant conditions in an offspring whose parents are phenotypically normal?
Yes
Such as Achondroplasia, hemophilia, and some bone diseases
What is x-inactivation?
Females have 2 X’s
X-inactivation prevents females from having twice as many X chromosome gene products as males
The choice of which X chromosome will be inactivated is random in humans and other mammals
But once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism
Are all women mosaics?
Yes
What are the three ways that trisomy 21 can be inherited?
Nondisjunction (95%), translocation (4%), and mosaicism (1%)
How does nondisjunction result in trisomy 21?
Prior to or at conception, a pair of 21chromosomes in either the sperm or the egg fails to separate (nondisjunction)
As the embryo develops, the extra chromosome is replicated in every cell of the body and accounts for an extra chromosome 21
How does translocation result in trisomy 21?
Part of chromosome 21 breaks off during cell division and attaches to another chromosome, typically chromosome 14
The total number of chromosomes in the cells remain 46 but the presence of an extra part of chromosome 21 causes the phenotype of Down syndrome
What is a ring chromosome?
A rare genetic condition caused by having an abnormal chromosome that forms a ring
One chromosome is intact, but the other forms a ring
How does a ring chromosome form?
The end of the chromosome breaks off and the two sticky ends fuse together
The broken fragments are lost, and with them any genes they may contain
Which chromosomes can turn into ring chromosomes?
Ring chromosome can occur in any chromosome but are more common in acrocentric chromosome
Are ring chromosomes inherited?
Mostly sporadic, sometimes inherited
In about 90% of familial cases the ring is inherited from the mother because ring chromosomes are associated with reduced fertility in men
Do ring chromosomes impact cell growth?
Yes
The formation of this chromosome alters division
The chromosome may become entangled, broken, or double in size
What can result in this abnormal division of a ring chromosome?
Cells may arise with the wrong amount of chromosome material, mosaicism
What is chimerism?
The presence of 2 sets of DNA, or organs that do not match the DNA of the rest of the organism
Very rare
Tends to occur very early in the embryonic development
Often the result of two non-identical twin embryos merging together instead of growing on their own
What characteristics do people with chimerism have?
Hermaphroditic characteristics, having both male and female sex organs, can be a sign of chimerism (infertility)
Can be seen in cases of bone marrow transplant
Alternately, small patches of different DNA can be present throughout the body
What is turner syndrome?
45, X0
Female phenotype
In 80% of cases, the paternal X is absent
Maternal age is not a factor
Monosomy in sex chromosomes
What are the clinical features of turner syndrome?
Short stature with thick or webbed neck
Wide chest with broadly spaced nipples and streak gonads
Patients are almost always infertile
IQ may be slightly below normal
Turner is a condition where an X-linked recessive trait may express phenotypically in females because only one X chromosome is present
What are the audiologic findings of turner syndrome?
Low-set, protruding pinna and narrow ear canals
Recurrent ear infections and chronic OM reported in >50% of cases
AAP recommends an otologic evaluation at every pediatric visit
What is klinefelter’s syndrome?
47, XXY
Male phenotype
Slightly higher risk with increased maternal age
Single most common cause of male infertility
Many men with an extra X chromosome do not develop KS
With higher number of X chromosomes, phenotypes tend to be more severe including severe heart defects and intellectual disability
What are some clinical features of klinefelters syndrome?
Tall and thin with disproportionately long legs
Development relatively normal till puberty when hypogonadism is more evident with gynecomastia
IQ in the low-normal range
Behavioral and psychosocial problems; poor attention & judgment
What are some audiologic features of klinefelters syndrome?
SNHL reported in ~ 20% of cases with poor auditory discrimination and delayed speech development
Are turner’s and klinefelter’s inherited?
No
Typically spontaneous mutation
Low fertility or infertility, so they can’t pass it on
What are the two most common AD syndromic syndromes?
- Waardenburg syndrome
- Branchio-oto-renal syndrome
What are the three most common AR syndromic syndromes?
- Usher’s syndrome
- Pendred’s syndrome
- JLNS
