Congenital Hearing Loss

Universal hearing screening is only a part of what?

A comprehensive habilitation program. First step is identifying HL, then work up and diagnosis, then management of a child with hearing loss

What is the primary group that requires NBHS?

Children with genetic HL and no other features - this is 50% of children with HL. They have no obvious abnormalities but some can develop hearing loss later on. Some SNHL without other abnormalities is idiopathic. Can be mild or unilateral hearing impairment. May not be detected until adulthood

What does DNA stand for?

deoxyribonucleic acid

What is *karyotype*?

The number and appearance of chromosomes. Pairs 1-22 are autosomes and pair 23 is sex chromosomes

What is the mitochondrial eve?

named after the biblical Eve. African women ancestor to all human beings. Eve's mitochondrial DNA is found throughout humanity

Define the terms congenital, familial, and genetic

*Congenital*: trait present at birth *Familial*: trait appears in more than one family member *Genetic*: condition resulting from change or variation in genes (can be inherited or a new mutation)

What are the two types of mitochondrial hearing loss?

*MELAS* and *Kearns-Sayre syndrome (KSS)) MELAS: mitochondrial encephalopathy lactic acidosis stroke Kearns-Sayre Syndrome is short stature, ataxia, ophthalmoplegia and SNHL

How common are extra or missing copies of chromosomes?

0.4% of live births. Often see extra copies of of a chromosome (trisomy 21, 18, 13). Occasionally see delete copy of a chromosome, or portions rearranged (deletion, duplication, translocation, and inversion). Some abnormaliities are not compatible with life

Genetic hearing loss is chromosomal hearing loss. What are the three types?

1. Autosomal - involves genes on the 22 autosomal chromosomes 2. X-linked - involves genes on the sex chromosomes 3. Mitochondrial - only passes from mother to child

How are hearing losses caused by genetics classified? (8)

1. No associated abnormalities 2. external ear abnormalities. 3. musculoskeletal abnormalities 4. ocular abnormalities 5. integumentary system abnormalities 6. metabolic renal disorders 7. nervous system disorders 8. cleft and craniofacial disorders

A gene is made up of how many base pairs of DNA?

1000

How many chromosomes total? How many pairs? long arm is called what? Short arm?

46 chromosomes total (23 pairs). 22 are autosomal and pair 23 is sex chromosomes. Short arm is *p arm* and long arm is *q arm*

What did the Yoshinaga-Itano study find?

Age of identification of hearing loss has a great impact on speech and language development. Poor hearing can affect so much like health (quality of life), economic (productive life), and morally we are challenged because if we have this good test that has such a huge impact should we not use it?

What is auditory neuropathy?

Aka auditory dyssynchrony. Impairment of sound transmission from inner ear to brain. Clinically, can be mild to profoumd loss with worse than expected speech discrimination. Hallmark of AN is inconsistent response to sound Familial form described with mutation in the otoferlin gene (DFNB9). It is autosomal recessive. There areno syndromic features or radiologic abnormalities. Can be seen in Charcot-Marie-Tooth, and Friedreich's ataxia. Some may benefit from cochlear implants. The outer hair cells still function properly, so OAE test won't show this problem. But the ABRs will be absent or severely abnormal

What is the significance of the Colorado NBHS study?

Almost 150 000 children were screened, and ~300 were diagnosed with hearing loss. 82% had SNHL, 71% bilateral, and 47% has one or more risk factors. ~70 000 children tested in 1999 and 1/650 was diagnosed with hearing loss (Mild 7%, moderate 49%, severe 38%, profound 6% ). Overall 92% of affected newborns diagnosed by 5 months of age *Risk factors* for hearing loss were ICU stay, low birth weight, hyperbilirubinemia, family history, maternal infection, syndromes *Important note: 50% of these children with congenital SNHL had NO risk factors* So, we determined that NBHS is ideal but costly. Costs approximately $25 per hchild but a false positive costs $10k per case

What do we need to ask about during the family history taking to learn about genetic HL?

Ask if any family members have hearing loss (esp childhood impairment). Do any family members have syndromes? Do any family members have special schooling? Any family members with speech and language problems? Permanent childhood hearing loss due to a genetic cause?

What does autosomal dominant mean?

Autosomal dominant is one of several ways that a trait or disorder can be passed down (inherited) through families. In an autosomal dominant disease, if you inherit the abnormal gene from only one parent, you can get the disease. Often, one of the parents may also have the disease. A parent with an autosomal dominant condition has a 50% chance of having a child with the condition. This is true for each pregnancy. *the syndrome will be seen in every generation* Ex is Huntington's It accounts for 10% of all congenital hearing loss. Typically, hearing impaired children of hearing impaired adults. Dominant genes may lack penetrance, meaning the gene may not be expressed. Dominant genes may show variabe expressivity (different degrees shown).

What does autosomal recessive mean?

Autosomal recessive is one of several ways that a trait, disorder, or disease can be passed down through families. An autosomal recessive disorder means two copies of an abnormal gene must be present in order for the disease or trait to develop. Genes come in pairs. One gene in each pair comes from the mother, and the other gene comes from the father. Recessive inheritance means both genes in a pair must be abnormal to cause disease. People with only one defective gene in the pair are called carriers. These people are most often not affected with the condition. However, they can pass the abnormal gene to their children. Children born to these parents have a 1/4 chance of being affected by the condition. There is a 1/2 chance of being a carrier, and a 1/4 chance of being unaffected This account for 35-40% of all congenital hearing loss (up to 60% with unknown genes). This is the most common pattern of genetic hearing loss.

What are the three types of genetic HL with no other features?

Connexin 26, connexin 30, and auditory neuropathy

What is the etiology of genetic hearing loss?

Deafness affects about 0.3% of people. Congenital SNHL is 50% genetic, 30% non-genetic, and 20% idiopathic For genetic hearing loss, it's 75% autosomal recessive, 20% autosomal dominant, and 5% x-linked or chromosomal 70% of genetic hearing loss is non-syndromic, although there are over 400 syndromes

What is *mild hearing loss*? Do they need amplification or referrals?

Defined as 20-35 dB permanent SNHL for childre. Typically, 5-10% of the total caseload of audios and SLPs. Most of the time yes they need both amplification and referrals

What is the incidence rate of congenital SNHL? Congenital CHL?

Estimates for congenital SNHL are between 1/600 and 1/2000. congenital CHL is much less common

American Academy of Pediatrics (AAP) and Joint Committee on Infant Hearing (JCIH) made a *High Risk Register for Hearing Loss*. What is that?

Describes who is at risk for HL and or who should have repeat hearing assessments 1. Cargeiver concern (hearing, speech, language, developmental delay) 2. Family history of permanent childhood HL 3. NICU stay of more than 5 days, assisted ventilation, ototoxic drugs, hyperbilirubinemia 4. Prenatal infections (TORCH) 5. Craniofacial anomalies 6. Physical findings associated with HL syndrome 7. Syndromes with associated HL 8. Neurodegenerative disorders associated with HL (e.g., Charcot-Marie tooth syndrome 9. Postnatal infections associated with HL like meningitis 10. Head trauma 11. Chemotherapy 12. Recurrent or chronic OM (at least 3 months

How are AABRs administered?

Electrodes are placed on the baby's scalp and we test brainstem response by playing click sounds for the baby then recording the action potentials generated (could be EEG or EMG). This is automated but it still takes longer than OAEs and this one needs to be administered by techs.

What is connexin? What happens when it's mutated?

Genes are named sequentially as they are discovered. DFN = deafness gene, A = dominant, B = recessive, - = X-linked, and # = order of discovery DFNB1 is the first identified mutation of an autosomal recessive gene causing hearing loss. Mutation in the connexin 26 protein. The DFNB1 gene = gap junction beta-2 gene (GJB2) found on chromosome 13. Normally, it encodes for Connexin 26 protein (or GJB2 protein). 6 connexin proteins join to form a junction channel between cells in the cochlea (straivacsularis, support cells, etc). These allow K+ to move through the cochlea - hearing is dependent on that. If you don't ahve K+ in balance, you get SNHL. Any difference in base pairs on that gene causes connexin loss. This is an autosomal recessive condition - so it requires mutation of both copies of the chromosome. DFNB1 accounts for up to 50% of AR deafness. (25% of all genetic deafness and 15% of all deafness) About 1/40 of the North American population carry the mutation in the Connexin 26 (1/6000 births affected). No vestibular abnormalities or radiographic abnormalities

How are genetic and congenital conditions related?

Genetic conditions are always congenital, but congenital conditions are not always genetic CMV is a viral infection passed through bodily fluids - can be passed from mother to infant at birth (congenital) but it is not

What is the protocol for doing the NBHS?

Give the child OAE, if they fail give it again. If they fail again, give them an AABR. Having both is the second stage of testing

What impact does mild or unilateral HL have on speech and language development?

Has an impact on phonological awareness, high level language skills (like narration text-less stories), verbal and non-verbal reasoning, frequency resolution ability (mild loss), and sound localization ability (unilateral loss)

How can you pass a NBHS but have hearing loss?

Hearing loss could be outside of frequencies tested. It could be there but milder than the 35 dB threshold. The technician could interpret the results. The equipment could malfunction. Hearing loss could develop after birth. The child could have audiotry neuropathy or dyssynchrony (OAE screens)

When are babies not tested?

Home births, parental refusal (like in Deaf community), the baby is transferred/discharged prior to the test, and certain hospitals may lack the capacity to perform the tests

Where else can you find DNA in the cell?

In the mitochondria - this is maternal DNA and will come from female parent

What is mitochondrial inheritance?

Inheritance is only through the maternal lines. Affected males do not pass the genes. If mom has it, all offspring are affected The mitochondria is the powerhouse of the cell. It is the site of energy creation to sustain life and growth. All mitochondria come from the mother. Its DNA is not divided or recombined and there is no contribution from the father

When do congenital disorders present themselves?

May present at birth but may not fully express themselves until later in life (*late onset*) Time of onset should be used to differentiate these from acquired

What is the most common form of congenital hearing loss? Least common?

Most common is recessive. Least common is X-linked

What's more likely to be offered treatment? Bi or unilateral HL? SNHL or CHL?

Mostly children with bilateral SNHL. They get referred for hearing aids, speech therapy, and other referrals

Does passing a NBHS guarantee normal hearing?

No, cant tell if if the infant truly has noramlhearing, and can't be used to predict future hearing

How are OAE administered?

Normal cochlea produces low-intesnstiy sounds (OAEs) via the OHCs as they expand and contract. This is a good test because we can record these with no behavioural response required from the baby and it literally only take a few seconds

How often do OAEs give false pos results? AABRs?

OAEs give false pos results 3-10% of the time AABRs do only 1-3% of the time

What are the two methods of NBHS?

Otoacoustic emissions and automated auditory brainstem response

Explain the connexin 30 mutation

Some people with SNHL only have one mutation in connexin 26. If it's AR, then why do they have SNHL? Many are also found to have a mutation in a nearby gene GJB6, which codes for connexin 30. Deafness may result in a single connexin 26 mutation AND single connexin 30 mutation

Genetic hearing loss can be split into two main divisions. What are they? What is each comprised of?

Syndromic and non-syndromic. *syndromic*: AR/AD. chromosomal, or x-linked non-syndromic: AR/AD, chromosomal, x-linked

What happens after a child fails the NBHS?

Testing is repeated before they leave the hospital. Automatic referral to audiology . In 2-3 months they go to an audiologist for diagnostic ABR. A lot of the time the child can have normal hearing

Why is it difficult to test children?

They can be uncooperative, they rip off electrodes etc. OAEs and AABRs require quiet, cooperative children. Luckily, we can test while they're asleep bc babies sleep a lot. But after 6 mos that goes down, so we have to sedate them *Otitis media* makes it hard to test children. The fluid in the ME can cause a CHL of 40 dB. BC testing is dificult in young children because of their unsutured skulls. BC ABR can be done but masking is hard for BC tests. Its' hard to know definitively if the HL is CHL or SNHL. *developmental delays or autism* can affect child. Behavioural testing is hard in these cases, and sedation is riskier in older children. If the child has an *audioneuropathy* then the OAE results can be misleading

What is transcription? What is translation?

Transcription is the unzipping of DNA and a strand of RNA that will code for a protein is created (this happens in nucleus). Then the strand goes into the cytoplasm where a ribosome will translate that strand of RNA into a protein. Even a single mutation of a base pair can cause a weird protein that will then cause hearing loss

What is another name for Down syndrome? What is it called when you have 3 chromosomes at 18?

Trisomy 21 Trisomy 18

Explain the connexin 26 (DFNB1) mutation presentation

USually presents as bilateral SNHL (typically more than 40 dB). 40% have severe to profound HL. 2% have mild HL and it's progressive so usually gets worse with age. It tends to do better than other types of deafness when fitted with cochlear implants. Testing can test for specific mutations but better to sequence the entire gene which costs about 300 Requires expertise in genetic counseling, particularly for testing non-affected family members for carrier status

Why do we do universal screening? What is the goal?

Universal means everyone ideally. That's a huge cost but is outweighed by the benefits. The cons are high financial cose, anxiety causes by false pos results. NBHS expanded to all of NS in 2007. Realistic aim is to screen more than 95% of kids by 3 months

What is X-link recessive??

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males (who are necessarily hemizygous for the gene mutation because they have one X and one Y chromosome) and in females who are homozygous for the gene mutation, see zygosity. So, males need to just have one copy, but females need two because if they get a fine X chromosome, then it can mask the mutated one Half of males will be affected., and half of females will be carriers If x-linked is dominant, which is RARE, the females are more likely to suffer from these disorders (since they have 2 X chromosomes)

What are the 4 bases of DNA? What are the base pairs?

adenine, guanine, thymine, and cytosine cytosine - guanine adenosine - thymine