The pattern of inheritance is Autosomal dominant if individuals in each generation are affected;
Both males and females are equally likely to be affected (Figure 2).
iii. Affected individuals are usually heterozygote's with one normal and one deleterious copy of the gene for the disorder, and each offspring of an affected individual has a 50% chance of inheriting the deleterious allele.
iv. There may be variable expression among affected individuals, and some who must have the deleterious allele may show no phenotypic signs.
I. Autosomal recessive inheritance
A. The mode of inheritance of a disorder is Autosomal recessive if the abnormal phenotype is expressed only in individuals who have two copies of the deleterious allele.
B. Heterozygotes are not affected and are often called carriers.
C. The probability that a child of carrier parents will be affected by one quarter;
D. The probability that an unaffected sibling is a carrier is two third.
E. If a hearing impaired parents has an affected sibling or the parents are related, the etiology is most likely to be deleterious gene with the mode of inheritance being Autosomal recessive.
F. Recessive inheritance probably explains most case of profound sensorineural hearing loss when family history is negative, and there is no known environment factor that could be responsible.
II. X - Linked inheritance
i. If a disorder has an X- linked dominant pattern of inheritance with complete penetrance, then all daughters of affected fathers are affected.
ii. In the case of an X- linked recessive trait, the majority of affected individuals are male because they have only one chromosome (Figure 3).
iii. Female have two X chromosomes and may be carriers, but are unlikely to be affected.
iv. Sons of carrier mother - 100% chance
v. Daughters - 50% and remaining will be 50% carriers.
vi. Note that, although females have two X chromosomes in
a cell, in general one of the two is randomly activated early in embryonic development.
vii. Thus, females are mosaic, with each cell having one or other X chromosome active.
III. Mitochondrial Conditions
a) Mitochondria are structures in the cell that produce the energy that cells need to survive.
b) Neither the mitochondria nor the cell can exist without the other.
c) Changes in the mitochondrial genes can also result in syndromes involving hearing loss.
d) Mutation in the mitochondrial genome can affect energy production through adenosine triphosphase synthesis and oxidative phosphorylation. Tissues that require high levels of energy are particularly affected.
e) Typically, mitochondrial diseases involve progressive neuromuscular degeneration with ataxia, ophthalmoplegia, and progressive hearing loss [11-20].
IV. Mitochondrial mutation and syndromic hearing loss
a) Systemic neuromuscular syndromes such as Kearns Sayre Syndrome, mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes etc frequently have hearing loss as one of their clinical signs. It is due to heteroplasmic mutation.
b) [Homoplasmic mutation- most healthy individuals appear to have only a single mitochondrial DNA gene type which is homophasic but in many mitochondrial diseases, the mitochondrial DNA population is mixed which is the heteroplasmic condition].
c) SNHL caused by Diabetes Mellitus is inherited by A3243G in the gene for tRNA.
d) Late onset HL develops after onset of diabetes
e) In addition to diabetes mellitus, diabetic insipidis, otic atrophy and hearing loss have been well described as the Wolfram syndrome usually an autosomal recessive condition.
a) Gene defect on mitochondrial DNA (mt DNA).
b) Associated with deletion in the mitochondrial genome.
c) A & G stand for - Adenine & Guanine.
d) 3243 stands for - position of transposition.
e) The convention adopted for describing transposition defects is to show the correct neucleotide (A), then show position of transposition (3243) and then incorrect nucleotide (G).
i. Majority of mutations are a cause of maternally inherited multisystem disorder.
ii. Mitochondrial inheritance is by MTRNR1 and MTTS1.
iii. May lead to severe to profound SNHL
iv. MTRNR1 causes mitochondrial inheritance which further induces HL by amino glycoside
I. Mitochondrial Determined Hearing Impairment
A. The mitochondrial DNA molecule encodes 13mRNA and 2 rRNA and 22 tRNA, that are required for assembling a functional mitochondrial protein synthesizing system.
B. The 13mRNAs are translated on mitochondrian specific genetic code into 13 proteins which are required to
form the five enzyme complexes required for oxi d ativg
F. The genes for 20 different connexin proteins are present in the human genome.
G. There are two types of connexins, alpha and beta, named GJA or GJ
B followed by a number
H. The connexins of one cell align symmetrically with those of its neighbor to create continuous aqueous pores that functionally couple the adjacent cells.
I. Connexins aggregate in the plane of the plasma membrane to form a gap junction plaque.
J. Connexin genes involved in deafness are GJBJ (Cx32), which is also responsible for X- linked Charcot Marie Tooth disease , GJB3 (Cx31) involved in both deafness and a skin disease.
K. Several connexin genes (GJB1, GJB2, GJB3, GJB6 and GJA1) have been found mutated in patients with non-syndromic and/or syndromic deafness indicating an important role of these proteins.
L. As development proceeds, expression of these two genes was found in various subtypes of fibrocytes, either within the spiral limbus or along the spiral ligament, as well as in the basilar membrane cells, in the Reissner’s membrane cells, and in subsets of the cellular elements of the cochlear ganglion.
M. The genes for 20 different connexin proteins are present in the human genome.
N. There are two types of connexins, alpha and beta, named GJA or GJB followed by a number
O. Gjb3 and Gjb1 expression was spatiotemporally modulated within the sensory hair cells and the various supporting cells that compose the developing organ of Corti.
P. A transitory expression of Gjb1 was found in the basal and intermediate cells of the stria vascularis of auditory system.
Q. Everyone has two copies of this gene, but if each parent has a flawed, recessive copy of the GJB2/ Connexin 26 gene, the baby may be born with hearing loss.
R. This is because the mutation is suspected of disrupting potassium flow in the inner ear.
S. Approximately 50% of childhood non syndromic recessive hearing loss is caused by mutations in the connexin 26 (Cx26 gene (GJB2/DFNB)
T. The most common mutation that is found in the connexin 26 gene is 35delG, which means that a G is deleted at position 35.
U. This is because the mutation is suspected of disrupting potassium flow in the inner ear.
V. Approximately 50% of childhood non syndromic recessive hearing loss is caused by mutations in the connexin 26 (Cx26 gene (GJB2/DFNB)
W. The most common mutation that is found in the connexin 26 gene is 35delG, which means that a G is deleted at position 35.
X. More than 90 different mutations have been found in the coding sequences of connexin 26.
Y. Most are rare, but a few are relatively common in particular populations (e.g. 267delT and 235 delC in Ashkenazi Jewish and Asian populations, respectively).
Some disorders appear to result from a combination of genetic factors interacting with environmental influences.
Examples of this type of inheritance associated with hearing loss include clefting syndromes, involving conductive hearing loss, and the microtia/hemifacial microsomia/Goldenhar spectrum.
Goldenhar's syndrome has been described as autosomal dominant in some families, although this may simply represent clustering.
Findings in this syndrome include preauricular tags/pits, vertebral anomalies such as hypoplastic or hemivertebrae in the cervical region, epibulbar dermoids, and coloboma of the upper lid. Other conditions believed to represent multifactorial inheritance are increased susceptibility to hearing loss and hyperlipidemia.
a) Middle ear and mastoid disease are often observe in Down syndrome children, but sensorineural hearing loss may also be present.
b) Trisomy 13, which is often lethal in the newborn period, can have significant sensorineural hearing loss in the survivors. Turner's syndrome, monosomic for all or part of one X chromosome, presents generally in female as gonadal dysgenesis, short stature, and often webbed neck or shield chest.
c) They will also have sensorineural, conductive, or mixed hearing loss, which can be progressive and may be the first evidence of the syndrome in prepubertal females.
Some cause pre-lingual deafness, progressive and affects all frequencies and sometimes downward sloping type hearing loss. Mostly post-lingual deafness affecting all frequencies and begins in any decade of life.
Some cause post-lingual deafness, can be stable or progressive and causes moderate to profound hearing loss. Most of them cause pre lingual, can be stable or progressive and causes moderate to profound hearing loss.(Tables 1 & 2).
A. Type I -Waardenburg syndrome is characterized by evidence of dystopia canthorum and the full symptomatology of the disease.
I. Narrow nose
II. Marked hypoplasia of the nasal bone,
III. Short philtrum
IV. Short and retro positioned maxilla.
V. Convergent strabismus (blepharophimosis)
VI. Reduced visibility of the medial sclera
VII. The head circumference, clivus length, and facial depth are smaller in affected individuals with this syndrome.
B. Type II -Waardenburg syndrome are a heterogeneous group with normally located canthi (without dystopia canthorum).
I. Sensorineural hearing loss (77%)
II. Heterochromia iridium (47%) are the 2 most important diagnostic indicators for this type.
C. Type III- Waardenburg syndrome (Klein-Waardenburg syndrome) is similar to type I but is also characterized by musculoskeletal abnormalities
I. Aplasia of the first 2 ribs
II. Lack of differentiation of the small carpal bones
III. cystic formation of the sacrum1
IV. Abnormalities of the arms1
V. Amyoplasia and stiffness of the joints
VI. Bilateral cutaneous syndactyly
VII. mental retardation
IX. severe skeletal anomalies.
D. Type IV Waardenburg syndrome (Shah-Waardenburg syndrome) is the association of Waardenburg syndrome with congenital aganglionic megacolon (Hirschsprung disease).
a) Dystopia canthorum is found in 41.2-99% of persons with Waardenburg syndrome.
i. The distance between the inner angles of the eyelids is accompanied by increased distance between the inferior lacrimal points.
ii. Hageman and Delleman divided Waardenburg syndrome into 2 variants: with dystopia canthorum and without.
b) Congenital deafmutism occurs in 9-62.5% of persons with Waardenburg syndrome.
c) Different combinations of hearing loss occur: unilateral or bilateral, severe or moderate, total or moderate. Fisch separated Waardenburg syndrome into the following distinct types according to audiogram results.
d) Patients with total deafness and little residual hearing at the lower frequency
e) Patients with a moderate degree of deafness with uniform hearing loss in the lower and middle frequency with improvement in the higher frequency
f) Pigmentary disturbances of hairs in Waardenburg syndrome include 2 types of alterations: white forelock and premature graying of scalp hair, eyebrows, cilia, or body hair.
i. The white forelock is observed in 17-58.4% of persons with Waardenburg syndrome and involves the forehead (and both medial eyebrows), the vertex, or another part of scalp.
ii. The white forelock may be evident at birth or soon afterward, or it may develop later.
iii. Poliosis may persist throughout life or may disappear in the first years of life and reappear later.
iv. Patients with Waardenburg syndrome become prematurely gray in 7% of cases.
I. Wildervaank's syndrome is comprised of the Klippel- Feil sign involving fused cervical vertebrae, sensorineural hearing or mixed hearing impairment, and cranial nerve 6 paralysis causing retraction of the eye on lateral gaze.
II. This syndrome is seen most commonly in female because of the high mortality associated with the X-linked dominant form in males. Isolated Klippel-Feil sequence includes hearing impairment in about one third of cases.
III. The hearing impairment is related to bony malformations of the inner ear.
Jervell and Lange-Neilsen syndrome is a rare syndrome that consists of profound sensorineural hearing loss and syncopal episodes resulting from a cardiac conduction defect. Genetic studies attribute one form of Jervell and Lange-Neilsen syndrome to homozygosity for mutations affecting a potassium channel gene (KVLQT 1) on chromosome 11p15.5, which are thought to result in delayed myocellular repolarization in the heart. The gene KCNE1 has also been shown to be responsible for the disorder.
Isolated lateral canal defects -most common inner ear malformations-identified on temporal bone imaging studies. Superior semicircular canal deformities are always accompanied by lateral semicircular canal deformities. Lateral canal deformities often occur in isolation.
a) Recently, the genes responsible for development of microstructures in the cochlea have been identified.
b) For example, connexins are the channels that connect neighboring cells and allow passive transfer of small molecules.
c) It can be inherited by Autosomal recessive as in most cases and Autosomal dominant as in few cases.
d) These gap junction are important for the electric and metabolic coupling of neighboring cells.
e) These connexins development are coded in genes like Connexin 26, 30, 31
f) When these genes get mutated there will be non syndromic hearing loss.
Hearing loss is usually mixed and has a prevalence ranging from 26-78%. Autosomal dominant with variable expressivity and incomplete penetrance. Two genes for osteogenesis imperfecta have been identified,
1. COLIA1 on chromosome 17q
2. COLIA2 on chromosome 7q.
i. The hearing loss usually presents itself during the late 20s or early 30s.
ii. The conductive component of the hearing loss is attributed to the thickened and fixed stapes footplate, similar to what is seen in otosclerosis.
iii. The sensorineural component usually results from cochlear hair cell atrophy and atrophy of the stria vascularis.
iv. Also, anomalous bone formation in and around the cochlea may contribute to the sensorineural component of the hearing loss.
a) AN - clinically heterogeneous set of hearing disorders, neural functions are impaired but the OHCs of the cochlea appear to function normally.
b) Some families show autosomal dominant patterns of inheritance and affected members usually have peripheral neuropathy.
c) Kovach et al - mutation of PMP22 gene associated with Charcot- Marie - Tooth syndrome as a possible link to some of the characteristics of neuropathy, chromosome affected is 8q24.
I. PMP22 Gene
i. 'Peripheral Myeline Protein 22 gene' provides instructions for making protein called PMP22.
ii. This protein is major component of myelin. This is produced primarily by schwan cells.
iii. PMP22 may also play a role in regulating cell division and maturation, cell shape etc.
iv. Charcot-Marie-Tooth Disease and hereditary neuropathy are associated with PMP22 mutation
a) The early onset subtype usually progresses rapidly from onset at age 1 % years to profound loss by age 6.
b) Genetic linkage studies have identified at least 15 gene loci for recessive nonsyndromic hearing loss.
i. The gene DFNB2 on chromosome 13q may be the most common and has been identified as connexin 23.
ii. Another gene, DFNB1, also found on chromosome 13 codes for a connexin 26 gene gap junction protein.
i. Another condition associated with acquired heteroplasmic mutations and hearing loss is presbycusis.
ii. Since mitochondrial DNA mutations and the resulting loss of oxidative phosphorylation activity seem to play an important role in the aging process, it is not unlikely that mitochondrial mutations in the auditory system can also lead to presbycusis).
iii. These mutations are thought to be associated with insidious decline in physiological and biochemical performance of an organ and to contribute significantly to the ageing process and ultimately death.
iv. Accordingly, suggests that presbyacusis is due to deletions and in particular a 4977 nucleotide deletion which is also called "common deletion".
Otosclerosis is caused by proliferation of spongy type tissue on the otic capsule eventually leading to fixation of the ossicles and producing conductive hearing loss.
Hearing loss may begin in childhood but most often becomes evident in early adulthood and eventually may include a sensorineural component.
Otosclerosis appears to be transmitted in an autosomal dominant pattern with decreased penetrance, so only 25% to 40% of gene carriers show the phenotype. The greater proportion of affected females points to a possible hormonal influence.
Recent statistical studies suggest a role for the gene COLIA1 in otosclerosis, and measles viral particles have been identified within the bony overgrowth in otosclerotic foci, raising the possibility of an interaction with the viral genome.
This is the most common of the chromosome abnormality syndromes typified by a wide range of abnormalities.
Otolaryngologic findings are numerous in these patients and can affect every region of the head and neck.
This includes small ears with overfolding of the superior helix, stenotic EAC and eustachian tube dysfunction [36,44].
There is also an increased incidence of chronic ear disease in affected children due to increased incidence of upper respiratory infections, reduction of B and T cell function (immune system immaturity), and eustachian tube dysfunction.
The hearing loss in DS is usually conductive secondary to the chronic middle ear disease but can also be due to ossicular chain abnormalities, especially the stapes.
Upper airway obstruction are also problems encountered by children with DS due to the midface hypoplasia, and relative enlargement of the tongue, tonsils and adenoids in a constricted naso/oropharynx.
In terms of speech and behavior, most Down's syndrome patients exhibit dysarthria and articulation deficits in conjunction with some degree of mental retardation (IQ 30-50).
Trisomy of the 21st chromosome.
Gene located on 21q22.3
CHL, SNHL or mixed, chronic middle ear infection, serous otitis media and middle ear effusion, ET dysfunction, structural abnormalities of cochlea and decreased length
a) Referred to as facioauriculovertebral dysplasia (FAVD) and hemifacial microsomia (HFM), this disorder results from aberrant development of the first and second branchial arches.
b) HFM is estimated to occur in 1 in 5600 live births, perhaps making it the most significant asymmetric craniofacial disorder.
c) Otologic manifestations include microtia/anotia, preauricular tags, ossicular abnormalities, abnormal facial nerve course, and hearing loss (conductive > sensorineural).
i. The hearing loss is predominantly conductive secondary to the abnormal development of the structures derived from the first and second branchial arches.
ii. Facial abnormalities include unilateral hypoplasia of the maxilla, malar and temporal bones in addition to mandibular ramus and condyle hypoplasia.
iii. Macrostomia or pseudomacrostomia (lateral cleft-like extension of the oral commisures), cleft lip or palate and delayed dental development.
iv. Lastly, the mastoid is poorly pneumatized and their may exist agenesis of the parotid gland or displacement of the gland.
v. In terms of non-head and neck features, affected individuals can also have cardiac abnormalities such as coarctation of the aorta, ventricular septal defect.
vi. Renal ectopia and hydronephrosis can encompass the renal abnormalities.
vii. Limb deformities can be present as well as cerebral malformation and mental retardation.
viii. Ocular abnormalities include blepharoptosis, microopthalmia, epibulbar tumors, and retinal abnormalities leading to reduced visual acuity.
i. Consists of a triad characterized by deafness, congenital cataracts and heart defects.
ii. This disease is caused by an RNA togavirus and is transmitted postnatally via respiratory secretion, saliva, or direct contact.
iii. Transplacental transmission is the route responsible for congenital infection which can involve more sequelae if infection is present during the first trimester.
iv. In addition to the above listed triad, other abnormalities that may manifest are microcephaly, motor and neural retardation, hepatosplenomegaly, thrombocytopenia, encephalitis and interstitial pneumonitis.
v. The hearing loss in rubella is typically asymmetric and sensorineural with variable severity.
vi. The 500-2000 Hz frequencies are the most commonly affected.
vii. This hearing deficit usually manifests by 5 years of age and can be an isolated finding in 22%.
viii. Approximately 25% of patients will experience a progressive form of hearing loss.
CMV has an incidence of 0.2%-2.3% of live births making it one of the most frequently occurring viruses worldwide and the leading cause of congenital malformations and mental retardation in developed countries.
Of all the TORCH infections, CMV is the most common. Microcephaly, intrauterine growth restriction (IUGR), petechiae, encephalitis, hepatosplenomegaly, and deafness are some of the physical characteristics of a congenital CMV infection.
CMV is estimated to account for 1/3 of sensorineural hearing loss in young children.
Hearing impairment in CMV can be delayed (occurring months-years after birth), or fluctuating and progressive.
Interesting to note, infants with petechiae and IUGR are
2- 3 times more likely to have sensorineural hearing loss.
Post mortem temporal bone studies on infants who died from cytomegalic inclusion disease have revealed inclusion bodies in the stria vascularis, Reissner's membrane,
Endolymphatic hydrops was noted in the cochlear ducts (Tables 3-10)