Genetic Hearing Loss- Syndromes

Home , Crouzon syndrome, Syndactyly, Waardenburg syndrome

Global Journal of Otolaryngology ISSN 2474-7556

(Figure 1) Autosomal dominant Table 1: X- Linked NSHI. Locus Gene Type and Onset Frequencies Name Symbol Degree Progressive DFNX1 Post- sensorineural; PRPS1 All (DFN2) lingual severe to profound Progressive, mixed; DFNX2 POU3F4 Pre-lingual variable, but All (DFN3) progresses to profound Progressive DFNX4 sensorineural; SMPX Postlingual All (DFN6) mild to Figure 1: Non Syndromic Hearing loss. profound Locus name- DFNA Table 2: Mitochondrial NSHI. Gene a) Some cause pre-lingual deafness, progressive and Mutation Severity Penetrance Symbol affects all frequencies and sometimes downward sloping type Highly variable, hearing loss 961 different MT-RNR1 Variable aminoglycoside mutations b) Mostly post-lingual deafness affecting all frequencies induced and begins in any decade of life. 1494C>T Autosomal recessive 1555A>G MT-TS1 7445A>G Highly variable Locus name- DFNB 7472insC a) Some cause post-lingual deafness, can be stable or 7510T>C progressive and causes moderate to profound hearing loss. 7511T b) Most of them cause pre lingual, can be stable or Complete, progressive and causes moderate to profound hearing loss aminoglycoside (Tables 1 & 2) (Figure 2). Severe to associated; MT-CO1 7444G>A profound associated with MT-RNR1 1555A>G Apert Syndrome i. AKA= Acrocephalosyndactyly

Single gene autosomal dominant caused by the mutation of FGFR2 gene, located on the long arm of chromosome 10 at 10q26 Audiological findings a) CHL-mild to moderate

b) chronic middle ear disease

Figure 2: Syndromic Hearing loss. c) ossicular anomalies

Glob J Otolaryngol 5(3): GJO.MS.ID.555665 (2017) 00108 Global Journal of Otolaryngology

Symptoms b) Marked hypoplasia of the nasal bone, i. CNS growth affected c) Short philtrum

ii. craniofacial & limb abnormalities d) Short and retro positioned maxilla.

iii. mitten hand e) Convergent strabismus (blepharophimosis)

iv. low set ears posteriorly rotated f) Reduced visibility of the medial sclera

v. synostosis of one or more ossicles g) The head circumference, clivus length, and facial depth are smaller in affected individuals with this syndrome. vi. Fixation of footplate of stapes Waardenburg syndrome is a heterogeneous vii. Reduced ME space II. Type II: group with normally located canthi (without dystopia viii. ET dysfunction canthorum).

a) Sensorineural hearing loss (77%)

ix. x. SyndactylyBrachymelia of fingers and toes b) Heterochromia iridium (47%) is the 2 most important diagnostic indicators for this type. xi. MR III. Type III- Waardenburg syndrome (Klein- xii. Hydrocephaly Waardenburg syndrome) is similar to type I but is also characterized by musculoskeletal abnormalities xiii. Cognitive imparment Waardenburg Syndrome a) b) Lack Aplasia of differentiationof the first 2 ribs of the small carpal bones a) It is the most common form of inheritable congenital deafness. c) cystic formation of the sacrum

b) Genetic Analysis Distal end of band 2q35gene d) Abnormalities of the arms responsible is: PAX3 e) Amyoplasia and stiffness of the joints

f) Bilateral cutaneous syndactyly expression in this syndrome. c) There is a significant amount of variability of g) mental retardation There may be unilateral or bilateral sensorineural hearing loss in patients and the phenotypic expressions may include h) Microcephaly pigmentary anomalies and craniofacial features. i) severe skeletal anomalies.

Symptoms IV. Type IV: Waardenburg syndrome (Shah-Waardenburg a) Marked facial asymmetry syndrome) is the association of Waardenburg syndrome with congenital aganglionic megacolon (Hirschsprung disease). b) Lagophthalmos A. Dystopia canthorum is found in 41.2-99% of persons c) A drooping right corner of the mouth. with Waardenburg syndrome.

d) Absence of naso-frontal angle a) The distance between the inner angles of the eyelids e) Eyebrow hypertrichosis is accompanied by increased distance between the inferior lacrimal points. f) Upturned nasal tip b) Hageman and Delleman divided Waardenburg g) Shortened upper lip syndrome into 2 variants: with dystopia canthorum and h) Pronounced cupid’s bow. without.

I. Type I: Waardenburg syndrome is characterized by I. Congenital deafmutism occurs in 9-62.5% of persons evidence of dystopia canthorum and the full symptomatology with Waardenburg syndrome. of the disease. II. Different combinations of hearing loss occur: a) Narrow nose unilateral or bilateral, severe or moderate, total or moderate.

00109 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665.. DOI: 10.19080/GJO.2017.05.555665. Global Journal of Otolaryngology

Fisch separated Waardenburg syndrome into the following distinct types according to audiogram results. b. Seventy-five percent of patients with branchio-oto- a) Patients with total deafness and little residual Treacherrenal syndrome Collins have Syndrome significant hearing loss. hearing at the lower frequency a. Conductive hearing loss is present 30% of the time, b) Patients with a moderate degree of deafness with but sensorineural hearing loss and vestibular dysfunction can uniform hearing loss in the lower and middle frequency with also be present. improvement in the higher frequency b. Ossicular malformations are common in these i. Pigmentary disturbances of hairs in Waardenburg patients. syndrome include 2 types of alterations: white forelock and c. The syndrome is transmitted autosomal dominant premature graying of scalp hair, eyebrows, cilia, or body hair. with high penetrance gene located on 5q-32-q33.1, TREACLE ii. The white forelock is observed in 17-58.4% of persons Neurofibromatosis with Waardenburg syndrome and involves the forehead (and both medial eyebrows), the vertex, or another part of scalp. 1) Mental retardation, blindness, and sensorineural hearing loss can result from central nervous system tumors. iii. The white forelock may be evident at birth or soon afterward, or it may develop later.

iv. Poliosis may persist throughout life or may disappear 2) 3) Autosomal Neurofibromatosis dominant is 22q12.2.classified as types 1 and 2. 4) NF2 is a tumor supressor gene in thev. firstPatients years of withlife and Waardenburg reappear later. syndrome become 5) Acoustic neuromas are usually unilateral and occur in prematurely gray in 7% of cases. only 5% of affected patients. Stickler Syndrome a) Cleft palate and severe myopia are its characteristics distinct disorder, is characterized by bilateral acoustic 6) Neurofibromatosis type 2, which is a genetically features. neuromas. 7) Bilateral acoustic neuromas are present in 95% of hearing loss is present in about 15% of cases, whereas hearing affected patients and are usually asymptomatic until early b) Significant sensorineural hearing loss or mixed loss of lesser severity may be present in up to 80% of cases. adulthood. c) Autosomal dominant- COLI1A1, COLI1A2,COL2A1, Ushers Syndrome COL2A2 and several others a. Usher’s syndrome has a prevalence of 3.5 per 100,000 Norrie Syndrome populations. Norrie syndrome is a sex-linked disorder that includes b. Sensorineural hearing loss and retinitis pigmentosa congenital or rapidly progressive blindness characterize the syndrome. Alport Syndrome I. Usher type 1 patients have congenital bilateral profound hearing loss and absent vestibular function a. Alport syndrome involves hearing loss associated with renal impairment of varying severity. II. Type 2 patients have moderate losses and normal vestibular function. b. When a genetic mutation occurs, connecting structures in both the inner ear and kidney become increasingly III. Type 3 demonstrate progressive hearing loss and fragile, resulting in progressive hearing impairment and variable vestibular dysfunction and are found primarily in the kidney disease Norwegian population. c. Eustation tube dysfunction occurs secondarily to the Pendred Syndrome cleft palate and results in conductive hearing loss. a. Pendred’s syndrome includes thyroid goiter and d. Ossicular abnormalities may also be present. profound sensorineural hearing loss. Branchio-oto-renal Syndrome b. Hearing loss is progressive in about 15% of patients. a. Branchio-oto-renal syndrome is estimated to occur in The majority of patient present with bilateral moderate to 2% of children with congenital hearing impairment. severe sensorineural hearing impairment, with some residual hearing in the low frequencies.

00110 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665. DOI: 10.19080/GJO.2017.05.5556665. Global Journal of Otolaryngology

Otopalatodigital Syndrome Charge a) Otopalatodigital syndrome includes hypertelorism, a. Coloboma, Heart anomalies, Atresia, Choanae, Retarded growth and development, Genital hypoplasia and ear midface, small nose, and cleft palate. anomalies craniofacial deformity involving supraorbital area, flat b. Autosomal dominant inheritance and toes that vary in length, with an excessively wide space b) Patients are short statured with broad fingers and vestibular anomalies c. CHL, SNHL or mixed, trough shaped configuration c) Conductive hearing loss is seen due to ossicular between the first and second toe. Symptoms malformations. Affected males manifest the full spectrum of the disorder and females may show mild involvement. a. CNS impairment

d) The gene has been found to be located on chromosome b. Brain malformation Xq28. c. Facial paresis

Wildervaank Syndrome d. Facial assymetry a. Wildervaank’s syndrome is comprised of the Klippel- e. Microcephaly Feil sign involving fused cervical vertebrae, sensorineural hearing or mixed hearing impairment, and cranial nerve 6 f. Low set posteriorly rotated ears paralysis causing retraction of the eye on lateral gaze. g. Micrognathia b. This syndrome is seen most commonly in female h. Nasal root because of the high mortality associated with the X-linked dominant form in males. Isolated Klippel-Feil sequence i. Semicircular canal includes hearing impairment in about one third of cases. j. Hypoplasia c. The hearing impairment is related to bony k. Heart anomalies malformations of the inner ear. Jervell and Lange-Neilsen Syndrome l. m. Genital Tracheoesophageal anomalies fistula a. Jervell and Lange-Neilsen syndrome is a rare syndrome that consists of profound sensorineural hearing loss n. Scoliosis and syncopal episodes resulting from a cardiac conduction o. Short neck defect.

b. Genetic studies attribute one form of Jervell and Crouzon syndrome (Craniofacial dyostosis) Lange-Neilsen syndrome to homozygosity for mutations I. Mutation of single gene FGFR2 located on the long affecting a potassium channel gene (KVLQT 1) on chromosome arm of chromosome 10 at 10 q 26 11p15.5, which are thought to result in delayed myocellular II. Autosomal dominant inheritance with variable repolarization in the heart. The gene KCNE1 has also been expression shown to be responsible for the disorder. III. CHL common. Mild to moderate stenosis of EAC, Hereditary Meniere’s syndrome chronic middle ear disorder and ossicular anomalies a. Recurrent severe unilateral headaches Symptoms b. variable results of vestibular function tests a. Maxillary hypoplasia c. Vertigo and vomiting b. Malocclusion

c. Soft tissue hypertrophy of hard palate Unilateral or bilateral Audiological findings: fluctuating SNHL d. Cognitive impairment Assymetrical and progressively deteriorates e. Increased intracranial pressure Mild to severe HL f. Bulging eyes Autosomal recessive transmission g. Dental crowding

00111 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665.. DOI: 10.19080/GJO.2017.05.555665. Global Journal of Otolaryngology

h. Abnormality of cranial and facial bones Apert syndrome i. Cleft palate i. AKA= Acrocephalosyndactyly

j. synostosis Single gene autosomal dominant caused by the mutation of FGFR2 gene, located on the long arm of chromosome 10 at Down Syndrome 10q26 a. Trisomy of the 21st chromosome. Audiological findings b. Gene located on 21q22.3 a. CHL-mild to moderate c. CHL, SNHL or mixed, chronic middle ear infection, b. chronic middle ear disease serous otitis media and middle ear effusion, ET dysfunction, structural abnormalities of cochlea and decreased length c. ossicular anomalies Symptoms Symptoms a. CNS impairment i. CNS growth affected

b. Mental retardation ii. craniofacial & limb abnormalities

c. Alzheimer’s disease iii. mitten hand

d. Hypotonia iv. low set ears posteriorly rotated

e. Cerebral and cerebellar hypoplasia v. synostosis of one or more ossicles

f. Brachycephaly vi. Fixation of footplate of stapes

g. Microcephaly vii. Reduced ME space

h. Macroglossia viii. ET dysfunction

i. Small ears, stature

j. Obesity ix. x. SyndactylyBrachymelia of fingers and toes xi. MR

k. l. Branchydactyly Small fingers xii. Hydrocephaly Hunter syndrome xiii. Cognitive imparment a. X- linked recessive inheritance. Gene mapped to Xq 28 Waardenburg syndrome and is labelled as IDS a. It is the most common form of inheritable congenital b. CHL, Chronic middle ear disorder, glue ear, progressive deafness. HL b. Genetic Analysis Distal end of band 2q35gene Symptoms responsible is: PAX3 i. Short stature, expression in this syndrome. ii. cognitive defects, c. There is a significant amount of variability of There may be unilateral or bilateral sensorineural hearing iii. Thick lips, loss in patients and the phenotypic expressions may include iv. alveolar ridge hypertrophy, pigmentary anomalies and craniofacial features. v. thickening of palate, Symptoms vi. abnormal retinal pigmentation, a. Marked facial asymmetry

vii. retinal degenration, b. Lagophthalmos

viii. corneal opacities, c. A drooping right corner of the mouth.

ix. heart, liver and spleen problems d. Absence of naso-frontal angle

00112 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665. DOI: 10.19080/GJO.2017.05.5556665. Global Journal of Otolaryngology

e. Eyebrow hypertrichosis ii. Hageman and Delleman divided Waardenburg syndrome into 2 variants: with dystopia canthorum and f. Upturned nasal tip without. g. Shortened upper lip b) Congenital deafmutism occurs in 9-62.5% of persons h. Pronounced cupid’s bow. with Waardenburg syndrome.

A. Type I: Waardenburg syndrome is characterized by c) Different combinations of hearing loss occur: evidence of dystopia canthorum and the full symptomatology unilateral or bilateral, severe or moderate, total or moderate. of the disease. Fisch separated Waardenburg syndrome into the following a) Narrow nose distinct types according to audiogram results.

b) Marked hypoplasia of the nasal bone, a) Patients with total deafness and little residual hearing at the lower frequency c) Short philtrum b) Patients with a moderate degree of deafness with d) Short and retro positioned maxilla. uniform hearing loss in the lower and middle frequency with e) Convergent strabismus (blepharophimosis) improvement in the higher frequency

f) Reduced visibility of the medial sclera c) Pigmentary disturbances of hairs in Waardenburg syndrome include 2 types of alterations: white forelock and g) The head circumference, clivus length, and facial premature graying of scalp hair, eyebrows, cilia, or body hair. depth are smaller in affected individuals with this syndrome. d) The white forelock is observed in 17-58.4% of persons B. Type II: Waardenburg syndrome are a heterogeneous with Waardenburg syndrome and involves the forehead (and group with normally located canthi (without dystopia both medial eyebrows), the vertex, or another part of scalp. canthorum). e) The white forelock may be evident at birth or soon a) Sensorineural hearing loss (77%) afterward, or it may develop later. b) Heterochromia iridium (47%) are the 2 most f) Poliosis may persist throughout life or may disappear important diagnostic indicators for this type.

C. Type III: Waardenburg syndrome (Klein- g) Patients with Waardenburg syndrome become Waardenburg syndrome) is similar to type I but is also in the first years of life and reappear later. prematurely gray in 7% of cases. characterized by musculoskeletal abnormalities Stickler Syndrome i. Cleft palate and severe myopia are its characteristics a) b) Lack Aplasia of differentiationof the first 2 ribs of the small carpal bones features. c) cystic formation of the sacrum

d) Abnormalities of the arms hearing loss is present in about 15% of cases, whereas hearing ii. Significant sensorineural hearing loss or mixed loss of lesser severity may be present in up to 80% of cases. e) Amyoplasia and stiffness of the joints iii. Autosomal dominant- COLI1A1, COLI1A2,COL2A1, f) Bilateral cutaneous syndactyly COL2A2 and several others g) mental retardation Norrie Syndrome h) Microcephaly Norrie syndrome is a sex-linked disorder that includes i) severe skeletal anomalies. congenital or rapidly progressive blindness D. Type IV: Waardenburg syndrome (Shah-Waardenburg Alport Syndrome syndrome) is the association of Waardenburg syndrome with i. Alport syndrome involves hearing loss associated congenital aganglionic megacolon (Hirschsprung disease). with renal impairment of varying severity. a) Dystopia canthorum is found in 41.2-99% of persons ii. When a genetic mutation occurs, connecting with Waardenburg syndrome. structures in both the inner ear and kidney become increasingly i. The distance between the inner angles of the eyelids fragile, resulting in progressive hearing impairment and is accompanied by increased distance between the inferior kidney disease lacrimal points. iii. Eustation tube dysfunction occurs secondarily to the

00113 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665.. DOI: 10.19080/GJO.2017.05.555665. Global Journal of Otolaryngology cleft palate and results in conductive hearing loss. Pendred Syndrome iv. Ossicular abnormalities may also be present. i. Pendred’s syndrome includes thyroid goiter and profound sensorineural hearing loss. Branchio-oto-renal Syndrome ii. Hearing loss is progressive in about 15% of patients. a) Branchio-oto-renal syndrome is estimated to occur in 2% of children with congenital hearing impairment. iii. The majority of patient present with bilateral moderate to severe sensorineural hearing impairment, with some residual hearing in the low frequencies. b) Seventy-five percent of patients with branchio-oto- Otopalatodigital Syndrome Treacherrenal syndrome Collins have Syndrome significant hearing loss. a. Otopalatodigital syndrome includes hypertelorism, i. Conductive hearing loss is present 30% of the time, but sensorineural hearing loss and vestibular dysfunction can midface, small nose, and cleft palate. also be present. craniofacial deformity involving supraorbital area, flat

ii. Ossicular malformations are common in these and toes that vary in length, with an excessively wide space patients. b. Patients are short statured with broad fingers

iii. The syndrome is transmitted autosomal dominant betweenc. theConductive first and secondhearing toe. loss is seen due to ossicular with high penetrance gene located on 5q-32-q33.1, TREACLE malformations. Affected males manifest the full spectrum of Neurofibromatosis the disorder and females may show mild involvement. a. Mental retardation, blindness, and sensorineural d. The gene has been found to be located on chromosome hearing loss can result from central nervous system tumors. Xq28. Wildervaank Syndrome i. Wildervaank’s syndrome is comprised of the Klippel- b. c. NeurofibromatosisAutosomal dominant is 22q12.2.classified as types 1 and 2. Feil sign involving fused cervical vertebrae, sensorineural d. NF2 is a tumor supressor gene hearing or mixed hearing impairment, and cranial nerve 6 e. Acoustic neuromas are usually unilateral and occur in paralysis causing retraction of the eye on lateral gaze. only 5% of affected patients. ii. This syndrome is seen most commonly in female because of the high mortality associated with the X-linked distinct disorder, is characterized by bilateral acoustic dominant form in males. Isolated Klippel-Feil sequence f. Neurofibromatosis type 2, which is a genetically neuromas. includes hearing impairment in about one third of cases.

g. Bilateral acoustic neuromas are present in 95% of iii. The hearing impairment is related to bony affected patients and are usually asymptomatic until early malformations of the inner ear. adulthood. Jervell and Lange-Neilsen Syndrome Ushers syndrome a. Jervell and Lange-Neilsen syndrome is a rare a. Usher’s syndrome has a prevalence of 3.5 per 100,000 syndrome that consists of profound sensorineural hearing loss populations. and syncopal episodes resulting from a cardiac conduction defect. b. Sensorineural hearing loss and retinitis pigmentosa characterize the syndrome. b. Genetic studies attribute one form of Jervell and Lange-Neilsen syndrome to homozygosity for mutations i. Usher type 1 patients have congenital bilateral affecting a potassium channel gene (KVLQT 1) on chromosome profound hearing loss and absent vestibular function 11p15.5, which are thought to result in delayed myocellular ii. Type 2 patients have moderate losses and normal repolarization in the heart. The gene KCNE1 has also been vestibular function. shown to be responsible for the disorder.

iii. Type 3 demonstrate progressive hearing loss and Hereditary Meniere’s syndrome variable vestibular dysfunction and are found primarily in the a. Recurrent severe unilateral headaches Norwegian population. b. variable results of vestibular function tests

00114 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665. DOI: 10.19080/GJO.2017.05.5556665. Global Journal of Otolaryngology

c. Vertigo and vomiting ii. Malocclusion

Audiological finings- iii. Soft tissue hypertrophy of hard palate

Unilateral or bilateral fluctuating SNHL iv. Cognitive impairment Assymetrical and progressively deteriorates v. Increased intracranial pressure

Mild to severe HL vi. Bulging eyes

Autosomal recessive transmission vii. Dental crowding Charge viii. Abnormality of cranial and facial bones a. Coloboma, Heart anomalies, Atresia, Choanae, ix. Cleft palate Retarded growth and development, Genital hypoplasia and ear x. synostosis anomalies

b. Autosomal dominant inheritance Down Syndrome a) Trisomy of the 21st chromosome. and vestibular anomalies b) Gene located on 21q22.3 c. CHL, SNHL or mixed, trough shaped configuration Symptoms c) CHL, SNHL or mixed, chronic middle ear infection, serous otitis media and middle ear effusion, ET dysfunction, a. CNS impairment structural abnormalities of cochlea and decreased length b. Brain malformation Symptoms c. Facial paresis a. CNS impairment

d. Facial assymetry b. Mental retardation

e. Microcephaly c. Alzheimer’s disease

f. Low set posteriorly rotated ears d. Hypotonia

g. Micrognathia e. Cerebral and cerebellar hypoplasia

h. Nasal root f. Brachycephaly

i. Semicircular canal g. Microcephaly

j. Hypoplasia h. Macroglossia

k. Heart anomalies i. Small ears, stature

j. Obesity l. m. Genital Tracheoesophageal anomalies fistula n. Scoliosis k. l. Branchydactyly Small fingers o. Short neck Hunter syndrome Crouzon syndrome (Craniofacial dyostosis) a. X- linked recessive inheritance. Gene mapped to Xq 28 a. Mutation of single gene FGFR2 located on the long and is labelled as IDS arm of chromosome 10 at 10 q 26 b. CHL, Chronic middle ear disorder, glue ear, progressive b. Autosomal dominant inheritance with variable HL expression Symptoms c. CHL common. Mild to moderate stenosis of EAC, a) Short stature, chronic middle ear disorder and ossicular anomalies b) cognitive defects, Symptoms c) Thick lips, i. Maxillary hypoplasia d) alveolar ridge hypertrophy,

00115 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665.. DOI: 10.19080/GJO.2017.05.555665. Global Journal of Otolaryngology

e) thickening of palate, h) corneal opacities,

f) abnormal retinal pigmentation, i) Heart, liver and spleen problems.

g) retinal degenration,

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00116 How to cite this article: Genetic Hearing Loss- Syndromes. Glob J Oto 2017; 5(3): 555665. DOI: 10.19080/GJO.2017.05.5556665.