TITLE: Pediatric Syn=
dromic He=
aring
Loss
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: September 24, 2009
RESIDENT PHYSICIAN: Ryan Ridley, MD
FACULTY PHYSICIAN: Shraddha Mukerji,
MD
SERIES EDITORS: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Qui=
nn, MS(ICS)
&q= uot;This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program = of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either expres= s or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosi= s or treatment without consulting appropriate literature sources and informed professional opinion."
An estimated 1 in 1,000 of the US population is born d= eaf or displays profound hearing loss early in childhood (Cotton and Myer). Of these, half are acquired prenat= ally while the remaining half will exhibit hearing loss as a result of hereditary-genetic factors. Approximately o= ne-third of children with genetic hearing loss will display phenotypic characteristi= cs of a syndrome while two-thirds will be nonsyndromic (i.e. hearing loss in t= he absence of other features). <= span style=3D'mso-spacerun:yes'> Whether the hearing loss is syndromic or nonsyndromic, it is of the utmost importance to identify these patients early so that the proper auditory reh= abilitation and corrective measures can be implemented in time to provide the best prognosis. The discussion bel= ow will focus on syndromic forms of hearing loss as there are a plethora of syndromes that manifest an auditory phenotype.
Most deformities that present congenitally are often t=
he
result of some insult that occurs during the gestational development of the
fetus. Knowledge of the embry=
ology
of the ear will serve as a good foundation with which to understand some of=
the
syndromic malformations that display ear abnormalities and hearing loss.
Mesenchymal tissue from the first and second branchial arches contain the Hillocks of H= is which organize to form the auricle at 4 weeks gestation. The auricle is completely formed b= y 12 weeks with deformities and/or absence traceable as early as 7-8 weeks. Generally speaking, the earlier the insult in the developmental timeline, a more severe def= ormity can be expected. This h= olds true for most embryologic processes.
The external auditory canal (EAC) begins forming at 8 = weeks when the ectoderm from the first branchial cleft joins the developing tympa= nic ring. The tympanic ring begins ossification at 12 weeks giving way to the bony EAC. At 28 weeks, the EAC begins to can= alize producing a three layered tympanic membrane, thus abnormalities of the EAC = are usually in conjunction with tympanic membrane abnormalities. Atresia occurs as a result of fail= ure of the EAC to canalize and stenosis as a failure of complete canalization. Both atresia and stenosis can be t= raced to approximately 28-30 weeks gestation.&nb= sp;
The formation of the stapes initializes ossicular development at 4 ½ weeks. The footplate begins to form at 7-9 weeks an d uninterrupted development is crucial to avoid malformations or absence of the oval window. At 12 weeks the anter= ior and posterior crura of the stapes become bowed and their ossification takes place between 18-24 weeks. Deformities of the stapes footplate and/or superstructure can be lin= ked to the 12 week point on the embryonic timeline. The development of the mall= eus and incus begins at 5 weeks from Meckel’s cartilage of the 1st arch and Reichert’s cartilage of the second arch. A fused malleus-incus mass o= ccurs when the middle ear mucosa fails to develop and separate the undeveloped ossicles from the tympanic cavity. The incus is the first ossicle to ossify at 15 weeks followed by the malleus at 16 weeks and is complete by 24 weeks.
The inner ear exists as the otic vesicle embryonically=
which
appears approximately week 4. The
otic vesicle then splits into a pars inferior and a pars superior (week 5
In continuity with establishing a foundation for understanding the pathology of syndromes, a brief discussion of inheritance patterns as well as definitions to some frequently used terminology will be addressed.
Autosomal Dominant: Disorders with this mode of inherit= ance are usually expressed with alteration of only one gene in a gene pair. Males and females are equally affe= cted and male-to-male transmission occurs. There is a 50% risk of an affected parents offspring being affected (male or female).= Several factors may influence the clinical presentation such as decreased penetrance, variation in expressivity= and age of onset.
Autosomal Recessive: Nearly one-third of mendelian diso=
rders
share this hereditary pattern. This
pattern occurs when both parents are unaffected carriers. Each parent transmits either the n=
ormal
or mutant gene to each of their offspring.=
As a result, there is a 25% risk of the children being affected. The risk of having siblings who are
unaffected carriers is two-thirds. <=
/span>Consanguinity
and reproduction among genetically isolated groups increases the risk of
X-linked inheritance: X-linked recessive disorders are always expressed in males because t= hey only have one copy of the X chromosome. In contrast, females are usually carriers since they possess two cop= ies of the X chromosome. Females = become carriers as a result of transmission from their affected fathers. Since males only receive Y chromos= omes from their fathers, father- son transmission does not occur. =
Mitochondrial Inheritance:= All mitochondrial genes, located in the ovum at the time of concepti= on, are inherited from the mother because sperm cells do not contribute mitochondria. conditions caused by mutations in the mitochondrial genome are described as following = maternal inheritance and affect both male and female offspring.
Penetrance: This refers to the modification of traits by other genes and/or environmental factors they may render them clinically absent although the g= ene responsible for the trait is present.
Expressivity: The variation in expression of a gene’s phenotype. The gene is present, but may expre= ss the phenotype in a mild, moderate or severe form which will correlate with dise= ase severity.
Pleiotropy: The multiple phenotypic effects in= an affected individual as a result of the mutant gene or gene pair.
Malformation:
Results when an abnormal developmental process is responsible for
Syndrome: The simultaneous presence of two or more malformations that are proven or assum= ed to be secondary to a single etiology.
Deformation: = Occur due to extrinsic mechanical forces; not related to genetic information. An = example would be plagiocephaly.
Disruption: T= his happens when processes such as ischemia, tissue breakdown, etc victimize a = normal developmental process. Amputa= tion of normally formed digits or limbs by free-floating amniotic bands as a res= ult of early amnion rupture would be an example.
Sequence: A p= attern of multiple defects that result from a single primary malformation. An example is Pierre Robin sequenc= e in which micrognathia results in tongue displacement which results in cleft palate.
Association: A pattern of anomalies that occur in conjunction with one another more freque= ntly than expected but have yet to be identified as a distinct syndrome or sequence. CHARGE association = is an example (coloboma, heart anomalies, choanal atresia, retardation, genital andear anomalies).
As stated earlier, genetic hearing loss can either be syndromic or nonsyndromic. Physical exam and lab tests/investigations aim to detect those with syndromic hearing loss which account for 30% of genetical= ly caused hearing loss. It is vi= tal to identify cases that have an obvious genetic etiology in order to make a diagnosis and begin early and aggressive hearing rehabilitation as this aff= ects prognosis in terms of speech and language development.
When taking an initial history for a pediatric patient= with hearing loss, the physician should entertain the possibility of a genetic c= ause. When taking the family history, the physician should specifically inquire regarding the hearing status of the parents. Although the parents= may appear to have no hearing deficits, the physician must bear in mind that on= e or both of the parents may be exhibiting variable expression of a mutant gene = or reduced penetrance. This could especially be true of normal hearing parents who report having parents with early onset of hearing loss. Alternatively, the case may involve X-linked inheritance in which no= ne of the parents themselves exhibit hearing loss despite a positive history in other family members. Often, = this information is not volunteered and must be sought by the astute clinician.<= span style=3D'mso-spacerun:yes'>
The pregnancy and birth history are also important inq= uiries to make; especially the rubella status of the mother. In addition, attention should be p= aid to the developmental history of the patient.&= nbsp; Isolated motor delay or global developmental delay could be clues to vestibular dysfunction or a syndrome diagnosis respectively. Also, reports of visual prob= lems manifesting in the child could also point the physician toward a syndrome diagnosis.
A thorough physical exam is an important adjunct to the history and must not be confined only to the head and neck. Checking for birth marks on the tr= unk and limbs as well as limb deformities can prove helpful in trying to arrive= at a syndrome diagnosis. It may = be helpful to ask the parents to bring old photo albums of themselves and fami= ly members to help delineate normal familial traits from those that may be syndromic.
Lastly, one the history and physical exam are complete, there are certain lab tests and investigations that may prove useful. Eudiometry of first degree relativ= es in addition to the patient, ophthalmology evaluation, serology for congenital infections (TORCHs), urinalysis (Export’s syndrome), EKG (Terrell and Lange-Nielsen syndrome), chromosome analysis and CT scans for profound or progressive hearing loss.
Waardenburg syndrome: Characteriz= ed by sensorineural hearing loss, abnormal pigmentation of the skin and hair, dys= topia canthorum (eye inner canthi are displaced later= ally), heterochromia iridis (iris colors do not match), and pinched nose.&nb= sp; This syndrome occurs anywhere from 1 in 20,000 to 1 in 40,000 and accounts for 1-2% of people with profound hearing loss. The hearing loss can be unilateral= or bilateral of varying severity. The syndrome has 4 subtypes classified according to the presence or absence of other abnormalities. In Type = 1, every patient exhibits dystopia canthorum.= The Type 2 phenotype is void of dystopia canthorum while Type 3 exis= ts with upper extremity abnormalities in conjunction with Type 1 characteristics. Type 4 exhib= its pigmentation abnormalities, Hirschsprung’s disease, plus findings shown in Type 2. Types 1 and 3 are linked t= o gene mutations in the PAX3 gene, while Types 2 and 4 are linked to the MITF and = EDNRB genes respectively.
Branchio-oto-renal syndrome: This syndro= me is estimated to be present in 2% of profoundly deaf children. The syndrome displays high penetrance although variable expressivity has been sh= own in families. Hearing impairment = is estimated to be present in 70-93% of affected people but the age of onset ranges from early childhood to young = adulthood. Likewise, there is varied severity ranging from mild to profound and the nature can be conductive, sensorineur= al or mixed. Common characteristics of the BOR phenotype include cup-shaped pinnae, preauricular pits, branchial cleft fistulae and bilateral renal anomalies. Other features displayed are preauricular tags, lacrimal duct stenosis, deep overbite and a long , narrow face. Inner ear anomalies like Mondini’s dysplasia and stapes fixation can als= o be present. The genetic etiology of this syndrome can be traced to the EYA1 gene. Based on the phenotypic anom= alies, criteria have been developed for E= YA1 testing: affected individuals= must have at least 3 major criteria; two major criteria and at least two minor criteria; or one major criteria with one first- degree family member meeting BOR criteria (see accompanied POWERPOINT SLIDE SHOW.presentation for table of criteria).=
Stickler Syndrome (STL):&n=
bsp;
In addition to having sensorineural hearing loss that is
progressive, these pat=
ients
usually display a cleft palate, abnormal development of the epiphysis,
vertebral abnormalities and osteoarthritis. There are three clinical subtypes =
that
exist. Type 1 develops progre=
ssive
myopathy, retinal detachment and vitreoretinal =
degeneration. Retina detachment is nonexistent i=
n type
2 due to lack of the COL11A2 gene in the retina. In Type 3 shares eye
and ear findings present in type 1 but has facial abnormalities.
Treacher Collins (TC): Also known as Fraceschetti-Zwahlen=
-Klein
Syndrome =
or
Mandibulo-Facial Dysostosis, this autosomal dominant entity is liked to
mutations on chromosome 5q11 and some reports mention an association of
maternal vitamin A hypersensitivity.
Diagnostic criteria include microtia and malformed ears, midface
hypoplasia, downslanting palpebral fissures, coloboma of outer 1/3 of lower=
eyelids,
and micrognathia. The upper airway narrowing can be a major issue in
infancy. The size of the
nasopharynx is 50% smaller than normal and affected infants are more prone =
to
OSA and SIDS. Hearing loss in=
this
syndrome is usually conductive with a wide array of middle ear anomalies
present such as monopodal stapes, ankylosed foot plate, malformed incus,
Osteogenesis imperfecta (OI): This is an autosomal dominant diso= rder displaying the triad of bone fragility, blue sclerae and hearing impairment. Other characteris= tics include triangular face, short stature, hypermobile mobile joints, cardiova= scular abnormalities and skin disorders. The incidence is estimated to be 1 in 20,000 to 1 in 30,000. Causati= ve mutations involve the COL1A1 or COL1A2 gene which regulate formation of typ= e I collagen. Hearing loss = is usually mixed and has a prevalence ranging from 26-78%. The hearing loss usually presents = itself during the late 20s or early 30s. The conductive component of the hearing loss is attributed to the thickened and fixed stapes footplate, similar to what is seen in otoscleros= is. The sensorineural component usually results from cochlear hair cell atrophy and atrophy of the stria vascularis. Also, anomalous b= one formation in and around the cochlea may contribute to the sensorineural component of the hearing loss.
Neurofibromatosis Type II (NF 2): Bilateral vestibular schwannomas a=
re the
hallmark of this disease with a prevalence of 1 in 210,000 people. Other features include meningiomas
(intracranial and spinal), ependymomas, gliomas, presenile lens opacities, =
and
schwannomas located in the cranial, spinal and peripheral nerves. The skin can also manifest
café-au-lait spots but not to the extent found in neurofibromatosis =
type
I. This
disease is caused by an NF 2 tumor-suppressor gene mutation on chromosome
22. Affected patients usually
present in the 2nd and 4th decade. Up to 41% present =
with
unilateral sensorineural hearing loss rather than bilateral sensorineural
hearing loss due to the fact that this percentage of patients do not present
with bilateral vestibular schwannomas.&nbs=
p;
Patients can also have tinnitus, disequilibrium, headache and cranial
nerve symptoms. Children <=
15
years old may commonly present with skin or spinal tumors prior to the onse=
t of
hearing loss or development of vestibular schwannomas. In addition to the <=
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Usher Syndrome: Usher syndrome is the most common cause of autosomal recessive hearing loss. The incidence of Usher syndrome is approximately 3-5 per 100,000 in the general population an d 1-10% among profoundly deaf children. The syndrome has se= veral subtypes based on severity of the deafness and the onset of retinitis pigmentosa (gradual retinal degeneration leading to decreased night vision, loss of peripheral vision, and blindness).= Type 1 has severe hearing loss and vestibular dysfunction. The onset of retinitis pigmentosa = is in childhood as opposed to type 2 where it begins after childhood. Mild to moderate hearing g lo= ss characterizes type 2 along with normal vestibular function. In type 3, hearing loss is progres= sive as is the vestibular dysfunction. Retinitis pigmentosa can occur anytime in life.
Pendred syndrome: Characterized by hearing impairment associated with abnormal iodine metabolism. The responsible gene is SLC26A4 (PDS). This encodes a protein= named pendrin which helps regulate iodine and chlorid= e ion transport . Most patients have a euthyroid goiter which is sometimes detected at birth but o= ften is not clinically evident until 8 years of age. Diagnosis of the thyroid abnormali= ty used to depend on perchlorate discharge tests (i= ndicates abnormal organification of nonorganic iodine) but this test is not specific= for Pendred syndrome and the sensitivity is unknown. Instead, thyroid function tests are used. The hearing loss in this syndrome is severe and can be present at birth or progress with age. In addition, CT scans have revealed cochlear dysplasia (Mondini’s) an enlarged vestibular aqueduct or both. =
Jervell and Lange-Nielsen Syndrome= : This syndrome, although rare, shou= ld be suspected in a child with hearing loss and seizures of unknown origin and/or a fam= ily history of sudden death. Patients are characterized by severe-profound hearing loss and prolongation of the QT interval EKG. The syncopal episod= es are due to a cardiac conduction defect which can manifest as early as the 2= nd or 3rd year of life. The cardiac conduction defects can be attributed to mutations in potassium chan= nel genes traced back to loci on the KVLQT1 and KCNE1 genes located on chromoso= mes 11p15.5 and 21q22 respectively.
Biotinidase
Deficiency: Infants w=
ith
severe biotinidase deficiency will display skin rashes, seizures, hair loss,
hypotonia, emesis and acidosis in the first few months of life. This syndrome occurs because the i=
nfant
lacks the enzyme responsible for proper biotin metabolism.
Alport syndrome: As a result of the mutation in typ= e IV collagen gene COL4A5, patients with Alport syndrome exhibit renal disorders= and ocular abnormalities in addition to progressive sensorineural hearing loss. Renal disorders include= glomerulonephritis, hematuria (“red diaper”), and renal failure. Early diagnosis is essential becau= se the renal disease is usually more severe in males causing death secondary to ur= emia prior to 30 year old. Congeni= tal cataracts are also common. The progressive sensorineural hearing loss mentioned earlier usually has an ons= et beginning in the 2nd decade of life.
Down’s syndrome:&nbs= p; This is the most common of the chromosome abnormality syndromes typi= fied by a wide range of abnormalities. Otolaryngologic findings are numerous in these patients and can affe= ct every region of the head and neck. This includes small ears with overfolding of the superior helix, stenotic EAC and eustachian tube dysfunction. There is also an increased inciden= ce 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 and OSA a= re 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. Other systems affected include cardiovascular (ventricular-septal defect, tetrology of Fallot, patent ductus arteriosis), genitourinary (micropenis, low testoster= one, infertility), musculoskeletal (atlanto-axial instability, short metacarpals= and phalanges) and ocular (speckled iris;Brushfield spots). 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).
Fetal Alcohol Syndrome (FAS): Of children born to alcoholic moth= ers, 30-40% suffer this syndrome. The amount of alcohol intake requi= red to cause FAS has not been clearly established. Alcohol and its major metabolit= e, acetaldehyde, may be teratogenic. The alcohol induced developmental abnormalities can be the result of restriction of cell growth during critical periods. Characteristics of the syndrome in= clude prenatal and postnatal growth deficiency, microcephaly, and mental retardat= ion (average IQ of 63). Behavior = is also affected as irritability and hyperactivity are common. Neural tube def= ects and seizure disorder may also be present. From an ophthalmology perspective, this syndrome causes hypoplasia of the optic nerve, increased tortuosity of= the retinal vessels, severe microophthalmia and colobomas. Almost no system is guaranteed to = be spared as cardiac, renal and skeletal anomalies may manifest themselves as = well as malignant neoplasms of embryonal origin. Common facial dysmorphisms include narrow forehead, short palpebral fissures, ptosis of eyelids, midface hypoplasia, short nose, smooth philthrum, thin upper lip a= nd hypoplastic mandible. In addi= tion, cleft palate or cleft lip may exist. Ten percent of patients have hearing loss that may be either conduct= ive or sensorineural.
Goldenhar’s Syndrome: Also referred to as facioauriculovertebral dysplasia (FAVD) and hemifacial microsomia (HFM), th= is disorder results from aberrant development of the first and second branchial arches. HFM is estimated to o= ccur in 1 in 5600 live births, perhaps making it the most significant asymmetric craniofacial disorder. Otolog= ic manifestations include microtia/anotia, preauricular tags, ossicular abnormalities, ab= normal facial nerve course, and hearing loss (conductive > sensorineural). The hearing loss is predominantly conductive secondary to the abnormal development of the structures derived from the first and second branchial arches. Facial abnormalities include unila= teral hypoplasia of the maxilla, malar and temporal bones in addition to mandibul= ar ramus and condyle hypoplasia. Macrostomia or pseudomacrostomia (lateral cleft-like extension of the oral commisures), cleft lip or palate and delayed dental development. Lastly, the mastoid is poorly pneumatized and their may exist agenesis of the parotid gland or displaceme= nt of the gland. In terms of non-head and neck featu= res, affected individuals can also have cardiac abnormalities such as coarctatio= n of the aorta, ventricular septal defect, tetrology of Fallot, and patent ductus arteriosis. Renal ectopia and hydronephrosis can encompass the renal abnormalities. Limb deformities can be present as= well as cerebral malformation and mental retardation. Ocular abnormalities include blepharoptosis, microopthalmia, epibulbar tumors, and retinal abnormalities leading to reduced visual acuity.
Rubella: Cons= ists of a triad characterized by deafness, congenital cataracts and heart defects. This disease is caus= ed by an RNA togavirus and is transmitted postnatally via respiratory secretion, saliva, or direct contact. Transplacental transmission is the route responsible for congenital infection which can involve more sequelae if infection is present during the first trimester. In terms of diagnosis, positive viral culture must be obtained, rubella-specific IgM antibody, or demonstration of significant rise in IgG antibody in acute (7-10days) and convalescent phase (2-3 weeks later). The virus can be cultured from blo= od, nasal secretions, urine, throat swab or CSF. In addition to the above listed triad, other abnormalities that may manifest are microcephaly, motor and ne= ural retardation, hepatosplenomegaly, thrombocytopenia, encephalitis and interst= itial pneumonitis. The hearing loss= in rubella is typically asymmetric and sensorineural with variable severity. The 500-2000 Hz frequencies are the most commonly affected. This hearing deficit usually manif= ests by 5 years of age and can be an isolated finding in 22%. Approximately 25% = of patients will experience a progressive form of hearing loss.
Cytomegalovirus (CMV):&nbs= p; 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 congen= ital malformations and mental retardation in developed countries. Of all the TOR= CH 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 progressiv= e. Interesting to note, infants with petechiae and IUGR are 2-3 times more likely to have sensorineural hearing loss. P= ost mortem temporal bone studies on infants who died from cytomegalic inclusion disease have revealed inclusion bodies in the stria vascularis, Reissner’s membrane, saccule, utricle and semicircular canals. Endolymphatic hydrops was noted in= the cochlear ducts.
The important fact to remember pertaining to syndromic hearing loss is that treatment of the hearing impairment is no different th= an treating a nonsyndromic patient with hearing loss. In other words, there isn’t a special hearing treatment for the profound sensorineural hearing loss in Us= her syndrome vs. the child who is profoundly deaf at birth without a syndrome.<= span style=3D'mso-spacerun:yes'> There have been studies documenting success in use of cochlear implants in syndromes manifesting sensorineural hearing loss such as Usher, Waardenburg, and Jervell and Lange-Nielsen syndrome. Likewise, when synd= romic patients have conductive hearing loss or a significant conductive component contributing to mixed hearing loss, the appropriate surgical procedures sho= uld be performed. This can range = from being as simple as a BM&T for the recurrent middle ear effusions in Down’s to performing a stapedotomy/ossiculoplasty in osteogenesis imperfecta. Basically, the me= thod of treatment should be selected to meet the individual needs of the patient= to achieve the most benefit. In = the end, the main purpose of arriving at a syndromic diagnosis is to identify t= hose that will have hearing loss so that early and aggressive hearing rehabilita= tion can be initialized.
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