Introduction

The ear is an incredible organ of hearing and equilibrium divided into three anatomic parts: the external, middle, andinternal ear. The external ear, or outer ear, consists of the auricle or pinna, and the tubular external auditory canal ending at the tympanic cavity. The external ear resonates and amplifies sound,and it directs sound towards the tympanic membrane. The middle ear's tympanic membrane converts energy from sound waves into mechanical energy as vibrations.The middle ear is essentially an air-filled cavity that houses three auditory ossicles: the malleus, incus, and stapes. The ossicles transmit sound vibrations from the tympanic membrane to theinternal or inner ear. Theinternalear, or labyrinth of the ear, houses the organs of hearing and balance. The internal earis composed of thevestibule, semicircular canals, and cochlea.The vestibule functions tosense linear acceleration, while the semicircular canals sense rotational movements. The cochlea'sorgan of Corti functions totransduce auditory signals into neuronal impulses that reach the brain via the vestibulocochlear nerve.The delicate structures of the internal, middle, and external ear must function in concert to transmit sound and sense movement.

The development of the earrequires contributions from allthree germ layers and involves a sophisticated process with intricate embryologic patterning. Each anatomic divisionof the ear has a distinct origin and unique developmental processes resulting in their typical form.[1]While the development of the ear continuespost-birth, a fetus can functionally hear by about 26 weeks of development. Notably, several anatomic variants and congenital conditions can arise from deviationsin the typical developmental processes.[2]

InternalEar

The internal ear is derived from ectoderm, and it is the first of the three anatomic parts of the ear to form. Development begins as a pair ofshort-lived thickenings of the surface ectoderm, the otic placode or otic disc, appear dorsolateral to the hindbrainaround the fourth week of developmentthe otic placode forms due to the induction of surface ectoderm by the nearby notochord and paraxial mesoderm. The otic placode is one of the first sensory placodes involved in the formation of special sensory organs to develop.

The otic placode invaginates into the mesenchyme adjacent to the rhombencephalon to form an otic pit. Thesides ofthe otic pit fold together and fuse to form a hollow piriform structure lined with columnar epithelium, called the otic vesicle. Rapidly, the otic vesicle moves deep to the surface ectodermand is instead enveloped in mesenchyme to form the otic capsule. The statoacoustic, or vestibulocochlear, ganglionarises as neurons delaminate duringthe formation of the otic vesicleand, later,the ganglion splits into cochlear and vestibular portions.

The otic vesicleforms two visible regions: a ventral saccular portion and a dorsal utricular portion. The ventral saccular portion gives rise tointernal ear structures involved in hearing, including the cochlear ducts and saccules. The dorsal utricular portion gives rise to the vestibular system, includingthe utricle, semicircular canals, and endolymphatic tube.[3][4]Ultimately, the otic vesicle will differentiate to form all of the components of the membranous labyrinth and theinternal ear structures associated with hearing and balance.

The otic vesicle elongates within the firstfour weeks to form a tube-like structure called the endolymphatic appendage. Soon after, a groove-like indentation forms and demarcates a tubular diverticulum on the medial side of the endolymphatic appendage. This diverticulum differentiates into the endolymphatic duct and sac and continues to grow until around the age of four.[5]

Internal Ear: Ventral Saccular Component

The ventral saccular component of the otic vesicleformsa tubular cochlear duct, the primordial cochlea, within the mesenchymeby the sixth week. The cochlear duct grows and spiralstwo and a halftimes to produce the membranous cochlea. Rapidly, the saccule connects to the utricle via a duct called the ductus reuniens.

Mesenchyme surrounding the otic vesicle is induced to form a cartilaginous otic capsule, which will ossify to produce theinternal ear's bony labyrinth later in development. The cartilaginous otic capsule then forms vacuolesthat coalesce into the fluid-filled perilymphatic space of the cochlea. The fluid, or perilymph, resides within the perilymphatic space and surrounds the membranous labyrinth. The perilymphatic space thenseparates into two divisions: the scala vestibule and the scala tympani. Two membranes separate the cochlear duct from the perilymphatic divisions. The basilar membrane demarcates thecochlear duct from the scala tympani, while the vestibular membrane separatesthe cochlear duct from the scala vestibule. Cells in the lateral aspect of the cochlear duct differentiate to form the organ of Corti, or spiral organ or spiral organ of Corti, within the scala media of the cochlear duct. The cochlear ductalso develops an attachment to the surrounding cartilage via connective tissue,the spiral ligament.

Theorgan of Cortiis formedwhen ridges of epithelial cells from the cochlear ductproduce rows of mechanosensory hair cells that are covered by the tectorial membrane. The spiral ganglion forms when ganglion cells derived from the vestibulocochlear nerve (CN VIII) migrate along the spirals of the membranous cochlea. Nervous processes then extend from the spiral ganglion to hair cells of the organ of Corti.

Thecartilaginous oticcapsule surrounding the membranous labyrinth ossifiesby about 23 weeks to form the true bony labyrinth.[6]Around this time, the internal earhas reachedits adult size and form.

Internal Ear: Dorsal Utricular Component

The dorsal utricular portion of the otic vesicle forms the utricle and semicircular canals, the organs of balance. During thesixth week, disc-like epithelial outpouchings extend dorsolaterally from the dorsal utricular portion of the primordial membranous labyrinth. The central portions of thesediscs approach each other, and their epithelium joins to form fusion plateswhich ultimatelyregress via programmed cell death. The peripheral unfused portions of thediscs that fail to regress form incipient semicircular ducts that attach to the utricle. Later, the semicircular ducts are incorporatedwithin the anterior, posterior, and lateral semicircular canals.

At one end of eachsemicircularduct, a dilatation of the ductdevelops and is called anampulla. Theampullae contain sensory hair cells that form crests with specialized receptor areas, the cristae ampullares. Similarspecialized areas form in the walls of the saccule and utricle. These regions sense changes in angular acceleration and serve as the sensory organ of rotation. Sensory cells of the cristae ampullaresgenerate impulses that reach the brain via vestibular fibers of the vestibulocochlear nerve.[7]

Middle Ear

The middle ear is composed of the tympanic cavity and the Eustachian,also known as the auditory or pharyngotympanic, tube. Structures of the middle ear are derived fromthetubotympanic sulcus, or tubotympanic recess, an endodermal extension from the first pharyngeal pouch. Around the 5th weekof development, the tubotympanicsulcusextends laterally to approach the floor of the first pharyngeal groove but remains separated by mesenchyme. During development, the endoderm of the tubotympanicsulcus and the ectoderm of the first pharyngealgroovefurther approacheach other, but they continue to maintain a layer of mesoderm between them. The end result is a trilaminar tympanic membrane made up of tissues derived from all three germ layers: ectoderm, mesoderm, and endoderm.

The tympanic cavity developsas an expansion of the distal portion of the tubotympanic sulcus. Anatomically, the tympanic cavity divides into upper (attic) and lower (atrium) chambers and gradually surrounds the ossicles, their attachments, and the chorda tympani. The Eustachian tube is formed from the proximal portion of the tubotympanic sulcus. The Eustachian tube is more horizontal, short, and narrow at birth than in later adulthood, which is a major reason infants have recurrent ear infections. Despite anendodermal origin, both the tympanic cavity and the Eustachian tube are ultimately lined by epithelium-derived from endoderm and neural crest cells. The Eustachian tube demonstrates the most growth during weeks 16 to 28 of the fetal period.[8]

The middle ear ossicles initially form around six weeks of development. Theyfirst appear in a cartilaginous form that arises from neural crest-derived mesenchymal cellswithin the first and second pharyngeal arches that condense at the dorsal end of the tubotympanicsulcus. The malleus and incus develop from Meckel's cartilage of the first pharyngeal arch. The stapes have a complex origin, partly arising from both neural crest cells and Reichert's cartilage of the second pharyngeal arch. As the tympanic cavity develops, theossicular cartilages go through endochondral ossification that continues throughout the entire fetal period. Late in thefetal period, the mesenchyme that fills the tympanic cavity andsurrounds the ossicles is resorbedto produce an air-filled tympanic cavity with ossicles suspended inside. Eventually, the tympanic cavity expands and forms the mastoid antrum.

The tensor tympani musclearises from the mesoderm of the first pharyngeal arch and is innervated by the mandibular branch of the trigeminal nerve. The stapedius muscle originates from the mesoderm of the second pharyngeal arch and is innervated by the facial nerve.[9][10]The middle ear continues to develop post-birthand through puberty.

External Ear

The external ear first developsin the lowercervical region, but it graduallymovesposterolaterally during development toreach its typical location.[11]The external ear's auricle develops from the mesenchymal proliferationof the first and second pharyngeal archesatthe end of thefourth week of development. Sixprominences, or auricular hillocks, form around the external auditory meatusand eventually fuse to form the auricle. Three auricular hillocks,hillocks 1to 3, arise from the first pharyngeal archto formthe tragus, helix, and cymba concha; andthree auricular hillocks, hillocks 4to 6, arise from the second pharyngeal arch toform the concha, antihelix, and antitragus.

The external auditory meatus arises from the dorsal portion of the first pharyngeal groove. The meatus first develops as an invagination of ectoderm between the first and second pharyngeal arches that extends toward the developing middle ear structures. Around the fifth week,the ectodermal diverticulum extends toward the pharynx andhouses proliferating ectodermal cells thatproducean epithelial plug, the meatal plug, that will fillsits entire lumen. At approximately tenweeks of development, theend of the meatal plug expands circumferentially to create a disc-like structure. Eventually, thedisc-like meatal plug contacts the primordial malleus, divides, and leaves behind a thin ectodermal layer forming anincipienttympanic membrane. A continuation of the thin skin of the pinna lines the entire external auditory meatus and the outer surface of the tympanic membrane. By 18 weeks, the external auditory meatus is completely patent and expands to produce itstypical morphology.

The auricle and externalauditory canal are both lined with keratinized squamous epithelium. The externalauditory canal is formed partly of cartilage and partly of bone. The internal bony segment has tiny hairs and cerumen-producing apocrine glands along its lining.

The tympanic membrane separates the external ear from the tympanic cavity and has a trilaminar structure with contributions from all three germ layers. The outerlayer of the tympanic membrane is composed of keratinized stratified squamous epithelium and is continuous with the surrounding external skin. The epithelium ofthe outer layer originates from the ectoderm of the first pharyngeal groove. The middle layer of the tympanic membrane is a thin fibrous connective tissue layer derived from mesoderm and composed of collagen and elastic fibers called the lamina propria. The inner mucosal layer of the tympanic membrane is derived from the endoderm of the first pharyngeal pouch. The mucous membrane is composed of a non-keratinized squamous epithelium that is continuous with the lining of the tympanic cavity.

The utricle and saccule are otolith organs located in the vestibule that detect movement in different planes. The utricle and saccule consist of sensory areas called maculaecomposed of supporting cells and hair cells covered in a gelatinous acellular matrix called the otolithic membrane. The otolithic membrane is embedded with calcium carbonate crystals called otoliths. The crista ampullaris of the semicircular ducts have a sensory epithelium similar to that of the macula, also consisting of hair cells and supporting cells. The hair cells of the cristae project into a gelatinous material called the cupula, which does not contain otoliths, and serves to detect rotational acceleration.

The organ of Corti is located on the basilar membrane and consists of a variety of supporting cells and two groups of hair cells: inner hair cells and outer hair cells. The inner hair cells account for approximately 95% of the sensory input into the auditory system and arrange in one line along the entire basilar membrane. The outer hair cells account for about 5% of sensory input and serve primarily as acoustical pre-amplifiers. The outer hair cells receive efferent input and contract when stimulated, resulting in amplified sound waves. The supporting cells include Hensen cells, Corti pillars, Deiters cells, and Claudius cells. The supporting cells play essential roles in the function and maintenance of theinternal ear and primarily serve structural and homeostatic functions.[12]

Proper formation and axial positioning of the components of the ear occur through complex reciprocal interactions between the epithelium and mesenchyme of the pharyngeal arches and hindbrain. These complex interactions involve a wide variety of essential genes, morphogens, and transcription factors that ultimately determine the fate of cells in theinternal ear. Members of the Wnt, Sonic Hedgehog (SHH), and fibroblast-growth-factor (FGF) families, combined with retinoic acid signals, regulate transcription factor genes within the primordialinternal ear to regionalize neurogenic activity and establish the axial identity of the ear.

Otic placode induction is dependent on Wnts and FGFs provided by the hindbrain and surrounding head mesenchyme. After induction, the otic placode continues to be influenced by signaling information from surrounding tissues that determine its positional identity along the dorsal-ventral, anterior-posterior, and medial-lateral axes. The anterior-posterior axis is the first axis to be specified. It requires retinoic acid, a key morphogen, to confer proper anterior and posterior identities of theinternal ear. Somites express high levels of Raldh2, a retinoic acid synthesizing enzyme that serves as the primary source of retinoic acid for patterning theinternal ear. Retinoic acid signaling results in proper anterior-posterior patterning of theinternal ear and establishes the neural-sensory-competent domain (NSD) in the anterior otic cup.

The neural-sensory-competent domain gives rise to neurons of the cochleovestibular ganglion, as well as prosensory cells of theinternal ear that differentiate into supporting cells or sensory hair cells. Neurogenin1 is a proneural gene that encodes a basic helix-loop-helix region (bHCH) transcription factor and is one of the earliest molecular markers determining the neurogenic fate of cells in theinternal ear. The anterior portion of the NSD contains Ngn1-positive cells that ultimately leave the otic epithelium and coalesce to become neurons of the cochleovestibular ganglion. The remaining sensory epithelium of the NSD develops into supporting cells, sensory hair cells, and some nonsensory cells.[13][14][15]

Proper patterning of theinternal ear dorsal-ventral axis involves the secretion of Wnts transcription factors from the dorsal hindbrain and the release of Sonic Hedgehog from the notochord and ventral floor plate. The patterning of the medial-lateral axis of theinternal ear has not been well studied. It is thought to involve hindbrain signaling mediated by the transcription factor Gbx2 from the otic epithelium.

Sonic Hedgehog is not only imperative in determining the dorsal-ventral axis of theinternal ear, but it is also responsible for regulating and determining auditory cell fates within theinternal ear. Sonic Hedgehog is released from the notochord and ventral hindbrain and allows for proper cochlear duct and semicircular canal development. The mesenchyme encasing the developinginternal ear is also essential for shaping the semicircular canals and cochlear duct into their final form through both structural and molecular means.

Although the mechanisms and molecules involved in the process of semicircular canal formation are largely unexplored, studies have implicated a variety of mesenchymal genes in canal formation, such as Prx and Pou3f4. Proper extension and outgrowth of the cochlear duct are dependent on Sonic Hedgehog secretion from the notochord and the release of transcription factors called Tbx1 and Pou3f4 from the otic mesenchyme. Studies have shown that an absence of Pou3f4 or Tbx1 in the otic mesenchyme results in abnormal shortening or coiling of the cochlear duct.[16][17][18]

Congenitalanomalies involving the ear maybe of significant physical and psychosocial concern to patients and the parents of afflicted children, given that these conditionsmay affect physical appearance, hearing, and balance.[19]In addition, the financial cost of such conditionscan be significant given the potentialfor long-termspecial education, healthcare, and accessibility needs. Around 15to 20% of neonates are estimated to be born with congenital abnormalities of the ear, and around 30% of these will resolve without intervention by six weeks of age.

While a wide variety of congenitalanomalies ofthe ear exist, those that impact hearing are particularly concerning.[2] Neonatal hearing loss may becomplete or partial, andapproximately 1 in 1,000neonates is estimated tohave "significant" congenitalhearing loss. Developmentalanomalies of the ear that result in conductive hearing loss tend to involve the external and/or middle ear, while those that result in sensorineural hearing loss often involve the inner ear. Additional congenital causes of sensorineural hearing lossimpact anatomicstructures outsideof the ear,including the vestibulocochlear nerve and auditory regions of the brain. The various developmentalanomaliesof the ear mayresult from genetic and/or environmental factors, the latteroften caused byviral infections, neonatal exposures, ornoise.

Internal Ear

Neonatal hearing loss is sometimes duetodevelopmentalanomalies of the neurosensory components of the internal ear. The most common cause, Enlarged Vestibular Aqueduct Syndrome (EVA), is an autosomal recessive condition in which there is a bilateral enlargement of the endolymphatic duct and vestibular aqueduct.[20]

Maternal infection with rubella isanother source of neonatal hearing loss that may hinder the development of the organ of Corti inthefourth week of development, resulting in its malformation. Similarly, maternal infection with cytomegalovirus is another potential causeof congenital sensorineural hearing loss.Other relatively commoncongenital anomalies of the internal earinclude Mondini dysplasia and autosomal dominant nonsyndromic hearing loss.

Middle Ear

Congenitalanomalies of the middle ear are relatively rare and include congenital fixation of one or more of the ossicles, a rare primary bone dysplasia called familial expansile osteolysis, and acyst-like abnormal accumulation of skin cells called cholesteatoma. Developmentalmalformationsof the middle ear structures responsible for sound conversion and transmission contribute to neonatal hearing loss.

External ear

Numerous congenitalanomalies of theexternal ear have been recorded in the literature.[21][22]Congenital anomalies of the external ear can potentially impact physical appearance or hearing.Given the role of the pharyngeal arches inthedevelopment of the external ear,anomalies of the external ear are associated with other pharyngeal arch anomalies and a variety of chromosomal disorders.

Preauricular tags, or simply ear tags, are common and usually benign findings in neonates that involve cutaneous, fatty, or cartilaginous growths. Occasionally, preauricular tagsmay be associated with other pharyngeal arch anomalies or genetic syndromes.Developmentally, accessory auricular hillockssometimes produce auricular appendages,preauricular tags, or an accessory auricle.

Microtia is a developmental anomaly of the external ear involving an under-developmentof the typical mesenchymal proliferationsthat formthe external ear. This condition presents at birth as an unusually small and sometimes misshapen external earandis highly variable inits degree of severity. Microtia is associated with conductive hearing loss due to the possibility of middle and external ear malformations and the potential for complete agenesis of the external auditory canal.[19]Bilateral microtia is aclassic indicator ofTreacher-Collins Syndrome (TCS) and is present in approximately 85% of patients with TCS.[23]

Cryptotiais a malformation of the cartilage of the external ear that involvespart of the externalear, usually the superior portion, being buried under the adjacent skin.[21]

Another external ear congenital anomaly, unilateral or bilateral atresia of the external acoustic meatus, occurs in individuals who retain the meatal plugdue to a failureof canalization. In most cases, the external acoustic meatus is only superficially obstructed by fibrous or bony tissue.Given its relationship to the first pharyngeal groove, atresia of the external acoustic meatushas been associated with variousmalformations. Finally, the complete absence of the external auditory meatus is a rare congenital anomaly of the external ear; this condition occurs due to a failure in the mesenchymal proliferation arising from the first pharyngeal groove.

Anatomy of the outer, middle, and inner ear. Image created for publication by Diana Peterson.

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