EYE AND EAR DEVELOPMENT AND THEIR MALFORMATIONS

Embryological Development of the Human Eye

The development of the human eye is a complex process involving interactions between the
ectoderm, mesoderm, and neural crest cells. The primary steps occur between the third and
tenth weeks of gestation, starting with the formation of the optic vesicles and culminating in
the formation of the functional eye. Below is an overview of the process:

1. Formation of the Optic Vesicles (Day 22–Day 28)

The eyes begin as a pair of optic grooves on either side of the developing forebrain.

These grooves deepen to form optic vesicles, which are evaginations of the diencephalon.

The optic vesicles grow laterally toward the surface ectoderm, with the proximal region
remaining connected to the forebrain via the optic stalk.

2. Formation of the Optic Cup (Week 4)

As the optic vesicle approaches the surface ectoderm, it induces thickening of the ectoderm,
forming the lens placode.

The optic vesicle invaginates to form a double-walled optic cup:

Outer Layer: Forms the retinal pigment epithelium (RPE).

Inner Layer: Differentiates into the neural retina.

3. Development of the Lens (Week 4–Week 7)

The lens placode invaginates into the optic cup, forming the lens vesicle.

The lens vesicle detaches from the surface ectoderm and lies within the optic cup.

Primary lens fibers elongate from the posterior lens epithelium to fill the lumen of the
vesicle, forming the lens.

4. Formation of the Cornea (Week 5–Week 6)

The surface ectoderm overlying the lens vesicle differentiates into the corneal epithelium.

Neural crest cells migrate to form the corneal stroma and endothelium.
Mesodermal cells contribute to the formation of the corneal stromal layers.

5. Development of the Retina (Week 6–Week 12)

The inner layer of the optic cup differentiates into:

1. Outer Neural Retina: Contains photoreceptors.

2. Inner Ganglion Cell Layer: Forms axons that contribute to the optic nerve.

The outer layer of the optic cup becomes the retinal pigment epithelium (RPE).

6. Formation of the Optic Nerve (Week 6–Week 8)

Axons of the ganglion cells in the retina converge to form the optic nerve.

The central portion of the optic stalk becomes the lumen of the optic nerve.

Myelination of the optic nerve begins later in development, around the seventh month of
gestation.

7. Formation of the Choroid and Sclera (Week 6–Week 10)

Neural crest cells migrate to form the vascular choroid and the fibrous sclera, surrounding
the optic cup.

8. Development of the Eyelids and Extraocular Muscles (Week 8–Week 12)

Eyelids develop as folds of ectoderm filled with mesenchyme that meet and temporarily fuse.

The extraocular muscles arise from the paraxial mesoderm.

9. Vitreous Body Formation

Mesenchyme enters the optic cup to form the primary vitreous, which is replaced by the
secondary vitreous derived from the retina.

10. Further Maturation (Post-Week 10)

Iris: Formed from the anterior portion of the optic cup and the stroma derived from neural
crest cells.

Ciliary Body: Develops from the anterior edge of the optic cup, with ciliary muscles and
processes forming later.

2. Development of the Optic Vesicle

(Source: BRS Embryology, 5th Ed. Chapter 9)

The development of the optic vesicle begins at day 22 with the formation of optic sulcus,
which evaginates from the wall of the diencephalon as the optic vesicle, consisting of
neuroectoderm.

The optic vesicle invaginates and forms a double-layered optic cup and optic stalk.

PAX6 is the master homeotic gene in eye development. PAX6 is expressed predominately in
the optic cup and lens placode. PAX2 is expressed predominately in the optic stalk.

The optic cup and its derivatives. The double-layered optic cup consists of an outer pigment
layer and an inner neural layer. 1. Retina: a. The outer pigment layer of the optic cup gives
rise to the pigment layer of the retina. b. The intraretinal space separates the outer pigment
layer from the inner neural layer. Although the intraretinal space is obliterated in the adult,
it remains a weakened area prone to retinal detachment. c. The inner neural layer of the otic
cup gives rise to the neural layer of the retina (i.e., the rods and cones, bipolar cells, ganglion
cells, etc.). 2. Iris. a. The epithelium of the iris develops from the anterior portions of both
the outer pigment layer and inner neural layer of the optic cup, which explains its
histological appearance of two layers of columnar epithelium. b. The stroma develops from
mesoderm continuous with the choroid. c. The iris contains the dilator pupillae muscle and
sphincter pupillae muscle, which are formed from the epithelium of the outer pigment layer
by a transformation of these epithelial cells into contractile cells. 3. Ciliary body. a. The
epithelium of the ciliary body develops from the anterior portions of both the outer pigment
layer and inner neural layer of the optic cup, which explains its histological appearance of
two layers of columnar epithelium. b. The stroma develops from mesoderm continuous with
the choroid. c. The ciliary body contains the ciliary muscle, which is formed from mesoderm
within the choroid. The ciliary processes are components of the ciliary body. d. The ciliary
processes produce aqueous humor, which circulates through the posterior and anterior
chambers and drains into the venous circulation via the trabecular meshwork and the canal
of Schlemm. e. The ciliary processes give rise to the suspensory fibers of the lens (ciliary
zonule), which are attached to and suspend the lens.

II. Development of Other Eye Structures

A. Sclera. The sclera develops from mesoderm surrounding the optic cup. The sclera forms
an outer fibrous layer that is continuous with the dura mater posteriorly and the cornea
anteriorly.

B. Choroid. The choroids develop from mesoderm surrounding the optic cup. The choroids
form a vascular layer that is continuous with the pia/arachnoid posteriorly and iris/ciliary
body anteriorly.

C. Anterior chamber

1. The anterior chamber develops from mesoderm over the anterior aspect of the eye that is
continuous with the sclera and undergoes vacuolization to form a chamber.

2. The anterior chamber essentially splits the mesoderm into two layers:

a. The mesoderm posterior to the anterior chamber is called the irido - pupillary membrane,
which is normally resorbed prior to birth.
b. The mesoderm anterior to the anterior chamber develops into the substantia propria of
the cornea and corneal endothelium.

D. Cornea

1. The cornea develops from both surface ectoderm and mesoderm lying anterior to the
anterior chamber.

2. The surface ectoderm forms the anterior epithelium of the cornea.

3. The mesoderm forms the substantia propria of the cornea (i.e., Bowman layer, stroma,
and Descemet membrane) and corneal endothelium.

Choroid, Sclera, and Cornea

At the end of the fifth week, the eye primordium is completely surrounded by loose
mesenchyme. This tissue soon differentiates into an inner layer comparable with the pia
mater of the brain and an outer layer comparable with the dura mater. The inner layer later
forms a highly vascularized pigmented layer known as the choroid; the outer layer develops
into the sclera and is continuous with the dura mater around the optic nerve.

Differentiation of mesenchymal layers overlying the anterior aspect of the eye is different.
The anterior chamber forms through vacuolization and splits the mesenchyme into an inner
layer in front of the lens and iris, the irido-pupillary membrane, and an outer layer
continuous with the sclera, the substantia propria of the cornea. The anterior chamber itself
is lined by flattened mesenchymal cells. Hence, the cornea is formed by (a) an epithelial
layer derived fromthe surface ectoderm, (b) the substantia propria or stroma, which is
continuous with the sclera, and (c) an epithelial layer, which borders the anterior chamber.
The iridopupillary membrane in front of the lens disappears completely, providing
communication between the anterior and posterior eye chambers.

Accessory Structures of the Eyeball

Overview

The accessory structures of the eyeball include: eyelids, conjunctival sac, lacrimal gland,
lacrimal sac, and nasolacrimal duct.

Eyelids

The upper and lower eyelids develop from reduplication of surface ectoderm above and
below the cornea,respectively. These ectodermal folds contain a core of mesoderm. As the
upper and lower folds grow, they approach and fuse with each other. Thus, enclosing a
space between them and cornea called conjunctival sac. Therefore, the conjunctival sac is of
ectodermal origin and lined by ectoderm. The eyelids remain fused with each other till the
beginning of 10th week and remain adhered to each other until 28th week (seventh month)
of IUL. Thereafter the eyelids get separated from each other to form the upper and lower
eyelids, respectively. (cf. In many lower mammals, viz., cats, the offsprings are born with
closed eyelids). The central core of the mesoderm in the ectodermal folds (developing
eyelids) forms tarsal plate and connective tissue of the eyelids. The eyelashes and glands in
the eyelids develop from surface ectoderm covering the eyelids in a similar manner as in the
skin.

Lacrimal Glands

Each lacrimal gland develops from 15 to 20 buds that grow from the superolateral angle of
the conjunctival sac. These buds elongate and get canalized to form the ducts. The secretary
acini develop at the ends of these ducts. The ducts of lacrimal gland therefore open in the
conjunctival sac. Lacrimal Sac and Nasolacrimal Duct They develop from the ectoderm of
nasolacrimal/naso-optic groove present along the line of fusion of maxillary and lateral
nasal processes. The lacrimal canaliculi develop from canalization of the ectodermal buds
that grow from the margin of each eyelid near their medial ends to the lacrimal sacs.

Molecular Regulation of Eye Development:

PAX6 is the key regulatory gene for eye development. It is a member of the PAX (paired box)
family of transcription factors and contains two DNA binding motifs that include a paired
domain and a paired type homeodomain. Initially, this transcription factor is expressed in a
band in the anterior neural ridge of the neural plate before neurulation begins. At this stage,
there is a single eye field that later separates into two optic primordia. The signal for
separation of this field is sonic hedgehog (SHH ) expressed in the prechordal plate. SHH
expression up-regulates PAX2 in the center of the eye field and downregulates PAX6. Later
this pattern is maintained so that PAX2 is expressed in the optic stalks and PAX6 is expressed
in the optic cup and overlying surface ectoderm that forms the lens. As development
proceeds, it appears that PAX6 is not essential for optic cup formation. Instead, this process
is regulated by interactive signals between the optic vesicle and surrounding mesenchyme
and the overlying surface ectoderm in the lens-forming region. Thus, fibroblast growth
factors (FGFs) from the surface ectoderm promote differentiation of the neural (inner layer)
retina, while transforming growth factor β (TGF-β), secreted by surrounding mesenchyme,
directs formation of the pigmented (outer) retinal layer. Downstream from these gene
products the transcription factors MITF and CHX10 are expressed and direct differentiation
of the pigmented and neural layer, respectively. Thus, the lens ectoderm is essential for
proper formation of the optic cup such that without a lens placode no cup invagination
occurs. Differentiation of the lens is dependent upon PAX6, although the gene is not
responsible for inductive activity by the optic vesicle. Instead, PAX6 acts autonomously in
the surface ectoderm to regulate lens development. The process begins with PAX6
expression in the neural plate that upregulates the transcription factor SOX2 and also
maintains PAX6 expression in the prospective lens ectoderm. In turn, the optic vesicle
secretes BMP-4, which also upregulates and maintains SOX2 expression as well as
expression of LMAF, another transcription factor. Next, the expression of two homeobox
genes, SIX3 and PROX1, is upregulated by PAX6, while BMP-7 expression in the lens
ectoderm is increased to maintain expression of SOX2 and PAX6. Finally, the combined
expression of PAX6, SOX2, and LMAF initiates expression of genes responsible for formation
of lens crystalline proteins, while PROX1 expression regulates genes controlling cell
proliferation.

Summary of Eye Development

(Source: BRS Embryology)

The eyes begin to develop as a pair of outpocketings that will become the optic vesicles on
each side of the forebrain at the end of the fourth week of development. The optic vesicles
contact the surface ectoderm and induce lens formation. When the optic vesicle begins to
invaginate to form the pigment and neural layers of the retina, the lens placode invaginates
to form the lens vesicle. Through a groove at the inferior aspect of the optic vesicle, the
choroid fissure, the hyaloid artery (later the central artery of the retina) enters the eye.
Nerve fibers of the eye also occupy this groove to reach the optic areas of the brain. The
cornea is formed by (a) a layer of surface ectoderm, (b) the stroma, which is continuous with
the sclera, and (c) an epithelial layer bordering the anterior chamber. PAX6, the master gene
for eye development, is expressed in the single eye field at the neural plate stage. The eye
field is separated into two optic primordia by SHH, which up-regulates PAX2 expression in
the optic stalks while down-regulating PAX6, restricting this gene’s expression to the optic
cup and lens. Epithelial-mesenchymal interactions between prospective lens ectoderm, optic
vesicle, and surrounding mesenchyme then regulate lens and optic cup differentiation.

The eyes first appear early in the 4th week in the form of a pair of lateral grooves, the optic
sulci, which evaginate from the forebrain neural groove to form the optic vesicles. As soon
as the distal tip of the optic vesicle reaches the surface ectoderm, it invaginates,
transforming the optic vesicle into a goblet-shaped optic cup that is attached to the
forebrain by a narrower, hollow optic stalk. The adjacent surface ectoderm simultaneously
thickens to form a lens placode, which invaginates and pinches off to become a hollow lens
vesicle. Posterior cells of the lens vesicle form long, slender, anteroposteriorly oriented
primary lens fibers. Anterior cells develop into a simple epithelium covering the face of the
lens and give rise to the secondary lens fibers, which make up most of the mature lens.

The inner wall of the optic cup (the former optic disc) gives rise to the neural retina, whereas
the outer wall gives rise to the thin, melanin-containing pigmented epithelium. The
differentiation of the neural retina takes place between the 6th week and the 8th month. Six
types of neuronal cells and one glial (Muller) cell are produced in the outer layer of the
neural retina, which is proliferative, forming three layers in the mature retina: the ganglion
cell layer; an inner nuclear layer containing the amacrine, horizontal, and bipolar cells; and
an outer nuclear layer containing the rods and cone photoreceptors. Axons from the neural
retina grow through the optic stalk to the brain, converting the optic stalk to the optic nerve.

Blood is supplied to the developing lens and retina by a terminal branch of the ophthalmic
artery, the hyaloid artery, which enters the optic vesicle via a groove called the choroidal
fissure. The portion of the artery that traverses the vitreous body to reach the lens
degenerates during fetal life as the lens matures; the remainder of the artery becomes the
central artery of the retina.

As the optic vesicle forms it is enveloped by a sheath of mesenchyme that is derived from
neural crest cells and head mesoderm. This sheath differentiates to form the two coverings
of the optic cup: the thin inner vascular choroid and the fibrous outer sclera. The
mesenchyme overlying the developing lens splits into two layers to enclose a new space
called the anterior chamber. The inner wall of the anterior chamber, overlying the lens, is
called the pupillary membrane. Deep layers of this wall undergo vacuolization to create a
new space, the posterior chamber, between the lens and the thin remaining pupillary
membrane.

Early in fetal life, the pupillary membrane breaks down completely to form the pupil. The
rim of the optic cup differentiates to form the iris and ciliary body. Mesoderm adjacent to
the optic cup differentiates in the 5th and 6th weeks to form the extrinsic ocular muscles.
The connective tissue components of the extrinsic ocular muscles are derived from neural
crest cells. The eyelids arise as folds of surface ectoderm and are fused from the 8th week to
about the 5th month.

Golden Facts to Remember (about the Eye):

The first indication of the development of eye is the formation of optic sulcus (optic groove).
The most important refractive medium of the eye is the Cornea.

Congenital Malformations of the Eye

Retinal detachment: There is a separation of pigment epithelium from the neural layer of
the retina in retinal detachment. Detached retina may result from head trauma or may be
congenital. The site of detachment is between the outer and inner layers of the optic cup
(i.e., between the retinal pigment epithelial layer and outer segment layer of rods and cones
of the neural retina). The retinal detachment may be congenital or can occur because of a
blow to the eye. This can be easily explained embryologically because during development
the two layers of the retina are separated by a space called the intraretinal space, which
later on gets obliterated. The integrity of the retina depends upon the pressure of the
vitreous humor in adults, which keeps the two layers of the retina adhered to each other.
When a hole or tear occurs in retina, then the fluid may accumulate between the pigment
and neural layers of the retina and may separate these layers.

Papilledema: The optic nerve is surrounded by three meninges that were invaginated by
developing optic vesicle and stalk. Consequently, it is surrounded by subarachnoid space
(filled with CSF), which is continuous with the subarachnoid space around the brain.
Therefore, an increase in CSF pressure due to increased intracranial pressure hampers the
venous return from retina. As a result, fluid accumulates in optic disc leading to its swelling
(papilledema).

Cataracts: The cataract is opacity of the lens. It may be congenital or acquired. 1. Congenital
cataracts: The congenital cataracts are opacities of the lens since birth. They are usually
bilateral. They are caused by rubella virus, toxoplasmosis, Down’s syndrome (trisomy 21), or
galactosemia (an inborn error of metabolism due to enzymatic deficiency). Note: The lenses
are vulnerable to rubella virus between fourth and seventh week, when the primary lens
fibers are formed. B. Congenital cataracts (Figure 9.4) are opacities of the lens and are
usually bilateral. They are fairly common and may result from the following: rubella virus
infection, toxoplasmosis, congenital syphilis, Down syndrome (trisomy 21), or galactosemia
(an inborn error of metabolism). The photograph in Figure 9.4 shows lens opacities in both
eyes. In congenital cataracts the lens becomes opaque during intrauterine life. Although this
anomaly is usually genetically determined, many children of mothers who have had German
measles (rubella) between the fourth and seventh weeks of pregnancy have cataracts. If the
mother is infected after the seventh week of pregnancy, the lens escapes damage, but the
child may be deaf as a result of abnormalities of the cochlea. 2. Acquired cataract: They
occur due to ageing. In old age central part of the lens becomes harder than peripheral part.
Old primary lens fibers complete their lifetime and degenerate. As a result, there is
accumulation of a special set of proteins called crystalline within the lens, which causes
opacity of the lens.

Anophthalmia (absence of an eye): It occurs when the optic vesicle fails to form.
Microphthalmia (a small eye): It occurs when the optic vesicle is small or there is
underdevelopment of eye. The lens is usually not formed. The microphthalmia is usually
associated with intrauterine infections from toxoplasma, rubella virus, cytomegalovirus,and
herpes simplex virus group of organisms.

Cyclopia (single eye): The cyclopia is severely uncommon anomaly of the face. There
develops a single median eye. The nose is usually absent at the normal site but may be
represented by a tubular appendage called proboscis above the median eye. The cyclopia is
transmitted by recessive inheritance. The two eyes may fuse (synophthalmia) to form a
single eye.

Persistent pupillary membrane: The pupillary membrane may persist as a whole or it may
persist in the form of few strands of connective tissue. It may obstruct the vision completely
or partially. Persistent iridopupillary membrane consists of strands of connective tissue that
partially cover the pupil; however, it seldom affects vision.

Coloboma of the iris. (Gr. Coloboma = a part that is cut off or missing): It is a congenital
notch or cleft on the inferior aspect of the iris. It occurs due to failure of choroid fissure to
close. Coloboma iridis is a cleft in the iris caused by failure of the choroid fissure to close in
week 7 of development and may extend into the ciliary body, retina, choroid, or optic nerve.
A palpebral coloboma, a notch in the eyelid, results from a defect in the developing eyelid.
Coloboma may occur if the choroid fissure fails to close. Normally this fissure closes during
the seventhweek of development. When it does not, a cleft persists. Although such a cleft is
usually in the iris only—coloboma iridis —it may extend into the ciliary body, the retina, the
choroid, and the optic nerve. Coloboma is a common eye abnormality frequently associated
with other eye defects. Colobomas (clefts) of the eyelids may also occur. Mutations in the
PAX2 gene have been linked with optic nerve colobomas and may play a role in the other
types as well. Renal defects also occur with mutations in PAX2 as part of the renal coloboma
syndrome.

Congenital aniridia (complete absence of the iris): It occurs from an arrest of development
at the rim of the optic cup.

Congenital glaucoma (buphthalmos): Congenital glaucoma (buphthalmos) is increased

intraocular pressure due to abnormal development of the canal of Schlemm or the
iridocorneal filtration angle. It is usually genetically determined but may result from
maternal rubella infection. In other words, it is an increased intraocular pressure that results
due to impaired drainage of the aqueous humor, following abnormal development ofcanal
of the Schlemm or iridocorneal filtration angle.

Congenital aphakia (aphakia: absence of the lens of the eye): It occurs if lens placode fails to
develop following failure of lens induction by the optic vesicle.

Microphthalmia: This refers to a small eye. In microphthalmia the eye is too small; the
eyeballmay be only two-thirds of its normal volume. Usually associated with other ocular
abnormalities, usually associated with intrauterine infections from the ‘TORCHes ’ group of
microorganisms (Toxoplasma, rubella virus, cytomegalovirus, and herpes simplex virus).

Anomalies of Accessory Structures of the Eye

Anomalies of the eyelids: (a) Coloboma of eyelid: A congenital condition in which part of
the eyelid is missing. Coloboma of eyelid usually occurs as a small notch in the upper eyelid.
The coloboma of inferior eyelid is rare. (b) Entropion and ectropion: When the lid margins
are turned inward then the condition is called entropion, and when the lid margins are
turned outwards then the condition is called ectropion. (c) Congenital ptosis (drooping of
the upper eyelid): It occurs if the levator palpebrae superioris muscle fails to develop; it may
be transmitted as an autosomal dominant trait. (d) Epicanthus: It is the development of
crescentic fold of skin that extends from upper eyelid to canthus. It is a normal feature in
Mongolian races. (e) Cryptophthalmos (L. Krybtos = hidden): It occurs due to congenital
absence of the eyelids. The eyeball is small and defective. It is covered by the skin (i.e.,
absence of palpebral fissure between the eyelids).

Anomalies of the lacrimal apparatus: (a) Lacrimal gland may be absent or nonfunctional. (b)
Complete absence of lacrimal passages in whole, in part, or atresia of some part. (c)
Supernumerary puncta or canaliculi. (d) Presence of cysts in any part of the lacrimal
apparatus, mostly close to the lacrimal puncta.

Anophthalmia: Anophthalmia is absence of the eye. It is due to failure of the optic vesicle to
form. In some cases histological analysis reveals some ocular tissue. The defect is usually
accompanied by severe cranial abnormalities.
Cyclopia (single eye): Cyclopia is a single orbit and one eye. It is due to failure of median
cerebral structures to develop.
Cyclopia and synophthalmia (fusion of the eyes) comprise a spectrum of defects in which
the eyes are partially or completely fused.
The defects are due to a loss of midline tissue that may occur as early as days 19 to 21 of
gestation or at later stages when facial development is initiated. This loss results in
underdevelopment of the forebrain and frontonasal prominence. These defects are
invariably associated with cranial defects, such as holoprosencephaly, in which the cerebral
hemispheres are partially or completely merged into a single telencephalic vesicle. Factors
ffecting the midline include alcohol, mutations in sonic hedgehog, (SHH) and abnormalities
in cholesterol metabolism that may disrupt SHH signaling
Retrolental fibroplasia (retinopathy of prematurity) is an oxygen-induced retinopathy seen
in premature infants.
Papilloedema: is edema of the optic disk (papilla) due to increased intracranial pressure. In
other words, papilloedema is oedema of the optic disk (papilla) due to increased intracranial
pressure. This pressure is reflected into the subarachnoid space, which surrounds the optic
nerve (CN II). This pressure is reflected into the subarachnoid space, which surrounds the
optic nerve (CN II).
Retinitis pigmentosa (RP): Hereditary degeneration and atrophy of the retina. May be
transmitted as an autosomal recessive, autosomal dominant, or X-linked trait, characterized
by a degeneration of the rods, night blindness (nyctalopia), and “gun barrel vision.” It may
also be due to abetalipoproteinemia (Bassen-Kornzweig syndrome), which may be arrested
with massive doses of vitamin A.

Hereditary retinoblastoma:
1. Hereditary RB is an autosomal dominant genetic disorder caused by a mutation in the RB1
gene on chromosome 13q14.1 for the
retinoblastoma (RB) protein.
2. More than 1000 different mutations of the RB1 gene have been identified, which include
missense, frameshift, and RNA splicing
mutations that result in a premature STOP codon and a loss-of-function mutation.
3. RB protein binds to E2F (a gene-regulatory protein) such that there is no expression of
target genes whose products stimulate the cell
cycle at the G1 checkpoint. RB protein belongs to the family of tumor-suppressor genes.
4. Clinical features include a malignant tumor of the retina that develops in children younger
than 5 years of age, a whitish mass in
the pupillary area behind the lens (leukokoria; the “cat’s eye”), and strabismus.
The hyaloid artery may persist to form a cord or cyst. Normally the distal portion of this
vessel degenerates, leaving the proximal part to form the central artery of the retina.
DEVELOPMENT OF THE HUMAN EAR
(Source: Vishram, S. Textbook of Clinical Embryology)
Overview
The ear is an organ of hearing and balance. It consists of three anatomical parts. From the
lateral to medial side, they are arranged as follows:
External ear consisting of the pinna and external auditory meatus. Middle ear consisting of a
slit-like cavity containing three small ear ossicles.
Internal ear consisting of bony and membranous labyrinths. The external, middle, and
internal ears develop from three distinctly different sources. However, in adults they form a
single anatomical unit to serve the function of hearing as well as balance. 1. The external ear
collects the sound waves.
The middle ear transfers the sound waves from the external to internal ear.
The internal ear performs dual functions. (a) It converts sound waves into nerve impulses
that lead to hearing. (b) It registers changes in equilibrium and balance, and subsequently
maintains them. N.B. • Developmentally internal ear appears first. • Internal ear, tympanic
cavity (middle ear), mastoid antrum, and ear ossicles assume adult size at the time of birth.
External Ear
External auditory meatus: It develops from ectodermal first pharyngeal cleft. At first it gets
filled with the ectodermal cells forming a temporary solid meatal plug. These ectodermal
cells are derived from lining ectodermal epithelium of the first pharyngeal cleft. The meatal
plug gets canalized at birth to form external auditory meatus.
Auricle or pinna: It develops from six mesodermal thickenings (called auricular
hillocks/tubercles) around the first pharyngeal cleft, three along caudal border of the
mandibular arch,and three along cephalic border of the hyoid arch. These hillocks fuse with
one another to contribute in the formation of auricle of the ear. It is believed that the tragus,
crus of helix, and helix are derived from auricular hillocks of the mandibular arch while
antihelix, antitragus, and ear lobule are derived from auricular hillocks of the hyoid arch.
Tympanic Membrane: It develops by the apposition of the tubotympanic recess and first
pharyngeal cleft, i.e., from the first pharyngeal membrane. 1. The outer cuticular layer of
the tympanic membrane is derived from the ectodermal lining of the first pharyngeal cleft.2.
The inner endodermal layer of the tympanic membrane is derived from the endodermal
lining of the first pharyngeal pouch. 3. The intermediate fibrous layer of the tympanic
membrane is derived from the mesoderm intervening between the first pharyngeal cleft and
the first pharyngeal pouch. N.B. The handle of malleus and chorda tympani nerve extends
into the tympanic membrane between its intermediate fibrous layer and inner endodermal
(mucous) layer. N.B. The ear is most sensitive to teratogens during fourth to ninth weeks of
gestation.
Middle Ear:
The middle ear (tympanic cavity) develops from the distal part of tubotympanic recess,
which develops mainly from the dorsal part of the first pharyngeal pouch with a little
contribution from the second pharyngeal pouch. The mastoid antrum and mastoid air cells
are formed by extensions of the tympanic cavity.
The ear ossicles (malleus, incus, and stapes) develop as follows:(a) The malleus and incus
develop from the cartilage of the first pharyngeal arch—the Meckel’s cartilage. (b) The
stapes develops from the cartilage of the second pharyngeal arch––the Reichert’s cartilage.
The ear ossicles are initially embedded in mesenchyme. When the mesenchyme surrounding
the ossicles dissolves then the endodermal epithelial lining of primitive tympanic cavity
extends along the newly developing space and connects the ossicles with the wall of
tympanic cavity in a mesentery-like fashion. The supporting ligaments of the ossicles
develop later within the mesenteries.
Mastoid Antrum : The dorsal expansion of tympanic cavity gives rise to the mastoid antrum.
The mastoid antrum is almost of adult size at birth;however mastoid air cells are not present
in the newborn infants. The mastoid air cells develop at the age of 2 years.
Muscles of Middle Ear:
1. Tensor tympanic muscle: It is attached to the upper part of handle of malleus and also
develops from the first pharyngeal arch like malleus. It is supplied by mandibular branch of
trigeminal nerve—the nerve of the first arch.
2. Stapedius muscle: It is attached to the stapes and also develops from the second
pharyngeal arch like stapes. It is supplied by facial nerve—the nerve of the second
pharyngeal arch.
Pharyngotympanic Tube (Auditory tube/Eustachian tube) (Fig. 24.14) It is derived from
narrow proximal part of the tubotympanic recess. It connects the tympanic cavity with
nasopharynx.
Internal Ear
The internal ear is first of the three parts of the ear to develop. Early in the fourth week, the
surface ectoderm on either side of myelencephalon shows a localized thickening called otic
placode. The otic placode soon invaginates the underlying mesoderm to form otic pit.
Margins of the otic pit approach each other and fuse together to form otic vesicle (Fig.
24.15). The otic vesicle gets separated from the surface. The otic vesicle is primordium of
the membranous labyrinth. Otic vesicle then grows and forms various parts of the
membranous labyrinth of the internal ear as follows: The otic vesicle divides into two
components: ventral saccular portion and dorsal utricular portion. 1. The saccular portion
of otic vesicle gives rise to saccule, cochlear duct (organ of Corti), and spiral ganglion of
vestibulocochlear nerve. 2. The utricular portion of otic vesicle gives rise to utricle,
semicircular ducts, endolymphatic duct and sac, and vestibular ganglion of
vestibulocochlear nerve. All these components, viz., cochlear duct, saccule, utricle, and
endolymphatic duct and sac together constitute the membranous labyrinth.
Saccule, Cochlear Duct, and Organ of Corti: During the sixth week, the saccule forms a
tubular diverticulum—the cochlear duct that grows in a spiral fashion till it completes two
and half turns. Later its connection with the saccule becomes narrow forming ductus
reuniens. The mesenchyme condenses around the membranous labyrinth. This
condensation is converted into cartilage to form otic capsule. The space between the otic
capsule and membranous labyrinth is called perilymphatic space. Cartilage of the otic
capsule is converted into bone to form bony labyrinth. The perilymphatic space between the
bony labyrinth and membranous labyrinth is filled with a fluid called perilymph. The
membranous labyrinth is filled with a fluid called endolymph. Special sense organs for
hearing and equilibrium develop in the wall of membranous labyrinth. They are innervated
by vestibulocochlear nerve that is attached to the brain stem at junction of pons and
medulla. The mesenchyme of the bony labyrinth forms two perilymphatic spaces around the
cochlear duct: ● Scala vestibuli above the duct and
● Scala tympani below the cochlear duct. The scala vestibuli is separated from the duct by
vestibular membrane (Reissner’s membrane) and scala tympani is separated from the duct
by basilar membrane. The lateral end of the cochlear duct is attached to the surrounding
cartilage by spiral ligament, whereas its medial end is connected to a long cartilaginous
process the modiolus—the future axis of bony cochlea.
Two ridges develop on the basilar membrane. These are called inner and outer ridges.
1. Cells of the inner ridge form spiral limbus, which gives attachment to membrana tectoria.
2. The cells of outer ridge form two rows of inner hair cells and three or four rows of outer
hair cells. The hair cells are sensory cells of the auditory system. (a) These sensory cells and
tectorial membrane together form organ of Corti. (b) When the membrana tectoria touches
the hair cells then it produces sound waves in the form of vibrations that are carried to brain
through auditory nerve. Utricle and Semicircular Canals During the sixth week of IUL, three
semicircular canals develop as out-pouchings of the utricle. One end of each duct dilates to
form the ampulla, whereas its other end remains narrow to form crus nonampullare. The
crus ampullare of anterior and posterior semicircular canals fuse. As a result, the three
semicircular canals communicate with utricle by five openings. The cells in the crus
ampullare form a crest called crista ampullaris—the sensory receptors of equilibrium. The
cristae ampullare are sensory receptors for kinetic balance. In the same manner, maculae
(the sensory receptors for static balance/gravity) develop in the medial walls of utricle and
saccule.

Development of the Internal Ear

Overview

(Source: BRS Embryology, Chapter 8)

The ear is the organ of balance and hearing. It consists of an internal, a middle, and an
external ear.

Development of the Internal Ear

The internal ear develops during the fourth week, from a thickening of the surface ectoderm
called the otic placode. The otic placode invaginates into the connective tissue
(mesenchyme) adjacent to the rhombencephalon and becomes the otic vesicle. The otic
vesicle divides into utricular and saccular portions.

Utricular portion of the Otic Vesicle: gives rise to the following:

1) Utricle contains the sensory hair cells and otoliths of the macula utriculi. The
utricle responds to linear acceleration and the force of gravity.
2) Semicircular ducts contain the sensory hair cells of the cristae ampullares. They
respond to angular acceleration.
3) Vestibular ganglion of cranial nerve (CN) VIII lies at the base of the internal
auditory meatus.
4) Endolymphatic duct and sac is a membranous duct that connects the saccule to
the utricle and terminates in a blind sac beneath the dura. The endolymphatic
sac absorbs endolymph.

Saccular portion of the Otic Vesicle gives rise to the saccule, cochlear duct and spiral
ganglion of CN VIII:
a) Saccule: contains the sensory hair cells and otoliths of the macula sacculi. The saccule
responds to linear acceleration and the force of gravity.
b) Cochlear duct (Organ of Corti): is involved in hearing. This duct has pitch (tonopic)
localization whereby high-frequency sound waves (20,000 Hz) are detected at the base
and low-frequency sound waves (20 Hz) are detected at the apex.
c) Spiral ganglion of CN VIII: lies in the modiolus of the bony labyrinth.

Derivatives of Various Components of the Ear

Embryonic Structure Adult Derivative
Internal ear: Saccular portio; Saccule and cochlear duct;
Utricular portion Utricle, semicircular ducts,
endolymphatic duct, and sac
Middle ear: First pharyngeal Malleus, incus, and tensor
arch; Second pharyngeal arch; tympani muscle; Stapes and
First pharyngeal pouch; First stapedius muscle;
pharyngeal membrane Pharyngotympanic tube and
middle ear (tympanum;
Tympanic membrane)
External ear: First pharyngeal External auditory meatus;
cleft; Auricular hillocks in Pinna/auricle
mandibular and hyoid arches

The Membranous and Bony Labyrinths of the Ear

(Source: BRS Embryology, Chapter 8)

The membranous labyrinth consists of all the structures derived from the otic vesicle.

The membranous labyrinth is initially surrounded by neural crest cells that form a
connective tissue (mesenchyme) covering. This connective tissue becomes cartilaginous and
then ossifies to become the bony labyrinth of the temporal bone.

The connective tissue closest to the membranous labyrinth degenerates, thus forming the
perilymphatic space containing perilymph. This sets up the interesting anatomical
relationship by which the membranous labyrinth is suspended (or floats) within the bony
labyrinth by perilymph.

Perilymph, which is similar in composition to cerebrospinal fluid, communicates with the

subarachnoid space via the perilymphatic duct.

The Middle Ear :

Ossicles of the middle ear:

The ear ossicles consist of:

(i) Malleus: Malleus develops from cartilage of pharyngeal

arch 1 (Meckel’s cartilage) and is attached to the
tympanic membrane. The malleus is moved by the
tensor tympani muscle, which is innervated by CN V3.
 (ii) Incus: Incus develops from the cartilage of pharyngeal
arch 1 (Meckel’s cartilage). The incus articulates with
the malleus and stapes.
(iii) Stapes: Stapes develops from the cartilage of
pharyngeal arch 2 (Reichert’s cartilage). The stapes is
moved by the stapedius muscle, which is innervated by
CN VII. It is attached to the oval window of the vestibule.

Auditory Tube and Middle Ear Cavity: Auditory tube and middle ear cavity both develop
from pharyngeal pouch 1.

Tympanic membrane: develops from pharyngeal membrane 1. This membrane separates

the middle ear from the external auditory meatus of the external ear. It is innervated by CN
V3 and CN IX.

External Ear

External ear is composed of the: (i) Auditory meatus, and (ii) Auricle (pinna).

External auditory meatus: develops from the pharyngeal groove 1. The meatus becomes
filled with ectodermal cells, forming a temporary meatal plug that disappears before birth.
The meatus is innervated by CN V3 and CN IX.

Auricle (or pinna): develops from six auricular hillocks that surround pharyngeal groove 1.
The auricle is innervated by CN V3, CN VII, CN IX, and CN X and cervical nerves C2 and C3.

Clinical Relevance of Ear Embryology

When something goes wrong with the normal embryological process of the ear, some
congenital anomalies may arise; these include: (i) Congenital anomalies of the external ear
(namely:congenital deafness, anotia, microtia, pre-auricular appendages and pits, atresia),
auricular sinus, minor auricular malformations, low – set slanted auricles(ii) Other anomalies
of the ear (namely: ear infections and external ear defects).

A. Congenital Anomalies of External Ear

(Source: BRS Embryology; Chapter 8)

Minor auricular malformations: are commonly found and raise only cosmetic issues.
However, auricular malformations are seen in Down syndrome (trisomy 21), Patau
syndrome (trisomy 13), and Edwards syndrome (trisomy 18).

Low-set slanted auricles: are auricles that are located below a line extended from the corner
of the eye to the occiput. This condition may indicate chromosomal abnormalities as
indicated earlier. Example is an infant with Stickler Syndrome: a type of skeletal dysplasia
caused by a mutation either in the COL2A1 gene on chromosome 12q12-13.2 for collagen a-
1(II) chain protein or the COL11A1 gene on chromosome 1p21 for collagen -1(XI) chain
protein.
Preauricular sinus: is a narrow tube or shallow pit that has a pinpoint external opening that
is most often asymptomatic and of minor cosmetic importance, although infections may
occur. The embryological basis is uncertain but probably involves pharyngeal groove 1.

Auricular appendages: are skin tags that are commonly found anterior to the auricle (i.e.,
pre-tragal area) and raise only cosmetic issues. The embryological basis is the formation of
accessory auricle hillocks.

Atresia of the external auditory meatus: A complete atresia consists of a bony plate in the
location of the tympanic membrane. A partial atresia consists of a soft tissue plug in the
location of the tympanic membrane. This results in conduction deafness and is usually
associated with the first arch syndrome. The embryological basis is the failure of the meatal
plug to canalize.

Congenital cholesteatoma (epidermoid cyst): is a benign tumor found in the middle ear
cavity that results conduction deafness. The embryological basis is the proliferation of
endodermal cells lining the middle ear cavity.

Microtia (Severely disorganized auricle): is associated with other malformations resulting in

deafness. The embryological basis is impaired proliferation or fusion of the auricular hillocks.

Congenital deafness. The organ of Corti may be damaged by exposure to rubella virus,
especially during weeks 7 and 8 of development.

Anotia (absence of the auricle): It occurs due to failure of mesenchymal proliferation to

form auricular hillocks. It is rare but commonly associated with first arch syndrome.

Preauricular appendages and pits: These are skin tags and shallow depressions that are
usually seen anterior to the ear. The preauricular appendages occur due to development of
accessory hillocks, whereas the preauricular pits occur due to abnormal development of
auricular hillocks. Most of the anomalies of the external ear are associated with various
chromosomal syndromes such as Down’s syndrome (trisomy 21), Patau’s syndrome (trisomy
13), and Edward’s syndrome (trisomy 18).

Atresia of the external auditory meatus: It occurs due to failure of the meatal plug to
canalize. Clinically it presents as conduction deafness and is often associated with first arch
syndrome.

Other Anomalies of the Ear

1. Ear infections: Many factors affecting the developing ear will result in deafness.
Most are caused by genetic factors but some environmental factors are involved.
The rubella virus can affect the development of the organ of Corti if infected in the
seventh to eighth week of development. Other factors known to cause deafness are
cytomegalovirus, hyperbilirubinemia (jaundice) and bacterial meningitis.
2. External ear defects: are quite common as the fusion of the auricular hillocks is
complicated. Anomalies are often associated with other malformations. Most
common chromosomal disorders have ear malformation as one of their traits. For
example, trisomy 13 (Patau syndrome) gives an underdeveloped tragus and lobule,
trisomy 21 (Down syndrome) gives microtia, and Ehlers–Danlos syndrome causes lop
ears that stand away from the head and are often larger than normal. Less severe
 anomalies can include pits and appendages (or sinuses and tags). These are
remnants of the developing hillocks.

Clinical Taster

(Source: Larsen’s Human Embryology; Chapter 17, P. 587)

A 2-year-old boy with profound hearing loss is admitted to the pediatric service for fever and
vomiting. Urinalysis showed leukocytes and bacteria. He is diagnosed with pyelonephritis
(urinary tract infection with kidney involvement) and started on intravenous antibiotics. The
boy’s hearing loss was detected by a local Department of Health newborn hearing screening
program and verified with a sedated brainstem auditory evoked response (BAER). His
hearing loss was determined to be both conductive (caused by abnormalities of the external
or middle ear) and sensorineural (caused by defects of the cochlea or cranial nerve VIII). He
had been using hearing aids since 4 months of age. A renal ultrasound done on admission
showed small, dysplastic kidneys and hydronephrosis (dilation of the ureter and renal pelvis)
on the right side. Later that night, while researching the differential diagnosis of hearing loss
and kidney abnormalities, themedical student on call finds the description of branchio-oto-
renal (BOR) syndrome. Intrigued by this possibility, the student returns to the patient’s
bedside and finds that the boy has cup-shaped ears, preauricular pits, and small cysts over
the sternocleidomastoid muscle. These cysts are later determined to be pharyngeal
(branchial) cysts (persisting rudiments of the pharyngeal apparatus, as discussed in Ch. 16).
During his hospital stay, the patient has a thin-cut CT (computed tomography) of the
temporal bone that shows malformations of the middle ear bones and hypoplastic cochlea.
As suspected by the medical student, the combination of pharyngeal (branchial) arch, otic
(ear), and renal (kidney) abnormalities seen in the patient suggests the diagnosis of BOR.
Also known as Melnick-Frasier syndrome, BOR is most often caused by mutations in the EYES
ABSENT HOMOLOG 1 (EYA1) gene. As the name suggests, mutations in the Drosophila
homolog of this gene (Eya) affect the eyes. Humans with EYA1 mutations rarely have
abnormalities of the eyes, likely due to functional redundancy of multiple EYA genes (there
are four EYA homologs present in humans) during eye development.

Summary of the Development of the Ear

 Development Initiation (Week 3-4): The development of the ear begins with the
formation of the otic placodes around the 22nd day of fertilization. These are thickened
regions of ectoderm located on either side of the hindbrain.
 Formation of the Inner Ear: : The otic placodes invaginate to form the otic vesicles (or
otic sacs), which are the precursors of the inner ear. This process occurs around the
fourth week of gestation. The otic vesicles then differentiate into various structures of
the inner ear including the cochlea, vestibule, and semicircular canals. Each of these
structures is responsible for different functions related to hearing and balance.
 Development of the Middle Ear: The middle ear develops from structures associated
with the first and second pharyngeal arches. The tympanic cavity (middle ear) begins to
form from the first pharyngeal pouch, which also gives rise to the eustachian tube. The
ossicles (malleus, incus, and stapes) originate from cartilaginous pre-cursors arising from
the neural crest cells in the first and second arches around six weeks of development.
 Formation of the External Ear: The auricle (ear pinna) develops from the first and
second pharyngeal arches and adjacent mesenchyme. This occurs during weeks 4 to 5.
 The external auditory canal is derived from the first branchial cleft, which becomes more
pronounced as the embryo grows.
 Maturation and Functionality: By the end of the 8th week, the basic structure of the ear
is in place, but it continues to mature throughout fetal development. The movements
and rotations of the auricle contribute to its final position.}

GOLDEN FACTS TO REMEMBER (ABOUT THE EAR)

1. The first of the three parts of the ear (external, middle, Internal ear and internal) to
develop is internal ear.
2. The most common cause of congenital deafness is failure of canalization of the
meatal plate.
3. The ear is most sensitive to teratogens during Weeks 4–9 of embryological
development.
4. Parts of the ear which assume adult size at birth are: Middle ear, Ear ossicles,
Mastoid antrum, and Internal ear.
5. Embryological Development of the Human Ear