HEAD & NECK CME

ABBREVIATION KEY
AMPK ⫽ 5= adenosine
monophosphate-activated protein
kinase is an enzyme that plays a
role in cellular energy homeostasis
ATP ⫽ adenosine triphosphate
BAT ⫽ brown adipose tissue
BMP ⫽ bone morphogenetic protein
Embryology and Anatomy of the Skin, BMZ ⫽ basement membrane zone
cadherin ⫽ Cadherins are a class of
Its Appendages, and Physiologic type-1 transmembrane proteins
that play a role in cell adhesion

Changes in the Head and Neck CNS ⫽ central nervous system

dermo1 ⫽ dermal marker
Dsg ⫽ desmoglein a family of
P.M. Som, J.T. Laitman, and K. Mak cadherins that play a role in the
formation of desmosomes
ECM ⫽ extracellular matrix
FGF ⫽ fibroblast growth factor
IL ⫽ interleukin
CME Credit keratin ⫽ K a family of fibrous
The American Society of Neuroradiology (ASNR) is accredited by the Accreditation Council for Continuing Medical Education structural proteins that protects
(ACCME) to provide continuing medical education for physicians. The ASNR designates this enduring material for a maximum of one epithelial cells from damage or
AMA PRA Category one creditTM. Physicians should claim only the credit commensurate with the extent of their participation in the
stress
activity. To obtain credit for this activity, an online quiz must be successfully completed and submitted. ASNR members may access
this quiz at no charge by logging on to eCME at http://members.asnr.org. Nonmembers may pay a small fee to access the quiz and LTMR ⫽ low-threshold
obtain credit via http://members.asnr.org/ecme. mechanoreceptor
MC1R ⫽ melanocortin 1 receptor
melanocortin ⫽ melanocortins are a
group of peptide hormones, which
ABSTRACT include adrenocorticotropic
Although often overlooked as a significant factor in the head and neck, the skin plays an hormone and the different forms
of melanocyte-stimulating
important role in body thermoregulation as well as in detecting pain, pressure, and itch.
hormone they are derived from
Knowledge of the embryology of the skin allows a better understanding of the role that skin the pituitary gland
plays not only during gestation but also in everyday life and how skin changes with certain MITF ⫽ melanogenesis associated
nonpathologic circumstances. This review was illustrated to help the reader follow the text. transcription factor
MSH ⫽ melanocyte-stimulating
Learning Objective: The reader will learn about the development of the skin and the critical hormone
role that skin plays in both prenatal and postnatal life. MYF5 ⫽ myogenic factor 5
MYFS ⫽ myogenic regulatory factor
myogenic regulatory factors are
INTRODUCTION cles, and sebaceous glands but does have basic helix-loop-helix transcription
This review discussed the embryology of sweat glands. It varies in thickness from factors that regulate myogenesis
the integumentary system, which consists 400 to 1400 ␮m (equivalent to 1.4 mm). It
of the skin and its appendages. The skin is is also known as glabrous skin (nonhairy
Received December 22, 2015;
the largest organ in the body, which aver- skin). The focus of this review was on thin accepted October 11, 2016.
ages 12%–15% of the total body weight, skin because it is the type of skin that cov- From the Departments of
and it plays a critical role in human life, ers the head and neck. Thin skin contains Radiology (P.M.S.), Otolaryngology
(P.M.S., J.T.L.), and Medical
acting as a protective barrier to separate hair follicles, arrector hair muscles, seba- Education (J.T.L., K.M.), the Ichan
the body from the environment.1 The skin ceous glands, and sweat glands, and it var- School of Medicine at Mount Sinai,
New York, New York.
is also impervious to water and most infec- ies in thickness from 75 to 150 ␮m.2-4
Please address correspondence to
tions, and it plays an important role in reg- Peter M. Som, MD, Department
ulating body temperature and detecting THE EPIDERMIS of Radiology, The Mount Sinai
Hospital, One Gustave Levy Place,
pressure and pain. The skin is composed of The development of the ectoderm was dis- New York, NY 10029; e-mail:
2 layers: the epidermis, which is derived cussed in an earlier review in this series.5 Peter.Som@MSSM.edu
http://dx.doi.org/10.3174/ng.9170210
from the ectoderm, and the dermis, which, By 2–3 weeks, the ectoderm that covers the
in the head and neck, is derived from neu- surface of the embryo consists of a single Disclosures
Based on information received
ral crest mesenchyme. layer of cuboidal undifferentiated cells sep- from the authors, Neurographics
Based on the thickness of the epidermis, arated from the underlying mesenchyme by has determined that there are no
Financial Disclosures or Conflicts of
the skin is classified as being either thick or a basement membrane. Initially, as as- Interest to report.
thin. Thick skin covers the palms and soles, sessed on light microscopy, the basement
and lacks hair follicles, arrector hair mus- membrane was thought to be a thin band

390 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org

 immediately beneath the basal layer) then develops under the periderm. This forms a
NOTCH ⫽ A transmembrane
ectoderm. However, with
receptor for Delta and Serrate,
continuous layer, usually only 1 cell deep. The cells of the
the use of the electron mi-
mediating cell–cell interactions periderm are continually undergoing desquamation due to
PAR2 ⫽ protease-activated croscope, it became clear apoptosis and are primarily replaced by cells that arise from
receptor 2 that this “membrane” was the basal layer, although there may be some replacement
protein kinase C ⫽ plays a crucial
actually a specialized struc- of the periderm from the peridermal cells themselves.9 With
role in signal transduction for a
variety of biologically active
ture, and early in its devel- the development of this bilaminar epidermis, the periderm
opment, it is composed of
substances that activate cellular and the basal layer become defined (Fig 1).2,4,10,11 Initially,
functions and proliferation collagen fibers and lamin- these epidermal cells are widely separated, being connected
SHH ⫽ sonic hedgehog, a protein, a
ins attached to the ectoder- only by interlocking villous processes and a few desmo-
ligand in the Hedgehog pathwaymal cells through binding somes. The cells in the basal layer are poorly stabilized, with
TYR ⫽ tyrosinase
UCP ⫽ uncoupling of protein
of both integrin and nonin- the cells being flattened and containing a band of cytoplas-
UCP1 ⫽ mitochondrial carrier tegrin cell membrane re- mic filaments adjacent to the BMZ. This may compensate
ceptors, with infrequent
proteins that catalyze a regulated for the limited support of the epidermis until the hemides-
proton leak across the inner desmosomes, which lack mosomes develop. The BMZ is also incomplete until the
mitochondrial membrane the typically associated fil-
UV ⫽ ultraviolet
mesenchymal cells of the dermis produce a connective tissue
UVA⫽ the longest wave length of
aments.6 However, by the matrix.12
UV 12th week, the basement In the 8th–11th weeks, proliferation of the basal layer
WAT ⫽ white adipose tissue membrane has nearly ma- produces a new intermediate layer, deep to the periderm.
WNT ⫽ Wingless/int1 family of tured, and, with the devel- This intermediate layer is the forerunner of the outer layers
secreted signaling opment of additional lay- of the mature epidermis. The basal layer, or stratum germi-
ers, it is often referred to as nativum, constitutes the layer of stem cells that will con-
the basement membrane tinue to replenish the epidermis throughout life. By the 10th
zone (BMZ). This is an important site for the mutual induc- week, the cells in the basal layer already have hemidesmo-
tions that occur between the BMZ and the future epidermis, somal and desmosomal proteins. Between the 12th and
both pre- and postnatally. The BMZ is also critical to the 16th weeks, the intermediate layer gradually thickens and
integrity and stability between the epidermis and the future eventually differentiates into typical stratified keratinizing
dermis because the BMZ is responsible for the binding of squamous epithelium. By 14 weeks, basal keratins are ex-
the epidermis to the dermis (Fig 1). pressed by the basal cells and the cells of the intermediate
In the fourth to sixth weeks, this ectoderm proliferates to layer contain keratin proteins and tonofilaments, which are
form a new outer layer of flattened simple squamous epi- characteristic of differentiated epidermis. These cells are
thelium, which is the primordium of the epidermis. This now known as keratinocytes (Fig 3).2-4,10,13
new layer is the periderm, and it represents the first stage in The BMZ has matured and now has hemidesmosomes,
epidermal formation. The periderm seems to act as a tem- which act as anchoring bridges between the keratin cyto-
porary protective membrane for the future underlying epi- skeleton of the early basal epidermal cells, or keratinocytes,
dermis, and it initially plays a role in water, sodium, and and the basement membrane. Within the cytoplasm of the
glucose exchange between the embryo and the surrounding keratocytes, tonofilaments cluster at the site of the hemides-
amniotic fluid. This fluid exchange occurs in both directions mosome and form a plaque that anchors the hemidesmo-
across the interface of the periderm and reaches a peak at some. These hemidesmosomes extend from the deepest ker-
12–16 weeks, after which the periderm undergoes a trans- atinocytes, down toward a layer that has developed in the
formation into a layer of flattened squamous cells with a upper BMZ, the lamina densa, which contains fibrillary
purely filamentous internal structure. The periderm is sug- structures known as anchoring filaments. From the lower
gested to play a major role in the production of the amniotic lamina densa, anchoring fibrils extend into the uppermost
fluid during the period of maximal development of the per- papillary layer of the developing underlying dermis, or the
iderm, and its associated regression corresponds with the fibrillar zone, where they associate with basement mem-
taking over of this function by the umbilical cord epithelium branelike structures known as anchoring plaques, which
(Fig 1).7 are in the papillary dermis. The lamina densa represents a
During the first trimester, each flattened periderm cell stable sheetlike meshwork primarily composed of collagen
develops a superficial bulge, which enlarges into a single IV.
elevated vesicle or bleb. In the second trimester, the single By the second month, there is a continuous lamina densa;
bleb becomes modified into multiple blebs that project from the hemidesmosomes appear in the third month. The BMZ
each cell. Near the end of the second trimester, all of these constitutes the anchorage zone for both the anchoring fila-
surface modifications regress and the periderm transforms ments that originate in the epidermis and the anchoring
into an ineffective cellular layer that is sloughed into the fibrils in the fibrillar zone of the dermis (Figs 1B and 4). The
amniotic fluid (Fig 2).8 A second layer, the basal or germi- lamina densa is thicker in men than in women, with an
native layer (stratum germinativum or the stratum basale or average thickness of 30 – 60 nm. The anchoring filaments

Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org 兩 391

Fig 1. A, Serial drawings illustrate the basic development of the layers of the epidermis and the development of the dermis (modified with permission
from Carlson BM. Human Embryology and Developmental Biology. 4th ed. China: Mosby Elsevier; 2009:176 [Fig 9 –1]). B, The illustration shows the
components of the BMZ between the basal layer of the epidermis and the upper layer (papillary layer) of the dermis (modified from http://www.
cram.com/flashcards/mss-08-basement-membrane-zone-bmz-3433975, accessed in 2013).

Fig 2. A diagrammatic representation of the bleb formation on the peridermal cells from approximately 3 months to approximately 4 months of
gestation.

are composed of collagen types IV and VII. In thin skin, the
type of skin that covers the head and neck, there is no
lamina lucida. However, in thick skin, as found in the soles
and palmer regions, immediately under the epidermis and
above the lamina densa is the lamina lucida. Within the
lamina lucida is the hemidesmosomes complex, with
threadlike anchoring filaments that extend down into the
lamina densa. The role of the BMZ is not only to tightly
bind the epidermis to the dermis, but it has the additional
roles of determining the polarity of the basal keratinocytes
and serving as a selective barrier that controls the molecular
and cellular exchanges between the 2 compartments.14
Keratin is an intermediate cytoskeleton filament protein
of epithelial cells that is required for the mechanical stability
and integrity of the epidermis. Humans have 54 functional
keratin genes, and the keratins are divided into 2 types: type
I, the acid keratins (K9 –K28 in epithelial cells and K31–
K40 in hair and nails); and type II, the basic keratins (K1–

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Fig 3. A drawing, illustrating the various levels of the epidermis and the location of some cellular and extracellular proteins that help stabilize the
epidermis (modified with permission from http://www.rci.rutgers.edu/⬃uzwiak/AnatPhys/APFallLect7.html, accessed in 2013).
K8, K71–K80 in epithelial cells and K81–K86 in hair and
nails). Keratins form heterodimers that assemble into het-
eropolymeric keratin filaments.15
By the 15th–16th weeks, the greater part of the periderm
has been desquamated, in part, due to the eruption of the
hairs. Because the periderm remains, in part, with the epi-
dermis after the growth of hairs, it was originally termed the
epitrichium. To the layer of castoff peridermal cells are
added sebaceous secretions, and, as development continues,
more ectodermal cells from the outermost layer of the skin.
The stratum disjunctum refers to the surface cells that are
partially detached from the outer skin layer. Together, they
form a whitish cheesy substance, the vernix caseosa, which
often persists to full term, and covers most of the skin,
especially in the hair, back, and the joint creases. The vernix
may have a function in protecting the underlying epidermis
from maceration by the amniotic fluid and from the high
urine content in the amnion.3,10 When much of the vernix
remains on the neonate infant, these children are referred to
as collodion babies. This vernix will either shed spontane-
ously or is easily removed.1-4,16,17 In summary, by the end
of the first trimester, all of the epidermally derived primor-
dia are present, and they will differentiate into definitive
structures in the second and third trimesters. At this time,
the epidermis is 3 to 4 cell layers thick and relatively undif-
ferentiated, except on the head, where hair follicles have
already begun to develop.12
During the early fifth month, after the periderm is shed,
the intermediate layer is replaced by the 3 definitive layers
of keratinocytes: an inner stratum spinosum (spinous
layer), a middle stratum granulosum (granular layer, so
named because of the cellular granules of keratohyalin),
Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
and an outer stratum corneum (horny or cornified layer).
This transformation starts at the cranial end of the fetus and
proceeds caudally (Fig 3). In areas that have thick skin,
which do not occur in the head and neck, there is an addi-
tional layer, the stratum lucidum, which is a thin, clear layer
of dead cells immediately below the stratum corneum and
above the stratum granulosum. Although the stratum spi-
nosum is permeable to water, the overlying stratum granu-
losum and stratum corneum are impermeable to water.
However, damage to the epidermis may render areas of
the skin permeable, and this may constitute a medical emer-
gency.18 As the basal keratinocytes extend upward and
reach the stratum granulosum, they release specialized epi-
dermal organelles or lamellar bodies that contain free fatty
acids, cholesterols, and ceramides. They bud off the Golgi
complex and at the transition from the granular layer to the
cornified layer, the lamellar bodies fuse with the cell mem-
brane and extrude their contents into the extracellular space
as lamellar granules, which form an intercellular lipid sheet
that seals off the intercellular space, especially in the stra-
tum corneum.19
The periderm cells do not produce keratohyalin, which is
essential for keratin formation and is a signature of epider-
mal cells. However, as development proceeds, the earlier
cells to appear just deep to the future stratum corneum
contain less keratohyalin than those cells that are deeper
and thus are developed later in the epidermis. This reflects
the fact that the deeper cells are derived from more mature
basal cells that contain larger amounts of keratohyalin, and
their more completely keratinized state indicates that kera-
tohyalin plays an essential role in the maturation of the
epidermis (Fig 3).7
兩 393
Fig 4. A, A drawing, illustrating the various types of cell-to-cell junctions that occur in the epidermis (modified from http://higheredbcs.wiley.com/legacy/
college/tortora/0470565101/hearthis_ill/pap13e_ch04_illustr_audio_mp3_am/simulations/figures/cell_junctions.jpg, accessed 2013). B, The drawing il-
lustrates both the desmosomes and hemidesmosomes that stabilize the epidermis and the epidermal-dermis interface (modified from https://www.
studyblue.com/notes/note/n/02-epithelium-i/deck/7484110, open access).

Presumptive keratinocytes are constantly produced by
the stratum germinativum. These keratinocytes are the pre-
dominant cell type in the epidermis, which represents
⬎90% of the cells.14 As they pass outward to the stratum
corneum, they differentiate and are finally sloughed from
the surface of the skin. Specifically, keratohyalin granules
begin to appear in the cells of the stratum spinosum and are
prominent components of the stratum granulosum. These
keratohyalin granules are composed of protein aggregates
rich in either histidine or sulfur, and they are closely asso-
ciated with bundles of keratin filaments. As the keratino-
cytes move into the stratum granulosum, their nuclei be-
come flattened with attenuated masses of chromatin. These
are signs of apoptosis and terminal differentiation.2-4,10
The cells of the stratum germinativum are the only divid-
ing cells of the normal epidermis. These cells contain a
number of keratin filaments specific to this layer, including
K5 and K14. These cells are also connected by desmosomes
and adherens junctions that together result in a tight struc-
ture resistant to water and infection (Fig 4). The desmo-
somes also help distribute forces evenly throughout the
epidermis. As already noted, the cells of the stratum germi-
nativum are connected to the basement membrane by hemi-
desmosomes. This attachment is essential for cell survival
and determines the orientation of cell divisions. As the cells
in the stratum germinativum move into the overlying 4 – 8-
cells-thick stratum spinosum, K5 and K14 are replaced by
K1 and K10. These keratins are cross-linked by disulphide

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bonds to provide further strength. As already noted, lipid-
containing granules (lamellar granules) are also produced in
cells in the stratum spinosum. As the cells ascend into the
stratum granulosum and eventually the stratum corneum,
the lipid is extruded and helps seal the skin.2-4,10
This progression, from a single-layered ectoderm to a
stratified epithelium, requires the activation of the tran-
scription factor p63, possibly in response to signals from the
underlying dermal mesenchyme. Subsequently, p63 tran-
scription must be turned off for cells within the stratified
epidermis to embark on their terminal differentiation pro-
gram, which involves leaving the cell cycle.2-4,10 Once the
cells are in the stratum granulosum, in addition to the la-
mellar granules, these cells produce envelope proteins, such
as involucrin, loricrin, and envoplakin, which line the inner
surface of the plasma membrane, and the enzyme transglu-
taminase, which cross-links these envelope proteins. At
week 15, this layer also produces the histidine-rich protein
filaggrin, which is derived from one of the granular compo-
nents of keratohyalin. Within the stratum granulosum, the
cells contain profilaggrin as inactive granules. Through a
multistep process, filaggrin is formed and creates aggregates
with the keratin filaments to form tight bundles that inter-
connect the cells in this layer. Together with other lipids and
cornified proteins, filaggrin forms the “skin barrier.” The
cells of the stratum corneum, depending on the region of the
body, accumulate from 15–20 layers of dead cells, which, as
noted, are eventually shed. This shedding, or desquamating
process, involves degradation of the lamellated lipid in the
intercellular spaces and loss of the residual intercellular des-
mosomal interconnections.14
The final process in cornification occurs when lytic en-
zymes are released within the cells, which results in the
ceasing of metabolic activity and enucleation, with the re-
sulting loss of all cell contents. When the keratinocytes fi-
nally enter the stratum corneum, they are flattened, densely
packed, terminally differentiated keratinocytes or squames.
It is a calcium gradient that promotes keratinocyte differ-
entiation, with the lowest concentration of calcium in the
stratum basale and the highest concentration in the stratum
granulosum. The stratum corneum has a very low or non-
existent calcium concentration because these cells are dry
and unable to dissolve the calcium ions. Vitamin D3 also
regulates keratinocyte proliferation and differentiation by
modulating the calcium concentrations and by regulating
the expression of the genes involved in keratinocyte differ-
entiation. The keratinocyte is the only cell in the body that
contains the entire vitamin D metabolic pathway from vi-
tamin D synthesis to catabolism and receptor expression.4
In summary, the formation of new keratinocytes in the
basal layer gradually pushes the previously formed cells
upward through the stratum spinosum. As the cells ap-
proach the stratum granulosum, they accumulate intracel-
lular keratin and they secrete a waxy lipid that contains
material into the intercellular space. As the maturing kera-
tinocytes seal off the intercellular spaces through which
Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
they receive nutrients, they start to die and form the stratum
corneum, a tough and relatively impermeable layer of hard-
ened, dead cells. Eventually, as the cells are sloughed off,
they are replaced within approximately 2 weeks.
Intercellular Junction
There are several types of cellular junctions that link kera-
tinocytes together and which are responsible for the me-
chanical, biochemical, and signaling interactions between
these cells. These junctions include desmosomes, hemides-
mosomes, adherens junctions, gap junctions, and tight junc-
tions. Desmosome can be thought of as “rivets” through the
plasma membrane of adjacent cells. Intermediate filaments
of keratin attached to membrane-associated proteins within
the cytoplasm of a cell form an attenuated plaque on the
inner plasma cell membrane. Cadherin molecules form the
actual anchor by attaching to the cytoplasmic plaque in 1
cell and then extending through the cell membrane to
strongly bind to cadherins that extend from an adjacent cell.
This strong adhesive state distinguishes the desmosomes
from other intercellular junctions. These junctions are also
dynamic structures whose adhesiveness can alternate be-
tween high and low affinity states during processes such as
embryonic development and wound healing. This switching
between adhesive states is controlled by signaling of protein
kinase C. Desmosomes may also act as signaling centers,
regulating the availability of signaling molecules and
thereby participating in fundamental processes such as cell
proliferation, differentiation, and morphogenesis (Fig 4).14
Hemidesmosomes have a strong electron microscopic re-
semblance to one-half of a desmosome and thus the name.
However, they are quite distinct. Although, as with desmo-
some, they attach to intermediate filaments within the cell
cytoplasm, their transmembrane anchors are integrins
rather than cadherins. Within the cytoplasm of a keratino-
cyte, there is a plaque to which the cell’s tonofilaments
converge. On the outside of the cell is a second plaque, the
subbasal plaque, and the plasma membrane is sandwiched
between these plaques. Integrins are transmembrane gly-
coproteins that are a major component of the hemides-
mosome, which mediate the transfer of information be-
tween the extracellular matrix and the cell’s interior.
These hemidesmosomes thus aid in modulating the orga-
nization of the cytoskeleton, its proliferation, and its
differentiation (Fig 4).
Adherens junctions are similar to desmosomes in that
they are anchored to cytoplasmic actin filaments. However,
their transmembrane anchors are E-cadherins, and the for-
mation of the mature junction requires a reorganization of
the cell’s actin cytoskeleton. The cytoskeleton actin fila-
ments that tie to the adherens junctions are contractile pro-
teins, and, in addition to providing anchoring, these junc-
tions are believed to participate in folding and bending of
epithelial sheets (Fig 4). Tight junctions regulate the para-
cellular pathway for the movement of ions and solutes in
between cells. Tight junctions consist of the transmembrane
兩 395
Fig 5. A, A drawing, illustrating the extensions of a melanocyte into the epidermis (modified from Le Physique, Personal Training. http://www.
lephysique.com/sunburnt-again. Open access). B, The drawing shows the positions of a Langerhans cell, a melanocyte, a Merkel cell, and a Meissner
corpuscle within the layers of the epidermis (modified from https://www.studyblue.com/notes/note/n/02-epithelium-i/deck/7484110, accessed
2013).

proteins occludin and claudin as well as cytoplasmic scaf-
folding proteins (Fig 4).20 Gap junctions are clusters of
intercellular channels that allow direct diffusion of ions and
small molecules between adjacent cells. The intercellular
channels are formed by head-to-head docking of hexam-
eric assemblies called connexons (Fig 4). The close mem-
brane apposition required to allow the docking between
connexons sterically excludes most other membrane pro-
teins, which leaves only approximately a 2-nm extracel-
lular “gap,” for which the junction is named. The gap
junctions allow various molecules, ions, and electrical
impulses to pass directly through a regulated gate be-
tween cells (Fig 4).21
Melanocytes
In addition to cells that originate from the ectoderm, the
epidermis also contains cells that are derived from the neu-
ral crest and mesoderm. In the early second month, neural
crest– derived melanoblasts migrate into the mesenchyme of
the embryonic dermis. As their migration reaches the der-
moepidermal junction, these cells differentiate into melano-
cytes. Under the regulation of Wingless/int1 family of se-
creted signaling (WNT), the process of differentiation from
melanoblasts into melanocytes proceeds, and this involves
the transition of premelanosomes (nonpigmented mem-
brane-bound vesicles) to melanosomes (intracellular organ-
elles that are the site of synthesis, storage, and transport of
melanin) and, finally, the production of pigment granules.
The epidermal melanocytes occur in an approximately 1:10
ratio with the basal keratinocytes, and each melanocyte
distributes melanin to approximately 40 overlying su-
prabasal keratinocytes via elongated dendrites and cell-to-
cell contact (Fig 5). As the keratinocytes migrate to the
surface, they carry with them the ingested melanin to form
a critical barrier against the environment. It is not only the
melanin within the basal melanocytes but also the melanin
within the keratinocytes in the more superficial layers that
gives the skin its characteristic color.22
Recognizable pigment does not occur until 4 –5 months,
and the production of melanin begins earlier and is more
extensive in individuals with darker pigmentation than it is
in people with lighter skin. In lightly pigmented skin, the
melanosomes are small, aggregated in membrane-bound
clusters. In darker pigmented skin, there is increased
melanization, decreased melanosome degradation, and
larger melanosomes singly distributed, and there are larger
and more dendritic melanocytes. There, however, are no
differences in the number of melanocytes between different
races; the differences are in the size, distribution, and num-
ber of melanosomes. The synthesis of melanin, which oc-
curs in the melanosomes, is stimulated by melanocyte-stim-
ulating hormone (MSH). The melanin produced can be
either pheomelanin (creating a red-to-yellow color) or eu-
melanin (occurring as either brown or black in color).
During fetal life, melanocytes are also present in the un-
derlying dermis. However, most of these cells are likely in
the process of migrating to the epidermis, a migration that
may only take a few days. It is between 40 and 50 days that
the melanocytes finally enter the epidermis. In the 10th
week, a number of these melanocytes become associated
with the developing hair follicles, where they donate pig-
ment to the follicles. The melanocytes also provide the

396 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org

deeper skin layers with protection from solar radiation.
Overall, melanocytes represent 5%–10% of the cells in the
epidermis in the adult.2-4,10
Langerhans Cells
Although the skin was initially thought to be a passive bar-
rier between the body and the environment, it is now clear
that the skin has a highly sophisticated system of immune
surveillance. Key to this system are the Langerhans cells,
which are a specialized subset of dendritic antigen-present-
ing immune cells that populate the skin. They are derived
from the bone marrow monocyte–macrophage– histiocyte
lineage and are present in the epidermis at approximately
12 weeks. They are present in all of the layers of the skin,
most numerous in the stratum spinosum. They also are
present in the papillary dermis, especially about the blood
vessels. These cells are the immune macrophage cells of the
skin, and they function in immune surveillance as well as in
contact sensitivities. The Langerhans cells are present in low
numbers in the first 2 trimesters but then increase several
fold to comprise 2%– 6% of the total number of epidermal
cells in the adult epidermis. They will continue to migrate
into the epidermis throughout life (Fig 5B).23 In addition,
mast cells are located in the subpapillary dermis, mainly
around blood vessels, nerves, and appendages, and they can
migrate through the basal lamina into the epidermis. They
play a role in innate and adaptive immunity, and are asso-
ciated with atopic dermatitis, celiac disease, scleroderma,
and immune-bullous disorders.
Merkel Cells
The Merkel cells are generally believed to arise from neural
crest cells and appear between 4 and 6 months.2,4 They are
slow-reacting pressure-detecting mechanoreceptors that lie
at the basal layer of the epidermis and are associated with a
single underlying nerve ending from the dermis. Cytoplas-
mic protrusions of the Merkel cell and hemidesmosomes
physically link the Merkel cells to the surrounding keratin-
ocytes. These are the only “immigrant” cells that form des-
mosomes with the adjacent basal layer keratinocytes and
hemidesmosomes with the BMZ. In the prevalent theory of
the neural crest origin of the Merkel cells, it is thought that
they arise in the dermis and then “travel” into the epider-
mis. However, an alternate theory of their origin has been
proposed in which the Merkel cell is derived from epidermal
cells, which then migrate into the upper dermis. Support for
this etiology comes from the observation that Merkel cells
are not present in the dermis before week 12 and that their
epithelial nature is demonstrated by the presence of desmo-
somes and desmosomal proteins (eg, cytokeratin), whereas
neural markers, neurofilaments, and glial filaments are not
present.24
THE DERMIS
Without the presence of the dermis, the epidermis does not
divide, differentiate, or maintain its orientation. In addi-
Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
tion, epidermal-mesenchymal (dermal) interactions are nec-
essary for the development of the dermal papillae and their
relationship to the hair follicles and the dermal ridges.12
The dermis, or corium, contains blood vessels, hair follicles,
nerve endings, and sensory receptors. There is very little
vascularization of the dermis before 10 weeks. The dermis
and the hypodermis (subcutis) in the head and neck origi-
nate from neural crest cells.25 In the second month, under
the influence of ectodermal WNT signaling, neural crest–
derived mesenchymal cells closest to the ectoderm are
specified to become dermal cells, which express the der-
mal marker dermo1. The embryonic dermis is very cellu-
lar, and, by the second month, the dermis and subcutis
are indistinguishable.
Early in the third month, the developing dermis under-
goes a transition from its initial highly cellular embryonic
composition to one that has mesenchymal cells differenti-
ated into fibroblasts with the production of increasing
amounts of a fibrous intercellular matrix. This matrix is
primarily composed of type I and III collagen fibers and
elastic fibers. When compared with the adult extracellular
matrix (ECM), the fetal ECM principally has collagen type
I and a higher ratio of collagen type III than in the adult
ECM. The fetal ECM also has higher levels of glycosami-
noglycans, hyaluronic acids, and chondroitin sulfates than
in the adult ECM.26 The progressive differentiation of the
dermis also includes the organization and maturation of
nerves and the vascular plexuses. At about the time that the
epidermis is forming the intermediate layer, the morpho-
genesis of the skin appendages commences.9
The predominant connective tissue component of the
dermis is collagen. The texture of the collagen distinguishes
2 layers of the dermis. The papillary layer lies adjacent to
the epidermis and consists of relatively small, finely tex-
tured collagen fibers. This is the dermal layer, which forms
the dermal papillae that protrude up into the epidermis. The
reticular layer of the dermis lies beneath the papillary layer
and consists of larger, more coarsely textured collagen fi-
bers. The connective tissue of the dermis then grades into
the hypodermis (subcutaneous tissues) without a sharp or
distinct boundary (Figs 1A, 3, and 6).
By the fifth month, the papillary and reticular layers be-
come distinct, and soon the connective tissue sheaths are
formed around the hair follicles. At 22 weeks, elastic fibers
are present. Thus, this future dermis is initially a loose ag-
gregate of mesenchymal cells that are highly interconnected
by focal tight junctions on their cellular processes. These
early dermal precursors secrete a watery intercellular ma-
trix that is rich in water, glycogen, ions, fibronectin, elastin,
and hyaluronic acid.2-4 This embryonic dermis is richer in
cells than the adult dermis, with many of the mesenchymal
cells being involved in essential signaling, which regulates
the ectodermal differentiation. On average, the dermis is
only 1- to 2-mm thick. In the eyelids, it is only 0.5-mm
thick, whereas it is thicker (several millimeters) in the
back.7,10,14
兩 397
Fig 6. A drawing of an oblique section of skin, which illustrates the various layers of the epidermis and dermis; note the dermal papillae that cause the
dermal ridges (modified with permission from Shier DN, Bulter JL, Lewis R, eds. Hole’s Human Anatomy and Physiology. 8th ed. Albany, NY: Skin and
the Integumentary System. McGraw-Hill; 1999 [Fig 6.3]).
The dermis is fully differentiated by the second and third
trimesters. It is thin at birth and thickens progressively
through infancy and childhood. The papillary layer is richly
supplied by capillaries, whereas larger vessels are found in
the reticular layer. As noted, deep to the dermis is the sub-
cutaneous fatty connective tissue or the hypodermis (sub-
corium). Between the third and fifth months, the papillary
layer of the developing dermis proliferates to form upward
protruding ridgelike dermal papillae that extend into the
overlying epidermis. Between these dermal protrusions, the
overlying epidermis extends downward, and this process
results in the creation of surface epidermal ridges and
grooves. The patterns of these skin ridges and grooves pro-
duced by the dermal papillae varies from one area of the
body to another. Thus, in palmer and plantar surfaces of the
hands and feet, the pattern is one of whorls and loops. In
the eyelids, there is a diamond-shaped pattern, whereas, on
the upper surface of the trunk, the ridges resemble cobwebs.
During the 10th–12th weeks, the first skin ridges to appear
are the whorls on the palmar and plantar surfaces of the
digits. By the early fifth month, the entire system of surface
ridge patterns is established, and the epidermal ridges are
permanently established by 17 weeks.2-4
BLOOD SUPPLY
In the fourth week, dermal blood vessels that originate
from the mesenchyme start as simple endothelial-lined
structures. By the fifth week, via angiogenesis, new cap-
illaries develop from the primordial vessels.3 That is, the
dermal vasculature is generally thought to develop in situ
by transformation of angiogenic mesenchymal cells. By 6
weeks, underneath the ectoderm, the closed endothelial
channels contain nucleated red blood cells. By 8 weeks,
the primitive vessels are arranged in a single plane paral-
lel to the epidermis. They ultimately form a subpapillary
plexus. The dermis then becomes highly vascularized,
398 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
with an early capillary network transformed into layers
of larger vessels.2 Between 7 and 10 weeks, a second
deeper horizontal plexus develops and both plexuses ex-
tend by budding to attain their final prenatal pattern of
arterioles, venules, and capillaries (Fig 7). Pericytes then
appear, arising from mesenchymal cells. The adult mor-
phology is reached after birth.
The dermal blood vessels branch and then follow nerves
within the dermis to become associated with hair follicles. It
has been estimated that neonatal skin contains 20 times
more blood vessels than it needs to support its own metab-
olism. This excess is believed to be required for thermoreg-
ulation. It is during the first few weeks of postnatal life that
most of the definitive vasculature of the skin develops.4 The
eventual blood supply to the skin has 3 sources. There is the
direct cutaneous system, the musculocutaneous system, and
the fasciocutaneous system. In the direct cutaneous system,
the vessels are derived from the main arterial and venous
vessels that course in the subcutaneous fat and parallel the
skin surface.
In the musculocutaneous system, perforating vessels
arise from the intramuscular vasculature and pass from the
muscle to pierce the deep fascia and then reach the skin by
spreading out in the subcutaneous tissues. In the fasciocu-
taneous system, perforating branches from deeply located
vessels below the fascia pass along intermuscular septa and
then fan out at the level of the deep fascia to finally reach the
skin (Fig 7A). It was the knowledge that the main blood
supply of the skin comes from the perforating vessels from
the underlying muscles and fascia that heralded the use of
the myocutaneous flaps that are so often used in surgical
reconstructions.11 In the deeper layers of the dermis, arte-
riovenous anastomoses are common and are under auto-
nomic vasomotor control. When these vascular shunts are
relaxed, blood is diverted away from the superficial plexus
Fig 7. A, A drawing of the layers of the vascularity within the skin. B, The drawing illustrates the papillary and reticular vascular plexuses and their
interconnecting vessels (modified with permission from https://www.carecreations.basf.com/news-media/photos-and-illustrations/photosand
illustrations-detail/2006/1/14/the-skin-s-blood-vessel-system, accessed 2013). Credit www.skin-care forum.basf.com.

Fig 8. A, A drawing, illustrating the lymphatics of the skin. B, The close layered relationship of the lymphatic and blood vessels in the skin is shown; red
indicates the arteries, blue are veins, and yellow are the lymphatics (modified with permission from Ref 27, Fig 1).

of vessels, which reduces heat loss and at the same time
ensures deep cutaneous circulation to the nerves.
The Lymphatics
With specific reference to the lymphatics of the skin, the
lymphatics start with closed endothelial lymphatic capillar-
ies in the papillary layer of the dermis. They are formed by
mesenchymal cells, which become organized to enclose
pools of proteinaceous fluid that has leaked from the devel-
oping capillaries. These pools drain into a superficial plexus
just deep to the subpapillary dermal venous plexus. The
lymph then drains via vertically oriented branches into a
series of larger lymphatic vessels, which form the deeper
plexus at the level of the reticular layer and the subcutis.
From this deeper plexus of lymphatic vessels, the collecting
vessels may extend over considerable distances before
draining into the deeper lymphatic channels (Fig 8). When
there is extension of a cancer to the skin or there is a dermal
metastasis, after the metastasis has been surgically re-
moved, soon, numerous additional dermal metastases often
develop around the primary area. This phenomenon is ex-
plained by the long reach of the collecting lymphatic
vessels.27,28
HYPODERMIS
The hypodermis, or subcutis, lies immediately below the
skin and, depending on the location in the body, may be
primarily adipose or fibrous. Over most of the body,
the hypodermis is characterized by a thick layer of adi-
pose tissue. However, at the sites of “dimples,” the hy-
podermis is fibrous and binds the dermis to the underly-
ing structures. In general, the transition from dermis to
hypodermis is irregular and poorly defined. Adipocytes
or “fat cells” comprise approximately one-third of adi-
pose tissue, with the remaining portions being composed
of small blood vessels, nerves, fibroblasts, and adipocyte
precursor cells or preadipocytes. The adipocytes exist in
2 cytotypes, white and brown. White adipose tissue
(WAT) is colored white or yellow and contains predom-
inately white adipocytes. Brown adipose tissue (BAT)

Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org 兩 399

appears brown and contains predominantly brown adi-
pocytes, which have a high content of metabolically ac-
tive large mitochondria. Both BAT and WAT have vas-
cular and nerve supplies.29
WAT
Several studies on multipotent clonal cell lines have indi-
cated that the adipocyte lineage derives from an embry-
onic stem cell precursor with the capacity to differentiate
into the mesodermal cell types of adipocytes, chondro-
cytes, osteoblasts, and myocytes.30 Before week 14, the
tissue that will become fat consists of a loose connective
tissue composed of an amorphous ground substance and
fibers. Adipogenesis is first recognized by the aggregation
of an attenuated mass of mesenchymal cells. This mesen-
chymal condensation marks the end of an undifferenti-
ated stage in adipocyte development, and it is associated
with the proliferation of primitive blood vessels. During
this stage, from each small vessel, a rich capillary net-
work develops, around which mesenchymal cells differ-
entiate into stellate preadipocytes. These mesenchymal
lobules, which do not contain lipid droplets at this stage,
are organized within a vascular structure or glomerulus,
and will ultimately form the definitive fat lobule. The
future development of early fat cells within the mesen-
chymal lobules coincides with further development of the
vascular network. Within the mesenchymal lobular prea-
dipocytes, fine fat vacuoles form in the cytoplasm and
soon increase in number. At this time, the primitive fat
lobule includes the vascular glomerulus and densely
packed vacuolated fat cells adjacent to small vessels. In
the final stage of adipogenesis, definitive fat lobules are
surrounded by perilobular mesenchyme, which rapidly
condenses and progressively thickens to form interlobu-
lar septae.
It is between the 14th and 16th weeks that fat tissue
differentiates, and fat lobules are the earliest structures to be
identified before typical vacuolated fat cells appear. After
the 23rd week, the total number of fat lobules remains
relatively constant. From the 23rd to the 29th week, the
growth of adipose tissue is mainly determined by an in-
crease in the size of the lobules. Thus weeks 14 –23 are the
most-sensitive period for fat lobule development.29 The fat
lobules become more densely packed and become more ir-
regular in shape as the fetus gets older. It is after week 14
that the first adipose tissue in the face occurs in the cheek
(the future buccal fat pad). The development of this adipose
tissue then progresses from the deep subcutaneous region
toward the more superficial dermis. Later, adipose tissue
appears in the limbs and the retroperitoneal region. The
expansion of WAT takes place rapidly after birth as a result
of both increased fat cell size and an increase in fat cell
numbers.
The mature adipocytes, which are the main compo-
nent of WAT, are uniquely equipped to function in en-
ergy storage and balance, and they are under tight hor-
400 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
monal control. The adipocytes also function by secreting
factors known to play roles in immunologic responses,
vascular diseases, and appetite regulation. In fact, leptin,
the obese gene product, is a hormone that is primarily
made and secreted by mature adipocytes, and binds to its
receptor in the hypothalamus. Leptin may function in
regulating body mass. Taken together, the white adi-
pocyte behaves not only in regulating energy balance but
also has the potential to play a dynamic role in a variety
of other physiologic processes.30 During the final phase
of differentiation, adipocytes markedly increase their li-
pogenesis and acquire sensitivity to insulin.30
BAT
The development of BAT begins in week 20 and contin-
ues until shortly after birth.31,32 Unlike the white adi-
pocyte, the brown adipocyte has a thermogenic potential
that is the result of the uncoupling of protein (UCP) 1,
which “uncouples” adenosine triphosphate (ATP) syn-
thesis from energy substrate oxidation. That is, brown
adipose tissue has been shown to be a major source of
nonshivering heat production, especially as seen in neo-
nate babies.33 The brown fat cells in classic BAT share
their origin with myogenic factor 5 (MYF5) expressing
myoblasts. The development of these progenitor cells
into a brown adipocyte lineage apparently is triggered by
bone morphogenetic protein 7, which stimulates inducers
of brown fat cell differentiation. The control of brown fat
cell development and activity is under the supervision of
the sympathetic nervous system, which densely inner-
vates the BAT. The sympathetic system mediation of
thermogenesis is primarily governed by hypothalamic
and brain stem neurons. In addition, the leptin–melano-
cortin pathway seems to be a major factor in controlling
brown adipocyte thermogenesis. The involvement of this
homeostatic pathway further supports the role of the
brown adipocyte in energy balance regulation. Brown fat
is present in the neck and shoulder, and in the floor of the
mouth, especially in young, lean female subjects.34
As with the unilocular white adipocytes in WAT, the
multilocular brown adipocytes in BAT also accumulate and
store lipids. However, the brown adipocytes are distinct in
that their more abundant mitochondria are enriched with
UCP1, which, as noted, uncouples substrate oxidation from
ATP production so that heat can be produced. Although
WAT is far more common than BAT in terms of percentage
of body mass, when activated, BAT is an important con-
tributor to nutrient partitioning and utilization as well as
body weight regulation. UCP1 expressing thermogenic
adipocytes can also be found in WAT in the form of beige
adipocytes. Under conditions of chronic cold exposure,
these beige adipocytes can be recruited in the WAT,
which results in the “browning” of WAT.35 With partic-
ular attention to the origins of these adipocytes, the cur-
rent understanding is that WAT adipocyte precursors can
be derived from either MYF5⫹ or MYF5⫺ lineages,
whereas BAT adipocyte precursors are derived exclu-
sively from a MYF5⫹ lineage. The beige adipocytes
can be derived from WAT adipocyte precursors and po-
tentially directly from mature white adipocytes. Brown
adipocytes can also be generated from stem-cell–like
skeletal muscle satellite cells, and both brown and white
adipocytes may derive from endothelial precursors
(Fig 9).35
SKIN DERIVATIVES
In the head and neck, the skin has specialized structures that
include sebaceous glands; hair and sweat glands, and tem-
perature, pressure, and pain receptors.4 The glandular
structures all arise as a result of epithelial–mesenchymal
interactions that are secondary to inductive stimuli from the
dermis and which cause the development of an ectodermal
placode. After this, there is condensation of the underlying
mesenchyme and then invagination of the epithelium into
the underlying dermis.4
Hair
The earliest development of the hair rudiments occurs be-
tween 9 and 12 weeks in the regions of the eyebrow, upper
lip, and chin.36 This occurrence represents the initial re-
sponse to the first of 3 discrete mesenchymal– epithelial ex-
changes that orchestrate hair follicle formation.37 The first
sign of a hair follicle is a crowding of nuclei in the basal
layer or stratum germinativum of the epidermis. This is
referred to as the primitive hair germ or pregerm stage (Fig
10), which occurs in response to signaling from the subja-
cent mesenchyme. The hair pregerm is also believed to in-
duce the aggregation of dermal cells that form a dermal
condensate under it and that promotes further differentia-
tion of the hair germ. The pregerm then rapidly passes into
the hair germ stage as the basal cells become high and their
nuclei become elongated. These hair germ cells then prolif-
erate and grow downward into the dermis.
At the same time, in response to a second series of signals
from the enlarging epithelial cells, the mesenchymal cells
and fibroblasts near the base of the hair germ increase in
number to form the rudiment of the hair papilla beneath the
hair germ. This stage, which occurs in the fifth month of
development, is known as the hair peg. As the hair peg
develops further, it grows obliquely downward, and the
advancing lower portion becomes bulbous and concave
downward, and gradually envelops the mesodermal pa-
pilla. The bulbous region is known as the hair bulb, and the
epithelial cells of the hair bulb from the overlying prolifer-
ating ectoderm will constitute the germinal matrix that will
later produce the hair shaft. Proliferation and differentia-
tion are then enhanced by a third series of signals emanating
from the dermal papillae. It is at this bulbous hair-peg stage,
that 2 epithelial swellings appear on the posterior wall of
the follicle. The lower one is the bulge to which the arrector
pili muscle will attach, and the upper one is the rudiment of
the associated sebaceous gland (Fig 10).2,14,25,38 When
Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
these arrector muscles contract, they aid in squeezing the
sebum from the gland follicle. The bulb can be divided into
2 distinct portions, above and below a line drawn through
the widest part of the bulb (critical level of Auber). The cell
matrix below the line remains undifferentiated, with a high
cellular turnover rate, whereas the cells above the line retain
some mitotic activity but differentiate to give rise to the hair
shaft and the inner root sheath.38
By the middle of the second trimester, it is the epidermal
cells lining the developing follicular canal that constitute the
inner epidermal root sheath, while the surrounding mesen-
chymal cells differentiate into the dermal outer root sheath.
Proliferation of the germinal matrix produces cells that then
undergo keratinization and are added to the base of the hair
shaft. The growing hair shaft thus is pushed outward
through the follicular canal. The hair shaft becomes kera-
tinized, with the process of keratinization forming granules
of trichohyalin, a protein that imparts hardness to the hair.
The hair shaft thus is a column of dead keratinized cells that
are gradually extruded from the hair follicle. The elonga-
tion of the presumptive hair follicle into the mesenchyme
takes an oblique direction, and this seems to be directed by
the cluster of mesenchymal cells, which accumulate beneath
it. If the hair is to be colored, then the maturing keratino-
cytes incorporate pigment produced by the melanocytes of
the hair bulb.4 The different mesenchymal– epithelial cues
involve several signaling pathways, including NOTCH,
sonic hedgehog (SHH), and WNT as well as contributions
from fibroblast growth factors (FGF) and bone morpho-
genetic proteins (BMP). There also are marked changes in
certain cell adhesion proteins, notably E-cadherin and
P-cadherin.14
The primary hair germs appear randomly at rather reg-
ular distances from each other and develop in a scattered
manner on the surface of the body. As the fetus grows, the
distance between the first hair germs enlarges, and when a
critical distance between the original hair germs is reached,
new primary hair germs appear. Later, secondary hair
germs develop and form hair groups, usually arranged in
groups of 3, in short lines perpendicular to the slant of the
hair follicle. The melanocytes associated with the hair bulb
develop from melanoblasts that migrate into the hair bulbs
and then differentiate into melanocytes. The melanin pro-
duced by these cells is transferred to the hair-forming cells
in the germinal matrix several weeks before birth, and the
relative amount of melanin transferred accounts for the
different hair colors.14,38
The arrector muscles of hairs are small collections of
smooth-muscle fibers that differentiate from the mesen-
chyme surrounding the hair follicles in the papillary layer of
the dermis. Contractions of the arrector muscle lifts the hair
shaft to a nearly vertical position while depressing the skin
over its attachments. This results in small pockets of de-
pressed skin with normal intervening skin, and this creates
the tiny “goose bumps” on the surface of the skin, especially
noted when the skin is exposed to cold. The hairs that
兩 401
Fig 9. A, A diagram of the lineages of white, brown, and beige adipocytes, and a representation of the development of the adipocyte (modified with
permission from Ref 35, Fig 1). B, The diagram illustrates the different responses of WAT and BAT to cold stimulation (modified with permission from
Harms M, Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013;10:1252– 63 [Fig 2]).

develop in the face have poorly developed arrector pili mus- the follicular epithelium that periodically regenerate the fol-
cles, and the hairs that form the eyebrows and the cilia of licle during postnatal life are located near the attachments
the eyelashes have no arrector muscles.3 The stem cells of of the arrector pili muscles.

402 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org

Fig 10. A, The serial drawing illustrates the development of the hair follicle and its associated sebaceous gland (modified with permission from Carlson
BM. Human Embryology and Developmental Biology. 4th ed. China: Mosby Elsevier; 2009:182 [Fig 9 – 8]). B, Drawings illustrate the anatomy of the hair
follicle as seen in a frontal view and in cross-section of the hair root (modified from https://image.slidesharecdn.com/biol121-chp5-pp-fall10-
101011140901-phpapp01/95/biol-121-chp-5-the-integumentary-system-64-638.jpg?cbⴝ1408031385, accessed 2013). C, The drawing illustrates the
various normal phases of hair cell replacement as noted in the text (modified from http://www.clevelandclinicmeded.com/medicalpubs/disease
management/dermatology/hair-disorders/, accessed 2013).

Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org 兩 403

 By 15–17 weeks, the hair canal is fully patent within the
dermis and the epidermis, but it neither pierces the epider-
mal surface nor contains hair. The first hairs appear on the
brow and forehead at 16 –17 weeks and cover the entire
scalp by 18 weeks.12 Hair follicles do not appear in the
remaining body until the fourth month. By the fifth month,
most, if not all, hair follicles are present. Overall, it is esti-
mated that approximately 5 million hair follicles develop in
both males and females, with the differences in distribution
and the various kinds of hair found in boys and girls at
puberty, which results from differing concentrations of cir-
culating sex steroid hormones.4 Thus, in males, the finer
body hair is replaced by coarser hair in the axilla and pubic
region as well as on the face and back.4 There are different
types of hair, ranging from the coarse hairs of the eyelashes
and eyebrows, the axillae, and the pubis to the barely visible
hairs on the abdomen and back.
The first generation of hairs formed are fine-downy, soft,
and lightly pigmented or unpigmented. They are collec-
tively called lanugo. The lanugo hairs are closely spaced and
may be first noted by the end of the 12th week. They are
plentiful by 17–20 weeks. These lanugo hairs help to hold
the vernix caseosa on the skin. During the perinatal period,
the lanugo is replaced by either vellus hair or terminal hair.2
Vellus hair is soft and short, usually ⬍2 mm long. It is the
general surface hair and is usually colorless. Terminal hair is
large and coarse, with a medulla and pigment. It is of vary-
ing length and is found at birth in the scalp, eyebrows, and
eyelashes. During life, the same hair follicle can produce
first vellus hair and then terminal hair. This is most event in
the axillary hair of both male and female children and
in the beard of males as they attain puberty. In male bald-
ness, the terminal follicles regress and give origin to vellus
hair.38 The normal cycle of hair growth has been character-
ized into 4 stages. The first stage refers to the growth of the
hair and is referred to as the anagen phase. The next stage is
the regression or catagen phase, which is followed by the
resting or telogen phase. The final phase is the shedding or
exogen phase.4,39
The anagen phase is the active hair growing phase and it
usually lasts 2– 6 years. It is in this phase that the hair shaft
is at its maximum length. In the anagen phase, hair growth
recapitulates normal hair follicle development, with the for-
mation of a new lower hair follicle that begins with the
proliferation of the secondary germ cells in the hair bulge.
The germinal matrix will form the hair shaft while the bulb
will provide the stem cells that migrate down to form the
lateral disk and thus provide germ cells for the next hair
growth cycle. When the growth phase is completed, the
hair stops growing and the catagen phase is entered. The
hair shaft becomes small and round and detached from
the germinal matrix and is referred to as a club hair. The
lower two-thirds of the hair follicle goes through a highly
controlled process of involution, primarily reflecting the
onset of rapid apoptosis in most follicular keratinocytes.
404 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
At this time, the hair-associated melanocytes also stop
growing. Toward the end of the catagen stage, the dermal
papilla condenses and moves upward to come to rest under-
neath the hair follicle bulb. If the dermal papilla fails to
reach the bulb, then the follicle stops cycling and the hair is
lost. The hair shaft then fully detaches from the germinal
matrix. The catagen phase usually lasts approximately 1–2
weeks. In the next phase, or telogen phase, the dermal pa-
pilla separates from the follicle and the hair goes into a
resting phase, which last 5– 6 weeks. In the last or exogen
phase, the hair follicle falls out and a new hair root begins
making a new hair as the anagen phase starts anew. Be-
tween the telogen phase and the exogen phase, the club hair
may wedge itself into the follicle until it gets brushed or
washed out. Alternately, the club hair remains in the follicle
until the follicle restarts the growth cycle (anagen phase)
and the new hair shaft pushes the club hair out (Fig
10C).4,39 At any one time, 90%–95% of the scalp hairs are
in the anagen phase, ⬍1% are in the catagen phase, and
5%–10% are in the telogen phase. In the exogen phase,
normally, 50 –100 hairs fall out per day.
GLANDS
Several types of glands are produced by the downward
growth of the epidermis. Three types of glands are the fol-
lowing: the sebaceous glands, the apocrine glands, and the
sweat glands are widely spread over the body. Of these,
only the sweat and sebaceous glands occur in the head and
neck.
Sebaceous Glands
The sebaceous glands first appear as hemispherical protu-
berances on the posterior surface of the hair peg. The cells
contain moderate amounts of glycogen, but the cells in the
center lose this and become larger and foamy as they accu-
mulate droplets of lipid. Between 13 and 15 weeks, the
sebaceous glands become differentiated. The gland bud
grows into the dermal tissue and branches to form a small
system of ducts that end in expanded secretory acini. The
acini secrete by a holocrine mechanism, that is, the entire
secretory cell is filled with vesicles of secretory product that
then are released by rupturing the cell membrane and thus
destroying the cell. The basal layer of the acinar epidermis
consists of proliferating stem cells that constantly renew the
supply of maturing secretory cells.14
The sebaceous glands produce the oily sebum (a mixture
of lipids) that is released into the hair follicle and then
passes to the surface of the skin, which lubricates both the
skin and the hair. Thus, cells formed by mitosis at the base
of the gland are pushed toward the surface as new cells are
formed beneath. Along the way, the cells become packed
with lipid and then undergo apoptosis. The secretions con-
sist of breakdown products of the cells, which are extruded
into the lumen of the associated hair follicle (Fig 11). The
prenatal and early postnatal growth of the sebaceous gland
is thought to be controlled by steroid hormone metabolism

Fig 11. The drawing illustrates the relationship of a hair follicle, its asso-
ciated sebaceous gland, and, next to it, a sweat gland (modified from
http://www.lucianoschiazza.it/Documenti/Eruptive_syringoma_eng.
html, open access).
by the fetal epidermis as well as maternal androgens and by
endogenous steroid synthesis of the fetus.12 Mature seba-
ceous glands are present on the face by 6 months. Sebaceous
glands are highly active in the fetus, and the sebum they
produce combines with desquamating epidermal cells and
remnants of the periderm to form a waterproof protective
coating for the fetus, the vernix caseosa. After birth, the
sebaceous glands become relatively inactive, but, at pu-
berty, they again begin to secrete large quantities of sebum
in response to the surge in circulating sex steroids. The
sebaceous glands are especially plentiful in the skin of the
nose and the forehead.
Sweat Glands
There are several million sweat glands that cover the human
body. They serve as the primary source of cooling and hy-
dration of the skin. The sweat glands (eccrine or merocrine
glands) first appear at approximately 14 –15 weeks as buds
of stratum germinativum that grow down into the underly-
ing dermis to form unbranched, highly coiled glands. The
intraepidermal portion of the gland duct develops as a result
of a coalescence of groups of intracytoplasmic cavities
formed within adjacent inner cells. However, the intrader-
mal portion of the duct portion forms by dissolution of the
desmosomal attachments between the cells that comprise
the inner core of the duct germ.14 The peripheral cells dif-
ferentiate into an inner layer of secretory cells and an outer
layer of myoepithelial cells, which are innervated by sym-
pathetic fibers. These cells contract to expel sweat from the
gland (Fig 12). The inner layer of cells of the developing
sweat duct gradually lose their initial expression of the ker-
atins K5/K14 and differentiate into K8/K18 expressing lu-
minal cells. The outer basal layer cells remain positive for
K5/K14 and differentiate into myoepithelial cells. The se-
Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
cretory cells secrete fluid directly across the plasma mem-
brane. That is, in eccrine glands, the secretions are the result
of the secretory intracytoplasmic vesicles fusing with the
cell membrane and then being released without destruction
of the membrane of the secretory cell.4 The epithelial at-
tachment of the developing gland to the epidermis forms the
primordium of the sweat duct, and the sweat glands begin
to function shortly after birth.3 The sweat glands are espe-
cially plentiful in the scalp.
The sweat ducts are uniquely lined by 2 layers of cuboi-
dal epithelial cells. This stratified cuboidal epithelium is
rarely found elsewhere in the body, and these cells function
in mediation of sodium from the sweat to prevent loss of
electrolytes. As noted, the sweat glands are vital to thermo-
regulation. When the ambient temperature is higher than
the body temperature, evaporation of sweat can cool the
skin below the core temperature. Often, normal thermoreg-
ulation occurs insensibly because sweat evaporates as
quickly as it is formed. However, dripping sweat, as occurs
during exercise, is much less efficient because the body at-
tempts ineffectively to compensate for the rising core tem-
perature.26 A normal hair follicle, a sweat gland, and a
sebaceous gland are compared in Figure 11.
INNERVATIONS
Dermal Corpuscles
The skin is the largest sensory organ of the body, recogniz-
ing and transmitting the sensations of pain, temperature,
itch, and touch to the central nervous system (CNS). In
addition, there are nerves that control blood flow, secretion
of sweat, and piloerection. In particular, there are 4 primary
types of encapsulated mechanoreceptors that are special-
ized to provide the CNS with information regarding touch,
pressure, vibration, and cutaneous tension, and these recep-
tors are Meissner corpuscles, Pacinian corpuscles, Merkel
cells, and Ruffini corpuscles, respectively. These mechano-
receptors are collectively referred to as low-threshold or
high-sensitivity receptors because even weak mechanical
stimulation of the skin can induce these to produce an ac-
tion potential. All of these low-threshold mechanoreceptors
(LTMR) are innervated by relatively large myelinated ax-
ons (type A␤), which ensure a rapid transmission of the
tactile information to the CNS. In addition, there are noci-
ceptors that sense painful stimuli, pruriceptors that convey
the sense of itch, thermoreceptors that detect temperature,
and LTMRs that sense nonpainful stimuli or touch. These
LTMRs are divided into subtypes that are distinguished by
their unique sensitivities and conduction velocities, and
their adaptation to sustained mechanical stimulation.40
The tactile Meissner corpuscles are the last corpuscular
mechanoreceptors to develop. The initial wave of sensory
innervation is directed to the Merkel cells and later on to the
Pacinian and Ruffini corpuscles. The differentiation of
Meissner corpuscles occurs only after the dermal papillae
and epidermal papillary ridges have formed. Meissner cor-
兩 405
Fig 12. Drawings illustrate the development of a sweat gland (modified with permission from Moore KL, Persaud TV. The Developing Human Clinically
Oriented Embryology. 8th ed. China: Saunders Elsevier; 2008:443 [Fig 19 – 4]).
Table: Sensory skin receptors in the head and necka
Receptor Type Location
Free nerve endings All of the skin
Meissner corpuscles Lips and nonhairy skin
Pacinian corpuscles Subcutaneous tissues
Merkel cells All of the skin and the hair follicles
Ruffini corpuscles All of the skin
a
Modified from Ref 43, Table 9.1.
puscles are LTMRs that are responsible for sensitivity to
light touch. They have the highest sensitivity and thus the
lowest threshold when sensing vibrations between 10 and
50 Hz. They are rapidly adaptive receptors, and, in the head
and neck, they are most concentrated in the lips. Meissner
corpuscles begin their differentiation at the apices of the
dermal papillae, and they project axonal processes into the
epidermis, with Schwann cells growing along and making
contact with the epidermal cells. The intraepidermal axonal
processes characteristic of Meissner corpuscles may deter-
mine and ensure their position at the top of the dermal
papillae, close to the epidermis.
Pacinian, or lamellar, corpuscles are the only other pha-
sic tactile LTMRs. They are located deeper in the dermis,
and they detect deep, quick pressure changes and vibrations
in the skin. They do not detect pain, which is exclusively
signaled by free nerve endings. The optimal sensitivity of
Pacinian corpuscles is 250 Hz. There also are some free
nerve endings that may detect deep pressure. The Pacinian
corpuscles start as a cylindrical sensory terminal sur-
rounded by a layer of cells that are the presumptive inner
core cells, which will accumulate around the terminal and
which are derived from Schwann cells. By birth and shortly
thereafter, the inner core lamellae increase in number and
become concentrically tightly packed together.41
As previously mentioned, Merkel cells are slow reacting
pressure-detecting mechanoreceptors that lie at the basal
layer of the epidermis and are associated with a single un-
derlying nerve ending from the dermis. They identify static
touch stimuli. Ruffini corpuscles are elongated, spindle-
406 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
Function Adaption Rate Threshold
Pain, temperature Slow High
Touch, dynamic pressure, crude touch Rapid High
Deep pressure, dynamic vibrations Rapid Low
Static pressure touch Rapid Low
Stretching of skin Rapid Low
shaped receptors located in the deeper skin, with their long
axis aligned with the stretch lines in the skin. As such, they
are believed to respond to stretching of the skin.40 The
primary skin receptors, their function, and adaptation and
threshold rates are summarized in Table 2.
There are a number of classes of primary afferent nerves
that respond to thermal stimuli. The afferent nerve fibers
that mediate the sensation of nonpainful warmth or cold
seem adapted to convey this thermal information over a
particular temperature range. In contrast, nociceptive affer-
ents are often activated by both painful cold and heat stim-
uli.42 Nociceptors are unspecialized nerve endings, “free
endings” that initiate the sensation of pain. They arise from
cells in the dorsal root ganglia of a spinal nerve or, in the
case of the face, from the trigeminal ganglion. They send
one axon to the periphery and the other into the spinal cord
or directly into the brain stem. The axons associated with
nociceptors conduct the impulses slowly, being either
lightly myelinated or unmyelinated. This is in distinction to
the LTMRs described above, which are myelinated and fast
conducting. Thus, axons that convey pain stimuli can fol-
low either a fast- or slow-conducting pathway.43 These no-
ciceptors may also play a role in the sensation of itch. These
free nerve endings have no specialized associated structures
and terminate in the epidermis, penetrating almost to the
stratum corneum.
More specifically, the sensory nerves in the skin fall into
2 categories. In the epidermis, skin–nerve organs consist of
“free” nerve endings, or hederiform (ivy-shaped) nerve or-
gans, such as the Merkel cells. In this case, the term free

Fig 13. A drawing of the corpuscles and nerves in the skin (modified from
https://en.wikipedia.org/wiki/Tactile_corpuscle. Open access).
terminal nerve refers to a slight axon expansion that still
contains perineural cells, including cytoplasm of Schwann
cells and multiple cell organelles. In the dermis, free sensory
nerve endings are either associated with the hair complex
(Pinkus disk) or they have encapsulated nerve endings as
found in Ruffini and Meissner corpuscles, and so forth44
The different structures of these nerves and corpuscles and
their primary locations within the skin are illustrated in
Figure 13.
It is well known that the itch sensation can be reduced by
the “painful” sensation caused by scratching. However, not
only is itch inhibited by the enhanced input of pain stimuli,
the opposite is true. Thus, the inhibition of pain processing
may also reduce its inhibitory effect, which results in an
enhancing itch. There clearly are complex interactions be-
tween pain and itch, and, although there is an obvious an-
tagonistic interaction between pain and itch under normal
conditions, the patterns of peripheral and central sensitiza-
tion phenomena for pain and itch are surprisingly similar,
and, in the periphery, anti-inflammatory therapy will re-
duce both the sensitization for pain and for itch.45
Cutaneous Innervations
The cutaneous innervation of the head and neck primarily
lies in the dermis, and it comes from the branches of the
trigeminal nerve and from the upper 4 or 5 cervical spinal
nerves (Figs 14 and 15). The sensory nerves are derived
from outgrowths from the neural crest via the dorsal root
ganglia. The autonomic system supplies the motor fibers to
the arterioles, arrector pili muscles, and myoepithelial cells
of the sweat glands. Within the dermis, the autonomic
nerves form a deep reticular plexus that has branches ex-
tending into the papillary layer. Small axons are present
early when the epidermis is bilaminar, and, by 8 weeks,
there already are functioning plexuses. By the fourth
month, the dermal plexuses are very well developed, and
Meissner and Pacinian corpuscles are present.8
Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
In summary, the third trimester is a period of quiescence
in the ontogeny of the epidermis. All of the epidermis has
become keratinized, whereas the periderm has completely
sloughed. The subcutaneous appendages are formed and
are functioning. It is only as the fetus nears birth that there
is a sudden increase in thickness of the stratum corneum.12
The major events in the development of the skin and its
appendages, and when they occur during embryogenesis are
summarized in Figure 16.
PHYSIOLOGIC SKIN CHANGES
Age-Related Skin Changes
The functions of the skin, such as protection, thermoregu-
lation, and perceiving touch and itch, are all compromised
with aging. There is an overall tendency for atrophy, espe-
cially in the upper dermis, and the aging of the skin vascu-
lature produces changes in skin structure and distribution.
In normal skin, the blood capillaries have perpendicular
loops that drain into a horizontal venous plexus (Figs 7 and
8). In normal young skin, there are approximately 60 loops
to every square centimeter. However, with aging, there are
far fewer loops, and this results in thinning of the upper
dermis, which may become transparent so that a poorly
supported and dilated subpapillary plexus may be visible to
an observer. As an example, in the head and neck, there may
be a 40% reduction of papillary loops in the forehead. In
addition to the capillary changes, the adnexal structures,
such as the hair follicles and sebaceous and sweat glands, all
atrophy at different rates.46
As already noted, the skin has adipose tissue that projects
into the dermis. This fat has numerous blood capillaries but
no lymphatics. Rather, the lymphatics pass deeply through
the skin septa along with the arterioles that supply the der-
mis and the veins that drain it. The adipose tissue also
shows increasing heterogeneity with aging, much of it re-
lated to sex differences and the affects of sex hormones.
These changes affect the function of the fat as a determinant
of body shape as well as its role in pressure dispersal and
insulation. In each of these functions, an aging blood supply
also plays a role. The endothelial cells respond to the me-
chanical forces of blood pressure and flow by regulating
vascular tone and by shape change. The capillaries become
less well supported by the age-related epidermal rete ridges
and the decrease in dermal connective tissue, and, as a re-
sult, senile purpura tears and pressure ulcers are a conse-
quence. With aging, body shape, thermoregulation, and
pressure from weight bearing all alter the skin texture, func-
tion and appearance.46
The lymphatic vessels also have a greater attenuation
and wider lumen in young people than in older subjects, and
there is an involution of the lymphatics that occurs with
age. Sclerosis and varicosity of the main lymphatic trunks
also occur. To function effectively, the lymphatic endothe-
lial cell must be sensitive to any deforming tissue stresses so
that lymph is encouraged to move easily into the lymphat-
兩 407
Fig 14. The drawing illustrates the nerves that supply innervation to the skin.
Fig 15. A drawing of the ansa cervicalis and the cervical nerves (in green) that supply the skin of the neck and posterior scalp (modified with permission
from Netter FH. Atlas of Human Anatomy. 5th ed. Saunders Elsevier; 2011 [Fig 32]).
ics. In healthy skin, this process is helped by the “snap
back” provided by a closely applied and appropriately ori-
entated elastin fiber network. The orientation of elastin in
the upper dermis allows it to take up some of the strain in an
expanded upper dermis and to restore it rapidly to its nor-
mal width. However, with age, elastin tends to be replaced
by a less flexible degenerated form that provides rigidity
instead of pliability and elasticity. These age-related
changes are also highly associated with an overload of the
lymphatics by a failing venous system.46
In summary, in the third decade of life, the skin slowly
begins to show the consequences of aging. These changes
occur slowly and almost imperceptibly. The first signs of
aging are seen in the skin of the face, where tiny lines of
expression result from the repeated tensions of the facial
muscles that draw on the deepest parts of the dermis. Over
time they form deeper wrinkles. Often, this is first noticed in
the corners of the eye as “crows’ feet.” This process evolves
over years before becoming visible, and the wrinkles then
spread slowly over the entire face and neck. The underlying
loss of dermal elasticity is not only seen in the appearance of
wrinkles but also as looseness of the skin, commonly noted
in the neck.47 Some of the skin changes associated with
aging are summarized in Figure 17.
408 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
In addition, the vascularization of the dermis is also re-
duced, and, in people with light skin, the skin color gradu-
ally becomes pale, even yellowish, especially in the neck and
nape area. There also is a diminution of dermal and epider-
mal hydration, primarily due to age-related decreases of
glycosaminoglycans. The dermis is the most deeply altered
compartment of the skin during the process of aging; how-
ever, there also is a reduction of epidermal thickness while,
at the same time, the thickness of the stratum corneum layer
increases. With progressive aging, melanocytes are less
active and have larger melanosomes. This causes pig-
mented “age” spots to occur mainly in the hands. The
hypodermis is also thinner, which results in the collaps-
ing of the skin.
Ultraviolet (UV) exposure also affects the changes asso-
ciated with aging, and, in effect, UV radiation amplifies and
speeds the chronological aging. Typically, in covered areas,
wrinkles are finer and not as deep as in exposed areas. In the
face and neck, UV exposure causes deep wrinkles, rough-
ness, loose skin, and pigmentation as well as damage to
fibroblasts and elastic fibers. A few weeks after sun expo-
sure, the tan fades, but the deep rooted harmful effects to
the skin remain. These affects accumulate over years and
end up producing deep wrinkles and spots of pigmentation.
Fig 16. The figure summarizes the timing of major events in epidermal differentiation (modified from Table 1, p 311 in Holbrook KA. Human epidermal
embryogenesis. Int J Dermatol 1979;18:329 –56).

These changes are primarily due to an excessively slow der- fibers, which, rather than being positioned perpendicular to
mal renewal. The most striking change in the dermis caused the skin surface, as in young healthy skin, are positioned
by UV exposure is the accumulation of bundles of elastin parallel to the skin surface.47

Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org 兩 409

Fig 17. Drawings illustrate the major skin changes associated with aging.
Obesity
Obesity has become a public health problem, especially in
the United States, where it is estimated that one-fourth to
one-third of adult Americans and one-sixth of adolescents
are obese.48 In addition to its impact on numerous health
issues and diseases, obesity is related to a number of effects
on skin physiology. Skin barrier functions are altered in
people who are obese, with an increase in transdermal wa-
ter loss and an increase in erythema, with a tendency to-
ward dry skin. Obesity also affects the sebaceous glands,
with an increased proliferation of basal keratinocytes
within the pilosebaceous duct. There is an incomplete sep-
aration of the ductal corneocytes from one another, which
leads to subsequent obstruction of the pilosebaceous duct.
This, in turn, is related to an increase in acne.49,50
Compared with people who are not obese, people who
are obese have larger skin folds and sweat more profusely
after becoming overheated. This is likely due to thicker
layers of subcutaneous fat, with an increase in both the
frictional and moisture components of the skin. Obesity
also impedes lymphatic flow in the subcutaneous tissues,
which often results in lymphedema. Lymphedema is associ-
ated with dilatation of tissue channels and reduced oxygen-
ation, and, in this setting, progressive fluid accumulation
can lead to fibrosis and chronic inflammation.49 Obesity is
associated with altered collagen structure and function, and
thus impaired wound healing. This may be secondary to a
failure of collagen deposition to match the increase in skin
surface area.51 Obesity is also associated with significant
changes in cutaneous micro- and macrocirculation. Specif-
ically, obesity is one of the primary causes of dysfunction of
the skin microcirculation, and this likely contributes to mi-
croangiopathy and hypertension.49 Lastly, in adults who
are not obese, the subcutaneous fat is composed almost
entirely of white (yellow) fat, which provides insulation and
acts as an energy depot. In contrast, brown fat, which is
more prevalent in people who are obese is not as effective in
these roles.31,52
410 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
Obese fat is immunologically different from lean fat.
Macrophages that encourage local inflammation are re-
ferred to as M1 macrophages, whereas those that are asso-
ciated with decreased inflammation and that encourage tis-
sue repair are referred to as M2 macrophages. This
difference results from the macrophage’s unique ability to
metabolize the amino acid arginine into either nitric acid,
which can be considered a “killer-type” molecule, or orni-
thine, a repair-type molecule. In lean adipose tissue, there
are small adipocytes and alternatively activated M2 mac-
rophages that secrete adipocytokines such as interleukin
10 (IL-10) and adiponectin, a protein hormone produced
and secreted exclusively by adipocytes that regulate the
metabolism of lipids, fatty acids, and glucose. It is the
activation of 5= adenosine monophosphate-activated
protein kinase (AMPK), an enzyme that plays a role in
cellular energy, that inhibits the production of proin-
flammatory cytokines and chemokines, increases adi-
ponectin secretion, and inhibits macrophage recruitment
and M1 polarization. These proteins all help maintain an
anti-inflammatory environment.
It has also been postulated that physical damage to blood
vessel endothelium as a result of either the sheer increased
size of the adipocytes, crowding as a result of the adipocyte
size, and the number or oxidative damage from an increas-
ing lipolytic environment could play a role in macrophage
recruitment, similar to that seen in atherosclerosis.53 How-
ever, in obese adipose tissue, the adipocytes enlarge due to
increased storage of triglycerides, become hypertrophic,
and then necrotic. There is an associated infiltration of M1
macrophages, which tend to accumulate around necrotic
adipocytes that form crownlike structures. The secretory
products produced by the M1 macrophages and the hyper-
trophic adipocytes further exacerbate the local inflamma-
tory environment. In addition, T cells accumulate in obese
fat. Together, this adipose inflammation has been linked
to obesity-related insulin resistance and type 2 diabetes (Fig
18).53,54
Fig 18. Schematic drawing, illustrating the differences between lean and obese fat, and the different metabolic environments that they present. Also
listed are some of the receptor sites known to be on adipocytes.
Adipose tissue has also been shown to play a major role
in energy homeostasis, lipid metabolism, the immune re-
sponse, and reproduction. Steroids, and, in particular, es-
trogens, promote, maintain, and control the typical distri-
bution of body fat, overall fat mass, adipose deposition,
adipose differentiation, and adipocyte metabolism. A defi-
ciency in estrogen leads to an increase in adipose tissue,
especially in visceral fat, and these changes have, in turn,
been linked to adipose dysfunction and a variety of diseases,
including type 2 diabetes, hyperlipidemia, hypertension,
and cardiovascular diseases as well as a number of
malignancies.55,56
Cellulite
The term cellulite describes a peau d’orange (peel of the
orange) or a cottage cheese-type dimpling of the skin that
occurs most commonly in women who are postmeno-
pausal, primarily in their thighs and buttocks. Some degree
of cellulite is present in 85%–90% of women who are post-
menopausal but is rarely found in men. The actual term
cellulite comes from the French literature from 1920 and
synonyms include the following: adipose edematosa, der-
mopanniculosis deformans, status protrusus cutis, and gy-
noid lipodystrophy. Because there is no known morbidity
or mortality associated with cellulite, it truly cannot be
described as a pathologic condition of the skin.52
Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
There are 2 primary theories regarding the etiology of
cellulite. In the most prevalent theory, the etiology may be
based on sex differences in the structural characteristics of
the subcutaneous fat lobules and the connective tissue septa
that divide them. The cause of the dimpling is the result of
herniation of fat, termed “papillae adiposae,” that pro-
trudes from the subcutis through the inferior surface of a
weakened dermis at the dermo– hypodermal interface (Fig.
19). In fact, women have been shown to have a discontin-
uous dermo– hypodermal interface, whereas men have a
continuous interface. A second suggested etiology main-
tains that the skin dimpling results from continuous and
progressive vertically oriented stretching within the hypo-
dermal collagen fibrous strands that are well below the
dermo– hypodermal interface, a process that weakens the
connective tissue buttress, and this allows the fat hernia-
tion. There are 2 less-accepted theories: one that relates the
dimpling to vascular changes, and the other relates to the
presence of inflammation in the fibrous septae.52,57,58
Postmenopausal Skin Changes
Sex-steroid hormones have effects on skin elastic fibers and
collagen content. There is a decrease in the amount of skin
collagen by approximately 2% each year after menopause,
and the mean skin collagen content was ⬎48% in women
who are postmenopausal and treated with estrogen therapy
兩 411

Fig 19. The drawing illustrates the herniation of fat through the fascia,
which results in enlargement of the fat lobule and pushing of the overly-
ing epidermis upward; the septations between the lobules shorten, de-
pressing the overlying skin; together, these changes cause the dimpling
associated with cellulite.
than in women who were not treated. Similarly, there is a
decrease in the number and thickness of elastic fibers in the
skin by nearly 50% in women who are postmenopausal.
These estrogen-related deficiencies lead to an increase in
“age-associated” skin changes, such as wrinkling and thin-
ning, and dryness, all of which are increased in the post-
menopausal years or in cases of estrogen deficiency.59-63
WHEN THINGS GO WRONG
There are a great number of dermatologic diseases and con-
ditions. This section only mentioned a few that often are
related to the embryology of the skin and its aging.
Desmosomal Abnormalities
Examination of the fundamental mechanisms by which the
cytoskeletal proteins contribute to the architecture and
function of the skin has revealed the role that keratin gene
mutations play in skin diseases, especially in autoimmune
epidermal blistering disorders. The major cell-surface at-
tachment sites for these intermediate filament networks are
the desmosomes and hemidesmosomes.64 Because these
structures play a key role in maintaining tissue integrity,
perturbations in their structure and function are responsible
for epidermal autoimmune diseases, such as alopecia
areata, bullous pemphigoid, epidermolysis bullosa, pem-
phigus foliaceous, pemphigus vulgaris, and vitiligo; and
skin fragility syndromes, such as ectodermal dysplasia–skin
fragility syndrome and epidermolysis bullosa simplex
(Fig 20).64
As examples, autoantibodies directed against the desmo-
somal proteins result in diseases such as pemphigus for
example, whereas autoantibodies against hemidesmosomal
proteins result in diseases such as bullous pemphigoid for
example. More specifically, autoantibodies against specific
adhesion interface proteins, for example, desmogleins
(Dsg), play a role in disruption of cell– cell adhesion. Thus,
autoantibodies against Dsg3 are implicated in pemphigus
vulgaris, whereas autoantibodies against Dsg4 are related
412 兩 Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org
to autosomal recessive hypotrichosis. Autoantibodies
against plakoglobin and plakophilin-1 (desmosomal plaque
proteins) cause Naxos disease (a recessive association of
arrhythmogenic right ventricular cardiomyopathy with
wooly hair and palmoplantar keratoderma or similar skin
disorder) and ectodermal dysplasia and skin fragility syn-
drome, respectively.64 In addition, mutations in the various
forms of keratin have been associated with specific diseases.
Thus, mutations in K5 and K14 are related to epidermolysis
bullosa simplex. Mutations in K1 and K10 cause epidermo-
lytic hyperkeratosis, whereas mutations in K1 and K9 cause
palmoplantar keratoderma epidermolytic disease.
Melanocyte Abnormalities
Human skin pigmentation normally varies greatly from ex-
tremely fair to extremely dark, depending primarily on ra-
cial and ethnic backgrounds. However, the constitutive me-
lanocyte attenuation in the skin can also be affected by the
environment so that chronic UV exposure can increase me-
lanocyte attenuation 3– 4 –fold, whereas, conversely, toxic
compounds, for example, hydroquinone, can selectively
and permanently destroy melanocytes in the skin.22 UV
radiation is the most significant factor that influences
changes in human skin pigmentation. As a direct effect of
UV exposure, especially UVA (the longest wave length of
UV), there is an immediate pigment darkening that occurs
within minutes and persists for several hours. This is fol-
lowed by persistent pigment darkening, which occurs
within several hours and lasts for several days. These rapid
increases in pigmentation are not the result of acute melanin
synthesis but rather the result of oxidation and polymeriza-
tion of existing melanin and the redistribution of the exist-
ing melanosomes. Delayed tanning also occurs several days
after UV exposure, but this takes longer because it actually
involves the activation of the melanocyte function.
UV exposure leads to an increased expression of mi-
crophthalmia-associated transcription factor (MITF) (the
master transcriptional regulator of pigmentation) and its
downstream melanogenic proteins, which eventually lead
to increases in melanin content. In addition, UV exposure
also increases levels of PAR2 (protease-activated receptor
2) in keratinocytes, and this increases the uptake and distri-
bution of melanosomes by keratinocytes in the epidermis.
Melanocytes protect the skin from UV exposure damage as
noted by the fact that lightly pigmented skin has a 15–70 –
fold increased risk of developing skin cancers compared
with dark skin.65 The pigmentation of the skin is primarily
regulated by melanocortin 1 receptor (MC1R) (or alpha
melanocyte stimulating hormone receptor), which regulates
MITF and melanogenesis and dendricity. As such, MC1R is
often referred to as the susceptibility gene for melanoma
and other skin cancers.22 By comparison, albinism results
from dysfunctional tyrosinase (TYR) and other melano-
genic proteins, and leads to impaired pigmentation of the
skin, hair, and eyes. Diminished skin color most commonly
is caused by decreases in epidermal melanin content as a
Fig 20. A, The drawing illustrates some of the autoimmune bullous diseases and genodermatoses bullous diseases that are related to the cell– cell
attachments (modified from https://www.slideshare.net/DrYugandar/inflammatory-cells-of-skin. Open access). B, The drawings illustrate more
specifically the differences in the targets of autoimmune blistering diseases; when the autoantibodies are targeted against desmosomes, the blistering
occurs in the epidermis in diseases, for example, pemphigus. when the autoantibodies are directed against the hemidesmosomes, the blistering occurs
at the epidermal-dermal interface in diseases, for example, bullous pemphigoid (modified from https://www.mblintl.com/products/skin-blistering-
diseases/?_storeⴝdefault).

result of defects in melanin formation (leukoderma and hy-
popigmentation). In addition, the absence or loss of mela-
nocytes is found in vitiligo, whereas increased numbers of
melanocytes that produce excessive amounts of melanin are
seen in epidermal melanosis and freckles.22
In summary, constitutive skin pigmentation is deter-
mined by a number of factors, including the migration of
melanoblasts during development, their survival and differ-
entiation into melanocytes, the attenuation of melanocytes,
the expression of enzymatic and structural constituents of
melanosomes, the synthesis of different types of melanin,
the transport of melanosomes to dendrites, the transfer of
melanosomes to keratinocytes, and, finally, the distribution
of melanin in epidermal layers above the basal layer.22
Dermal and Hypodermal Abnormalities and Aging
As previously noted, after the age of 20 –30 years, the skin
slowly begins to show the consequences of chronological
aging, which causes the appearance of the skin to slowly
and imperceptibly change. Examples of abnormalities that
effect the dermis and subcutaneous fat include the follow-
ing: striae, solar elastosis or senile atrophy, white fibrous
papulosis of the neck, lichen sclerosus et atrophicus, Wer-
ner syndrome or adult progeria, and acrogeria. Many of
these entities are related to decreased fibroblastic and col-
lagen production, and faulty elastic fibers as well as gene
dysfunctions.
Hair Follicle Abnormalities
Abnormalities of the hair follicle can occur; some examples
are as follows: androgenetic alopecia, which is due to min-
iaturization of genetically predisposed follicles as seen in
male baldness; alopecia areata, which is the result of an
autoimmune response of hair follicles in the anagen stage;
and telogen effluvium, in which an increased proportion of
follicles enter the telogen stage, commonly caused by med-
ications and fevers.39 Hypertrichosis or Ambras syndrome
is the abnormal growth of hair over the body. When exten-
sive, it has been called the “werewolf syndrome,” and it has
a congenital form (present at birth) or an acquired form that
appears later in life. Hirsutism is a type of hypertrichosis
exclusive to women and children, and it is related to exces-
sive male hormone levels. The causes of hypertrichosis in-
clude transforming hair from the small vellus type to the
larger terminal type and an increase in the anagen phase of
hair growth.66
Sebaceous Gland Abnormalities
Some disorders that affect the sebaceous glands include the
following: comedones or blackheads, milia or whiteheads,
acne (overactive sebaceous glands related to hormonal
changes during adolescence), seborrhea (overactivity and
excessive secretions of the sebaceous glands), rosacea, ker-
atosis pilaris, steatoma or sebaceous cyst, sebaceous hyper-
plasia, asteatosis (partial or absolute deficiency in sebum),
and furuncle.
Sweat Gland Abnormalities
Hyperhidrosis is an abnormal increase in the amount of
sweat, and it may occur in a generalized or local form.
Bromhidrosis is the production of malodorous sweat
mainly in the feet and axillary regions. Hypohidrosis or
anhidrosis is the retention or limitation in sweat produc-
tion. The sweat glands are no longer functioning properly,
and this condition can result in overheating, heat stroke, or
even death. These conditions can be either congenital or
acquired.
CONCLUSION
The function of the skin and its importance to human ho-
meostasis were reviewed. The embryology of the skin and
its appendages were reviewed as were skin changes that
occur as a result of aging, hormonal changes, and geneti-
cally related disorders.

Neurographics 2017 September/October; 7(5):390 – 415; www.neurographics.org 兩 413

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