The integumentary system consists of skin and its appendages: sweat glands, nails, hairs, sebaceous glands, arrector muscles of hairs (arrector pili muscles), mammary glands, and teeth.
Development of Skin and Appendages
The skin is a complex organ system, and it is the body’s largest organ. The skin consists of two layers ( Fig. 19.1 ):
The epidermis is a superficial epithelial tissue that is derived from surface embryonic ectoderm.
The dermis, which underlies the epidermis, is a deep layer composed of dense, irregularly arranged connective tissue that is derived from mesenchyme .
Ectodermal (epidermal) and mesenchymal (dermal) interactions involve mutual inductive mechanisms that are mediated by a conserved set of signaling molecules, including WNT, fibroblast growth factor (FGF), transforming growth factor-β (TGF-β), and sonic hedgehog (SHH). Skin structures vary from one part of the body to another. For example, the skin of the eyelids is thin and soft and has fine hairs, whereas the skin of the eyebrows is thick and has coarse hairs. The embryonic skin at 4 to 5 weeks consists of a single layer of surface ectoderm overlying the mesoderm (see Fig. 19.1 A ).
Epidermal growth occurs in stages and with increasing epidermal thickness. By 2 to 3 weeks, the primordium of the epidermis is a single layer of cuboidal undifferentiated ectodermal cells (see Fig. 19.1 A ). During weeks 4 to 6, these cells proliferate and form an outer layer of simple squamous epithelium, the periderm , and a basal layer that consists of collagen fibers and laminin—the basement membrane zone (see Fig. 19.1 B and C ). The cells of the periderm continually undergo keratinization and desquamation (shedding of cuticle, the outer, thin layer), and they are replaced by cells arising from the basal layer . Keratinization of the skin begins at 19 to 20 weeks, initially with the palms, soles, head, and face. The exfoliated peridermal cells form part of a white, greasy substance (vernix caseosa) that covers the fetal skin (see Fig. 19.3 ). During the fetal period, the vernix protects the developing skin from constant exposure to amniotic fluid, with its high content of urine, bile salts, and sloughed cells. The vernix also facilitates the birth of the fetus.
By the 8 to 11 weeks, proliferation of the basal layer forms a layer of stem cells deep to the periderm. This stratum germinativum (see Fig. 19.1 B and D ) produces new cells that are displaced into the more superficial layers. By 14 weeks, cells from the stratum germinativum have formed an intermediate layer that differentiates and contributes to the formation of the mature keratinized epidermis (see Fig. 19.1 C ). Replacement of peridermal cells continues until approximately the 21st week; thereafter, the periderm disappears , and the stratum corneum forms from the stratum lucidum (see Fig. 19.1 D ).
Proliferation of cells in the stratum germinativum also forms epidermal ridges that extend into the developing dermis ( Fig. 19.2 ). These ridges begin to appear in embryos at 10 weeks and are permanently established by 19 weeks. Those of the hand appear approximately 1 week earlier than ridges in the feet. The epidermal ridges produce grooves on the surface of the palms and soles, including the digits (fingers and toes). Fingerprints and footprints are already present in fetuses that are 6 months old. The type of pattern that develops is determined genetically and constitutes the basis for examining fingerprints in criminal investigations and medical genetics. Abnormal chromosome complements can affect the development of ridge patterns. For instance, approximately 50% of infants with Down syndrome have distinctive patterns on their hands and feet that have diagnostic value.
Late in the embryonic period, neural crest cells migrate into the mesenchyme of the developing dermis and differentiate into melanoblasts (see Fig. 19.1 C ). These cells migrate to the dermoepidermal junction and differentiate into melanocytes (pigment-producing cells; see Fig. 19.1 D ). Differentiation of melanoblasts into melanocytes involves the formation of pigment granules . The Wnt signaling pathway is implicated in this process.
Melanocytes appear in the developing skin at 40 to 50 days, immediately after the migration of neural crest cells. In Caucasians, the cell bodies of melanocytes are usually confined to basal layers of the epidermis (see Fig. 19.1 B ); however, the dendritic processes of the melanocytes extend between the epidermal cells (see Fig. 19.1 C ).
Only a few melanin-containing cells are normally present in the dermis (see Fig. 19.1 D ). The melanocytes begin producing melanin before birth and distribute it to the epidermal cells. Melanin production is regulated by intrinsic biosynthetic pathways and enzymatic reactions involving the enzyme tyrosinase. Pigment formation can be observed prenatally in the epidermis of dark-skinned races; however, there is little evidence of such activity in light-skinned fetuses. The relative content of melanin inside the melanocytes accounts for the different colors of skin.
The transformation of the surface ectoderm into the multilayered definitive epidermis results from continuing inductive interactions with the dermis. Skin is classified as thick or thin based on the thickness of the epidermis.
Thick skin covers the palms and soles; it lacks hair follicles, arrector muscles of hairs, and sebaceous glands, but it has sweat glands.
Thin skin covers most of the rest of the body; it contains hair follicles, arrector muscles of hairs, sebaceous glands, and sweat glands ( Fig. 19.3 ).
The dermis develops from mesenchyme, which is derived from the mesoderm underlying the surface ectoderm (see Fig. 19.1 A and B ). Most of the mesenchyme that differentiates into the connective tissue of the dermis originates from the somatic layer of lateral mesoderm; however, some of it is derived from the dermatomes of the somites (see Fig. 14.1 C and E ). By 11 weeks, the mesenchymal cells have begun to produce collagenous and elastic connective tissue fibers (see Figs. 19.1 D and 19.3 ).
As the epidermal ridges form, the dermis projects into the epidermis, forming dermal papillae, which interdigitate with the epidermal ridges (see Fig. 19.2 ). Capillary loops of blood vessels develop in some of the papillae and provide nourishment for the epidermis (see Fig. 19.3 ); sensory nerve endings form in other papillae. The developing afferent nerve fibers apparently play an important role in the spatial and temporal sequence of dermal ridge formation. The development of the dermatomal pattern of innervation of the skin of the limbs is described elsewhere (see Chapter 16 , Fig. 16.10 ).
The blood vessels in the dermis begin as simple, endothelium-lined structures that differentiate from mesenchyme (vasculogenesis) . As the skin grows, new capillaries grow out from the primordial vessels (angiogenesis) . These capillary-like vessels have been observed in the dermis at the end of the fifth week. Some capillaries acquire muscular coats through differentiation of myoblasts developing in the surrounding mesenchyme and become arterioles and arteries. Other capillaries, through which a return flow of blood is established, acquire muscular coats and become venules and veins. As new blood vessels form, some transitory ones disappear. By the end of the first trimester, the major vascular organization of the fetal dermis is established.
The glands of the skin include eccrine and apocrine sweat glands, sebaceous glands, and mammary glands. They are derived from the epidermis and grow into the dermis.
Sebaceous glands are derived from the epidermis. Cellular buds develop from the sides of the developing epidermal root sheaths of hair follicles (see Fig. 19.3 ). The buds invade the surrounding dermal connective tissue and branch to form the primordia of several alveoli (hollow sacs) and their associated ducts. The central cells of the alveoli break down, forming an oily substance (sebum), which is a secretion from sebaceous glands that protects the fetal skin against friction and dehydration. The secretion is released into hair follicles and passes to the surface of the skin, where it mixes with desquamated peridermal cells (see Fig. 19.3 ).
Sebaceous glands, independent of hair follicles, such as those of the glans penis and labia minora, develop as cellular buds from the epidermis that invade the dermis.
The Wnt/β-catenin signaling plays a critical role in the development of the skin, glands, and hair follicles and hair .
Coiled, tubular eccrine sweat glands are located in the skin throughout most of the body. They develop as cellular buds from the epidermis that grow into the underlying mesenchyme (see Fig. 19.3 ). As the buds elongate, their ends coil to form the bodies of the secretory parts of the glands ( Fig. 19.4 ). The epithelial attachments of the developing glands to the epidermis form the primordia of the sweat ducts . The central cells of these ducts degenerate, forming lumina (canals). The peripheral cells of the secretory parts of the glands differentiate into myoepithelial and secretory cells (see Fig. 19.4 D ). The myoepithelial cells are thought to be specialized smooth muscle cells that assist in expelling sweat from the glands. Eccrine sweat glands begin to function soon after birth.
Distribution of the large sudoriferous (producing sweat) apocrine sweat glands is mostly confined to the axillary, pubic, and perineal regions and to the areolae surrounding the nipples. The glands develop from downgrowths of the stratum germinativum of the epidermis (see Fig. 19.3 ). As a result, the ducts of these glands do not open onto the skin surface, as do eccrine sweat glands, but into the canals of the hair follicles superficial to the entry of the sebaceous gland ducts. Secretion by apocrine sweat glands is influenced by hormones and does not begin until puberty.
The central nervous system and the skin share a common ectodermal origin, and therefore mutations affecting such cells and cell lineages can result in the development of neurocutaneous syndromes. Such syndromes can demonstrate both neurologic and dermatologic consequences. These syndromes and their manifestations include the following:
Tuberous sclerosis complex (TSC)—benign tumors that can be found in almost any organ system, but most commonly the brain and skin. Almost all patients have hypomelanotic lesions and. in some cases, tumors under the fingernails or toenails (ungula tumors). The consequences of brain lesions include seizures (often the presenting symptom of TSC), behavioral issues, and other symptoms depending on the area of the brain affected.
Sturge–Weber syndrome—this is a rare neurocutaneous disorder with specific vascular malformations of the eye, skin, and brain.
Neurofibromatosis (NF)—there are two forms, NF1 and NF2; the former has a prevalence of 1 in 3000 and results from a defect in the NF1 gene responsible for the formation of neurofibromin; the latter is much more rare (1 in 60,000), with a genetic defect in NF2 that results in lack of formation of merlin. NF1 includes pathognomic café-au-lait spots on the skin (by early childhood), gliomas, and peripheral nervous system neurofibromas. Management of NF1 is highly complex.
Ichthyosis is a large group of relatively rare genetic skin disorders resulting from abnormal epidermal differentiation and excessive keratinization of skin ( Fig. 19.5 B ). The skin is characterized by dryness and scaling, which may involve the entire surface of the body.
Harlequin ichthyosis results from a rare keratinizing disorder that is inherited as an autosomal recessive trait with a mutation in the ABCA12 gene. Infants with Harlequin ichthyosis are usually born prematurely. The skin is markedly thickened, ridged, and cracked. Affected neonates require intensive care, and even so, more than 50% die early.
A collodion infant, usually born prematurely, is covered by a thick, shiny, taut membrane that resembles collodion (a protective film) or parchment. The membranous skin cracks with the first respiratory efforts and begins to fall off in large sheets. Deficiency of transglutaminase 1 (TGM1) is the most common cause. Complete shedding may take several weeks, occasionally leaving normal-appearing skin.
Lamellar ichthyosis is an autosomal recessive disorder. A neonate with this condition may appear to be a collodion baby at first; however, the scaling persists. Growth of hair may be curtailed, and development of sweat glands is often impeded. Affected infants usually suffer severely in hot weather because of their inability to sweat.
X-linked ichthyosis results from a deletion or mutation in the STS gene, which causes a deficiency of steroid sulfatase. Most male neonates have pink or red skin with large translucent scales that shed after birth.
Epidermolytic ichthyosis or epidermolytic hyperkeratosis is an autosomal dominant condition resulting from mutations in the KRT1 and KRT10 genes. The skin of the infant at birth may have blisters and appear to be peeling.
Congenital ectodermal dysplasia represents a group of rare hereditary disorders involving tissues derived from ectoderm. The teeth are completely or partially absent, and the hairs and nails often are affected. Ectrodactyly–ectodermal dysplasia–clefting syndrome is a congenital skin condition that is transmitted as an autosomal dominant trait. It involves ectodermal and mesodermal tissues and consists of ectodermal dysplasia (incomplete development of epidermis and skin appendages; the skin is smooth and hairless). The dysplasia is associated with hypopigmentation of skin , scanty hair and eyebrows, absence of eyelashes, nail dystrophy, hypodontia and microdontia, ectrodactyly (absence of all or part of one or more fingers or toes), and cleft lip and palate. This appears to be caused by a defect in the TP63 gene, which codes for a transcription factor.
Angiomas are vascular anomalies . Transitory or surplus primitive blood or lymphatic vessels persist in these developmental defects. Those composed of blood vessels may be mainly arterial, venous, or cavernous angiomas, but they are often a mixed type. Angiomas composed of lymphatics are called cystic lymphangiomas or cystic hygromas (see Chapter 13 , Fig. 13.55 ). True angiomas are benign tumors of endothelial cells that usually are composed of solid or hollow cords; the hollow cords contain blood.
Nevus flammeus denotes a flat, pink or red, flame-like blotch that often appears on the posterior surface of the neck. A port-wine stain (hemangioma) is a larger and darker angioma than a nevus flammeus and is typically anterior or lateral on the face or neck ( Fig. 19.6 ). It is sharply demarcated when it is near the median plane, whereas the common angioma (pinkish red blotch) may cross the median plane. A port-wine stain in the area of distribution of the trigeminal nerve is sometimes associated with a similar type of angioma of the meninges of the brain and seizures at birth (Sturge–Weber syndrome) . Hemangiomas are among the most common benign neoplasms found in infants and children. When multiple, they may be associated with internal hemangiomas that affect the airways, or if in the liver, they may cause hematologic disturbances such as platelet consumption (Kasabach–Merritt syndrome).
In generalized albinism , which is an autosomal recessive condition, the skin, hairs, and retina lack pigment; however, the iris usually shows some pigmentation. Albinism occurs when the melanocytes fail to produce melanin because of the lack of the enzyme tyrosinase or other pigment enzymes. In localized albinism (piebaldism) , which is transmitted as an autosomal dominant trait, patches of skin and hair lack melanin.
Mammary glands are modified and highly specialized types of sweat glands. Gland development is similar in male and female embryos. The first evidence of mammary development appears in the fourth week when mammary crests (ridges) develop along each side of the ventral surface of the embryo. These crests extend from the axillary region (armpit) to the inguinal region ( Fig. 19.7 A ). The crests usually disappear except for the parts at the site of the future breasts (see Fig. 19.7 B ).
Involution of the remaining mammary crests in the fifth week produces the primary mammary buds (see Fig. 19.7 C ). These buds are downgrowths of the epidermis into the underlying mesenchyme. The changes occur in response to parathyroid hormone–related peptide (PTHrP) signaling and inductive influence from the mesenchyme. Each primary mammary bud soon gives rise to several secondary mammary buds , which develop into lactiferous ducts and their branches (see Fig. 19.7 D to E ). Expression of the epithelial transcription factors TBX3 and LEF1 initiates the formation of the mammary crests and buds. Canalization of these buds is induced by placental sex hormones entering the fetal circulation. This process continues until the late fetal period, and by term, 15 to 19 lactiferous ducts are formed. The fibrous connective tissue and fat of the mammary glands develop from the surrounding mesenchyme. The structural remodeling and branching of the lactiferous ducts are controlled by hormones, including progesterone, estrogen, and prolactin.
During the late fetal period, the epidermis at the site of origin of the mammary glands become depressed, forming shallow mammary pits (see Fig. 19.7 E ). The nipples are poorly formed and depressed in neonates. Soon after birth, the nipples usually rise from the mammary pits because of proliferation of the surrounding connective tissue of the areola , the circular area of pigmented skin around the nipples. The smooth muscle fibers of the nipples and areolae differentiate from surrounding mesenchymal cells.
The rudimentary mammary glands of male and female neonates are identical and are often enlarged. Some secretion (galactorrhea) may be produced. These transitory changes are caused by maternal hormones that pass through the placental membrane into the fetal circulation (see Chapter 7 , Fig. 7.7 ). The breasts of neonates contain lactiferous ducts but no alveoli . In the lactating mammary gland, these are the sites of milk secretion.
In girls, the breasts enlarge rapidly during puberty ( Fig. 19.8 ), mainly because of development of the mammary glands and the accumulation of the fibrous stroma (connective tissue) and fat associated with them. Full development occurs at approximately 19 years (see Fig. 19.8 F ). Normally, the lactiferous ducts of boys remain rudimentary throughout life.
Several transcription factors, including the MYC protein, which is a basic helix-loop-helix transcription factor, are essential for the formation of the lactiferous ducts and the function of the female breast .
The rudimentary lactiferous ducts in boys normally undergo no postnatal development. Gynecomastia refers to the development of the rudimentary lactiferous ducts in the male mammary tissue. During midpuberty, approximately two thirds of boys develop various degrees of hyperplasia ( enlargement ) of the breasts. This subareolar hyperplasia may persist for a few months to 2 years. A decreased ratio of testosterone to estradiol is found in boys with gynecomastia. Approximately 40% of boys with Klinefelter syndrome have gynecomastia (see Chapter 20 , Fig. 20.9 ), which is associated with an XXY chromosome complement.
Absence of nipples (athelia) or breasts (amastia) may occur bilaterally or unilaterally. These rare birth defects result from failure of development or disappearance of the mammary crests. They may also result from failure of mammary buds to form. More common is enlargement (hypoplasia of breast) , which often is associated with gonadal agenesis (absence or failure gonads to form) and Turner syndrome (see Chapter 20 , Fig. 20.4 ). Poland syndrome is associated with hypoplasia or absence of the breast or nipple. In these cases, there is often associated rudimentary development of muscles of the thoracic wall, usually the pectoralis major (see Chapter 15 , Fig. 15.5 ).
An extra breast (polymastia) or nipple (polythelia) occurs in approximately 0.2% to 5.6% of the female population ( Fig. 19.9 ); it is an inheritable condition. An extra breast or nipple usually develops just inferior to the normal breast. Supernumerary nipples are also relatively common in males; often they are mistaken for moles ( Fig. 19.10 ). Polythelia is often associated with other congenital defects such as renal and urinary tract anomalies. Less commonly, supernumerary breasts or nipples appear in the axillary or abdominal regions of girls. In these positions, the nipples or breasts develop from extramammary buds that develop from remnants of the mammary crests. They usually become more obvious in women when they are pregnant. Approximately one third of affected persons have two extra nipples or breasts. Supernumerary mammary tissue rarely occurs in a location other than along the course of the mammary crests (milk lines). It probably develops from tissue that was displaced from these crests.