Skin Anthony J. Mancini, MD ABSTRACT. Human skin provides a barrier between hazardous or infectious agents and a vulnerable tar- the host and the physical, chemical, and biological envi- get of environmental toxins. During the past several ronment. It is also a potential portal of entry for hazard- decades, we have witnessed important strides in our ous or infectious agents and a potential target of envi- understanding of skin vulnerability, the cutaneous ronmental toxins. Cutaneous vulnerability may take on susceptibility to potentially noxious stimuli. Al- many forms in the embryo, infant, child, and adolescent. though the differing vulnerabilities of the skin of the Teratogenic agents may occasionally target skin, as ap- preciated in the proposed association of the antithyroid embryo, infant, child, and adolescent still are not medication methimazole, with the congenital malforma- completely understood, much has been learned tion known as aplasia cutis congenita. Percutaneous based on current knowledge of cutaneous embryo- absorption of topically applied substances and the po- genesis, epidermal barrier formation and function, tential for resultant drug toxicities are important consid- and the cumulative effects of ultraviolet (UV) radia- erations in the child. Many topical agents have been tion on photocarcinogenesis. These cutaneous vul- associated with systemic toxicity, including alcohol, nerabilities are the focus of this section. hexachlorophene, iodine-containing compounds, eutectic mixture of local anesthetics, and lindane. Percutaneous toxicity is of greatest concern in the premature infant, SKIN DEVELOPMENT in whom immaturity of the epidermal permeability bar- Skin is a complex tissue derived from both embry- rier results in disproportionately increased absorption. onic mesoderm and ectoderm. Its presence is vital for Immature drug metabolism capabilities may further the functions of mechanical protection, thermoregu- contribute to the increased risk in this population. Ultra- lation, immunosurveillance, and maintenance of a violet (UV) radiation exposure, which increases an indi- barrier that prevents insensible loss of body fluids. vidual’s risk of cutaneous carcinogenesis, may be a par- The development and growth of human fetal skin is ticularly significant risk factor when it occurs during marked by a series of sequential, patterned steps that childhood. The “critical period hypothesis” suggests that UV exposure early in life increases the risk of eventual are tightly controlled and dependent on a variety of development of malignant melanoma. Other risk factors interactions of the numerous cell types that compose for malignant melanoma may include severe sunburns the organ. As early as 6 weeks’ estimated gestational during childhood, intense intermittent UV exposure, and age (EGA), the human embryo has a covering of increased susceptibility of pediatric melanocytes to UV- surface ectoderm that includes a basal layer and a induced DNA damage. Last, percutaneous exposure to more superficial layer termed the “periderm.” At environmental toxins and chemicals, such as insecticides approximately 8 weeks, stratification of the develop- and polychlorinated biphenyls, may differ between chil- ing epidermis begins, with a resulting increase in its dren and adults for several reasons, including behavioral thickness. The periderm is a transient embryonal patterns, anatomic and physiologic variations, and devel- layer that is shed approximately at the end of the opmental differences of vital organs. Pediatrics 2004;113: 1114–1119; skin, vulnerability, teratogen, percutaneous, second trimester, the cells of which become a com- 1 ultraviolet light, toxin. ponent of the vernix caseosa. Also around this time, additional stratification and maturation of the epi- dermal cell layers is occurring, and it is at this stage ABBREVIATIONS. UV, ultraviolet; EGA, estimated gestational that the fetal epidermis begins to function as a barrier age; MMI, methimazole; PTU, propylthiouracil; ACC, aplasia cutis congenita; MM, malignant melanoma. to the external environment. Keratinization, which is a marker for terminal differentiation of epidermal cells, starts in a “follicular” (surrounding hair folli- uman skin has the important function of pro- cles) pattern at 11 to 15 weeks’ EGA but does not viding a barrier between the host and the start to occur in the remainder of the epidermis (“in- physical, chemical, and biological environ- terfollicular keratinization”) until 22 to 24 weeks’ H 1 ment. As such, it is also a potential portal of entry for EGA. The keratinized (or “cornified”) cell layers continue to increase in number during the third tri- mester. From the Departments of Pediatrics and Dermatology, Northwestern Uni- versity Feinberg School of Medicine, Children’s Memorial Hospital, Chi- The most superficial layer of skin, the stratum cago, Illinois. corneum, is the foundation of the epidermal perme- Received for publication Oct 7, 2003; accepted Oct 20, 2003. ability barrier in terrestrials. The stratum corneum of Reprint requests to (A.J.M.) Division of Dermatology, Children’s Memorial premature infants is thinner and markedly less effec- Hospital, 2300 Children’s Plaza #107, Chicago, IL 60614. E-mail: amancini@ northwestern.edu tive than that of full-term infants or adults. These PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- (premature) infants therefore have a dysfunctional emy of Pediatrics. epidermal barrier and experience resultant difficul- 1114 PEDIATRICS Vol.Downloaded 113 No. 4 from April www.aappublications.org/news 2004 by guest on September 30, 2021 ties with fluid homeostasis, thermoregulation, and gestational hyperthyroidism (with PTU being the infection control. They are also at a disproportion- more commonly used drug in the United States). The ately increased risk of systemic toxicity related to association between MMI and a specific congenital topically applied substances. Transepidermal water cutaneous malformation (aplasia cutis congenita loss, which increases proportionate with immaturity [ACC]) has long been hypothesized. Patients with of the epidermal permeability barrier, is 10-fold ACC are born with focal defects in skin, most com- greater in a 24-week premature infant compared monly involving the scalp, and may present with an with a term neonate.2 In surviving premature in- ulcer, blister, scar, or glistening membrane that lacks fants, the cutaneous barrier usually matures rapidly, hair (Fig 1). In some instances, the defect may extend over 2 to 4 weeks, although in ultra low birth weight to the subcutaneous tissues or, rarely, to bone and infants, it may take significantly longer.3 dura. Although the majority of cases of ACC are idiopathic, there are multiple reports of affected in- CUTANEOUS VULNERABILITY OF THE EMBRYO, fants who were born to mothers who were treated INFANT, CHILD, AND ADOLESCENT with MMI during pregnancy, both as a sole manifes- There are remarkably few prospective scientific tation or as part of “MMI embryopathy” (dysmor- data on skin vulnerability in the pediatric popula- phism, choanal and/or esophageal atresia, develop- tion, especially with regard to the differing sensi- mental delay, and growth retardation).6 The exact tivities between adults and children. Many of the exposure period of risk is unclear, although the published reports are based on anecdotal case obser- greatest risk for the gastrointestinal malformations vations. Ethical considerations impose a certain de- seems to be between 3 and 7 weeks’ EGA. Although gree of limitation on the design of prospective stud- the association between MMI and ACC remains un- ies, and extrapolation from adult data is of uncertain proven, several authors now recommend PTU validity (excluding the case of premature infants, in (which has not been reported in association with which the differences in epidermal barrier function ACC) as a first-line agent in the management of make any such extrapolation meaningless). Wester et hyperthyroidism during pregnancy.6,7 al4 elegantly described an animal model for human percutaneous absorption, finding the isolated per- Percutaneous Toxicity From Topical Agents fused porcine skin flap system to be a good model for Percutaneous absorption of topically applied sub- predicting such absorption relative to humans. This stances and the potential for resultant systemic tox- system, however, was compared with adult volun- icity are important considerations in the child. Ab- teers; therefore, the applicability to children is uncer- sorption of drugs via the skin is influenced by both tain. Percutaneous absorption characteristics of the physical and chemical characteristics of the drug and newborn rhesus monkey have also been studied,5 the barrier properties of the skin. The majority of but the relevance of this model to the human new- cases of percutaneous drug toxicity have been re- born (especially premature) remains unclear. ported in newborns, although cases in infants and young children have also been noted. The direct Teratogenic Agents correlation between risk and younger age is related Teratogenic risks as they relate to skin have most to the higher surface area-to-weight ratio in infants. frequently centered on antithyroid drugs, most no- Other susceptibility factors include immature drug tably methimazole (MMI). This agent and propyl- metabolism systems and, in the case of the prema- thiouracil (PTU), both members of the thioamide ture infant, immaturity of the epidermal