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TEXTBOOK OF ETHNIC DERMATOLOGY Edited by Dr. F.F.V. Hamerlinck, Prof. dr. J.R.M.G. Lambert en Prof. dr. H.A.M. Neumann

www.ethnic-dermatology.com ISBN: 978-94-90826-14-7

TEXTBOOK OF ETHNIC DERMATOLOGY

Edited by Dr. F.F.V. Hamerlinck Prof. dr. J.R.M.G. Lambert Prof. dr. H.A.M. Neumann


TEXTBOOK OF ETHNIC DERMATOLOGY

Edited by

F.F.V. Hamerlinck MD PhD Prof. J.R.M.G. Lambert MD PhD Prof. H.A.M. Neumann MD PhD


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Preface

Nowadays, patients with skin of color are encountered worldwide. This large-scale dispersal or distribution of people throughout the world is called “diaspora”. One of the best examples of diaspora is described in the introduction by R. Dors (sociologist, affiliated with the National Institute for the Study of Dutch Slavery and its Legacy) and Prof. Dr. H. Lamur (Emeritus Professor of Anthropology at the University of Amsterdam). Since I started my practice in 1991 in Amsterdam Southeast, where more than 170 nationalities live together, I realized that diagnosing skin diseases in pigmented skin requires extensive experience in recognizing efflorescences on skin of color. Using the book “Précis de dermatologie” by J. Darier (Masson & Cie Editeurs, Paris, 1928) as an example, I subdivided this book into two parts. The first part involves the morphology of the skin and describes the efflorescences of pigmented skin together with a clinical histological examination. As Darier writes, “qu’en dehors de la graine il faut considerer le terrain”, in the second part of this book, nosology, different skin diseases are described but some etiological factors are described as well. There has been much debate about the meaning and origin of the term ‘ethnicity’. After consulting various sources and dictionaries, an acceptable definition might be: belonging to a group that shares the same characteristics, such as country of origin, language, religion, ancestry and culture. Ethnicity is considered a matter of biological and historical fact that is not changed by the culture in which a person grows up. Hopefully, this “Textbook of Ethnic Dermatology” will provide dermatologists working in a multi-ethnic society with a better understanding of the physiology and pathophysiology of skin conditions related to people with skin of color. Freddy F.V. Hamerlinck, MD PhD


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CONTENTS

DIASPORA Suriname, tolerance pur sang R. Dors MA, Prof. H. Lamur PhD PART I MORPHOLOGY Efflorescences in Pigmented Skin F.F.V. Hamerlinck MD PhD, A.C. van der Wal MD PART II NOSOLOGY

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1. Normal Variants of Black Skin F.F.V. Hamerlinck MD PhD

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2. Molecular Genetics of Human Skin Pigment Variation H.C. de Vijlder, J.J.M. de Vijlder

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3. Variations in Epidermal Permeability Barrier Homeostasis in Relation to Ethnic Origins Prof. J.P. Hachem MD PhD, T. Roelandt MD PhD, Prof. D. Roseeuw MD PhD

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4. Ethnicity, Vitamin D3, Immunity and Immune-mediated Dermatoses K. de Vries MD, Prof. E.P. Prens MD PhD

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5. Ethnic Itch? E. Hajdarbegovic MD, H.B. Thio MD PhD

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6. Pigmentary Disorders: Post-inflammatory Hyperpigmentation and Melasma E.B. Handog MD, M.J.E. Macarayo MD

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7. Atopic Eczema in Ethnic Skin R.J.T. van der Leest MD, E. Hajdarbegovic MD, H.A.M. Neumann MD PhD

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8. Vitiligo in Ethnic Dermatoses J. de Leeuw MD PhD

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9. Inflammatory Diseases on Ethnic Skin Prof. J.R.M.G. Lambert MD PhD

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10. Parasitology of Black Skin E. van den Enden MD PhD

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11. Tropical Bacteriology and Mycology Prof. J. De Weert MD

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12. Sexually Transmitted Diseases in Ethnic Skins M. Waugh MB FRCP

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13. Skin Manifestations in HIV-infection Prof. J.R.M.G. Lambert MD PhD

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14. Bullous Diseases M.M. de Waard MD, Prof. M.F. Jonkman MD PhD

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15. Skin Cancers J.C. Martens MD, G.A.M. Krekels MD PhD MBA

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16. Genodermatoses Prof. M.A.M. van Steensel MD PhD, Prof. P.M. Steijlen MD PhD

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17. Venous Disturbances W.J. Koeyers MD

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18. Cosmetic Science and Care for Darker Skin M. Verschoore MD, N. Hainault

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Correspondence

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List of Authors

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Diaspora Suriname, tolerance pur sang R. Dors MA Prof. H. Lamur PhD Translation: Amy Abdou The republic of Suriname, a former Dutch colony that became independent in 1975, lies on the north eastern coast of South America. On the north, it borders the Atlantic; on the east, French Guyana, on the west Guyana and on the south Brazil. The multi-ethnic Suriname is home to approximately 500,000 inhabitants, composed from an estimated 10 different ethnic subdivisions. The two largest ethnic groups in Suriname are the descendants of Africans, also called Creoles, and the descendants of the contract workers from India, or Hindustanis. Each of these groups constitutes 30% of the Surinamese population. The third largest group, 25% of the population, consists of descendants of the contract workers from Java. Other groups include the Maroons (descendants of the enslaved Africans who escaped the plantations during slavery) and the Amerindians. The majority of Maroons and Amerindians lives in tribes. Smaller populations include Surinamese of European, Chinese, Jewish and Lebanese origin. The ancestors of most of these groups came originally from Africa, Asia, Europe or the Middle East [Jews, Lebanese]. Therefore their descendants live, in a diaspora. This does not apply to the Amerindians, the only autochthonous population in Suriname. The term ‘diaspora’ from the ancient Greek, indicates the large-scale dispersal or distribution of a people throughout several parts of the world. Frequently, this word is used to describe the condition of the Jews and for a long time this was the only meaning of the word. But the term ‘diaspora’ applies to many populations (http:// nl.wikipedia.org/wiki/Diaspora). According to Brubaker (2005), the term ‘diaspora’ has three essential aspects; namely, dispersion, home orientation and boundary maintenance. Therefore, from Brubaker's perspective, it concerns distribution, orientation towards the country of origin and conservation of borders, as the following quotation illustrates. (Brubaker, 2005:5,6). 1. “Dispersion. This is today the most widely accepted criterion, and also the most straightforward. It can be interpreted strictly as forced or otherwise traumatic d ­ ispersion; more broadly as any kind of dispersion in space, provided that the dispersion crosses state borders; or (in the increasingly common metaphorical extensions of the term), more broadly still, so that dispersion within state borders may suffice. 2. Homeland orientation. The second constitutive criterion is the orientation to a real or imagined ‘homeland’ as an authoritative source of value, identity and loyalty. 3. Boundary-Maintenance. The third constitutive criterion. I will call boundary-maintenance, involving the preservation of a distinctive identity vis-á-vis a host society (or societies). Boundaries can be maintained by deliberate resistance to assimilation through


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self-enforced endogamy or other forms of self-segregation (Armstrong 1976,pp.3945;Smith 1986) or as an unintended consequence of social exclusion” (Laitin 1995). These characteristics apply, to a greater or lesser degree, to most of the groups that were brought to Suriname or established themselves there. This raises the question, how does a country with so much ethnic diversity develop into one of the most tolerant, socially integrated multi-ethnic societies in the world? To answer this question, we’ve provided a short historical sketch below. Establishment of the different ethnic groups in Suriname The different ethnic groups in Suriname were not established within the same time frame. According to Bruijning and Voorhoeve (1977, 316) there exists no single history of how the Jews came to be established in Suriname. Shortly after 1632, Jews from the Netherlands and Italy established themselves in the region upstream from the Suriname river. In 1652, a number of English Jews came with Lord Willoughby to the colony, which established itself in the savannah at the Cassipora creek. After Brazil was reconquered by the Portugese, and taken away from the Dutch, they established themselves in Cayenne, French Guyana. After Cayenne was occupied by the French in 1664, the Jews left for Suriname. A second group that arrived in Suriname came originally from Africa. Between 1650 and 1811, an estimated 250,000 Africans were enslaved and brought to Suriname to work on the plantations. After the abolition of slavery in 1863, the number had been reduced to approximately 30,000. Over time, they were called Creoles and later the term Afro-Surinamers was used to describe this population. In addition, there existed groups of Maroons composed of former slaves who fled plantations during the period of slavery and established independent communities in the jungle of Suriname. In 1853, ten years before the abolition of slavery in 1863, a small group of Chinese contract workers from Java was commissioned to work on the plantations. Between 1858 and 1870 more than 2500 Chinese were brought to Suriname, whereupon the immigration stopped since the majority did not extend their contracts and they did not remain working in agriculture. In the period that followed, the Chinese generally established themselves on their own initiative in Suriname as goldsmiths, traders and tradesmen (Ankum-Houwink, 1974:539). This development continued up until the present day. In 1853, Dutch farmers arrived and attempted an agricultural colonization of Suriname. Their descendants are called “Boeroes” (Bruijning and Voorhoeve, 1977: 75). In the period before emancipation, around 1853, Portugese from Madeira came to live in Suriname. Between 18531864, the migration for plantation labour from Madeira was restricted. In that time, 500 workers were brought. Today, they are no longer distinguishable as a separate ethnic group but have socially and biologically joined the Creole population (Bruijning and Voorhoeve 1977, 503). After the abolition of slavery in 1863, the emancipated slaves refused to continue to work because of labour disputes with plantation owners on the plantations. To guarantee a constant supply of workers to the plantations, contract workers from the Caribbean area, China, India and Java were imported (Dors and Lamur 2000: 2).


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From 1873-1916, a total of 34,304 Hindustani immigrants from India, consisting primarly of Hindus and Muslims, were transported to Suriname (Bruijning and Voorhoeve, 1977: 277). Approximately 33,000 Javanese immigrants were imported in the period between 1890-1939 (Bruijning and Voorhoeve, 1977: 309, see also van Wengen 1990:890). The Lebanese formed the so-called trade minorities in Suriname. The first Lebanese probably arrived in the 1890’s. They were not brought in as contract workers but came voluntarily to Suriname (Bruijning and Voorhoeve, 1977:380). As we have already mentioned, each of these groups have maintained their own culture and peacefully coexist with each other, as the image below illustrates regarding the Jewish and ­Islamic groups. Nowhere in the world does a mosque stand beside a Jewish synagogue.

Tolerance as the norm With that, we return to the question: How is it possible that a country with so much ethnic diversity has developed to become one of the most tolerant, socially integrated, multi-ethnic societies in world? In the two Caribbean countries that have a similar multiethnic structure to Suriname, bloody conflicts between Creoles and Hindustanis have occurred in the past: Guyana [approx. 1960] and Jamaica [approx. 1970]. In Suriname, conflict of this nature has never been a problem. To the contrary, harmony between different ethnic groups has become a cultural norm. Two factors have contributed to the rise of a tolerant, socially integrated multiethnic society in ­Suriname. 1.

In the 1950s, the leaders of the two largest ethnic groups in Suriname, Pengel [Creole] and Lachmon [Indian] assumed political power. They also agreed to a ‘convenant’, with the aim of preventing violent ethnic conflicts by solving disagreements through means of negotiation. In the course of the subsequent decades, this convenant, known under the name ‘fraternization’ (verbroederingspolitiek), has been gradually accepted in broad circles of the society as a social norm, a directive which controls the thoughts and actions of Surinamers. We can illustrate the aforementioned directive with a quote from J.A. Pengel, President of the National Party Suriname during a public meeting of the states of Suriname on 14 September 1961.


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“Creoles, Hindustani, Indonesians, Chinese and all other ethnic groups who come together here must understand one thing well; it is important for all groups to know that they live mutually in peace and work together for the advancement of our beloved country and people. And I hope that it never can be said that we failed to understand that. We must understand it.” (Sedney, 1997: 46).

2. A consequence of this principle is the respect that Surinamers have for the language and the culture of other ethnic groups; an attitude which they have received throughout their lives through parental guidance and education. Many Surinamers know the meaning behind the religious holidays of other ethnic groups and also sometimes participate in the activities. References 1.

Ankum-Houwink C. Chinezen in Suriname, Bussum: Fibula/Van Dishoeck overdruk uit Spiegel Historiael 9 (1974)10, pp. 538-545. 2. Bruijning CFA, Voorhoeve J. Encyclopedie van Suriname, Amsterdam-Elsevier-Brussel,1977. 3. Brubaker R. The ‘diaspora’ diaspora. In: Ethnic and Racial Studies Vol. 28 No. 1 January 2005 pp. 1-19. 4. Lamur HE, Dors R. Population census, and skin colour identity among Creoles in Suriname, 2000, Unpublished article. 5. Sedney J. De toekomst van ons verleden. Democratie, etniciteit en politieke machtsvorming in Suriname, Paramaribo, Vaco N.V ,1997. 6. Waal de Malefijt A. The Javanese of Suriname, segment of a plural society, Assen: van Gorcum, 1963. 7. Wengen GD van. 1890-1990: Honderd jaar Javanen in Suriname, Amsterdam, Meulenhof, 1990. 8. Oudschans Dentz F. De kolonisatie van de Portugeesch Joodse natie in Suriname en de geschiedenis van de Joden Savanne, Amsterdam: Hertzberger, [1927]. 9. Zijlmans GC, Enser HA. De Chinezen in Suriname: een geschiedenis van immigratie en aanpassing 1853-2000: met een bibliografie en een tijdtafel 1800-2000, Barendrecht: Batavia, 2002. 10. http://nl.wikipedia.org/wiki/Diaspora


PART I MORPHOLOGY


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Efflorescences in Pigmented Skin F.F.V. Hamerlinck MD PhD A.C. van der Wal MD 1. Bulla Clinical description A bulla is a fluid-filled space between two layers of tissue in the skin. By definition, this area is larger than 1 cm, which distinguishes the lesion from small vesicles. Clinically, however, there is an overlap between bullous and vesiculous dermatitis; therefore, it is better to refer to blisterforming diseases in general. Bullae may be hard or soft to the touch, depending on their localisation in the skin. Epidermal blisters, such as in pemphigus, feel soft and are more delicate as a rule. Brown crusts appear in dark skin. Bullae in the transition from dermis to epidermis, such as in parapemphigus, often remain for a longer period of time. Sometimes they are surrounded by a red halo, which indicates an accompanying inflammatory reaction. This is difficult to recognise in darker skin, however. The bulla may contain clear (serous) fluid, purulent or seropurulent liquid. Of course this content is significant in determining the colour of the blister. With clear fluid-filled blisters, white skin has a greyish-white shiny surface. But in darker skin, with pigmented epidermis as blister roof, they may appear to be ‘filled’, due to a yellow-brown colour. The blisters in bullous impetigo contain pus and appear on an erythematous base (figure 1). The most predominant etiologic agent causing bullous impetigo is staphylococcus aureus. This spreads very rapidly on the skin surface and is highly contagious. The lesions usually heal without forming scar tissue.

Figure 1: Bullous impetigo on the arm.


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In dermatitis herpetiformis, however, lichenification of the skin and post-inflammatory hyperpigmentation may appear due to accompanying itching from scratching and rubbing. This will be discussed in more detail later on. Pemphigus, a group of chronic, autoimmune-mediated blister-forming diseases, affects all types of skin. However, pemphigus vulgaris is more common among Semitic people. Fogo selvagem (wild fire) is a variant of pemphigus foliaceus, which is characterised by superficial blister formation. The disease is endemic to Brazil, but is not associated with poor local conditions. A prurigo nodularis-like figure and hyperpigmentations may also remain. Histological description The histological classification of blister-forming diseases is based on the systematic determination of the following features. First, the splitting level is determined, which may be localised in the epidermis (subcorneal, mid-epidermis or suprabasal), or directly subepidermally. The mechanism of blister-formation is also important: is spongiosis (intercellular oedema as in acute eczema) present, or is it associated with acantholysis (disruption of the intercellular cementing substances or plasmodesmata, such as in pemphigus). Attention is also paid to the presence of inflammation and, if present, which inflammatory cells dominate in the infiltrate. More than thirty diseases that cause blisters of a highly divergent nature can be distinguished in this way. Most blisters develop due to physical trauma; they are usually localised subepidermally and hardly show inflammation, but of course they are almost never biopsied. Blister-forming infectious diseases, auto-immune diseases and genodermatoses also occur. To diagnose these dermatoses, the blisters selected for histological examination should always be fresh, preferably not older than 24 hours. The biopsy should be taken from the edge of the blister, if possible. After some time, impetiginisation, ulceration and reepithelialisation can mask the nature of the abnormality (figure 2). Figure 2 shows a case of impetigo bullosa in a child: an acantholytic blister in which neutrophil granulocytes and bacteria occur. Examination of the ‘roof ’ and content of the blister can also provide sufficient information for making a diagnosis, and it is not always necessary to take a punch biopsy (figure 3).

Figure 2: Overview of a blister in bullous impetigo.


PART II NOSOLOGY


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1. Normal Variants of Black Skin F.F.V. Hamerlinck MD PhD Futcher’s or Voight’s lines Demarcation lines between the dark pigmented part (dorsal) and light pigmented part (volar) of the arms. These lines are often symmetrical on both arms and can continue on the skin of the chest to the medial line.

Futcher’s or Voight’s lines.


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Linea alba Hypopigmented zone in the median, running from the xiphoid process to the pubic symphisis. In pregnancy, this is exactly where hyperpigmentation can appear (see picture

Linea alba.

Mongolian spot The Mongolian spot is a poorly defined, blue-grey, round to oval discoloration with a diameter of 10 -12 cm, particularly in the lumbosacral region. The spot appears in slightly to moderately pigmented skin types such as Asians, Central Americans, Latin Americans and certain African races. The bluish pigmentation is caused by melanocytes located deep in the dermis as well as melanin pigment located freely in the dermis. The spot is generally present at birth or appears some time after birth, usually disappearing around puberty. However, it can also persist until adulthood.

Mongolian spot.


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Pigmentation of the nails Changes in the nail occur in many systemic disorders. They may be the key to the diagnosis. In Negroids, dark brown ribbon-shaped longitudinal discolorations are a common, normal symptom.

Pigmentation of nails.

Pigmentation of tongue and mucous membrane of the mouth Oral pigmentation is seen on the gingiva, the hard palatum, mucous membranes of the mouth and the tongue. The pigment formation of the mucous membranes of the mouth range in colour from a light to darker macula to a light blue discoloration. The darker the skin colour, the more often this symptom will appear.

Pigmentation of tongue.


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2. Molecular Genetics of Human Skin Pigment Variation H.C. de Vijlder J.J.M. de Vijlder Introduction Previous to the discussion of pigmentation and pigmentation variation it is essential to deal with the synthesis and regulation of melanin production. Melanin is the main pigment of the skin, hair and eyes. Other chromophores, such as hemoglobin, play a minor role in skin pigmentation. Melanocytes originate in the neural crest. For development, migration to the correct sites and differentiation into cells that produce normal pigmentation a large number of genes are involved. The melanocytes in the basal layer of the epidermis are lysosome – like organelles, in which melanin production takes place. The amino acid tyrosine is the major starting substrate for melanin synthesis. After synthesis, formation of melanin granules, the melanosomes, takes place. The melanosomes are transferred to adjacent keratinocytes in the basal layer through the dendritic structures of the melanocytes. The ingested melanosomes move along with the proliferating and differentiating keratinocytes, to skin surface forming a critical barrier against environmental influences like UV light. In fair skin poorly pigmented melanosomes tend to cluster, whereas in dark skin heavily pigmented melanosomes are distributed individually in the keratinocytes. Depending on body site there are differences in melanocyte density, the variation in the number of melanocytes does not seem to be a major factor explaining the pigmentation differences among human populations. The distribution of skin pigmentation differs from that of other phenotypic traits. Most genetic markers in humans of major geographic groups give a variation of 10 to 15% of the total diversity. The variation of skin pigmentation is much larger. Relethford (2002) estimated that 88% of the total skin pigmentation variation can be explained by pigmentation differences among major geographic groups with a strong correlation between skin pigmentation and latitude. Besides to the combination of genetic, biochemical and cellular approaches, the access to the complete human genome sequence and the documented SNPs in several populations has enhanced the contribution to the discovery of novel genes important for pigmentation.


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List of Abbreviations ACTH: adrenocorticotropic hormone ASIP: agouti signaling protein CREB: cAMP responsive element binding protein DAG: diacylglycerol DCT: DOPAchrome tautomerase DHI: 5,6-dihydroxyindole DHICA: 5,6-dihydroxyindole carboxylic acid DQ: dopaquinone HNF-1α: hepatocyte nuclear factor-1α MAPK: mitogen-activated protein kinase MC1R: melanocortin-1 receptor MITF: microphthalmia transcription factor

PAR2: PKA: PKC-β: SCF: SNP: TYR: α1-AR: α-MSH: β2-AR: IP3: RACK:

protease-activated receptor 2 phosphokinase A Phosphokinase C-β stem cell factor single nucleotide polymorphism tyrosinase α1- adrenoreceptor α-melanocyte stimulating hormone β2 –adrenoreceptor inositol-1,4,5,triphosphate Receptor for Activated C-Kinase

SNPs: single nucleotide polymorphism A SNP is a unique site in DNA where a common basepair is substituted by another. SNPs are frequent and distributed over genomic DNA. They can be considered as fingerprints. Sometimes SNPs cause life-threatening mutations, but they are rare. Most of them are compatible with life and can be used for instance in population studies. They are also very useful in genotype – phenotype correlation studies when they cause changes in characteristic genotypic traits. Melanin synthesis The major steps in melanogenesis and the enzymes involved are given in scheme 1. The tyrosinase enzyme complex catalyzes the conversion of tyrosine into various types of melanin polymers. Melanin polymers can be classified into three groups, insoluble brown to black pigments termed DHI- eumelanin, lighter colored slightly soluble DHICA – eumelanin and reddish-brown alkali-soluble pheomelanin. All these types of melanin derive from the common intermediate dopaquinone (ortho-quinone of 3,4-dihydroxyphenylalanine). Dopaquinone plays a pivotal role in the control of melanogenesis. Cysteinyldopa isomers are formed in the presence of cysteine together with (external) regulators. These isomers are subsequently oxidized through redox reactions with dopaquinone to cysteinyldopaquinones leading to pheomelanin. In the absence of sulfhydryl compounds dopaquinone cyclizes intramolecularly to cyclodopa, which rapidly oxidizes by a redox reaction with dopaquinone to dopachrome. This intermediate rearranges spontaneously and gradually into DHI–eumelanin. Dependant to the extent that a distinct melanogenic enzyme, DCT, is present, DOPAchrome will tautomerize without losing its carboxylic acid group and form DHICA which can be oxidized and polymerized to form DHICA-melanin. Differences in pigmentation are due to two major factors: the amount and type of melanin synthesized in the melanocytes (e.g., ratio of eumelanin to pheomelanin), and the shape and the distribution of the melanosomes. Darkly pigmented skin has more melanin, which is mainly enriched in DHI-eumelanin.


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3. Variations in Epidermal Permeability Barrier Homeostasis in Relation to Ethnic Origins Prof. J.P. Hachem MD PhD T. Roelandt MD PhD Prof. D. Roseeuw MD PhD Epidermal Barrier Structure and Function Keratinocytes form the essential brick stone that assembles the epidermal edifice. They transit as viable cells from the basal layer of the epidermis to the stratum granulosum (SG) and finish their journey by a phenomenon of programmed apoptotic cornification to end within the stratum corneum (SC) before shedding away by desquamation. The stratum granulosum (SG) has been qualified as the keratogenous zone of the epidermis. The thickness of the SG is proportional to the SC and rarely exceeds 2 to 3 layers. Keratinocytes become diamond-shaped or flattened and possess a highly basophilic cytoplasm filled with keratohyaline granules. Three major proteins, among others, are found in these granules: profilaggrin, keratin, and loricrin.1 Profilaggrin a histidine rich, polyphosphorylated, intermediate-filament-associated protein, is synthesized in the granular layer.2 Conversion of this high molecular mass (>400 kDa) molecule to monomeric peptides, filaggrin, induces aggregation of keratin.3 This event is responsible of the cornification of the keratinocyte at the transition SG/ SC interface.4 At this level, profilaggrin is cleaved by the proprotein convertases, a family of four Ca²+-dependent serine proteases, specifically furin and PACE4, at a site between the amino terminus and the first filaggrin repeat.5 Finally, filaggrin contributes to the apoptosis associated with terminal differentiation in the SC.6 The key step for competent skin barrier formation that takes place at the granular layer is the assembly of membrane bound secretary organelles originating from the Golgi apparatus, the lamellar bodies (LB).7 LB contain lipids and hydrolytic enzymes.8 Phospholipids, free sterols and glycosphingoloipds are assembled in membranous disks inside the LB and form intercellular lamellar sheets in the extracellular spaces. This edge to edge fusion process requires the presence of calcium and the action of the secreted hydrolytic enzymes.9 The outermost surface of the body is covered by the SC, an effective barrier that protects the internal milieu of the organism from the external environment.10 This structure is made of layered cornified cells, produced by terminal differentiation of keratinocytes in the stratified squamous epithelium.11, 12 The thickness of the SC varies with the anatomical site, age, sex and disease. The corneocytes are large, flattened and polyhedryal. The cytoplasm is filled with keratin embedded in a filaggrin-rich matrix. Many inherited or acquired skin disorders show aberrations in SC structure and consequently in skin barrier function. The process of keratinization proceeds according to a complex and elaborately controlled differentiation program coordinated by the expression of genes encoding specialized components, enzymes, and regulatory molecules.13, 14


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SC corneocytes are anucleated cells as a result of keratinization and the so-called programmed apoptosis. We recently found that permeability barrier requirements coordinately drive both the generation of the stratum corneum lipid-enriched extracellular matrix and the transformation of granular cells into corneocytes, in an serine protease and caspase-14-dependent manner, signaled by the protease activated receptor 2 (PAR2).14, 15 The structure of the SC provides the key elements for the skin barrier16 and consists of a heterogeneous system where the protein enriched corneocytes are embedded in an extracellular matrix composed of lipid bilayers.17 This characteristic configuration has been described by Elias et al. as the “brick and mortar model� (figure 1). In this chapter the ethnical influences on epidermal permeability barrier function are highlighted. We will discuss barrier response to stress in function of skin phototype as well as the physical and biochemical discrepancies between skin barriers from different ethnical backgrounds.

Figure 1: The mortar and brick model. Schematic presentation of the mortar and brick model (I) illustrates the electron microscopy (EM) examination of human stratum corneum (SC) (II). The lamellar bilayers (the mortar, indicated as*) surround the corneocytes (the brick, indicated as C). Few corneodesmosomes, the specialized desmosomes of the SC are observed on the EM micrographs (>).

Transepidermal water loss and water content Trans-Epidermal Water Loss (TEWL) is the quantity of water that passes from inside a body through the epidermal layer to the surrounding atmosphere via diffusion and evaporation processes. TEWL in mammals is also known as "insensible water loss" as it is a process over which organisms have little physiological control. Measurements of TEWL (grams per square meter per hour) is useful for identifying skin damage caused by certain chemicals, physical insult (such as "tape stripping") or pathological conditions such as eczema, as rates of TEWL increase in proportion to the level of damage even before the damage is clinically visible. Studies comparing TEWL loss in subjects of different race and sex showed minimal differences in basal permeability barrier function. However, such studies often did not assess the ability of the SC to withstand or recover from insults to the epidermal permeability barrier. Reed et al18 compared the response to barrier recovery following tape stripping induced barrier abrogation and found that neither the number of tape strippings required to perturb the barrier nor the rates of barrier recovery were significantly different in white vs Asian subjects. However, barrier function in


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4. Ethnicity, Vitamin D3, Immunity and Immunemediated Dermatoses K. de Vries MD Prof. E.P. Prens MD PhD Introduction The sun is the major inducer of vitamin D in man. Vitamin D has a great impact on human health, including the immune system. It has become apparent that growing up and living under conditions of abundant or minimal sun exposure may affect human health and the immune system. Besides latitude, ethnic backgrounds and cultural habits will depict vitamin D serum levels. Ethnicity or ethnical milieus also determine the exposure to environmental microorganisms such as helminths, commensals, mycobacteria and hepatitis A, and so the outcome of the immune response to allergens and auto-antigens. In this chapter the influence of ethnicity, vitamin D and environmental conditions on the human immune system and five immunemediated dermatological conditions is presented. Influence of the ethnical environment on vitamin D production Vitamin D is a secosteroid hormone that targets over 2000 genes in the human body. Vitamin D can be obtained from diet, such as oily fish or foods supplemented with vitamin D, or from exposure to sunlight. UVB irradiation of the skin forms an essential step in the conversion process of vitamin D into its biologically active form 1,25-dihydroxyvi足tamin D or calcitriol, in this chapter further simply referred to as vitamin D.25,57 Ethnicity is an important factor in determining the vitamin D status of an individual, in part due to dietary factors but mostly to skin coloration. Those with darker skin pigmentation are at much higher risk of vitamin D deficiency than those with a lighter skin. Evidently, the amount of melanin in the skin forms the most important factor affect足ing the efficacy of vitamin D conversion by UV light. Melanin acts as a natural sunscreen by competing for UVB photons and thereby reduces the production of vitamin D in darker skinned individuals. Vitamin D production after UV irradiation is higher in orientals and Caucasians than in blacks and Indians. Dark-skinned individuals need three to ten times higher UV doses in order to achieve vitamin D levels comparable to Caucasians. With the advance of years, i.e. after the age of 20, the vitamin D production capacity gradually decreases.16,18,31,34 Holick et al. have shown that at the end of the summer, 80 percent of African Americans living in Boston over age of 65 have a vitamin D deficiency.24 Other factors important in regulating cutaneous vitamin D production are the latitude, season, and time of day.16 In areas with latitudes higher than 42 degrees, the production of vitamin D almost completely ceases during winter.24 Some reports suggest that sun exposure is absolutely


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required for reaching adequate serum levels of vitamin D and that oral intake or supplementation may not be sufficient. However, even in sunny climates cultural habits such as religious dressing, strict sun avoidance or the use of sunscreens can prevent people from achieving adequate vitamin D levels, making oral supplementa­tion necessary.24,35,37,49 A phenomenon of the Western lifestyle such as obesity may lead to decreased serum vitamin D levels, probably due to the uptake of the fat-soluble vitamin D in the fat.59 Biological functions of vitamin D Vitamin D has several functions other than its well known effects on bone formation and calcium homeostasis. Vitamin D has effect on fertility, cardiovascular disease, cancer, type 1 diabetes and musculoskeletal disease but also on infection, regulation of the immune system and auto-immune disease, including several dermatological diseases.66 To exert its biologi­cal effects, adequate serum levels are required.10 A patient’s vitamin D status is determined by measuring his or her serum level of 25-hydroxyvitamin D. An adequate serum level of 25-hydroxyvitamin D is considered to be at least 75 nmol/l (30 ng/ml). De­ficiency is generally indicated as a level below 50 nmol/l (20 ng/ml).10,25 Vitamin D exerts its biological effects by entering the cell and binding to the nuclear vitamin D receptor (VDR). The VDR forms a complex with the retinoid receptor and this heterodimer binds to a vitamin D responsive element on a vitamin D responsive gene in our DNA.31 The VDR gene exhibits several polymorphisms. The prevalence of these polymorphisms may vary between races and some are considered to be associated with a reduced cancer risk or a reduced risk of auto-immune disease. However, the evidence is too premature and/or too inconsistent to draw adequate conclusions about the clinical implications.43,50,51,63 Influence of vitamin D on innate immunity Vitamin D is known to enhance the body’s antimicrobial defense in infections such as tubercu­ losis and influenza A (Table 1).1,2,13,45 One of the mechanisms by which vitamin D enhances antimicrobial activity is by inducing production of antimicrobial peptides (AMP). The promoter of the AMP gene cathelicidin (LL-37) contains a vitamin D responsive element, facilitating the induction of cathelicidin by vitamin D in myeloid cells, bronchial epithelial cells and keratinocytes.2,56 Cathelicidins are unique AMP’s that protect the skin through two distinct pathways: first, by direct antimicrobial activity and second, by initiation of a host response resulting in cytokine release, inflammation, angiogen­esis, and a wound healing response.1,2 Liu et al. showed an increased expression of the vitamin D converting enzyme and the vita­min D receptor after activation of macrophages by Toll-like receptor 2 (TLR2)-mediated recognition of mycobac­terium tuberculosis (TB). This indicates an autocrine feedback loop, whereby vitamin D induces its own receptor together with the induction of AMP and bacterial killing. In vivo, African Americans with low serum levels of 25-hydroxyvitamin D showed an inefficient induc­tion of cathelicidin mRNA and high TB susceptibility.32 Human beta defensin-2 (HBD2), forms a key link between innate and adaptive immunity by attracting immature dendritic cells and T cells.60 In response to vitamin D, HBD-2 is upregulated via the NF-κB pathway


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5. Ethnic Itch? E. Hajdarbegovic MD H.B. Thio MD PhD Itch is a frequent nuisance among all humans. Like pain, it is a sensation felt by the brain but which can only be localized in the skin or the mucosa. Itch evokes an itch reflex and it usually resolves quickly after brief scratching. The itch and the subsequent scratching help remove irritants from the skin. In persons with a skin disease however it sometimes becomes a major symptom for which treatment is sought. Moreover, the scratching reflex adds to the damage and inflammation of the skin. Almost all dermatoses can be accompanied by this poorly understood sensation but severe pruritus without a skin disease can also be encountered. Many studies have shown differences in skin physiology in individuals of different ethnic population. These differences are of variable significance. Is there such a thing as “ethnic itch�? Should pruritus in persons of non-Caucasian descent be approached in a different way? What would then be the basis of these differences? Although itch has been a major subject of investigation in the past years, no papers focusing solely on ethnic influences have been published as of yet. However, differences in morphology and function can be found throughout the entire itch pathway; from the epidermis to the cerebrum. In this paper we will discuss the itch pathway and possible ethnic differences in its various components. For the purposes of this paper, differences in exposure to exogenous elicitors of itch such as insects will be omitted. Epidemiology There have been studies which have shown different prevalence of itch as a symptom in different ethnic groups. Male immigrants from East Asia, Middle East and North Africa in Norway report to have itch significantly more frequently than Norwegians and emigrants from Western countries.1 This itch was associated with self reported dry or sore skin. An extensive review on itch by Weisshaar et al found multiple studies which supported a role of psycho-social and socio-demographic factors in the prevalence of itch with itch being more prevalent in lower classes.2 These factors might be confounders for ethnicity in the western world. Epidermis and dermis The skin and mucosal membranes are inseparably connected to itch as it can not be felt in any other organ. The etiology of itch can most frequently be found in the epidermis. Differences in skin structure are an obvious reason for explaining the ethnic differences in the prevalence of itch. A skin prone to xerosis due to increased transepidermal water loss (TEWL) is more likely to become itchy. Increased TEWL in individuals of African descent has been found in in vitro studies.3 Increased TEWL has also been found to correlate inversely with the amount


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of ceramides in the stratum corneum with Africans having the lowest amounts followed by Caucasians and then Hispanics.4 Highest TEWL after tape stripping has been found in Asians followed by Africans by Kompaore et al.5 The review by Berardesca concludes that the black skin is less susceptible to cutaneous irritants but also that in a model of damaged skin (removed stratum corneum) TEWL was higher in blacks and Hispanics after exposure to sodium lauryl sulphate.3 Damaged and irritated skin is most commonly found in patients with allergic or orthoergic contact dermatitis. Whenever assessing itch, investigators should control for these pruritic skin conditions. Asian skin seems to be more prone to development of contact dermatitis which is a pruritic skin condition pur sang. Epidemiologic studies show a decreased prevalence of contact dermatitis in Africans.6, 7 Sensitisation studies however, have shown conflicting findings. There seems to be an increased risk for development of latex allergy in non-Caucasian.8, 9 Patch testing on the other hand shows no significant difference between ethnic groups.10-12 Other prevalent pruritic skin diseases are atopic dermatitis, lichen planus, lichen sclerosus and urticaria. The prevalence of these conditions may vary across the continents. Of special interest are regional prevalences of atopic constitution which influences the prevalence of itch as a symptom. It is likely that atopy is not distributed evenly across the continents as it is a heritable disease with greatest prevalence in industrialized countries. The strongest risk factors for development of atopic dermatitis are mutations in the filaggrin gene. Mutations which lead to defective filaggrin en therefore defective skin barrier also increase the risk of development of ichtyosiform skin conditions which are pruritic. Different polymorphisms in genes encoding filaggrin have been found across continents.13 Furthermore, a defective skin barrier predisposes to development of other pruritic dermatoses like xerosis and contact dermatitis. One study has found a 5-fold increased prevalence in aquagenic pruritus in Nigerians when indirectly compared to Israelis.14 In the dermis the emigrant cells of non-epithelial origins play a role in pruritus. These immunocytes are largely involved in itch associated with inflammatory conditions. There is evidence for increased tryptase and larger mast cell granules in individuals of African origins.15 There is also evidence for difference in blood vessel reactivity.16 Although altered perfusion might play a role in pruritus no clinical evidence exists so far. Pruritogenic receptors and neuromediators The first step in the neuronal pathway of itch is the activation of the free nerve endings. A multitude of different receptors implicated in the neurophysiology of itch has made it very difficult to develop a simple unifying theory of neuronal activation. This also makes genome wide analysis between ethnic groups unattractive. The receptors which are involved in itch have not only been found on primary afferent neurons but also on keratinocytes and 足immunocytes. This fact makes it very difficult to exactly describe their functionality. On the primary afferents conducting itch


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we can find histamine receptors, protease- activated receptors (PARs) and transient receptor potential receptors (TRPs). Opioid receptors in the skin neurons seem to have an anti-pruritic effect while those at the spinal level can be pruruitic (μ-receptors) and anti-pruritic (κ-receptors).17 The difference in response to opiods has been shown by Cepeda et al.18 Native Indians were more susceptible to morphine depression of the ventilatory response. The existence of different response to opiods makes it probable that there could also be a difference in response to itch mediators. Moreover, opiods are known to disinhibit itch on the level of the spinal cord.19, 20 Free nerve endings can be stimulated to produce an intch signal directly by histamine, papain, kalikrein and interleukin-2. Many other substances can induce itch via histamine-release; chymase, trypsin, substance P etc. It is not known if levels and function of these molecules and their respective receptors differ among ethnicities. First and second order neurons The most distal part of the neuronal system responsible for conductance of itch is the axonal nerve endings found as superficially as the epidermis. Distribution of cutaneous nerve endings has not been investigated in an ethnical context. After peripheral excitation of these axons by itch mediators, first order neurons carry the signal towards the spinal ganglia from where it is conducted further towards the central nervous system. The main neurotransmitters in these fibers are substance P and calcitonin gene-related peptide. The existence of primary afferents specialized in conducting the itch signal was first demonstrated by Schmelz et al.21 Andrew and Craig later identified their spinal projections.22 Besides the specific “itch-fibers” which are mechano insensitive C-fibers, polymodal mechano and chemo sensitive but histamine insensitive C-fibers are also implicated recently.23 There is evidence which proves the even A-δ contribute to and modulate the itch sensation.24 It is not very probable that differences in neuron-fiber physiology exist between individuals of different ethnicities. However possible targets for further investigation would be the ion channels in these neurons. Polymorphisms in their genes could contribute to a difference in conductance. In an elegantly designed study, Komiyama et al have demonstrated ethnic differences in sensory and pain responses and even in motor reflex responses. They showed that Japanese subjects had lower pain thresholds than Caucasians when stimulated with a filament-prick on the cheek. Also Caucasian subjects required less electrical stimulation to produce a masseteric exteroceptive suppression reflex.25 These results can not be extrapolated for itch without further investigation. Cerebral cortex The sensation of itch always carries an emotional significance. This emotion is interpreted by the cortex. Cultural differences may influence the behavioral expression of this emotion. E ­ thnicity might have an influence on how often and how intense pruritus is experienced. Emerging new


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6. Pigmentary Disorders: Post-inflammatory Hyperpigmentation and Melasma E.B. Handog MD M.J.E. Macarayo MD Introduction In ethnic skin, pigmentary disorders, particularly melasma and post-inflammatory hyperpigmentation (PIH), can be frustrating and challenging. Both conditions may be easy to diagnose but really pose cautious and difficult treatment options for an already bothered patient. The determinants of the actual color of the skin are (1) the type of melanin, (2) the amount of melanin synthesized by the melanocyte and (3) its distribution pattern in the surrounding keratinocytes. From tyrosine, melanin is formed through the action of the enzyme tyrosinase, in the lysosome-related organelles (melanosomes) of melanocytes. Sufficient melanin production together with the proper transport of melanosomes within the melanocytes are both necessary for melanosome formation and pigmentation. The melanosomes are then moved from a melanocyte to a group of keratinocytes called the epidermal melanin unit, to which they provide melanin. Eumelanin is the primary pigment producing brown color of the skin. Pheomelanin is yellow or red, also produced solely in melanocytes.1 Pigmentary disorders can be aptly divided into hypomelanotic and hypermelanotic entities. In the classification presented by Lapeere H et al, hypermelanotic disorders were either congenital or acquired. PIH was classified under acquired circumscribed hypermelanosis and melasma under acquired diffuse non-figured hypermelanosis.2 Post-inflammatory Hyperpigmentation Definition Post-inflammatory hyperpigmentation is a common acquired excess of melanin pigment, with or without symmetry, caused by cutaneous insults from drug and phototoxic reactions, infections, physical injury or trauma, allergic reactions and inflammatory diseases.1-6 For pathologists, the term post-inflammatory pigmentary alteration (PIPA) befitted cases wherein the presenting dermal melanosis cannot foretell whether the end lesion will be darker or lighter.1


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Epidemiology PIH occurs with equal incidence among males and females and has no age preference. Although all skin types may be affected, Fitzpatrick skin types IV-VI are more afflicted with PIH. Inflammation can elicit heightened responses to the hyper-reactive melanocytes of darker skinned population.7 Compared to Caucasians, skin-of-color patients tend to develop PIH more frequently as shown in two separate studies wherein dyschromias, other than vitiligo, were on the top three most common dermatoses among African-Americans.8,9 In the Asian population, those with darker skin like the Malays and Indians tends to develop more PIH than the lighter skinned Chinese,10 suggesting that the degree of pigmentation rather than race or ethnicity contributes more to PIH evolution. Etiology PIH may be the end result of inflammatory processes that can either be endogenous (e.g. dermatophytoses, viral exanthems, impetigo, lichen planus, psoriasis, atopic dermatitis, acne vulgaris, sequelae from insect bites, contact dermatitis and medication-induced hypersensitivity reactions ) or exogenous (e.g. non-ionizing radiation, burns, phototoxic reactions, laser procedures and chemical peels).6,11,12 Acne vulgaris13 and pseudofolliculitis barbae14-16 are two common dermatoses among skin of color population that are also leading causes of PIH. Pathogenesis Two mechanisms may play a role in the formation of PIH: (figure 1) increased epidermal pigmentation by means of increased melanocyte activity or (figure 2) dermal melanosis from melanocyte damage and melanin dropout from the epidermis into the dermis.1 Arachidonic acid is oxidized to prostaglandins or leukotrienes as a response to injury. Leukotrienes (LTC4, LTD4), prostaglandins (PGE2, PGD2) and thromboxanes (TXB2) stimulate human melanocyte and dendritic enlargement, in vitro.17 Cytokines, inflammatory mediators (IL-1, IL-6, TNF-a, EGF) and reactive oxygen species as nitric oxide, have stimulatory effects on melanocytes, as well.11,18,19 This leads to an increase in melanin synthesis and pigment transfer to surrounding keratinocytes.12,20 Basal keratinocytes are damaged in dermal hypermelanosis. The large amounts of melanin are phagocytized by macrophages (melanophages) in the upper dermis;20,21 gathering of the melanophages at the injury site produce the deeper gray hue of some lesions. Clinical Presentation It presents clinically as tan, brown or gray pigmented macule(s) or patch(es) on the site of insult. It is asymptomatic, symmetric or asymmetric, circumscribed or diffuse, depending on the distribution of the original inflammatory dermatosis (figures 1-3). Degree of hyperpigmentation is worsened by long-term or relapsing inflammation and ultraviolet irradiation.22 Epidermal hypermelanosis may take months or years to resolve without therapy; dermal hypermelanosis may take a longer time to fade and may be permanent.12,19


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Figure 1: PIH noted after a chemical peeling procedure.

Figure 2: Facial PIH from acne vulgaris.

Figure 3: Upper Back PIH from acne vulgaris.


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7. Atopic Eczema in Ethnic Skin R.J.T. van der Leest MD E. Hajdarbegovic MD Prof. H.A.M. Neumann MD PhD Epidemiology Epidemiological data of atopic dermatitis in non-Caucasians are scarce. High prevalences of tuberculosis, aquired immunodeficiency syndrome (AIDS) and malaria in African countries make atopic diseases like atopic eczema (AE), allergic rhinitis and asthma less important for researchers and governments. However, in Western countries atopic dermatitis is a common skin disease with a rising prevalence in the past. Is this pruritic eczematous disease also a problem in Africa? Are there differences in disease severity in different skin types and habitats of the patients? To create new hypotheses it is interesting to compare this past trend in Western countries with the epidemiology of atopic dermatitis in Africa. The first large international study that calculated prevalences of asthma, allergic rhinitis and atopic dermatitis is the International Study of Asthma and Allergies in Childhood (ISAAC). In Phase I authors calculated prevalences in 56 countries by dividing self-reported symptoms of these disorders in a questionnaire by the number of completed questionnaires.1 A high variation in prevalences of symptoms of atopic eczema was reported in the different centres (0.3 – 20.5 %), the highest symptom prevalences included African countries like Nigeria, Ethiopia, Kenia and South Africa.1 ISAAC Phase III used similar questionnaires and identical methodology as Phase I to calculate time trends and added other centres in Africa including rather poor countries.2 Eczema prevalences ranged from 4.7 to 21.5 % and there was a wide variation between countries and centres in same countries.2 However, epidemiological data of atopic dermatitis must be interpreted with caution, because other common pruritic skin diseases in Africa could have been polluting the prevalence values. Another reason for high prevalences of atopic diseases in Africa, comparable with European countries, could be the increased ‘westernizing’ of particular areas. For example a high AE prevalence of 8.5 % was reported in Nigeria (1998 – 2000), compared with a Nigerian prevalence of 3.1% in 1986.3,4 In African adolescents eczema prevalences increased from 11.8% in 1995 to 19.4 % in 2002. They found that 6 % of the children reported night waking caused by eczema symptoms, indicating a strong impact of allergic diseases on quality of life.5 On the other hand a cross-sectional survey reported an absence of allergic diseases in school children in Nigeria. They showed a low incidence of atopic dermatitis in the lower socio-economic class, also described in other studies.6 Atopic diseases in Africa are becoming more and more important and could be a motivation for the African governments to invest in research and management of atopic diseases in Africa. Pathogenesis A substantial part of the pathogenetical fundaments of AE are filaggrin mutations.7-10 It is now generally accepted that mutations affecting the function of this natural moisturizing factor not


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Figure 1: Lichenification in a chronic atopic eczema patient.

Figure 2: Post-inflammatory hyperpigmentation, lichenification and papulous lichenoid lesions in atopic eczema patient.

Figure 3: Severe erythema and weeping excoriations.


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only cause atopic eczema but also play a role in the pathogeneses of atopic asthma and hay-fever i.e. they are a risk factor for the development of an atopic constitution.10 Dysfunction of natural moisturizing factor leads to a defective skin barrier. The more permeable epidermis permits diffusion of allergens towards the immunocytes. This sensitization causes a Th-2 mediated reaction which is later followed by a Th-1 type reaction.11 This immunological process is clinically accompanied by a dry, scaly, erythematous, lichenified and highly pruritic skin. There are no data which demonstrate a different course of this pathogenetic cascade in patients of non-Caucasian origins. However, different filaggrin mutations have been discovered in different populations, although not all ethnic groups have been mapped.12-15 There might be a difference in the exposure to allergens as patients from third world countries have to deal with a hotter, more humid climate in which bacteria and dermatophytes are more active. Also flawed hygienic and sanitary resources might play a role. It seems however that being born in a non-Western country has a protective effect on the onset of AE. Moreover, Western-born children of immigrants sometimes have higher rates of AE than European children.16 Migration to a Western country even increases the prevalence of atopic disorders before certain age.17-20 The physical, physiological and chemical properties of the skin differ between the races. Darker skin is more prone to xerosis. This is probably due to increased transepidermal water loss (TEWL), especially in damaged skin, in people of African descent which is ascribed to lower amounts of ceramids.21-23 The role of Vitamin D has been controversial. Darker skin may confer lower synthesis of vitamin D in dark skinned individuals living in Western countries.24 Vitamin D has frequently been implied as a modulator of immune responses. In atopic diseases however publications have been equivocal. One study has shown that supplementation of Vitamin D has a preventive effect on development of atopic diseases in the children to be born.25 Supplementation to children during infancy however has been shown to actually increase the risk of developing asthma and allergic rhinitis in one study.26 Diagnosis Atopic eczema is a common inflammatory pruritic skin disease predominantly occurring in infants and children and it is recognizable by relapses and remissions. It has an acute, subacute and chronic presentation (figure 1) and has a multifactorial etiology consisting of a polygenic inheritance mode and environmental factors. Certain criteria are developed to diagnose atopic eczema. Hanifin and Rajka27,28 made the most commonly used diagnostic criteria. Although their criteria describe the main features of atopic eczema well, the criteria are too complex to analyze in epidemiological studies. Clinical studies of the major and minor criteria showed various results. Ethnic background might be a possible explanation of these differences. Dermatologists in Africa communicated that the criteria had to be changed for usage in Africa, commonly


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8. Vitiligo in Ethnic Dermatoses J. de Leeuw MD PhD I. Definition Vitiligo is a non-contagious acquired pigmentation disorder characterized by sharply demarcated white macules.1 These de-pigmented macules occur in a localized or a generalized pattern. Vitiligo is currently classified into four categories:2 - Focal vitiligo (one or a few white patches in a segmental or a non-segmental distribution)

Figure 1: Focal vitiligo.

- Acro-facial vitiligo (white patches limited to the distal parts of the extremities, around the mouth and the eyes)

Figure 2: Acro-facial vitiligo.

- Vitiligo vulgaris (numerous, de-pigmented patches scattered over the whole body)

Figure 3: Vitiligo vulgaris.


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- Vitiligo universalis (more than 80% de-pigmentation on the body) The course of vitiligo is usually one of slow progression, but it may exacerbate rapidly or stabilize. Vitiligo may also re-pigment spontaneously, but only partially.2 Histopathological and histochemical examinations showed a reduction in the number and the function of melanocytes in vitiligo lesions.3 Generally, the clinical diagnosis is obvious and often skin biopsies for the histopathological evaluation are unnecessary. The prevalence of vitiligo in the general population is 1% to 2%, without race or gender predilection and with an onset peak at an age of between 10 and 30 years. A genetic component is likely because there is a positive family history in about 30% of the patients.4,5 Vitiligo is often considered to be only a cosmetic problem, but the implications of vitiligo extend far beyond the limits of a cosmetic disease. Its impact on the quality of life of the patient is comparable with that in psoriasis on the emotional and socially functioning scales, particularly in individuals with brown skin because of the pronounced contrast between the normal brown skin and the vitiliginous white areas.6-9 Although vitiligo occurs equally in all racial and ethnic groups, its effect on the quality of life is particularly distinct in people with pigmented skin, especially in those countries where there is confusion of vitiligo with leprosy in the public mind.7 From this point of view, vitiligo is not a real ethnic disease, but its impact on the quality of life is most certainly determined by the ethnic circumstances. Differential diagnosis encompasses halo nevus, idiopathic guttate hypomelanosis, post-inflammatory hypo-pigmentation, post-traumatic de-pigmentation, pityriasis alba, pityriasis versicolor, leprosy, piebaldism, topical or drug-induced de-pigmentation and mycosis fungoides associated de-pigmentation.10 II. Pathogenesis Melanocytes are absent in the involved skin areas in vitiligo.1 Many factors including infections, stress, neural abnormalities, melatonin receptor dysfunction, impaired melanocyte migration and genetic susceptibility have been implicated in the development of the disease, but to date the exact pathogenesis of vitiligo remains obscure.10-12 There are several hypotheses on the pathogenesis of vitiligo, but none of them fully explain the disease. The following four hypotheses are particularly important.13 1. The autoimmune hypothesis is based on the observation that several autoimmune diseases such as autoimmune thyroid disease and type I diabetes mellitus often accompany vitiligo. Moreover, vitiligo patients often have elevated serum levels of antibodies against melanocytic antigens such as tyrosinase and tyrosinase-related proteins 1 and 2.14-16 2. The neural hypothesis assumes that the altered reactions of melanocytes towards neuropeptides, catecholamines and their metabolites are responsible for the destruction of melanocytes. A close contact between melanocytes and nerve endings that is rarely seen in normal skin is observed in the de-pigmented skin. In addition, nerve endings at such sites showed aberrations in the expression of nerve growth factor and neuropeptides.13 3. The self-destruct hypothesis states that melanocytes destroy themselves due to defects in the protective mechanisms that are responsible for eliminating toxic melanin precursors. These defects lead to the accumulation of indole derivatives and free radicals, which are melanotoxic.17


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4. The biochemical hypothesis assumes an over-synthesis of hydrobiopterin, a cofactor of tyrosine hydroxylase, resulting in an increased synthesis of catecholamine. This also results in an increase in the reactive oxygen species toxic for melanocytes. Moreover, reduced levels of catalase in combination with higher concentrations of hydrogen peroxide were found in affected and unaffected skin of vitiligo patients.18 Ultimately, all of these different factors may act independently or in combination to produce the same effect, that is to say the destruction of melanocytes and thus the absence of pigmentation.12 Initially, only the epidermal melanocytes are affected and not the melanocytes in the hair follicles. However, as the condition progresses the hair follicle may also become involved in the process of melanocyte destruction, resulting in leucotrichia. From this moment the hair follicle is no longer able to provide new melanocytes for re-pigmentation.19 During the process of re-pigmentation, the follicular melanocytes proliferate and mature to an active state as they migrate into the epidermis.20 III. Therapy Therapeutic approaches in vitiligo are aimed at reversing the progressive loss of melanocytes and reconstituting the normal skin color. However, none of the current approaches is uniformly effective and side effects may occur. Most common methods for treatment are topical ­corticosteroids, topical calcineurin inhibitors, systemic and topical psoralen ultraviolet-A light (PUVA), broad- and narrow-band ultraviolet-B (BB-UVB, NB-UVB), topical khellin with UVA (KUVA) and topical khellin in liposomal solution in combination with UVB (KLUV).1,10,21-28 Recent guidelines on the treatment of vitiligo recommend the use of potent or very potent topical steroids for a trial period of no more than 2 months.10 For generalized symmetrical types of vitiligo, topical clobetasol used over 2-6 months re-pigments vitiligo to some degree. There is weak evidence for clinically meaningful re-pigmentation with topical betamethasone used for 4 months and topical fluticasone used for 9 months. Although benefits are observed, skin atrophy is a common side effect. In such cases topical treatment with tacrolimus or pimecrolimus is an alternative for topical steroids.10 III.1 Phototherapy Narrowband UVB phototherapy should be considered for the treatment of vitiligo only in patients who cannot be adequately managed with more conservative treatments, who have widespread vitiligo or have localized vitiligo associated with a significant impact on the patient’s quality of life (QoL).10 Unfortunately, in many patients refractory areas remain, particularly on the distal body sites such as the dorsal parts of the hands and the feet, but all body sites may be involved. PUVA and KLUV may be efficacious where aforementioned treatments have failed.23-28 Khellin, a furanochromone with a chemical structure resembling that of the psoralen family is activated by UVA and UVB.29 Topical KUVA with 5% khellin in water ⁄oil emulsion may induce re-pigmentation comparable with that induced by systemic PUVA, but requires a longer duration.26 The selection of the vehicle in which khellin is incorporated is important for the adequate availability of khellin in the skin because of its very low solubility in water.25 Liposomes are small vesicles of membrane lipids.30,31 They are used as microscopic carrier c­ apsules


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9. Inflammatory Diseases on Ethnic Skin Prof. J.R.M.G. Lambert MD PhD Some dermatological diseases have pecular aspects on ethnic skin. Others are very frequent or unique in ethnic skin. Psoriasis Psoriasis is rather uncommon in Africans, especially in West-Africans. This is probably partly due to genetic factors as African Americans also show a low incidence of psoriasis. Recently, the influence of dietary factors has been put forward as another explanation. In black skin, psoriatic lesions may present violaceous or bluish black, due to pigmentary incontinence. After clearing of the lesions, post-inflammatory hyperpigmentation may be present, which has cosmetic consequences.

Psoriasis vulgaris.

Treatment of psoriasis in ethnic skin is not different. (see table) In case of localized psoriasis the combination of local corticosteroids and vitamine D3 analogues is the just choice. Recently the results of the clinical trials concerning the efficacy and safety of the calcipotriol/betamethasone diprionate two compound scalp formulation and ointment in Hispanic/Latino and Black African American patients have been presented. The efficacy of the two compound scalp formulation is very similar to the efficacy of a large study of predominantly white non Hispanic


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patients. The proportion of patients with cleared or minimal disease was 71,9 % for the ethnic skin patients and 71,2 % for the white patients. A 52-week study of Xamiol速 gel and Dovobet速 ointment respectively in the treatment of psoriasis of the scalp and trunk, limbs showed to be a safe treatment in Hispanic/Latino and Black/African American patients. Even the combined use of both appeared to be safe.

Psoriasis after treatment.

In case of non-response to local treatment or more extended forms photo (chemo) therapy is indicated. The systemic treatments methotrexate, acitretin (which may be combined with photo (chemo) therapy and fumaric acid may be prescribed in severe psoriasis. Cyclosporine is preferably used as a short-time therapy, especially if a rapid improvement is needed. If all previous treatments are insufficient or contra-indicated, a treatment with biologicals has to be proposed. Indication

Treatment

Mild psoriasis, limited BSA

Combination topical corticosteroids ands vitD3 analogues

Moderate psoriasis

Photo(chemo)therapy

Severe psoriasis

Methotrexate Acitretin (+ photo (chemo)therapy) Fumaric acid

If need of rapid effect

Cyclosporine

Severe psoriasis (end of treatment)

Biologicals

Table: Treatment of psoriasis in ethnic skin.


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Pityriasis Rosea On black skin, the lesions have a dark brown or black color and the desquamation is slight gray and more prominent. The lesions may be papular or papulovesicular and a hyperpigmentation can persist for some months.

Pityriasis rosea.

In Black Africans the distribution of the lesions may be rather unusual with lesions on the face, the neck, the distal part of the extremities and lower abdomen. Oral lesions may be present also. Lesions tend to resolve quicker, i.e. 2 weeks. Facial Afro-Caribbean childhood eruption This eruption is typical in Afro-Caribbean children. It is a perioral granulomatous eruption, mainly in black-skinned boys. Monomorphic flesh-colored or hypo-pigmented papules are present, particularly around the mouth. It persists for several months and resolves spontaneously without scarring. The etiopathogenesis is unknown. Lichen Planus The prevalence of lichen planus seems to be higher in Africa and India. Generaly it is also more pronounced. The papules have a larger size and present regularly an annular distribution. Pruritus and secondary lichenifications may be very pronounced. Due to pigmentary incontinence lesions have a grey to black color, which may persist for a long time after the active phase of the disease. The hyperLichen Planus. trophic type is rather common in Africa and India.


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10. Parasitology of Black Skin E. Van den Enden MD PhD 1. Introduction Parasitic skin diseases occur worldwide, but are more common in resource-poor settings with lower standards of hygiene than in Western countries. Parasites which can lead to dermatological abnormalities include a number of helminths, a few protozoa, and ectoparasites. Some parasitic diseases, such as scabies, lice infestation and creeping eruption are limited to the upper epidermis. Other parasites, such as certain amoebae, filaria such as adult Loa loa and Onchocerca volvulus, as well as certain Leishmania sp. involve deeper layers of the dermis. Because of dark pigmentation, redness as a sign of inflammation (erythema) is more difficult to appreciate in Negroid skin. The other hallmarks of inflammation, such as pain, warmth, and swelling are independent of skin color. In comparison with white skin, the stratum corneum in black skin is equal in thickness, but more compact, about 16 cell layers versus 20 layers in black skin. The keratinocytes adhere stronger to one another in black skin, especially in the stratum corneum. As a consequence, black skin is more resistant to irritants. Scratching white skin leads often to excoriation and exsudative lesions, while a similar insult in black skin might lead to lichenification. Vesicles break easily in white skin, but remain intact longer in black skin. 2. Mites 2.1 Sarcoptes scabiei is a mite that leads to scabies. Human-tohuman transmission occurs especially when hygiene is poor. The majority of mites are found in burrows in the stratum corneum of wrists and fingers, with smaller numbers on elbows and elsewhere. A female lays 1-3 eggs per day and produces faecal matter (scybala), all of which will be present in the burrows and can be recognized in a microscopic preparation. The characteristic skin burrows usually only become visible after secondary infection or eczematous reaction. Repeated application of corticosteroid crème can lead to masking: “scabies incognito”. Scabies causes pruritus, particularly at night. In a patient who has never been exposed to scabies, the rash usually occurs 4-6 weeks after infection. In previously exposed people, it occurs much more rapidly, sometimes Scabies nodules on scrotum. These within just a few days. There will be itching at sites where the can persist for weeks after onset of mites are present, but also at uninfected body parts. The rash treatment. is due to hypersensitivity to mite allergens. Buttocks, groin, shoulders, arms, calves and ankles can become itchy. In immunocompetent persons, the rash almost never occurs on the


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head, palms of the hands nor soles of the feet. Despite effective treatment, symptoms and lesions of scabies can persist for weeks (e.g. scabies nodules on the scrotum and penis). In immunosuppression (AIDS, HTVL-1 infection) Norwegian scabies can occur. In this variant very numerous mites are present in desquamating hyperkeratotic skin crusts. The latter can occur on the face. The disorder is highly infectious. If the diagnosis is in doubt, examination of some skin scales after treatment with 10% KOH under a low magnification microscope is indicated. For treatment, gamma-benzene hexachloride has been phased out because of toxicity concerns. As an alternative topical 20-30% benzyl benzoate is used. Topical pyrethroids are effective (e.g. 5% permethrin). Malathion can be used as a lotion. Crotamiton is also sometimes used, but is less effective. Oral ivermectin produces good results and should preferably be repeated after a few weeks. It is the first choice in Norwegian scabies. Bedclothes are disinfected by washing at 60째C. Ironing clothes with a steam iron will help break the cycle of transmission. Without access to a human body the mites survive less than 4 days. 2.2 Various other mites. Harvest mites (Neotrombicula autumnalis) cause short-lasting pruritic dermatitis. The itching is most pronounced in areas where clothing is tight-fitting. For prevention, it is recommended that the grass should be kept short in gardens in infested areas. Demodex folliculorum and D. brevis mites are very small and live in hair follicles and sebaceous glands respectively.

Demodex folliculorum mites.The two black spheres are air bubbles.

Infections are practically almost always asymptomatic, although blepharitis can occur. Other problems caused by miscellaneous mites are allergic itchy skin reactions to mites (Tyrophagus sp, Pyemotes sp) found in all sorts of animal or plant products. Birds can be infested with mites that can cause pruritus in humans (gamasidosis).


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11. Tropical Bacteriology and Mycology Prof. J. De Weert MD In tropical Africa the majority of dermatological diagnoses are infections. In non-pigmented people too quite a lot of infections are observed. The factors that predispose to cutaneous infections in blacks are not due to racial or ethnic characteristics. Geographical and climatic factors as extremes of temperature, rainfall and humidity as socioeconomic factors as poor hygiene and malnutrition predispose to cutaneous infections. Bacterial infections occur when the interface between host and parasite is deranged by factors such as trauma, insect bites and dermatitis. Superinfected dermatitis.

Impetigo Impetigo is a superficial highly contagious skin infection caused by streptococci and/or staphylococci. It occurs most commonly in children and young adults. One has to distinguish clinically between nonbullous impetigo and bullous impetigo. The lesion of nonbullous impetigo begins as a slightly depigmented macula that rapidly evolves into a short-live vesicle or pustule. Later on superficial erosions with typical ‘honey-colored’ yellow crust and rapid extension are seen. Nonbullous impetigo commonly affects the face, but any area may be involved. Streptococcus pyogenes, Staphylococcus aureus or both are cultured. Five percent of the cases caused by Str. pyogenes result in an acute post Impetigo. streptococcal glomerulonephritis. The early lesions of bullous impetigo are small vesicles that enlarge to 1 – 2 cm superficial bullae. The flaccid transparent bulla may contain a purulent exudate. After rupture of the blister an eroded inflamed base with a yellow-brown crust is observed. The lesions of bullous impetigo are found on the trunk, extremities and buttocks of infants and young children. Bullous impetigo is caused by toxins A-D of Staph. aureus and can be considered as a localized form of staphylococcal scalded skin syndrome, a serious disease affecting small children.


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Ecthyma Ecthyma is an ulcerated form of nonbullous impetigo and occurs most commonly on the lower extremities, particularly in children. The disease starts with a large pustule and extends rapidly into the dermis leading to a sharply demarcated necrotic ulcer. Treatment Treatment with systemic antibiotics is indicated only if there is extensive impetigo. Removal of crusts with wet dressings is necessary. Topical antibiotic ointments favor the healing. Careful hygiene will prevent further spread. Erysipelas Erysipelas is a common acute infectious disease of the skin produced by streptococci or staphylococci Ecthyma. with diffuse swelling, fever and chills. The bacteria enter through a minor injury to the skin, such as a fissure between the toes in tinea pedis, ulcus cruris, folliculitis and rhagades in the nose. The infection begins with an acute dermal inflammation, edema and pressure pain. The affected area feels hot. There may be a peripheral streak of lymphangitis and on regularly finds painful swollen lymph nodes. Fever up to 40째 C and chills are not uncommon. The CRP is considerably elevated. Treatment Bed rest and systemic antibiotics are necessary. Penicillin is the drug of choice in erysipelas caused by the streptococcus. The portal of entry must also be treated e.g. tinea pedis in leg erysipelas, rhagades in the nasal orifice. Compressing bandages are required to treat the edema of the lower legs. In cases of frequent relapse a depot penicillin e.g. 1.2 x 10 6 IU benzathine penicillin i.m. every month is useful. Impetigo Non-bullous bullous Ecthyma

Topical antibiotics Systemic antibiotics In extensive cases

Erysipelas

Systemic antibiotics Bed rest

Cutaneous tuberculosis

Same as systemic tuberculosis

Leprosy

See WHO guidelines Prednisolone Thalidomide

Reaction 1 during treatment Reaction 2 during treatment

Yaws

Table: Treatment of bacterial infections.

Penicillin


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12. Sexually Transmitted Diseases in Ethnic Skins M. Waugh MB FRCP Contents This chapter will describe sexually transmitted diseases (STDs) in Ethnic Skins to enable clinicians and professional health workers to be able to spot symptoms and signs of STDs in people who are of skin colouration different from the native populations of Northern Europe. Thus correct investigation, diagnosis, treatment and follow up, and appropriate action such as counselling and contact tracing may be initiated. Historical and Social Background Classical descriptions especially of syphilis have evolved in Europe and North America from nineteenth century teachers in great metropolitan centres such as Vienna or Paris teaching on the poor of those cities whose skin colouring before the late twentieth century was predominately pale skinned. Thus illustrations in text books were of pale skinned patients until World War II. The entry of the United States of America on the side of democracy in that war meant that for the first time in photographic manuals aimed at giving instruction in venereal diseases (VD) to health workers black skins are widely seen in teaching aids. However even this generalisation does not always hold. In 1929 there were published excellent photographs of various stages of syphilis in Malays from what was then the Dutch East Indies in “Voordrachten over Tropische Huidziekten” the work of J.D. Kayser4 of the Tropical Diseases Institute of Rotterdam- Leiden. Yaws / Syphilis While in the past treatises had described in detail differences between venereal syphilis and yaws. With the World Health Organisation mass eradication campaigns of 1950s2 those differences were found to have no great practical application. ( Hackett CJ & Loewenthal LJA), 1960. As they explained, “The skin has a limited number of reaction patterns, so that similar lesions may result from different causes. This concept, so clearly explained by Brocq, may even apply to all the characters of an eruption, its method of development, its distribution and subjective symptoms, in addition to the morphology of its individual components. Only a few lesions are truly diagnostic of yaws and often the repetition of the same pattern in an endemic area tends to be taken as evidence of yaws.” They also pointed out in yaws endemic areas serologic tests to differentiate the treponematoses are of little value. Social Background- Racial and Genetic Factors In April 1997 Goodman1 wrote, “Even acknowledging that the idea of race is a legend we will not eradicate racism. Until researchers, even in good faith, will go on using the concept of race without clearly defining it, they will sustain the idea of race on a biological basis, thus


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misleading public opinion and encouraging racist attitudes.” Thus we must speak of groups of populations or ethnic groups, eliminating the term race not only because it does not exist on a biological plane but because it lacks all scientific foundation and is therefore useless on a clinical level (Morrone, Hercogova, Lotti), 2004.5 Thus references in the last 70 years from Western countries show differing levels of understanding of these concepts. Rudolph Kampmeir, 1943,3 practising in Nashville, Tennessee wrote that, “Race is a factor which cannot be disregarded with respect to the reaction between host and invader. Surely the clinician treating syphilis in both the white and Negro races is struck by the difference in the morphology of the skin reactions in the secondary stage of syphilis. Furthermore, cardiovascular syphilis is much more common in the colored than in the white patient, and by contrast it is generally accepted that the reverse is true with respect to the incidence of central-nervous-system syphilis”(Kampmeir, 1943). 34 years later Robert Morton, 1977,6 from Sheffield, England writing about population movement and rising gonorrhoea rates writes that; Immigration “has been a feature of the European scene for more than 20 years. Multiracialism is becoming an established fact particularly in France, Holland and the United Kingdom.” In England he went on to describe immigrants from the West Indies, Pakistan and Aden and by 2009, there are many more from all corners of the World. Young male immigrants often alone before their families in strange countries had before the advent of AIDS, high incidences of gonorrhoea. Morton 1977 referred to Oller and Wood (1970) who showed in Bradford,7 an industrial city in England from 1959 to 1968 of 5000 men with gonorrhoea 80% were immigrants. Verkeij (1976) in Rotterdam found gonorrhoea 6.7 times more common in immigrants than in Dutchmen and noted that the great majority of immigrants were infected by indigenous women.9 One only has to look in the streets of any large city in France, the Netherlands or England to see in the space of a few minutes how many different ethnic types pass by to the enrichment of Society and the genetic pool. Tips for Clinicians and Health Workers when caring for patients The care of STDS is very sensitive. However much braggadocio (boastful behaviour) young adults especially males may show at times when wanting help for STDs they often become like small boys wanting loving help. This is even more so for ones of Ethnic backgrounds where the concept of confidentiality when caring for STDs may be little understood. A calm and welcome atmosphere needs to be given either by the individual specialist or the treatment clinic. Staff may need to be multi-lingual and an understanding of local ethnic minority customs and sexual mores need to be understood. Examples that need to be considered are the care of refugees who may have endured awful torments, the young person from an intolerant religious background who is scared to tell the truth and worried about meeting someone who might know him. Ethnic minority young-men who come for help for STDs after having sex with men (MSM) may need very special care and sympathetic handling even for them to admit why they are seeking help in the first case. In some societies, Latin


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13. Skin Manifestations in HIV-infection Prof. J.R.M.G. Lambert MD PhD Skin manifestations related to HIV and AIDS are very frequent. They are even more frequent and more severe when the immune function is decreasing. Primary infection is symptomatic in 50 to 80 % of the cases. The clinical manifestations consist of a flu-like syndrome (90 % of the cases), an exanthema and lesions on the mucous membranes. Patients suffer from fever (38 – 39,5° C), asthenia, myalgia, general malaise, arthalgia, headaches, throat pain and retro-orbital pain. Other signs are a polyadenopathia (75 %), symmetrical and not painful, neurological and gastro-intestinal complaints. The exanthema is present in 60 to 70 % of the cases. It presents between the first and fifth day of the general complaints. It is located on the trunk, the neck and sometimes the face. Palms and soles may be affected. It is a morbilliform rash made of maculopapules. (diameter a few millimeters to 1 cm) not desquamating neither confluencing. Pruritus is rare and moderate. The eruption fades away after 5 to 10 days. Infectious diseases are very frequent. They may have atypical features: the extension of the lesions, the evolution and more resistance to therapy. Infections with unusual organisms also occur. Among the inflammatory dermatological diseases, seborrhoeic dermatitis, xeroderma, pruritic papular eruption, eosinophilic folliculitis, psoriasis and drug eruptions have to be mentioned. The clinical presentation of psoriasis in HIV patients can be more severe and often correlates with the degree of immunosuppression. HIV patients with pre-existing psoriasis may see a flare of lesions as their CD4 count decreases and their viral load increases. Psoriasis has been the presenting manifestation of HIV in some patients. Psoriatic arthritis is also more common and severe in the HIV-infected population. The treatment of psoriasis in HIV patients is a real therapeutic challenge. Many of the systemic treatments are immunosuppressive and can lead to severe complications. Recently, a consensus of the Medical Board of the National Psoriasis Foundation on therapy in psoriasis was published. Topical therapy is the first-line recommended treatment for mild to moderate psoriasis in HIV patients, e.g. calcipotriol, corticosteroids and the combination formulation of calcipotriol and betamethasone dipropionate. For moderate to severe disease photo(chemo)therapy and antiretrovirals are the recommended first-line treatment. Oral retinoids may be used as secondline treatment. For more refractory, severe disease, cautious use of cyclosporine, methotrexate, hydroxyurea and TNF-a-inhibitors may also be considered.


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Antiretroviral therapy for HIV is source of a lot of skin manifestations and drug interactions. Dermatologists play a keyrole in the diagnosis and management of these cutaneous side-effects. Antiretroviral-associated lipodystrophy syndrome is one of the most common cutaneous adverse events of antiretroviral therapy. A loss of fat is observed in the face, limbs and buttocks, as an accumulation of dorsocervical and abdominal visceral fat and gynecomastia. It is often seen in association with metabolic abnormalities. Lipodystrophy is most strongly associated with certain protease inhibitors and nucleoside reverse transciptase inhibitors (NRTIs). The cutaneous side-effects of the NRTIs and the nucleotide reverse transcriptase inhibitors (NTRTIs) are usually specific to each drug. Development of cutaneous toxicity does not necessitate avoidance of the entire class. Zidovudine and emtricitabine are associated with hyperpigmentation of nails, palms and soles of darkly pigmented patients. Abacavir can cause a potentially fatal hypersensitivity reaction characterized by a morbilliform exanthem or other cutaneous manifestations. Nonnucleoside reverse transcriptase inhibitors such as nevirapine are the most frequent class of antiretroviral therapy to cause morbilliform eruptions. The fusin inhibitor enfuvirtide has a very high incidence of injection site reactions. Since the introduction of highly active antiretroviral treatment (HAART), HIV patients are living longer in better health, presenting new medical problems. One such medical challenge is the wide spectrum of disorders related to immune reconstitution that manifests during HAART. These phenomena have become broadly known as immune reconstitution – associated disease (IRAD) or immune restoration inflammatory syndrome (IRIS). There is still much discussion over this terminology and these terms are frequently used interchangeably. The pathogenesis of IRAD is incompletely understood. The recovering immune system would recognize latent antigen under the influence of HAART and this results in antigen-directed pathological inflammation. Dermatological manifestations of IRAD are frequently observed. A lot of infections are observed. One of the most common is mucocutaneous herpes viruses (HSV). The number of episodes of recurrent oronasal or anogenital HSV is increased. In a few cases a persistent oronasal or anogenital ulceration is observed. HPV is manifest by a parodoxical increase of warts after introduction of the HAART therapy or by inflammation of existing warts. Precancerous anogenital HPV related disease is also increased in HIV. Molluscum contagiosum, Verrucae vulgares.


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14. Bullous Diseases M.M. de Waard MD Prof. M.F. Jonkman MD PhD Introduction: Bullae can originate from numerous causes. There are vesicles (<1 cm) and bullae (â&#x2030;Ľ1 cm) due to infections and bites, autoimmune diseases, hereditary disorders, drug reactions, metabolic diseases, and external causes such as burns and UV-light. Table 1 gives an overview of some of the most common diseases per group of causes. When approaching a bullous disorder one starts to investigate the level of the split. A subdivision in intraepidermal bullae and subepidermal bullae can be made. Each has its own differential diagnosis. In the epidermis vesicles and bullae may develop in the subcorneal/granular, spinous or suprabasal zones. Mechanisms of development include spongiosis, acantholysis and cytolysis/apoptosis of keratinocytes.1 Spongiotic intraepidermal vesiculobullous diseases include among others acute eczema, insect bites, spongiotic drug eruptions and miliaria. Examples of acantholytic dermatoses are staphylococcal scalded skin syndrome, pemphigus and Hailey-Hailey disease. Cytolysis occurs in herpes infections and friction blisters, while necrosis is typical for toxic epidermal necrolysis.1 Subepidermal bullae may form due to marked edema in the superficial epidermis (for example bullous insect bite, bullous lichen sclerosus), weakness in the basement membrane zone (autoimmune bullous dermatoses, hereditary bullous dermatosis), or a strong interface dermatitis that splits up the dermis form the epidermis (such as in erythema multiforme and in bullous lichen planus).2 In dark skin the cohesion between keratinocytes is stronger than in caucasian skin.3 Furthermore, the stratum corneum in dark skin has more layers that are arranged in a more compact fashion, while the thickness is equal to the thickness of stratum corneum of the caucasian skin.3 Therefore, superficial vesicles that are easily broken in white skin, may stay intact in dark skin.3 In superficial splits of caucasian skin such as, for example, in pemphigus foliaceus you hardly ever see intact bullae, whereas intact bullae are quite common in pemphigus foliaceus of the dark skin. Especially in the infections and bites subgroup geographical distribution plays an important role. Myiasis and tungiasis are frequently seen in the tropics, but in more temperate climates they are uncommon and are usually only seen in global travelers. Other infections like scabies and bullous impetigo are worldwide. However in these infections poverty plays a role in controlling outbreaks, and as such in the number of patients seen.


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Figure 1: Erythema multiforme. 1a. blisters and erosions on lips. 1b. targetlesions with central bulla on palms of hands.

Figure 2: Epidermolysis bullosa acquisita. 2a. typical milia on dorsae of hands. 2b. tense monomorph blister on friction area of foot, nail changes and milia.


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15. Skin Cancers J.C. Martens MD G.A.M. Krekels MD PhD MBA Introduction Skin cancer traditionally has been considered rare among non-Caucasians. This is of growing concern since the epidemic incidence of skin cancer in Caucasians results in focus (research, awareness, etc) on skin cancer in Whites. Another problem is that skin cancers in skin of color often present atypically or with advanced stage in comparison to Caucasian patients. Health care providers must maintain a high index of suspicion when examining skin lesions in skin of color. Doctors and patients should be aware that skin cancer does exist in non-Caucasians and that tumors are often clinically atypical compared to skin cancers in White patients. Cutaneous malignancies in skin of color present a number of management challenges: –– difficulties in early diagnosis in the dark/colored skin; –– late presentation (mostly because of lack of awareness in patients); –– access to adequate (and affordable) treatment; –– HIV/immunodeficiency is often co-existing; –– Worse overall survival. Epidemiology Skin cancer is the most common type of cancer in Caucasians and the incidence of skin cancer (melanoma and non-melanoma skin cancer) is still rising. In the USA skin cancer has reached epidemic numbers. One in every 5 Americans will develop skin cancer.1 Although the incidence of skin cancer in Caucasian has been increasing in the past decades, the incidence of skin cancer in non-Caucasians remains low. The actual incidence is difficult to estimate because non-melanoma skin cancers (NMSCs) are not consistently reported to most tumor registries. Furthermore data have been limited for nonwhite populations, making accurate determination of the incidence, morbidity and mortality difficult. Skin cancer in the United States presents approximately 45% of all neoplasm’s in Caucasians,2 4-5% in Hispanics, 2-4% in Asians,3 and 1-2% in Blacks.4 Although skin cancer is less common in persons of color than in Caucasians, the rates of morbidity and mortality associated with skin cancer often are significantly greater in darker-skinned ethnic groups. Increasing skin cancer rates in particular White people can be attributed to childhood sun exposure; increased outdoor recreational activities (even during the winter); use of sun beds; the aging of especially Western Societies and possible destruction of the ozone layer. There is also a trend toward increased skin cancer rates in some ethnic groups, for instance Hispanics in the USA.


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Genetics and Etiology The low incidence of skin cancers in darker skinned individuals is primarily a result of photoprotection provided by increased epidermal melanin, which provides an inherent sun protection factor. Darker-skinned groups have also an increased melanocyte activity and have larger, more dispersed melanosomes, which can filter twice as much ultraviolet B (UVB) radiation in contrast to less melanocyte activity and smaller, more grouped melanosomes in Caucasians.5 These unique features of ethnic skin serve to protect it against actinic damage, making sun-induced skin cancers less prevalent. The role UVR plays in the development of BCC and SCC in different races and ethnic groups is illustrated by differences in the distribution of these tumors. UVR may not be as significant an etiologic factor in the development of skin cancer in darker races because of protection provided by melanin pigmentation against solar carcinogenesis.6 Nevertheless UVR causes UV-induced DNA damage in keratinocytes. This again causes mutation, promotes the initiation step of carcinogenesis, and triggers the production of interleukin-10 (IL-10), which may contribute to tumor escape from the host immune response. IL-10 production by keratinocytes or tumor infiltration cells may contribute to the immunosuppressive and anti-inflammatory effects allowing the tumor to escape from the immune response. Reports demonstrate racial differences in IL-10 expression. For instance, Japanese have a low incidence of IL-10 expression (0-1%) compared to Caucasians (12â&#x20AC;&#x201C;19%).7

Patient with squamous cell carcinoma in the right medial canthus and left nasiolabial fold.

Inherited diseases with high incidence of skin cancer There is a variety of inherited diseases that are associated with a high incidence of skin cancer. The most important ones are Xeroderma Pigmentosum and Albinism. Less common diseases are Epidermiodysplasia Verruciformis, nevoid basal cell carcinoma syndrome, etc. UV protection is the of utmost importance in inherited skin cancer diseases in all races.


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16. Genodermatoses Prof. M.A.M. van Steensel MD PhD Prof. P.M. Steijlen MD PhD Many dermatological diseases, such as psoriasis, have a hereditary component. These diseases are considered to be polygenic, meaning that several different genetic loci influence their expression. Monogenic diseases are caused by a single gene defect, which means that their phenotype is determined by one major genetic locus. These diseases are rare individually but as a group they are rather common - in the Netherlands alone, there are an estimated 100,000 persons with a monogenic disorder. Some genodermatoses can be present at birth, whereas others can become manifest later during childhood. Genetically determined skin abnormalities can be isolated or be a part of a syndrome. Establishing a correct diagnosis is essential for genetic advice, prognosis and increasingly for therapy. The database “Online Mendelian Inheritance in Man” (OMIM; http://www.ncbi.nlm.nih.gov/ OMIM) includes approximately 4000 hereditary diseases.1 Thirty per cent of these feature major skin abnormalities that can often be the key to diagnosis. The following principles should guide the diagnostic process: –– Mode of inheritance by making a family tree. –– Careful physical examination with special attention not only to the skin but also to other organs including brain, skeleton, sensoneurinal system etc. (“holistic approach”) –– Try to establish a pattern of affected organs that can guide subsequent database searches. Querying databases with specific symptoms is rarely useful and can give wrong answers because they represent minor components of the phenotype. Rather, determine which organ systems or functionalities contain the major determinants of the phenotype and use those. As an example, oculo-dento-digital dysplasia (ODDD), a disorder caused by mutations in the GJA1 gene, will occasionally feature palmoplantar keratoderma. However, it is not a major distinguishing symptoms and using it in the search with other ODDD features such as syndactyly will lead to the wrong diagnosis. Mutation analysis can increasingly be used to confirm diagnosis and will probably in the near future be used to classify genodermatoses. Several disorders can now be be explained by the role of the causative gene defect in a certain biological pathway. Rather than morphology, pathobiology can then form the basis for disease classification. Finally, it must be realized that genodermatoses can present in a mosaic pattern.2 The definition of a genetic mosaic is when an individual, derived from a homogenous zygote, is composed of 2 or more genetically different cell populations. The mosaic can be due to X-chromosome inactivation, as is the case in X-linked dominant disorders such as incontinentia pigmenti ­(Bloch-Sulzberger). They can also be the consequence of a post-zygotic mutation during em-


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Figure 1: Pigmentary patterns associated with human mosaicism, ie, type 1a, lines of Blaschko, narrow bands (top left); type 1b, lines of Blaschko, broad bands (top center); type 2, checkerboard pattern (top right); type 3, phylloid pattern (bottom left); and type 4, patchy pattern without midline separation (bottom right). Note: reprinted with permission from Archives of Dermatology.

bryogenesis, as for example in McCune -Albright syndrome. Genetic mosaics can show different patterns (figureâ&#x20AC;Ż1). The clinician should be aware of those and realize that they can signify the presence of a pervasive genetic disorder. In this chapter we discuss several examples of genodermatoses. For references see the OMIM database. 1. Neurofibromatosis type 1, OMIM #162200 Neurofibromatosis peripheral type or Neurofibromatosis type I (NF1) is one of the most frequent genodermatoses with an incidence of 1 in 2,500 to 1 in 3,000 individuals. The disorder is inherited in an autosomal dominant fashion, but about 50% of cases represent de novo mutations. Individuals have increased susceptibility to the development of benign and malignant tumours. The disorder is caused by mutations in the neurofibromin gene that is localized on chromosome 17. Criteria for the diagnosis are summarized in table 1. The first signs are the presence of cafĂŠ-au-lait spots, axillary and inguinal freckling (figure 2). Later in childhood neurofibromas develop. Plexiform neurofibromas are deeply localized, thick and irregular, in contrast to their cutaneous and subcutaneous counterparts, which are well demarcated and do not


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17. Venous Disturbances W.J. Koeyers MD Introduction Venous disease is one of the most prevalent diseases in the Western world. Chronic venous disease may be accompanied with serious morbidity. It is reported in the literature that approximately 1-3% of the total health consumption is for the account of venous disease.1 The reported prevalence of chronic venous disease varies from 1-17% in men and from 1-40 % in women.2 A higher prevalence of varicose veins is reported in women in some studies. Selection bias may be a factor contributing to the difference in prevalence in these studies and in some of the studies there has not been an adjustment for age. Age and pregnancy are considered risk factors for the development of venous disease. Other factors probably aggravating the development of varicose veins are obesity or occupations and hobbies involving long standing hours. Geographic variations in prevalence data suggest a correlation with ethnicity. The prevalence of varicose veins has been reported to be higher in developed countries than underdeveloped countries. Most of the studies are survey studies based on visible disease. To our knowledge two studies by respectively Evans3 et al and Criqui et alš base their conclusions on the assessment of visible and functional disease. Criquiâ&#x20AC;&#x2122;s study of 2211 participants showed that compared with non- Hispanic whites, Hispanics, African American and Asians had a lower prevalence of visible and functional venous disease. Mekkyâ&#x20AC;&#x2122;s study in 1969 showed an overall prevalence of 32% in English women cotton workers compared to the 6% prevalence for the Egyptian women.4 A community study in Jerusalem by Abramson in 1981 showed a lower prevalence for varicose veins in people born in North Africa compared to the participants born in Asia, Europe, America or Israel.5 The cause for the difference in prevalence is not clear and insufficiently researched. The reason lies possibly in life style differences. This explanation is possibly backed up by the findings from Pannier-Fischer and Rabe6 that there are even differences between rural and urban areas within one Western country. Lifestyle differences proposed are position for defaecation or dietary differences for example low fiber diets with straining at stool with possibly higher abdominal pressures on the iliac vein that are passed on to the leg veins.5 Other possible related factors could be different occupations and different behavior in the underdeveloped countries for example less standing during non working hours.7 Anatomy Generally, the venous system of the lower limb can be divided in beisenreiser veins, reticulair veins, the main venous trunks, tributaries and the deep venous system. The superficial venous system consists mainly of the two venous trunks, the great and small saphenous veins. The great saphenous vein is located on the medial side of the leg and the small saphenous vein on the dorsal side of the lower leg. These veins and their tributaries are con-


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The venous systems of the lower limb.

nected to the deep veins by perforating veins and connected to each other by communicating veins. There are more than 150 perforating veins, but only a few are of clinical relevance.8 The deep venous system of the lower limb can be divided in the intermuscular veins, such as the popliteal vein and the femoral and the intramuscular veins such as the gastrocnemius veins and soleal veins. There can be a wide variation in the venous anatomy of the lower limb between individuals. A racial difference in venous anatomy has not clearly been researched. There are reports in the literature of differences in distribution of venous valves in the lower limbs.9 In Banjoâ&#x20AC;&#x2122;s study there is a lower incidence in the number of valves in Caucasians compared to black Africans. This may be one of the explanations for the difference in prevalence of varicose veins and chronic venous disease.


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18. Cosmetic Science and Care for Darker Skin M. Verschoore MD N. Hainault Introduction To identify ethnic skin characteristics is a prime step towards designing the best skin care, or even the most efficient treatment for skin diseases. Recent studies have focused on the specificities of cosmetics and hair care for black skin population living in northern Europe. This review is based on scientific papers that provide relevant data on ethnic skin to date. I â&#x20AC;&#x201C; Black skin Understanding black skin reactivity to environment is helpful to realize specific concerns of black skin population and to develop appropriate skin care products. In this part, we make an actual overview of black skin from a structural and functional standpoint. 1- Physiological characteristics A- Epidermis Layers Within the epidermis of black skin, we can identify some specific features of the different layers and especially regarding the stratum corneum (SC). The SC in black skin is as thick as in white skin, but in black skin it contains more corneocyte cell layers (mean 21.8 in black vs. mean 16.7 in white skin SC).1 This characteristic can be explained by greater intercellular cohesion in black skin, which leads to more cell layers and better resistance to tape stripping. Thus more cellophane tape strips are required to remove the SC from black skin, in comparison with white skin. Experiments have shown that the mean electrical resistance of adult black skin is twice that of adult caucasian skin, which may explain the increased cohesion of the SC in black skin.2, 3 Table I summarizes the most important characteristics of black skin SC. Number of SC layers

Increased1

Resistance to stripping

Increased1

SC Cohesion

Increased2

SC Thickness

Equal4

Electrical resistance

Increased5

Recovery after stripping

Increased6

Table 1: Stratum corneum main differences in black skin compared to Caucasian skin.


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Cells and molecular composition There is a great diversity of color in black skin, which depends on the amount of melanin packaged within melanosomes in the skin. Differences in skin color are not due to differences in melanocyte number, but depend on differences in melanosome number, size, shape and distribution.7 African skin is characterized by the largest melanosomes whilst Caucasian skin presents the smallest organelles. Moreover, melanosomes are present singly within keratinocytes in black skin, whereas they are aggregated in caucasian. Unlike in African skin, melanosomes are not present in the SC of Caucasian skin. Melanin content and melanin type (eumelanins) give a better protection to black skin against UV radiations.8 Another difference has been observed in the intercellular cement of the SC, namely the amount of ceramides which are found at a lower level in black skin: the total ceramide level is approximately 50% lower in the SC of black compared to caucasian skin.3

Figure 1: DEJ pattern in Caucasian skin (a, c) and African skin (b,d) (donors age in years: a: 25, b: 30, c: 25, d: 26). Scale bar: 50Âľm. Lâ&#x20AC;&#x2122;Oreal, data on file.

B- Dermal-epidermal junction Girardeau et al. (2009)9 carried out investigations into dermal-epidermal junction (DEJ) and the differences between Caucasian and African skin types. Primary DEJ function is to ensure the interface and the cohesion between the epidermis and the dermis so that communication and nutrients exchanges between the cells of the two compartments are made easier. African DEJ is characterized by a highly convoluted appearance compared to Caucasian, which is typi-


Textbook of Ethnic Dermatology