pigmentary disorders in oriental skin

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2 Pigmentary Disorders in Oriental Skin Mihoko Jimbow, MD, and Kowichi Jimbow, MD From the Diti of Lkrmatology and Cutaneous Sciences, University of Alberta, Faculty of ilfedicine, Edwwnton, Alberta, Canada. Supported in part by thx Alberta Heritage Foundation for Medical Research 0iology of Melanin Pig- and Types ofAbnormaIPigmenkrtion The color of normal human skin is related to the number, size, type, and distribution of cytoplasmic pigment granules called melanosomes, which contain a biochrome, melanin. These specialized organelles are the product of melanocytes that rest on the basal lamina and project their dendrites into the epidermis. Melanocytes transfer their products, the melanosomes, into the Malpighian cells (keratinocytes), and the melanosomes are thereby distributed throughout the epidermis by the outward movement of keratinocytes. No skin color attributable to melanin is visible unless melanin enters into the keratinocytes from the melanocytes in which it is synthesized. It is the amount of melanin in the keratinocytes that determines the pigmentation of the skin and hair. The various amounts of melanin in the keratinocytes produce the wide spectrum of human skin color found in the various races; albino skin is basically identical in all racial groups. Together, the melanocytes and associated keratinocytes form an epidermal melanin unit. Human skin contains a large number of these units, and its color is the visual impact of melanin within them. The subcellular processes for melanin synthesis underlying in the oriental skin are different from those of negroid black and Caucasian white skin. In the orientals, the melanosomes range c 0.6 X 0.3 pm in size, are mostly in stage 3 and 4 in melanocytes and are distributed as a mixture of single and complex forms of melanosomes. In negroid black skin, the melanosomes are large, c 1.0 X 0.5 pm, heavily pigmented in stage 4 in melanocytes and singly distributed in keratinocytes, whereas in white caucasian skin they are small c 0.5 X 0.3 pm, less-melanized in stage 2 or 3 in melanocytes and distributed as aggregates (melanosome complex) in keratinocytes (Fig. 2-l).l 11

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Page 1: Pigmentary disorders in oriental skin

2 Pigmentary Disorders in Oriental Skin

Mihoko Jimbow, MD, and Kowichi Jimbow, MD

From the Diti of Lkrmatology and Cutaneous Sciences, University of Alberta, Faculty of ilfedicine, Edwwnton, Alberta, Canada.

Supported in part by thx Alberta Heritage Foundation for Medical Research

0iology of Melanin Pig- and Types ofAbnormaIPigmenkrtion

The color of normal human skin is related to the number, size, type, and distribution of cytoplasmic pigment granules called melanosomes, which contain a biochrome, melanin. These specialized organelles are the product of melanocytes that rest on the basal lamina and project their dendrites into the epidermis. Melanocytes transfer their products, the melanosomes, into the Malpighian cells (keratinocytes), and the melanosomes are thereby distributed throughout the epidermis by the outward movement of keratinocytes. No skin color attributable to melanin is visible unless melanin enters into the keratinocytes from the melanocytes in which it is synthesized. It is the amount of melanin in the keratinocytes that determines the pigmentation of the skin and hair. The various amounts of melanin in the keratinocytes produce the wide spectrum of human skin color found in the various races; albino skin is basically identical in all racial groups. Together, the melanocytes and associated keratinocytes form an epidermal melanin unit. Human skin contains a large number of these units, and its color is the visual impact of melanin within them. The subcellular processes for melanin synthesis underlying in the oriental skin are different from those of negroid black and Caucasian white skin. In the orientals, the melanosomes range c 0.6 X 0.3 pm in size, are mostly in stage 3 and 4 in melanocytes and are distributed as a mixture of single and complex forms of melanosomes. In negroid black skin, the melanosomes are large, c 1.0 X 0.5 pm, heavily pigmented in stage 4 in melanocytes and singly distributed in keratinocytes, whereas in white caucasian skin they are small c 0.5 X 0.3 pm, less-melanized in stage 2 or 3 in melanocytes and distributed as aggregates (melanosome complex) in keratinocytes (Fig. 2-l).l

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Dermatoloclv

TYROSlNE&3PA~DOPAQUlNONE +CYCLIZED INTERMEDIATES) --~=~bJi~]

-CYSTEINE

FIG. 2-l. Epidermal melanin unit of oriental skin. In the melanocytes, the melanosomes (MS and PMS)

are mostly in stages 3 and 4. They are distributed as either single or complex unit in the keratinocytes.

There are three categories of melanin pigmentary disturbances: (1) brown hyperme- lanosis (melanoderma), (2) blue or gray/slate hypermelanosis (ceruloderma), and (3) hypomelanosis (leukoderma, white or lighter than the individual’s normal color). The three categories of hypermelanosis and hypomela- nosis are largely dependent on the location of melanin pigments in both the epidermis and dermis of the skin. In brown hypermelanosis, melanin pigments are mostly located in the epidermis. In gray and slate hypermelanosis. melanin pigments are predominant in the upper dermis, whereas in blue hypermelanosis they are present in the deep dermis. By contrast, hypomelanosis (leukoderma) derives from either a decrease in the number (amounts) of melanin pigments or their complete absence in both epidermis and dermis (Fig. 2-2).

This chapter describes only certain aspects of hypermelanoses and hypomelanoses of the skin, and emphasis will be made on those pigmentary disorders that are frequently and/ or characteristically seen in orientals.

Hypermelanosis Disorders

Brown Pigmentation

Brown pigmentation derives from increased melanin in the epidermis of the skin and usually reflects increased synthesis, size, and/ or melanization of melanosomes due to either an increased number of functioning melano- cytes or an increased function of melanocytes without changes of their number.

Hypermelanosis may be circumscribed or diffuse. Circumscribed lesions may be single or multiple in number, randomly distributed or confined to sun-exposed areas, and asso- ciated with systemic abnormalities or an isolated finding. Hypermelanoses are asso- ciated with increased melanin in melanocytes of the basal layer and in keratinocytes. Some brown hypermelanoses may be associated with dermal phagocytes or ectopic dermal melan- ocytes (blue) containing melanin to represent a mixed type of hypermelanosis. With Wood’s lamp examination the epidermal component becomes more apparent and the dermal

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April-June 1989 Volume 7 Number 2 Piamentarv Disorders in Oriental Skin 13

NORMAL PIGMENTATION WHITE LEUKODERMA

, . . . . . .

BROWN MELANODERMA WHITE LEUKODERMA

GRAY/SLATE CERULODERMA BLUE CERULODERMA

. . l . . . --

FIG. 2-2. Distribution of melanin and melanocytes

in the skin of various pigmentary disorders.

component is less apparent or unchanged in intensity.

Caf&au-Lait Macules

Cafk-au-lait macules are discrete, well- circumscribed, 2-20 cm, uniformly pale brown macules characterized by serrated or irregular margins, appear at or soon after birth, and tend to disappear with age. CafC-au-lait macules are common cutaneous findings but can be markers for multisystem diseases. These diseases include neurofibromatosis, Albright’s syndrome, Silver-Russel syndrome, WaterhoPs syndrome, Watson’s syndrome, and Bloom’s syndrome. Among these diseases, neurofibromatosis is the most common form in which caf&-au-lait macules are found in 90- 100% of affected patients (Fig. 2-3). The incidence of neurofibromatosis is equal in both sexes. Sixty percent to 75% of patients with multiple cutaneous neurofibromatosis have at least six such macules with 43% present at birth and 63% appearing in the first year. Multiple caf&au-lait macules in normal children younger than the age of five years

FIG. 2-3. Caf&au-lait macules in a patient with

neurofibromatosis.

are rare, and the presence of five or more such macules that are 0.5 cm or larger makes the diagnosis of neurofibromatosis mandatory until proven otherwise. Microscopic study of dopa-incubated split-skin preparations show giant pigment granules in melanocytes or keratinocytes or both. Such giant pigment granules are known as “macromelanosomes’q or melanin macroglobules.3These granules are helpful in distinguishing neurofibromatosis from Albright’s syndrome; however, the absence of macromelanosomes in caf&au-lait macules does not exclude the diagnosis of neurofibromatosis. A recent study of Japanese cases4 indicated that the population and structure of melanocytes differ greatly depending on the coloration of caf&au-lait macules. The light brown and brown macules show the normal population of melanocytes with an increase in the area and perimeter of whole cells. In contrast, the dark brown macules revealed a significant increase of epidermal melanocytes with a decrease in the area, perimeter, and diameter of cytoplasm as well as the area, length, and breadth of dendrites.

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FIG. 2-4. Becker’s hairy nevus on the left lateral

trunk.

Becker’s Melanosis (Pigmented Hairy Epidermal Nevus)

Becker’s melanosis is a fairly common lesion in the orientals, but it is also found in all races. is five times more common in men than women, and usually appears in the second or third decade. It is characterized by a uniformly fair to dark brown macule, a few to many centime- ters in diameter, and is demarcated by borders that are sharply outlined but highly irregular (Fig. 2-4). Five percent are pruritic. Spontane- ous fading is rarely noted. Association with underlying tissue hyperplasia has been reported. Time of onset, morphology, and presence of hypertrichosis distinguish this from caf&-au-lait macules. There is markedly increased melanin pigmentation of the basal and suprabasal layers. The number of melan- ocytes is usually normal or slightly increased. Although in men many of Becker’s nevi become hairy, usually in the later teens, in some (particularly in women) they do not form hypertrichosis. A recent study indicated that androgen stimulation plays a role in the pathogenesis of Becker’s nevus,” which is an organoid hamartoma with epithelial and mesenchymal elements.

Nevus Spilus

Nevus spilus is characterized by the pres- ence of two different clinical pictures, one with pigmented macules and the other with pig- mented papules, both overlying a caf&au-lait macule. News spilus is present at birth and is essentially a caff&au-lait macule containing darker macules or papules l-2 mm in diame- ter. Often it is necessary to use the Wood’s lamp to discern the cafe’-au-lait macule background. This disorder has also been reported as zosteriform lentiginous nevus. In most cases, nevus spilus is an idiopathic cutaneous anomaly.

Ephelides (Freckles) and freckle-like Pigmentation

Ephelides or freckles are small, usually less than 0.5 cm in diameter, discrete brown macules that appear on sun-exposed areas. Freckles appear in the first three years of life and are not found in unexposed areas or mucous membranes. The occurrence of freck- les in orientals is not so high as seen in Caucasian whites. Freckles may be an auto- somal dominant inheritance.

Dyschromatosis Symmetrica Hereditaria

Spotty (usually pinpoint size) or reticular macules of brown pigmentation and depig- mentation are scattered on the dorsal aspects of digits, feet, and hands, extending occasion- ally to the legs and arms. Freckling can also be seen on the face. The degree of pigmentation is usually more significant on the acral parts compared with the proximal parts of the extremities. The same diseases are called variously by several investigators: acropig- mentatio symmetrica, leukopathies pun&&a et reticularis symmetrica (Fig. 2-5). The pattern of freckling resembles that of xero- derma pigmentosum; thus, there is a sugges- tion that this disease is a variant of xeroderma pigmentosum; however, there is not any telangiectasia and sun-damaged skin as can be typically seen in xeroderma pigmentosum.

When freckling of brown pigmentation and depigmentation occurs on the entire body

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April-June 1989 Volume 7 Number 2 Piamentaw Disorders in Odenial Skin 15

FIG. 2-5. Dyschromatosis symmetrica hereditaria on the dorsal aspects of the hands.

surface, the disease is called dyschromatosis universalis hereditaria (Figs. 2-6 and 2-‘7).8

Acropigmentatio Retiiularis

Acropigmentatio reticularis refers to the reticular brownish pigmentation occurring on the dorsal surface of digits (toes, fingers), forearm, lower leg, and, rarely, the nape and shoulder (Fig. 2-8).

Each freckle follows the skin surface marks, thus forming irregular brownish polygonal pigmentation. Palms and soles are not involved. The disease occurs at late childhood and puberty?-”

FIG. 2-7. Dyschromatosis universalis hereditaria seen on the feet, legs, hands and arms. The same patient is shown in Figure 2-6.

FIG. 2-6. Dyschromatosis universalis hereditaria seen on the upper back, shoulder, and nape.

Peuiz-Jeghers Syndrome

Peutz-Jeghers syndrome is a phakomatosis characterized by gastrointestinal polyps and pigmented macules on the oral mucosa, lip, and skin. This syndrome was first reported by Peutz in 1927 describing pigmented macules of the lips, palms, and soles in association with intestinal polyposes. Later, in 1946, Jegher summarized the various features of clinical manifestations.

The first Japanese case of a clinical feature identical to Peutz-Jeghers syndrome was reported by Nagasu et al, in 1955, who de- scribed a case with abnormal pigmentation

FIG. 2-8. Acropigmentatio reticularis on the prox- imal parts of hands and feet.

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FIG. 2-10. Peutz-Jeghers syndrome, in which

brown spots appear on the toes.

and intestinal polyposis. The term Peutz- Jeghers syndrome was, however, first introduced by Yamazaki et al, in 1957.7

The Peutz-Jeghers syndrome is an autosomal dominant disorder. Bartholomew et al, found 41 of 75 cases (55%) occurring as a family basis.6 Soma et al. reported 46% of 127 occurring as a hereditary family basis. The pigmented macules may be present at birth or at childhood or at puberty. They are most common on the buccal mucosa and the lips. They are brown or dark brown in color. They are more common on the lower lip than the upper lip (Fig. 2-9) and often start from the oral angle toward the center of the lip. They may be seen on the hard palate and even nasal mucosa. The macules of the skin are usually found on the face, hands (especially palms and dorsa of fingers), and feet (soles). The lesions of the face resemble closely to those of freckles. The most characteristic skin manifestation is seen on the palmoplantar and volar areas where they can be prominent in the acral part of the fingers and toes (volar aspects) and anterior and posterior parts of the soles (lacking on the plantar arch) (Fig. 2-10). They are ellipsoidal rather than ovoid in shape, and their long axis corresponds along the skin marks. The pigmented macules of lip and skin may disappear with age, but those of buccal mucosa do not disappear.

Histologically, the brownish macular lesions of the lip reveal the lentiginous elongations of rete ridges with heavy deposits of melanin

FIG. 2-11. Multiple polyps in the jejunum of a

patient with Peutz-Jeghers syndrome.

pigments in the basal and spinous layers. The palmoplantar lesions reveal characteristic manifestations featuring a marked melanin pigmentation with a pigment blockade on the crista intermedia of epidermal rete ridges where sweat ducts are connected, whereas an absence of melanin pigments on the crista profunda limitans where sweat ducts are not connected.7

Gastrointestinal polyps may be found anywhere in the small bowel but especially in the jejunum (Fig. 2-11). The number and rate of growth of these polyps are variable. The polyps usually become symptomatic between the ages of 10 and 30 years and may cause ulceration with bleeding, obstruction, diar- rhea, and intussusception. Malignant changes are not a feature unless the polyps are found in the large intestines.

Melasma

Melasma, a name derived from the Greek word melas, meaning black, is used to describe an acquired brown or grayish brown hyper- melanosis involving the face and sometimes the neck. In the Japanese literature, chloasma is a term commonly used to connote melasma, and it is derived from the Greek word cloazein, meaning to be green. Clinically, melasma is

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a circumscribed light-brown to dark-brown macular hyperpigmentation of the face, neck, and, rarely, of the forearm (Fig. 2-12). Therefore, acquired hypermelanosis of the face should be correctly designated as melasma, rather than chloasma.

The pattern of distribution of melasma is strictly limited to the lightexposed areas. The hyperpigmentation develops slowly and often symmetrically; it may be linear, streaming down the cheeks, or confetti-like pigmented macules. The color is usually deep brown appearing splotchy, much like lentigo maligna. The pigmented lesions are located on the forehead (frontal), in arches capping the eyebrows (periorbital and supraorbital), on the dorsum of the nose, on the cheeks in a butterfly pattern (zygomatic and buccal areas), on the upper lip like a moustache, and sometimes perioral. Occasionally, hyperpigmentation may stream down the cheeks (mandibular areas) without involving the frontal areas and may extend to mental and submaxillary regions. Rarely, one may observe hypermela- notic areas extending below the chin, the V- neck area, or to the dorsum of the forearms. Three patterns of melasma can be recognized clinically: centrofacial, malar, and man- dibular.*

FIG. 2-12. Melasma on the face.

The pathogenesis of melasma is unknown, and many causative factors have been impli- cated as playing a role in its etiology. Pregnancy, contraceptives, estrogen, proges- terone, certain cosmetic ingredients, and certain drugs are known etiologic factorsa’ Sunlight and genetic predisposition appear to be major factors associated with melasma of Japanese cases. Although no sex, race, or age is exempt from developing melasma, it is far more common in women than men and in persons of oriental origin living in sunny locations.

Brown Pigmentation Secondary to Endocrinopathies

obscure, although parallels exist with the comparable phenomenon in frogs. Administra- tion of CY-MSH to human subjects results in a marked gross hyperpigmentation of the skin, characterized at the cellular level by increased numbers of melanosomes with keratinocytes and by dendritic melanogenic melanocytes. It is presently believed that MSH may cause a dispersion of melanosomes within melano- cytes, enhancing thereby both the movement of melanosomes in the dendrite and their melanogenic activity; there is also an asso- ciated increased transport within keratino- cytes. This biologic process is also controlled by increased level of cyclic AMP. Studies on the consequences of MSH administration to guinea pigs have yielded results comparable with those found in humans.

Hormones profoundly influence the melanin Marked regional variation appears to exist pigmentation of human skin and that of other in the sensitivity of the epidermal melanin mammalsi Their precise action at the cellular units to specific hormones. In the pregnant level (epidermal melanin unit) is still largely human female, there is increased pigmenta-

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FIG. 2-13. Pigmentation on the lip and gingiva in a patient with Addison’s disease.

FIG. 2-14. Addison’s disease: pigmentation on the

fingers.

tion of the nipples and areola accompanied to a lesser extent by increased pigmentation of the facial skin, the anterior abdominal wall in the midline, and the genitalia. Biopsies from the abdominal wall have confirmed that the darkening is associated with an increase in the number of active melanocytes. Similar find- ings have been made in guinea pigs. In both, it appears that the hormones primarily responsible for the color changes are estrogen and progesterone (and possibly MSH), to which epidermal melanocytes at different anatomic sites may possess differing responsiveness. Administration of androgens and estrogens to castrated guinea pigs supports the idea of such regional specificity in melanocyte responses to hormonal challenge. A certain number of endo- crinopathies cause brown hypomelanosis.1”

Addison’s Disease: Addison’s disease is often considered the prototype for diffuse hypermelanosis with accentuation in light- exposed areas, creases of palms and soles, folds, and recent scars. Normally deeply pigmented areas, such as nipples and genitalia, and buccal, conjunctival, and vaginal mucous membranes, may also darken. This results from increased ACTH and MSH production. Similarly, exogenous ACTH and ACTH- producing tumors (pancreas, lung) cause similar pigment darkening. Parenteral MSH administration has the same effect (Figs. 2- 13 and 2-14).

Cushing’s Syndrome, Acromegaly, Nel- son’s Syndrome, Carcinoid, and Hyperthy- roidism: These endocrinopathies may also give rise to a degree of hypermelanosis. The disorders in which increased ACTH and MSH are found may be characterized by brown or blue gingival or buccal macules. Addison-like hyperpigmentation with Cushing’s syndrome suggests a pituitary tumor and may also follow adrenalectomy, despite adequate replacement with cortisone. Ectopic ACTH production as from oatcell carcinoma results in hyperpig- mentation; this tumor has a distinct MSH-like component, which is more marked than the ACTH-like activity.

Slate/Blue Pigmentation (Ceruloderma)

The term ceruloderma (from Latin, caerul- leus, meaning blue) was introduced to describe the various clinical syndromes that are characterized by melanin or nonmelanin hyperpigmentation of the dermis.13 It derives from the following processes: (1) melanin formed in the dermal melanocytes (dermal melanocytotic hyperpigmentation); (2) melanin formed in the epidermis by epidermal melanocytes and transferred to the dermis (dermal melanotic hyperpigmentation), and (3) nonmelanin pigment that is deposited in the dermis (nonmelanin dermal pigmentation).

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An important fact regarding dermal slate/ blue hyperpigmentation is that melanin pigment deposits within dermal melanocytes do not become accentuated when viewed with the Wood’s lamp. This is in striking contrast to melanin pigmentation in the epidermis, which is markedly enhanced when viewed with the Wood’s lamp.

Mongolian Spots

The term Mongolian spot or congenital dermal melanocytosis refers to a blue-black pigmentation observed first at birth (congen- ital) in more than 90% of orientals (Asiatic races and American Indians), less frequently in blacks, and in less than 10% of whites.

It was Erwin Balz, a German professor teaching internal medicine at the Tokyo University, who reported first blue spots on the buttock of Japanese children and termed it “Mongolian spot.” The blue spots had been previously thought to be bleeding spots due to delivery.

The Mongolian spots derived from the dermal melanocytes that migrate from the neural crest to the dermis of the skin at 6- 8 weeks embryonic period but fail to migrate to the epidermis and remain in the dermis. It is not known why the melanocytes at the certain anatomic locations fail to migrate to the epidermis. It is also unknown why the racial difference in the incidence of Mongo- lian spots occurs. It may be possible that in Caucasians the Mongolian spots are not visible macroscopically because the size of melano- somes and their degree of melanization are lower compared with those of Mongolian (orientals) skin. This, however, does not explain the fact that the incidence of Mon- golian spots is also low in black negroid people. One possibility is that the Mongolian spots originate as the result of the introduc- tion of mutant gene 10,000 years ago in the Mongoloid people.14 Clinically two forms of Mongolian spots are noted: most frequent form of sacral spots and extrasacral spots (Fig. 2-15). The degree of pigmentation in the two forms is maximal at the age of 2 years; then they will gradually fade and disappear

Ra. 2-17. Ocular melanosis in the nevus Ota.

at the age of 6 or 7 years. The sacral Mon- golian spots are not seen in the perianal region.

New of Ota

The nevus of Ota is a congenital or acquired pigmentary disorder of the skin and mucous membranes, frequently observed in orientals (Mongolians). In 1937 this disorder was first reported by Ota. In 1939 and 1940, Tanino described the clinical features of 26 cases of nevus of Ota. In this disorder, the pigmentation is usually unilateral, being most pronounced on the eyelids and in the zygomatic and maxillary regions. These areas are innervated by the first and second branches of the trigeminal nerve. The pigmentation of nevus Ota is composed of brown and blue macules, and the size of the lesions varies from one to several millimeters in diameter (Figs. 2-16 and 2-17).‘6

Based on the distribution and the extent of pigmentation, nevus of Ota has been classified into four types: mild, type I, a and b; moderate, type II; intensive, type III; and bilateral, type IV.

In the mild orbital type (type Ia), the arrangement of the pigmented spots is scat- tered; they are distributed over the upper and lower eyelids, periocular, and temple regions. In the mild zygomatic type (type Ib), the pigmentation is found between the infrapal- pabral fold and the nasolabial fold and over the zygomatic region. There are two additional types, a mild forehead type (type Ic) and a mild

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FIG. 2-18. Oral pigmentation of patient with nevus Ota.

ala nasi type (type Id). In the moderate type (type II), the pigmented spots distribute over the upper and lower eyelids, periocular and zygomatic region, cheek, and temple. In the intensive type (type III), the lesions spread to the scalp, hard palate, forehead, eyebrow, ear, and nose (Fig. 2-18). In the bilateral type (type IV), the pigmentation shows a bilateral distribution.

The incidence of this disease was reported to be 0.4-0.8% in the Japanese literature. The sex ratio is 1:4.8, women being more frequently involved than men. The majority of the patients visit the hospital in early childhood or between 17 and 24 years of age. The two peaks of the onset of nevus Ota (one in the early childhood and another in the teens) suggest the activity of dermal melanocytes in this disease is stimulated in the two periodsifi

The skin pigmentation may be of various hues: black, black-purple, blue black, deep blue, blue, fading blue, slate blue, purplish brown, or faint brown. The intensity of skin pigmentation may vary from day to day, especially in female patients. An increase in pigmentation is noticed during or before menstruation. This fluctuation in color may be related to pituitary or ovarian hormonal stimulation of dermal melanocytes.

Ocular melanosis is a common complication that can be approximated to be 61.3% of the nevus of Ota. In a survey by Kukita et al.15 the incidence of the association of ocular and oral melanosis was 22.0% and lo%, respectively.

Other complications, such as neurologic symptoms or bone anomalies, are not usually found in this disease. No cases have been reported of malignant changes in nevus Ota in Japanese. This is a distinct contrast to the frequency of malignant nevus Ota in cauca- sians reported in the European and American literature.

In general, nevus Ota is not a hereditary disease. Although two families in which nevus Ota occurred in two members have been recorded, familial incidence is thought to be rare.

Nevus of Ota is a life-long pigmentary disorder and has no possibility of spontaneous regression. The major pathology of nevus Ota is seen in the dermis where melanocytes extend bipolar or stellate dendrites in the upper, middle, and lower reticular layer of the dermis. The long axis of dermal melanocytes is often parallel to the skin surface and is nearly in accordance with the course of the connective tissue. Pigment cells are also present around the small blood vessels, sweat glands, and sebaceous glands. Under electron microscopy, dermal melanocytes contain many melano- somes, 0.4-0.8 pm in diameter. They are fully melanized at stage 4 of development. Basal lamina and lamina lucida are recognized as surrounding some dermal melanocytes. Out- side the basal lamina or outside the plasma membrane of the dermal melanocytes, extra- cellular sheaths of varying thickness surround dermal melanocytes. The extracellular sheaths are periodic acid Schiff (PAS)-negative, com- prised of fine filaments of 20-40 A in diameter.

Nevus of Ito (Nevus Fusco-caeruleus Acromiodeltoides)

This is a variant of nevus Ota and was described by Ito in 1954.17 The nevus of Ota and nevus of Ito may occur in the same patient. In nevus of Ito, the skin involvement occurs in the distribution of the lateral supraclavic- ular and lateral brachial nevus. The pigmen- tation of the nevus of Ito has the same clinical features as the nevus of Ota except that the pigment is more diffuse and less mottled.

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lncontinentia Pigmenti

Incontinentia pigmenti is a specific neuro- utaneous hereditary disease often apparent at birth. Incontinentia pigmenti primarily affects women. Of reported cases, nearly 97% are women and 3% are men. The pattern of inheritance may be X-linked. The typical skin lesions occur in three stages of evolution in incontinentia pigmenti. Onset of the vesiculo- bullous stage of the disorder is at birth or within two weeks of birth in most cases (Fig. 2-19). Onset up to 1 year, or in adulthood, has also been described. The verrucous stage may begin from the second to the sixth week and the pigmentary stage from the 12th to the 26th week of age. Usually all three stages occur, but up to 14% of cases have only the pigmentary findings. The inflammatory vesiculobullous stage may persist for months. These vesicles, which may coalesce, are scattered, often linearly, over the trunk and extremities and may cross the midline but do not correspond to any dermatome or line of cleavage, corres- ponding occasionally to that of Blaschko’s line. The lateral trunk and the premammary areas are the most common sites of involvement; however, when the vesiculobullous stage is localized, lesions are most likely to occur on the extremities. Leukocytosis and up to 65% eosinophils may accompany this stage. The verrucous papillomatous or hypertrophic phase is superseded by whorls, strands, and bands of hyperpigmentation. Not all hyperpig- mentation seems to be postinflammatory. The pigmentary findings are bizarre, macular, hyperpigmented lesions that are brown, dirty brown, and slate gray. The color of these lesions steadily intensifies until about the age of two years, and then the pigmentation gradually fades and continues to do so through adoles- cence and early adulthood. In many cases, the discoloration completely disappears by the 20th year. Atrophic patches and streaks are uncommon. Up to 14% develop depigmenta- tion. The fact that some children are born exhibiting one or all stages of the disease simultaneously, including the hyperpigmenta- tion stage, suggests that the eruption begins and progresses in utero. Changes in hair such

as scarring alopecia, and nail changes, which include thin, flat, or spoon-shaped nails associated with longitudinal and transverse striae, have been described. Many other abnormalities have been reported in patients with incontinentia pigmenti, eg, ocular abnor- malities (20-33%), including strabismus, nystagmus, blindness, cataracts, blue sclera, optic nerve atrophy, retinal pigmentation, myopia1 pseudoglaucoma, exudative choriore- tinitis, papillitis, retinal detachment, and lesions that presented as masses in the posterior chamber. Skull deformities, dwarf- ism, spina bifida, cleft palate and cleft lip, and ear abnormalities are also rarely encountered. Dental abnormalities include delayed denti- tion, pegged teeth, impactions, and abnormal- ities in crown formation of the permanent teeth. Almost one-half of all the patients with incontinentia pigmenti exhibit various neuro- logic abnormalities. Mental retardation and spastic paralysis occur in over 10% of patients. Convulsions and microcephaly are also observed.

The histopathology of the skin lesions correlates with the corresponding clinical phase. In the vesiculobullous phase, eosino- philic spongiosis with vesicle formation and clusters of intraepidermal, whorled, variably dyskeratotic keratinocytes are diagnostic. In addition, the dermis contains an infiltrate of eosinophils, mononuclear cells, activated lymphocytes, and basophils. Moreover, baso- phils, eosinophils, and mast cells are noted in stages of partial degranulation.20

Degranulating cells are frequently asso- ciated with dyskeratotic keratinocytes, and are observed in inflammatory infiltrates sur- rounding vessels that exhibit evidence of endothelial cell swelling and luminal blebs. These vascular alterations and the nature of the associated inflammatory infiltrates sug- gests that the underlying defect in incontinen- tia pigmenti may be of immunologic origin. The presence of numerous basophils raises the possibility that the early lesions of incontinen- tia pigmenti are a form of delayed hypersen- sitivity reaction, perhaps similar to cutaneous basophil hypersensitivity. Delayed hypersen- sitivity reactions have been shown to exhibit

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activated lymphocytes and degranulation of basophils.21

It is possible that in the early stages of immunologic development an abnormal response to antigenic stimuli may occur, and, indeed, altered immunologic reactivity has been observed in some patients with inconti- nentia pigmenti.22~23

Eosinophils are numerous both within the superficial dermis and in the epidermis. Often, degranulation of eosinophils is associated with degenerative alterations of keratinocytes. Eosinophils have been shown to contain a major basic protein within their granules that is cytotoxic for epidermal cells in the guinea pig and in various experimental models.24 It is therefore likely that eosinophils play an important role in the pathogenesis of early epidermal alterations in incontinentia pigmenti.

In the second or verrucous phase, epidermal hyperplasia, hyperkeratosis, and scattered dyskeratotic cells with keratinocytes in a whorled pattern can be observed in association with a dermal infiltrate of mononuclear cells. In the third phase or pigmentary phase, melanin-laden macrophages are numerous in the upper dermis, and vacuolization of basal cells can be seen.

The underlying cause for the recruitment of the aforementioned inflammatory cells in incontinentia pigmenti is unknown. Presum- ably, an antigen as an expression of an inherited development anomaly triggers a response by activated lymphocytes. Both anticytoplasmic antibodies25 and chromosomal anomalies26 have been documented in this disorder. The localized pattern of cutaneous involvement may indicate a mosaic expression of an abnormal gene in incontinentia pigmenti.

I?iehl’s Melanosis

Riehl’s melanosis, first described by Gustave Riehl in 1917, is a black to brown-violet colored pigmentary disturbance, characterized by reticular pattern of arrangement and follic- ular hyperkeratosis on the face (forehead, cheek, ear), neck and nape.

Most patients affected are middle-aged women, but men are not exempt. Riehl first indicated that this disorder derives from an ingestion of noxious substances. Later, how- ever, Hoffmann and Habermann suggested that photosensitizing substances contained in the crude mineral oil may play a role in evoking a similar condition, “melanodermal toxica biodenoides et bullosa.”

In Japan Riehl’s melanosis was not common until after WWII. After 1943 the number of patients had increased rapidly, and it was called “melanosis facicii feminea” (Fig. 2-20).

A number of factors may play an important role for evolution of the disease: chemical irritation by an incriminated material, predis- position of individual, UV light, and rubbing with hands. In many cases UV exposure has been noted prior to the onset of melanosis.

Histopathologically, the lesions show the intercellular and intracellular edema of the epidermis, and inactivation of melanocytes with many melanosomes, well-developed Golgi apparatus and endoplasmic reticulum. In the dermis, a marked pigmentary incontinence can be seen.

Hypomelanosis

There are two kinds of hypomelanotic conditions: genetically or developmentally determined disorders, in which normal amounts of melanin are never present in the affected areas, and depigmentation, or loss of previously existing pigment. There are two additional features that facilitate the classifi- cation of the type of hypomelanosis. First is the pattern. The pigment change may be circumscribed with identifiable borders. Circumscribed lesions may be the vitiligo type, ie, diffusely scattered variously sized lesions of from 1 to over 20 cm, or the pigment change may occur in a quasidermatomal arrange- ment, the nevus depigmentosus type. Hypome- lanosis may also involve the entire skin so that there are no identifiable borders, as in oculocutaneous albinism. A second helpful feature is the degree of pigmentary dilution, ie, whether the area is completely devoid of pigment (amelanosis), as in vitiligo, or whether

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the area is particularly devoid of pigment (hypomelanosis), as in the white macules of tuberous sclerosis.

r4evusdeptgmentosus

Nevus depigmentosus is a relatively com- mon, congenital, nonfamilial, stable quasider- matomal leukoderma. Men and women are equally affected.

The unilateral macules are of varied size and are of pale-white to tan color with discrete, regular, or serrated margins. Lesions most commonly are present on the trunk, lower abdomen, and proximal extremities but may involve the face and neck. News depigmen- tosus may occur in one of three patterns@? (1) as an isolated, circular, or rectangular area of hypomelanosis distributed anywhere on the body but especially on the trunk, (2) in a typical dermatomal pattern of hypomelanosis, or (3) along atypical dermatomal pattern in which the hypomelanosis is a bizarre, sharply angulated streak, almost looking like artificial white paint or in whorls of hypomelanosis, roughly following Blaschko’s lines, which have also been described as incontinentia pigmenti achromians of Ito (Fig. 2-21). The histology is normal, but the dopa reaction shows the usual number of melanocytes that are less reactive than normal. Electron microscopy reveals poorly developed, stubby dendrites and melan- osomes that are normal in size, shape, and internal structure. Melanization is normal or decreased. There are decreased numbers of melanosomes in keratinocytes and occasional melanosome aggregation in melanocytes. Nevus depigmentosus appears to result from melanosome aggregation and a transfer block.

Patients with nevus depigmentosus are generally healthy, without having any neuro- logic abnormalities, such as seizures and mental retardation.

lnconlhrenHapl)llmentl~ or~dtto

Incontinentia pigmenti achromians is a bizarre, bilateral, irreguhrly shaped leuko- derma of the trunk and extremities. The name

FIG. 2-21. Nevus depigmentosus with dermatomal pattern.

derives from the observation that in this entity the leukoderma occurs in a pattern resembling the hypermelanosis of incontinen- tia pigmenti, ie, negative image of inconti- nentia pigmenti (Bloch-Sulzburger syn- drome).m Incontinentia pigmenti achromians that should be considered a neurocutaneous disorder is underscored by the observation that of 73 recently summarized cases, 54 had congenital anomalies.30 Hence, Jelinek et al.31 indicated that the disease should be called as hypomelanosis of Ito.

Incontinentia pigmenti achromians occurs 2.5 times as commonly in women (47 cases) as in men (19 cases). Two families with in- continentia pigmenti achromians have been reported.32 The depigmented patches usually are present at birth but may appear in early infancy or childhood. Nearly 75% have been reported with one or more anomalies of the central nervous system, eyes, hair, teeth, museuloskeletal system, or internal organs, particularly mental/motor retardation and seizures.

Clinically, the lesions are randomly distrib- uted with a whorled or streaked “marble cake” configuration over a bilaterally asymmetric distribution (Blaschko’s line) (Figs. 2-22 and 2-23). The trunk and extremities are most

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FIG. 2-22. lncontinentia pigmenti achromians on

the lateral trunk.

commonly involved. The margins of the lesions are serrated and blurred or sharply outlined. The lesions themselves are irregular in shape and variable in size. Occasional lesions may, on side lighting, appear slightly depressed.

Among the most common associated abnor- malities have been retardation, seizures, EEG abnormalities, strabismus, hypertelorism, language retardation, malformed ears, arm and leg length discrepancy, and epicanthal folds.

FIG. 2-23. Blaschko’s line.

Histopathologically, hypomelanotic skin possesses dopa-positive functioning melano- cytes. Their population appears to be similar to that of control-normal appearing skin. Their dopa activity is, however, decreased, indicat- ing the decrease of melanin synthesis. Under electron microscopic observation, the melan- ocytes reveal poorly developed organelles and decreased number of melanosomes.

Phenylketonuria

Phenylketonuria, an autosomal recessive disorder of phenylanine metabolism, is char- acterized by pigmentary dilution of skin, hair, eyes and, if not treated early, by mental retardation. The prevalence of phenylketonu- ria varies from 1:25,000 in the United States to 7-10:100,000 in Japan. Phenylketonuria patients in Caucasians typically have blond hair, blue eyes, and fair skin. Hair may vary from light blond to dark brown, but in most series, blond hair predominates. In the orientals, phenylketonuria is associated with dark brown hair that is readily distinguishable from the normal black hair color (Fig. 2-24). Most phenylketonuria patients have fair skin and sunburn easily. Other cutaneous features reported include acrocyanosis and scleroderma-like skin changes.

The characteristic untreated patient with phenylketonuria develops mental and growth retardation and has a reduced life expectancy. If diagnosis is delayed beyond the first year, infants will have already irreversibly lost up to 50 IQ points. Nearly all untreated patients have an IQ under 50. Various forms of neurologic abnormalities are observed.

Phenylketonuria patients have a metabolic block in the conversion of phenylalanine to tyrosine. Jervis found no transient rise in tyrosine levels after phenylanine loading and concluded that phenylalanine must be the metabolite that accumulates in phenylketonu- ria. Subsequent studies have demonstrated a deficiency of the hepatic enzyme phenylalanine hydroxylase (in type I phenylketonuria), which normally catalyzes the conversion of phenylal- anine to tyrosine, hence causing a decrease of tyrosine in the blood.33 Accumulated L-

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phenylalanine and its metabolites also inhibit tyrosine activity. Aromatic metabolites that accumulate in the urine include phenylpyruvic acid, phenylacetic acid, and acetylglutamine.

Chediak-Higashi Syndrome

Chediak-Higashi syndrome is a rare form of oculocutaneous albinism associated with hematologic and neurologic abnormalities and death by the early teens. It was first reported by Bequez,s later reported in North and South America, Europe, and Asia. Nearly one-half of the cases are from consanguineous mar- riages. Nearly all cases have pigmentary dilution of hair, skin, and eyes. Skin color is light cream to slate gray but may darken somewhat with sun exposure and time.25 Hair color is light blond to brunette but may assume a frosted metallic-gray sheen. Irides are blue- violet to brown. There may also be squint, photophobia, and decreased retinal pigmentation.

Melanocytes are normal in size and number and contain fully melanized stage 4 melano- somes. Whereas some melanosomes are normal in size, most are abnormally large and pass with difficulty to keratinocytes. These may result from fusion or abnormal synthesis. Similar granules are found in hair follicles, retina, choroid plexus, and pia-arachnoid membrane.36 p37

In Chediak-Higashi syndrome, leukocytes contain a few giant (to 4 pm) azurophilic- staining granules. Such lysosome-like orga- nelles are also found in buccal mucosa and many other organs. The mechanism of forma- tion of giant granules is unknown, but granulocyte studies suggest a membrane fusion defect.3

Chediak-Higashi syndrome patients present at an early age with recurrent staphylococcal and streptococcal infestion. At about the age of 5 years, convulsions and neuropathy develop and, later, anemia, thrombocytopenia, and neutropenia develop. In late stages, hilar ad- enopathy, hepatosplenomegaly, jaundice, leukemic-type gingivitis, and pseudomem- branous sloughing of buccal mucosa may

herald lymphoreticular malignancy and early death.

Vogt-Koyanagi-Hamda Syndrome

Vogt-Koyanagi-Harada syndrome is a rare multisystem disease characterized by uveitis, alopecia, poliosis, dysacousia, and vitiligo. This syndrome was first described as a single entity by Vogt in 1906.40 Harada in 192640 described five cases with bilateral posterior uveitis with retinal detachment. Koyanagi in 192941 completed the description of the syndrome; in his review of 16 cases, he found common features of headache, fever dysacousia, vitiligo, poliosis, alopecia, and bilateral anterior uveitis with occasional exudative retinal detachment.

Vogt-Koyanagi-Harada syndrome is rare. Although initial cases were among the Jap- anese, cases have been reported from North and South America, Europe, Asia, and Africa. Males and females are equally affected. Peak frequency is in the 30s but onset is reported from 10 to 52 years of age.

Vogt-Koyanagi-Harada syndrome appears in three phases. The first is the meningoen- cephalitic phase with prodomata of fever, malaise, headache, nausea, and vomiting. The second or ophthalmic stage of uveitis may appear rapidly and last for 10 years or more. Vitiligo, poliosis, and alopecia mark the convalescent stage as uveitis begins to abate. Rosen in 194545 found 90% with poliosis, 73% with alopecia, and 63% with leukoderma. White hair is usually noted after the onset of alopecia. Patches of hypomelanosis resemble vitiligo; they are symmetric, may enlarge centrifugally, and seem principally to involve the head, shoulders, neck, and eyelids. This hypomelanosis appears with or after the eye symptoms. The general health of the patient is unaffected.

Histolopathology of the skin shows edema and vasodilatation of the dermis, pigment within melanophages, and lymphocytic infil- trate. Others have found no abnormalities except for absence of melanin.43 Vogt- Koyanagi-Harada syndrome has been attrib- uted to a viral infection or is considered to be an autoimmune disease.

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Summary

Brown hyperpigmented disorders may be melanotic in which there is a normal number of epidermal melanocytes but melanin pig- ment is increased in the epidermis (eg, melasma), melanocytotic, in which melano- cytes are increased (eg, caf&au-lait macules), and nonmelanotic hyperpigmentation (eg, minocycline pigmentation). Blue hyperpig- mented disorders may also be melanotic in which there is a normal number of epidermal melanocytes, but melanin pigment is present in the upper dermis (eg, gray/slate pigmen- tation in Riehl’s melanosis), melanocytotic in which melanocytes are present in both the epidermis and dermis (eg, blue pigmentation in Nevus Ota and Mongolian spot), and nonmelanotic hyperpigmentation in which pigment is present in the deep dermis (eg, blue pigmentation in tattoos). Hypomelanosis (leukoderma) may be divided histopathologi- tally into melanocytopenic disorders on which melanocytes are absent (eg, Vogt-Koyanagi- Harada syndrome and vitiligo), melanopenic disorders in which melanocytes are present but melanin is reduced (eg, nevus depigmentosus and incontinentia pigmenti achromians), and nonmelanotic disorders in which melanin pigmentation is unaffected (nevus anemicus) and the pigmentary abnormality is caused by something other than melanin.

There are numerous pigmentary disorders in the oriental skin, and some of them are either characteristic to or established in the orientals. Importantly, a number of congenital hyper- melanotic and hypomelanotic diseases (eg. nevus depigmentosus, incontinentia pigmenti. and incontinentia pigmenti achromians, take a distribution following to the Blaschko’s line.

References

I. .Jlmbow K. Fitzpatrick TB, Quevedo WC-Jr. Formation chemical compositions and functions of melanin pigments in mammals. In: Matoltsy AG. ed. Bioloa of integument. Vol. 2. New York: 1986:278-291. Springer Verlag.

2. Jimbow K, Szabo G. Fitzpatrick TB. Ultrastructure of giant granules (macromelanosomes) in the cutaneous pigmented macules of neurofibromatosis. J Invest Dermatol. 1973:61:300-309,

:L Nakagawa H, Hori Y, Fitzpatrick TB. The nature and origin of the melanin macroglobule. In: Bognara J, Klaus SN. Paul E. et al, eds. Pigment cell 1985. Tokyo: liniversity of Tokyo Press, 1985:25-34.

1. lshido 0, Jimbow K. A computed image analyzing system for quantitation of melanocyte morphology in caf&au-lait macules of neurofibromatosis. J Invest Dcrmatol. 1987;88:287-291.

;). Parson JR, Longscope C. Becker’s nevus: An androgen- mediated hyperplaaia with increased androgen recep- tors. J Am Acad Dermatol. 1984;10:235-238.

ii. Bartholomew LG, Moore CE. Dahein DC, et al. Intestinal polyposis associated with mucocutaneous pigmentation. Surg Gynecol Obstet. 1962:1X?-11.

7. Yamada K. Matsukawa A, Hori Y, et al. Ultrastructural studies on pigmented macules of Peutz-Jeghers syndrome. J Dermatol. 1981:8:367-377.

-: I’athak MA. Clinical and therapeutic aspects of rnelasma: an overview. In: Fitzpatrick TB, Wick MM, Toda K. eds. Brown melanoderma. Tokyo: University of Tokyo Press. 1986:161-172.

!J.

10.

l!

1”.

I:<.

l,l.

15.

16.

1;.

IX.

I Il.

“0.

f’erez M, Sanchez JL. Aquilo F. Endrocrinologic profile of patients with idiopathic melasma. J Invest Dermatol. 1983:81:543-545.

Sanchez N. Pathak MA, Sate S. et al. Melaama: a clinical, light microscopic, ultrastructural and immu- nofluorescence study. J Am Acad Dermatol. 1981;4:698- 710.

snell RS. Hormonal control of pigmentation in man and other mammals. In: Advances in biology of skin. Vol. 8: The pigmentary system, Montague W. and Fiu II. eds. New York: Pergamon. 1967;447-466.

l.tzrncr AB. McGuire .JS. Melanocyte stimulating hormones and adrenocorticotropic hormones. N Engl .I Med. 1964;270:539-546.

f<‘itzpatrick TB, Ishihara M, Toda K, et al. Classification of dermal pigmentation (ceruloderma): blue skin. In: Fitzpatrick TB. Kukita A, Morikawa F, et al, eds. Biology and diseases of dermal pigmentation. Tokyo: I’niversity of Tokyo Press, 1981;65-66.

Kikuchi I. Mongolian spots remaining in school children: a statistical survey in central Okinawa. J Dermatol. 1980;7:213-216.

Kukita A. Hori Y. O’Hara K, et al. Nevus of Ota. In: Fitzpatrick TB, Kukita A, Morikawa F, et al. Biology and diseases of dermal pigmentation. Tokyo: University of Tokyo Press, 1981:67-82.

llidano H. Kajima H, Ikeds A, et al. Natural history of News of Ota. Arch Dermatol. 1967:95:187-95.

Ito M. Studies on melanin. Tohoku J Exp Med. 1954:60:10.

Wiklund DA, Weston WL. Incontinentia pigmenti: a four generation study. Arch Dermatol. 1980;116:701- 7n3.

(‘arney RG. Incontinentia pigmenti: a world statistical ;analysls. Arch Dermatol. 1976;112:535-542.

Mihm MC, Murphy GF, Kwan TH, et al. Character- ization of the nature of the inflammatory infiltrate of the reticular stage of incontinentia pigment. In: Fitzpatrick TB, Kukita A, Morikawa F, et al, eds.

Page 17: Pigmentary disorders in oriental skin

April-June 1989 Volume 7 Number 2 Piamentaw Disorders in Oriental Skin 27

21.

22.

23.

24.

25.

26

27.

28.

29.

30.

Biology and diseases of dermal pigmentation. Tokyo: Tokyo University Press. 1981:151-162.

Dvorak AM, Mihm MC Jr., Dvorak HF. Morphology of delayed-type hypersensitivity reactions in man: II. Ultrastructural alterations affectine the microvascul- ature and the tissue mast ceils. Lab Invest. 1976;34:179-191.

Dahl MV, Matula G, Leonards R, et al. Incontinentia pigmenti and defective neutrophil chemotaxis. Arch Dermatol. 1975;111:1603-1605.

33. Jervis GA. Phenylpyruvic oligophrenia defficiency of phenylalanineoxidizing system. Proc Sot Exp Biol Med. 1953;83:514-525.

Jessesn RT, Van Epps DE, Goodwin JS, et al. Incontinentia pigmenti. Evidence for both neutrophil and lymphocyte dysfunction. Arch Dermatol. 1978;114:1182-1186.

34.

35.

Gleich GJ, Frigas E, Loegering DA, et al. Cytotoxic properties of the eosinophil major basic protein. J Immunol. 1979;123:2925-2927.

Ogawa H, Miyazaki H, Ikeya T, et al. Presence of anti- cytoplasmic antibodies in a case of incontinentis pigmenti. J. Dermatol (Tokyo). 1975;2:93-97.

Emerit I, Levy A, Vaillaud JC. Incontinentia pigmenti: chromosomal study of a family. Ann Dermatol Venereol. 1978;105:119-121.

Lenz W. Half chromatid mutations may explain incontinentia pigmenti in males. Am J Genet. 1975;27:690-691.

Bequez CA. Neutropeniz cronica maligna familiare con granulaciones atipicas de 10s leucocitos. Bol Sot Cubana Pediatr. 1948;15:900-922.

Stegmaier OC, Schneider LA. Chediak-Higashi syndrome: dermatologic manifestations. Arch Der- matol. 1965;91:1-9.

36. Moran TJ, Estevez JM. Chediak-Higashi disease: morphologic studies of a patient and her family. Arch Pathol. 1969$8:329-339.

Jimbow K, Fitzpatrick TB, Szabo G, et al. Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol. 1975;64:50-62.

Ito M. A peculiar case of symmetric linear depig- mented nevus (Translated from Japanese). Jpn J Dermatol. 1951;61:31-32.

37.

38.

39.

40.

41.

Bedoya A. Pigmentary changes in Chediak-Higashi syndrome. Br J Dermatol. 1971;85:336-347.

Stossel TP, Root RK, Vaughan M. Phagocytosis in chronic granulomatous disease and the Chediak- Higashi syndrome. N Engl J Med. 1972;286:120-123.

Vogt A. Fruhzeitiges Ergrauen der Celien und Bemerkungen liber den sogenannten plotzlichen Eintritt dieser Veranderung. Klin Monatabl Augen- heilkd. lSO6;44:228-242.

Harada Y. Beitrag zur klinischen Kenntnis von nichteitriger Choroiditis. Nippon Ganka Gakkai Zasshi. 1926;30:356-378.

Koyanagi, Y Dysakusis, Alopecia, and Polio&s bei schwerer Uveitis nicht traumatischen Ursprungs. Klin Monatabl Augenheilkd. 1929;82:194-211.

Takematsu H. Sato S, Igarashi M, et al. Incontinentia 42. Rosenn E. Uveitis with polio&, vitiligo, alopecia and pigmenti achromians (Ito). Arch Dermatol. dysacousia (Vogt-Koyanagi-Harada syndrome). Arch 1983;119:391-395. Ophthalmol. 1945;33:281-292.

31.

32.

Jelinek JE, Bart RS, Schiff GM. Hypomelanosis of Ito (incontinentis pigmenti achromians): report of cases and review of the literature. Arch Dermatol. 1973;107:596-501.

Rubin MB. Incontinentia pigmenti achromians: multiple cases within a family. Arch Dermatol. 1972;105:424-425.

Address for correspondence: Kowichi Jimbow, MD, Division of Dermatology and Cutaneous Sciences, Faculty of Medicine, #420 Newton Research Building, Edmonton, Alberta, Canada T6G 2C2.