Brown Ocuuiocutaneous Albinism

Brown Oculocutaneous Albinism Clinical, Ophthalmological, and Biochemical Characterization RICHARD A. KING, MD, PhD, * RICHARD A. LEWIS, MD, MS, t DeWAYNE TOWNSEND, PhD, * ALVIN ZELICKSON, MD,t DAVID P. OLDS, MS, * JOHN BRUMBAUGH, PhD§

Abstract: The clinical, ophthalmological, and biochemical characteristics of a 28-year-old black woman with brown oculocutaneous albinism were determined. Hair color was medium brown and skin color was light brown, and a faint tan developed with sun exposure. The irides were light brown in the central onethird, blue-gray in the peripheral two-thirds, and showed punctate and radial translucency. Visual acuity was 20/60 in the right eye and 20/100 in the left eye. There was a moderate pendular nystagmus, and previous surgeries had corrected an exotropia. The foveal reflex was muted, and the retinal pigment was reduced. Hairbulb tyrosinase activity was 1.75 pmoles/120 min/hairbulb, hairbulb glutathione content 0.83 nmoles/hairbulb, and urine excretion of 5-$cysteinyldopa 174.9 ng/mg creatinine. Electron microscopy of hairbulb and skin melanocytes showed arrested melanosomal development. These findings suggest that there is a partial block in the distal eumelanin pathway in this form of albinism. The ophthalmological characteristics of six additional cases of this form of albinism are also presented. [Key words: brown oculocutaneous albinism, eumelanin block, iris translucency, melanocyte, melanosome, tyrosinase.] Ophthalmology 92: 1496-1505, 1985

Human oculocutaneous albinism (OCA) is defined by hypopigmentation of the skin, hair, and eyes, associated with nystagmus, photodysphoria, and reduced visual acu-

From the Department of Medicine: and Dermatology,:j: University of Minnesota, Minneapolis, the Cullen Eye Institute and the Departments of Ophthalmology and Medicine (Medical Genetics),t Baylor College of Medicine, the Birth Defects Center,t Texas Children'S Hospital, Houston, and the Genetics., 'Cellular and Molecular Biology Section,§ School of Biological Sciences, University of Nebraska, Lincoln. Supported in part by NIH grants AM 32407-02 and GM 22167-09, and by an unrestricted grant to Dr. Lewis from the Lillian Kaiser Lewis Foundation, Houston. Reprint requests to Richard A King, MD, Department of Medicine, PhillipsWangensteen Building, 516 Delaware SI. SE, Minneapolis, MN 554550311.

1496

ity and several distinct types of OCA have been described. 1,2 The clinical characteristics for the different types are given in Table I. The least pigmented variant is Type IA (tyrosinase negative), in which a total absence of melanin in the skin, hair, and eyes is associated with a complete absence of measurable tyrosinase activity in melanocytes. 3 Most other types of oculocutaneous albinism have some detectable pigment clinically, which accumulates gradually with age. There may be progressive darkening of the iris from gray-blue to hazel or lightbrown, darkening of the retinal pigment epithelium and improvement in visual acuity, and development of yellow or light brown hair. The skin rarely develops generalized pigment, but local pigmentation in the form of nevi and freckles may occur. Type IV or brown albinism (BA) was first described in black individuals in Nigeria, and was characterized clinically by cream to light tan skin, beige

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BROWN OCULOCUTANEOUS ALBINISM

Table 1. Characteristics of Human OculocutaneolJs Albinism (DCA), Types I-VII Color DCA type

Eponym

IA

Tyrosinase negative

AR

White

IB

Yellow

AR

White~

Inheritance

Hair

yellow blond

Iris

Skin

Tyrosinase Activity3

Blue

No pigment

Absent

Blue ~ hazel -> brown

No generaiized pigment; pigmented nevi, lentigines; slight tanning

Low-absent

~

II

Tyrosinase positive

AR

White -> yellow -> blond

Blue -> hazel ~ brown

No generalized pigment; pigmented nevi, lentigines

Normal-high

III

Minimal pigment

AR

White

Blue -> pigment ring

No generalized pigment

Absent

IV

Brown

AR

Light brown

Blue

Light generalized pigment

Normal

brown

Red

AR

Auburn

Brown

Light generalized pigment

VI

Hermansky-Pudlak syndrome

AR

White~

Blue -+ hazel -+ brown

No generalized pigment; pigmented nevi, lentigines

VII

Autosomal dominant

AD

Blond -+ light brown

Blue

Light generalized pigment; slight tanning

AR = autosomal recessive; AD = autosomal dominant;

-+

red

->

V

yellow -> blond -+ brown

~

~

hazel

? Absent-normal

?

= change with age.

to light brown hair, and blue-green to brown irides with moderate transillumination defects.4 We are unaware of any subsequent descriptions ofBA among the populations of Western Europe, or North and South America. We report the clinical, ophthalmological, biochemical, and ultrastructural characteristics of an American black woman with BA and summarize our clinical experiences with BA in the United States.

MATERIALS AND METHODS Over a three-year period, seven patients who met the criteria for brown oculocutaneous albinism were evaluated by a single examiner (RAL), from the Ophthalmic Genetics Service at the Cullen Eye Institute, Baylor College of Medicine, Houston, Texas. A summary of patient data is presented in Table 2. Case 1 is reported in detail.

CASE REPORT Case 1. The proband (IV-II in the pedigree) is a 28-year old black woman security guard and college student who was first seen at age 27 in January 1984 and subsequently evaluated at the University of Minnesota. Her mother's pregnancy and delivery were normal. At birth, her skin color was creamy-tan and her irides were light greytan, but a pendular nystagmus was noted at six months of age. Her mother questioned the possibility of albinism but was told

that it was not present. Her physical growth and developmental milestones were normal. She had no history of unusual or recurrent infections or bleeding tendencies. Her hair grew goldenbeige at approximately three months of age. Since then, the pigmentation in her hair and irides had darkened slowly. No abrupt changes were noted during periods of growth such as puberty. At age 10 to 12 months, a strabismus was noted and she was observed to turn her face to the side and to hold books close to her face while reading. At age 5, she had an ophthalmologic evaluation because of difficulty reading. Her vision was recorded as 20/80 (right eye, -2.00 + 2.00 X 85°; left eye, -3.00 + 2.00 X 90°). No diagnosis other than "congenital nystagmus" and "exotropia" was made. From grades 3 to 6 she attended special low-vision classes but during grades 7 through 12 maintained regular classes. Her school performance was good although she did have some difficulty reading. Her exotropia apparently became more noticeable cosmetically by age 16, when an ophthalmologist recorded her visual acuity as 20/200 in each eye (right eye, -0.25 + 1.50 cyl X 90 °; left eye, -1.00 + 1.25 cyl X 105°), pendular nystagmus, and 35° exotropia in all cardinal positions of gaze with oblique dysfunction. A recession of the left lateral rectus and resection of the left medial rectus muscle was performed with significant cosmetic improvement. The exotropia recurred and corrective surgery was performed again at age 19. In 1978 (age 21 years), a new diagnosis of "retinal agenesis and hypoplasia of the macula" was made. At age 24, she sought additional advice for recurrent exotropia. Her visual acuity was recorded as 20/80 in the right eye (-1.00 + 1.50 cyl X 85°) and 20/100 in the left eye (-2.00 + 2.50 cyl X 110°). Her face was slightly turned to the left and, despite her horizontal pendular nystagmus in all fields of gaze, a null point was recorded about 15° to the right of the midline. An A-pattern exotropia, varying

1497

~

1.0

00

USA

USA

USA

USA

26 yr, F

20 yr, M USA

USA

27 yr, F

15 yr, F

14 yr, F

11 yr, F

5 mo, F Nigeria

2

3

4

5

6

7

Family History

=

Creamylight brown

Light brown

Light brown

Light brown

Light brown

Light brown

Light brown

Skin

Medium brown

Medium brown

Light brown

Medium brown

Dark brown

Medium brown

Medium brown

Hair

Color

retinal pigment epithelium; 00

Parents are 4th cousins

Affected brother

Affected sister

2 Sisters, 1 brother affected

F = female; M = male; RPE

Country of Origin

Case No,

Age, Sex at Initial Exam

=

right eye; OS

Blue-green

Light brown centrally, green periphery

Medium brown

Brown

Grey-blue

Medium brown

Light brown

Iris

=

Horizontal Pendular Nystagmus

=

not available,

+

+ (slow)

+

+

+ (rapid, low amplitude)

+ (low amplitude)

+ (slow, low amplitude)

left eye; N/A

3+/4

3+/4

2+/4

2-3+/4

3+/4

3+/4

3+/4

Iris Transillumination defects

Orthotropia

Orthotropia

Orthotropia

Orthotropia

Orthotropia

Orthotropia

Exotropia, repaired

Extraocular Motility

Table 2, Patient Data

Blond

Light brunette

Light brunette

Blond to light brunette

Light brunette

Light brunette

Medium brunette

Fundus/ RPE Color

00 +0,25 + 2,00 X 60 0 OS +1.25 + 1.75 x 120 0 00 -9,50 + 5,50 X 105° OS -10,50 + 5,50 X 75° 00 -16,50 + 5,50 X 90° OS -15,50 + 5,00 X 90° 00 -0.75 + 2,00 X 90° OS -0.75 + 2,00 X 90° 00 -7,50 + 3.00 X 90° OS -10,00 + 4,50 X 90° 00 plano + 1.00 X 90° OS plano + 1.00 X 90°

00 plano + 2,00 X 87 0 OS -0,50 + 2.75 X 101 0

Cycloplegic Refractive Error

N/A

OS J4 20/80

Fix and follow OU

00 J4

OS J1 20/60

20/60

00 J1

OS J4 20/150

20/60

00 J4

OS J4 20/150

20/150

00 J2

OS J5

20/100

20/125

00 J7

OS J1

20/100

20/1 00

00 J1

Near Acuity

20/60

Corrected Visual Acuity

N/A

N/A

Normal

Normal

Normal

Normal

Normal

Color Vision

Congenital nystagmus

Congenital nystagmus

Congenital high myopia and nystagmus

Congenital nystagmus

"Ocular albinism" "Retinal dysgenesis" and "agenesis of the macula" Congenital nystagmus

Previous Diagnosis

Postaxial VI digit, Congenital left hand; nystagmus posterior embryotoxonous

Seizures from age 10 years

Other Abnormalities

-u

::0

m

(lJ

~

c

• z

I\)

<0

m

~

c

0 r

<

•

0'1

<0 CD

::0

m

(lJ

~

< m

0

z

•

-<

Gl

0 r 0

~

r

~

I

--I

I

0

KING, et al •

BROWN OCULOCUTANEOUS ALBINISM

Fig 1. Top and second row left, the proband (VI-II). Fig 2. Bottom left , forearm of the proband (middle), her normally pigmented aunt (individual V-5 in the pedigree) on the left, and a white with type I white skin on the right. Fig 3. Top right, the anterior segment of the left eye with normal cornea and iris. The anterior stromalleafis simplex without a defined collarette. The right iris is similar. Second row right, transillumination (through the pupil) of the iris of the right iris reveals diffuse punctate and peripheral radial defects. Symmetrical alterations were seen in the left iris. Fig 4. Third row right and bOllom, wide field color photographs of the fundus of the right eye (above) and left eye (below) show normal optic discs and retinal vasculature. The retinal pigment epithelial coloration is medium brunette with some visualization of the underlying choroidal vasculature increasing toward the periphery. The annular foveal light reflex is muted and the umbo cannot be seen.

from 25 in upgaze to 50 in downgaze, was recorded with marked (grade 4/4) overaction of each superior oblique muscle. Iris transillumination and "foveal hypoplasia" were also noted. After tenotomies of each superior oblique muscle and a left lateral rectus recession combined with resection ofthe left medial rectus, she was orthophoric in all positions of gaze. When she was 26 years old, she was evaluated by a low vision center with best corrected visual acuity 20/120, Jaeger 3, in both eyes. Color vision by pigment plates was normal and the presence

of congenital nystagmus and macular hypoplasia led to a diagnosis of "ocular albinism and nystagmus". The remainder of her medical history was unremarkable.

EXAMINA nON

When examined in 1984 (age 27), her height, weight, head circumference, and vital signs were normal. The 1499

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- Type .llZ (brown) OCA

. . - Type.u (tyrosmase

poslflve) OCA

IT

6RI 'CD f1T2l

m

CD

I = LIght brown eyes 2:: L Iqhf brown hOlr 3 =L IgIII brown skm

nz

1

2

3

4

~

6

1

•

9

10

11

12

13

Fig 5. Family pedigree. The proband is individual VI-II.

patient is shown in Figure 1. Scalp hair, eyebrows, and lashes were medium brown. Pubic and axillary hair and hair on the extremities were dark brown. Her skin was light brown (cafe-au-lait) in color with a faint tanning line in a bikini distribution. Figure 2 shows the forearm of the patient, her aunt (individual V-5 in the pedigree) and a white with type I white skin which does not tan. Two small (1 mm) typical pigmented nevi were located on the trunk. No erythema, freckles, lentigines, pachydermia, or keratoses were present. Minimal erythema testing to the buttocks with UVB light was carried out at 30 inches. There was no immediate or 24-hour erythema response after 2 minutes, 15 seconds of radiation (calculated minimal erythema dose of 9). A similar test with UVA light, consisting of 5 minutes of radiation through window glass (calculated minimal erythema dose of 10), gave no immediate or 24-hour response. Her visual acuity was correctable to 20/60 in the right eye (plano + 2.00 X S7°) and 20/100 in the left eye (-0.50 + 2.75 X 101°); with +3.00 spherical add, she read Jaeger 1 in both eyes. Although a moderate pendular nystagmus was present in all cardinal positions, her extraocular movements were otherwise normal, except for weakness of convergence. The biomicroscopic examination showed healed conjunctival peritomies from previous muscle surgery. Intraocular pressures by applanation were IS mmHg in both eyes. Each iris was light brown in its central one-third and blue grey in the peripheral two-thirds, and demonstrated punctate and radial translucency on globe transillumination (Fig 3). Ophthalmoscopy revealed a muted foveal light reflex and umbo but a normal optic disc in each eye. The retinal pigment epithelium was a medium red-brown color posterior to the equator with moderate covering of the underlying choroidal vasculature; in the periphery, however, the fundus was more blond (Fig 4). Color vision tested by conventional pigment plates was normal. The remainder ofthe general physical and neurological examinations were normal. 1500

FAMILY HISTORY

The pedigree of case 1 is summarized in Figure 5 and Table 3. The proband (VI-II) had four male full sibs, two male half-sibs, and three female half sibs. I-I and II-I were white. III-I had black hair, brown eyes, and light brown skin, and III-2 had auburn hair (definite red tint), and light brown skin with freckles. Eye color was unknown. IV-1 had medium brown skin, but her three sisters (IV-2, 3, and 5) and her brother (IV-S) had light brown skin, and none were known to have reduced visual acuity or nystagmus. Each of the proband's full siblings had medium to dark pigmentation. V-24 is a Type II (tyrosinase positive) oculocutaneous albino by history. TYROSINASE ASSAY

Hairbulb tyrosinase activity was determined for anagen scalp hairbulbs by a tritiated tyrosine method. 5,6 Ten fresh anagen hairbulbs were incubated in 0.2 ml of 0.1 M phosphate buffer, pH 6.S, with 0.5% Triton X-IOO for 60 minutes at room temperature to release tyrosinase from the hairbulb melanocyte. The hairbulbs were removed and the supernatant was used as the enzyme sample. The reaction mixture for the assay contained 0.01 ml of 0.02 mM L-tyrosine-3,5- 3H (Amersham, 2 or 50 Ci/mmole); 0.02 ml of 0.005 mM L-dopa, both in 0.1 M phosphate buffer, pH 6.S; 0.01 ml of phosphate buffer and 0.02 ml of enzyme sample. The reaction mixture was incubated at 37°C. At 0, 60, and 120 minutes, a 0.01 ml sample was removed and placed on a 0.7 X 2.0 cm Dowex 50W column equilibrated with 0.1 M citrate. The 3HOH was washed through the column with O.S ml citrate and the total wash was counted in a liquid scintillation counter. The samples were run in duplicate. After subtraction of appropriate blank counts, the enzyme activity was determined as picomoles of tyrosine oxidized per 120 minutes per hairbulb.

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Table 3. Skin, Hair, and Eye Color for Members of Family D Skin Color 1-1 1-2 11-1 11-2 111-1 111-2 IV-1 IV-2 IV-3 IV-4 IV-5 IV-6 IV-7 IV-8 V-1 V-2 V-3 V-4 V-5 V-6 V-7 V-8 V-9 V-10 V-11 V-12 V-13 V-14 V-15 V-16 V-17 V-18 V-19 V-20 V-21 V-22

Hair Color

Eye Color

U U U U LB LB MB LB LB U LB U U LB MB

U .U U U B A B DB DB U MB U U MB MB

U U U U MB U DB MB LB U H U U MB MB

MB U MB DB MB MB MB MB MB LB MB LB MB MB LB W W DB

B U MB B B B B B B B B LB B B LB R-BI R-BI B

DB U MB DB DB DB DB DB DB MB DB MB DB DB H BI BI DB

Other W B W B

Accepted as W No eye changes No eye changes Stillborn Stillborn Stillborn

No eye changes No eye changes Died at 3 months Died at 3 months

V-23 V-24 V-25 VI-1 VI-2 VI-3 VI-4 VI-5 VI-6 VI-7 VI-8 VI-9 VI-10 VI-11 VI-12 VI-13 VI-14 VI-15 VI-16 VI-17 VI-18 VI-19 VI-20 VII-1 VII-2 VII-3 VII-4 VII-5 VII-6 VII-7 VII-8 VII-9 VII-10 VII-11 VII-12 VII-13

Skin Color

Hair Color

Eye Color

U W LB LB DB DB

U BI LB LB B B

U BI H MB DB DB

DB DB DB MB MB LB DB DB MB MB MB MB MB MB U MB DB MB MB U U U U U U U U U

B B B B B LB B B B B B B B B U DB B B DB U U U U U U U U U

DB DB DB DB DB BI-B MB DB DB DB LB LB LB LB U MB DB MB DB U U U U U U U U U

Other Oculocutaneous Albino No eye changes No eye changes Crib death 2 months Neonatal death 4 hours

Proband

U = unknown; LB = light brown; MB = medium brown; DB = dark brown; W = white; B = black; A = auburn; R-BI = red-blond; H = hazel; BI = blue; BI-B = blue-brown; MBI = medium blond.

GLUTATHIONE ASSAY

Glutathione was measured by the method of Tietze. 7 Ten fresh anagen hairbulbs were placed in 250 III H 20 and sonicated for 15 seconds. A 100 III sample of the resulting solution was placed in each of two 1.5 ml microtubes, and 10 III of 1.0 nM reduced glutathione was added to one of the tubes for an internal standard and 10 III of H 20 to the other for determination of hairbulb glutathione. To each tube, 222 III of methanol was added and mixed, followed by 100 III of chloroform. The tubes were let stand at room temperature for 10 minutes, 1.178 ml of H 20 was added and the tubes were centrifuged for 2 minutes. A 600 III sample of the upper phase was placed in a glass tube and 0.4 ml of a solution containing 5 ml of phosphate buffer (12 gm NaH 2P04 and 1.86 gm Na2EDT A in 1 L, pH 7.5), 4 ml of H 20, 2 mg ofNADPH and 1 ml of a DTNB solution (0.2 gm DTNB, 0.82 gm NaCl, 0.1278 gm Na2HP04 and 0.0016 gm NaH 2P04 in

100 ml of HzO) were added. After adding 10 III of glutathione reductase (1870 units/ml), the reaction was monitored spectrophotometrically to determine the increase in optical density at 412 nm over 5 minutes as reduced glutathione was converted to oxidized glutathione. The results from the hairbulb sample were compared to a standard curve for determination of the reduced glutathione content of the hairbulbs. Results are expressed in nanomoles per hairbulb. CYSTEINYLDOPA QUANTITATION

The 5-S-cysteinyldopa was quantitated in the urine by isochratic, reverse-phase HPLC with electrochemical detection, according to the method of Hanson et al 8 and Bioanalytical Systems, Inc. (West Lafayette, Indiana). The HPLC apparatus (Beckman Series 341 System) was used with a Bioanalytical Systems electrochemical detector (LC-4B). The electrochemical detector was equipped with 1501

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a carbon paste working electrode and an Ag/AgCl reference electrode, and was maintained at a potential of +0.65 V vs. the reference electrode. The column was 4.6 X 250 mm, packed with Ultrasphere-ODS, particle size 5 ~m (Altex). The mobile phase contained 4 ml of methanesuI phonic acid and 2 ml of 85% phosphoric acid per 1000 ml of H 20, with 0.8% methanol and 1 mM Na EDT A, and was at pH 2.78. The internal standard was dihydroxybenyzlamine hydrobromide (DHBA). A 24-hour urine was obtained from the proband. Control urines were 24-hour collections. A 5.0 ml sample of the urine was mixed with 15 ml of 0.1 M phosphate buffer, pH 7.0, and the mixture was added to a Bio Rex 70 cation exchange column (Biorad, Richmond, California). The column was washed with 10 ml of H 20 , drained dry, and 1.3 ml of 0.7 M H 2S04 was added. The columns were again drained dry and the cysteinyldopa was eluted with 4.0 ml of 2 M (NH4hS04. To this eluate 50 mg of alumina was added, followed by 500 ~I of 3 M Tris/EDTA buffer, pH 8.6 and vigorous shaking. The alumina was allowed to settle, the supernatant was removed, the alumina dried and the cysteinyldopa was removed from the alumina with 0.1 M HCl04 and filtration. Chromatography was performed at room temperature, at a flow rate of 1.5 ml per minute and an injection volume of 20 JLl. Measured amounts of pure 5-S-cysteinyldopa, kindly supplied by Dr. Miles Chedekel, Johns Hopkins University, were used to establish the known chromatographic pattern. Quantitation of the urine cysteinyldopa was made by comparing the urine result to the known pattern. Results were expressed in nanograms per milligram of creatinine. ELECfRON MICROSCOPY

A 2 mm punch biopsy of normal skin from the buttocks was prepared for electron microscopy by standard techniques. Hairbulbs were prepared for electron microscopy with and without L-dopa incubation by standard techniques.

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Table 4. Biochemical Results Determination Tyrosinase Activity (pmolesj 120minjhb) Glutathione (nmolesjhb) 5-S-Cysteinyldopa (ngjmg Creatinine)

Normal Brown Hair Color

Source

Proband

Hairbulb

1.75

1.49 ±

0.79

Hairbulb

0.83

1.07 ±

0.41

Urine

174.9

252.4 ± 334.3

RESULTS The biochemical results are given in Table 4. Tyrosinase activity was 1.75 pmoles of tyrosine oxidized per 120 minutes per hairbulb, which is above the mean value but within the range for control brown hairbulbs. The hairbulb glutathione level was 0.83 nmoles per hairbulb. Urinary cysteinyldopa excretion was 174.9 ng per mg of creatinine. The electron microscopy of the hairbulbs and skin was abnormal. The general melanocyte architecture in the hairbulb was normal, as shown in Figure 6, left. Most of the melanosomes in the hairbulb melanocytes were elliptical eumelanosomes. 9 - 11 Some melanosomes were fully melanized (stage IV), but many had only minimal amounts of melanin, suggesting that they were arrested in an early premelanosomal stage (stage I and II premelanosomes). The normal progression of melanosomal development did not appear to be present. Incubation of the hairbulb in dopa produced no effect, as shown in Figure 6, right. There was no increase in melanin formation and no increase in the number of fully melanized melanosomes; however, a slight dopa reaction in the golgi region could be demonstrated.

Fig 6. Left, electron micrograph of hairbulb melanocyte without L-dopa incubation, showing mature and immature melanosomes (X20,OOO). Right, electron micrograph of hairbulb melanocyte with L-dopa incubation. There is no apparent darkening of the melanosomes although a slight darkening in the Golgi region is visible (arrow) (X20,OOO). Inset shows details of immature melanosome structure (X30,OOO).

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BROWN OCULOCUTANEOUS ALBINISM

Fig 7. Left, electron micrograph of skin melanocyte showing mature and immature melanosomes. Stage II and stage III premeianosomes and stage IV melanosomes are indicated (X4l ,000). Right, electron micrograph of skin keratinocyte showing melanosomal complexes (X4! ,000).

The general melanocyte architecture in the skin was normal but that of the melanosomes was abnormal, as shown in Figure 7, left. The melanosomes were generally small with irregular and incomplete pigmentation. Many were round with a granular internal pattern. Elliptical melanosomes were present but the typical internal banding pattern was replaced by an irregular granular pattern. Some melanosomes appeared fully melanized, but many were stage II and III immature premelanosomes with incomplete melanization. Large single stage IV eumelanosomes, as seen in normal black skin, were absent. The melanosomes in the keratinocytes were abnormal, as shown in Figure 7, right. The melanosomes were in membrane-limited melanosomal complexes, each complex containing from two to eight or more melanosomes. Some of the melanosomes were elliptical and fully melanized, but most were small, round and irregularly pigmented. Some premelanosomes (stage II and III) could also be observed in the complexes. Few single or large melanosomes were observed in the keratinocyte.

DISCUSSION Oculocutaneous albinism (OCA) is the most common inherited abnormality of human pigmentation, and is characterized by reduced or absent melanin formation in the hair, skin, iris, and the retinal pigment epithelium of the eye. I,2 Clinical, biochemical and family studies have defined six types of autosomal recessive OCA, as shown in Table I, with each segregating as a distinct entity in affected families. 1-3 Changes in the optic system, including nystagmus, reduced visual acuity with no alteration in color perception, and abnormal optic projections to the lateral geniculate and visual cortex, are common to all types of OCA, but the hypopigmentation of the skin, the hair and the eyes varies between types. 3 , 12- 14 Brown oculocutaneous albinism (BA) was first de-

scribed in 19 families in the black population in Nigeria with the general characteristics of light brown skin, light brown hair, and blue to brown irides.4 We have now extended these initial observations with cases recognized in the United States. Case 1 had light brown skin and medium brown hair. Her skin showed no evidence of chronic sun irritation, and this correlated with the resistance to erythema from UVA and UVB radiation. By history, her hair and iris pigment had increased with age. A similar increase in hair and iris pigment, as well as skin pigment; had occurred with age in cases 2 to 7, and none of these individuals had had difficulty with sunburning, or had evidence of chronic sun irritation such as pachydermia, keratoses, or skin malignancies. None had white or yellow hair as found with type IA (tyrosinase negative) or type II (tyrosinase positive) OCA. 1•3 The eye findings in our cases included nystagmus and reduced visual acuity. Strabismus was present in only one of our seven cases and had been present in only half of the Nigerian individuals with BA. The iris was brown in five of the seven cases, and blue-gray or blue-green in the remaining two cases; despite this, iris transillumination defects were readily noticeable on biomicroscopic examination in all cases. The retinal pigment epithelium was distinctly pigmented, particularly in the post-equatorial area, although it was often blond in the periphery. The posterior fundus color was generally equivalent to a light brunette fundus in a white. The expression ofBA in the Nigerian families was consistent with autosomal recessive inheritance as was the family expression in the seven cases reported here (4, King, unpublished observations). One individual was the product of a consanguineous mating (parents were fourth cOusins), and three additional cases had phenotypically normal parents and similarly affected siblings of both sexes (Table 2). The biochemical analysis of case 1 did not reveal the primary defect but these studies suggested that a partial block in the distal eumelanin pathway would explain this 1503

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phenotype. Hairbulb tyrosinase was within the normal range for hair color, and the urinary excretion of 5-Scysteinyldopa was within the normal range for Caucasian control individuals with brown hair. The hairbulb glutathione was normal; glutathione is thought to be one source of cysteine for cysteinyldopa formation. 15 The normal tyrosinase activity implies that BA is not the result of a defect in tyrosinase structure or function , and that the first steps of the melanin pathway, which are controlled by tyrosinase, are intact. The product of the first two steps is dopaquinone, which may enter the pheomelanin or the eumelanin pathway. If the eumelanin pathway is blocked then the dopaquinone would enter the pheomelanin pathway, producing cysteinyldopa which would be excreted in the urine. If the block in the eumelanin pathway is not complete, then reduced amounts of eumelanin would be formed. The electron microscopy supports the suggestion of a partial block in the eumelanin pathway. The melanosomes in the hairbulb are elliptical eumelanosomes, as would be expected with a black individual, but they are not fully melanized, and many are in an early premelanosomal stage of development. 9,16 In the skin, the melanosomes are small and are more typical of those found in Caucasian rather than Negro skin.17-2o They are incompletely melanized, particularly in the melanocyte, and packaged in membrane-limited complexes in the keratinocyte. These changes suggest an inability to synthesize a normal amount of melanin, resulting in immature, small melanosomes. A block in melanin formation in an individual genetically programmed to form eumelanin is the most obvious explanation of these changes. Brown albinism has been described in black individuals but the phenotype in Caucasians has not been recognized; Is it possible that BA is not a separate type of OCA but rather the expression of Type II which has been influenced by the ethnic background of the affected individual? The clinical and family data make this possibility unlikely. The most common OCA type in Nigeria and in the U.S. black population is Type II. 2,4 Affected black individuals have yellow to blond hair, lightly pigmented irides, and white skin. The only skin pigment is located in nevi and lentigines. The brown hair and skin in BA are very different, as seen in Figure 1. Furthermore, BA is the only type of OCA segregating in the 19 Nigerian families and the families of those cases reported here, and no individuals with Type II or other types of OCA were present in these families. 4 The evidence supports the view that BA and Type II are separate types of OCA, but it is possible that they are produced by homozygosity for separate alleles at a single locus, similar to the alleles producing Type lA and lB. Both appear to be the result of a block in the distal eumelanin pathway, and the difference in phenotype could be the result of differences in the degree of the block. The allele which produces BA in black individuals should also be expressed in other populations, but the fact that it produces only a moderate reduction in skin, hair, and eye pigment may make the recognition of the phenotype dif1504

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ficult. In whites, the expression would be expected to be mlld and the only obvious features could be the changes in the optic system. In more pigmented populations such as those of Puerto Rico, the optic system changes would be associated with a moderate reduction in skin; hair and eye pigment. Characterization of the specific biochemical defect in BA and Type II OCA and the identification of families in which both types are segregating, will be necessary to answer those questions; We have identified seven individuals with BA in the South Central United States over a short period of time, suggesting that this type of OCA is not rare. It is important that each individual with congenital nystagmus or ocular albinism, particularly if they are Negro, undergo an evaluation for hypopigmentation of their skin, iris, and peripheral retinal pigment epithelium. Appropriate diagnosis of BA will be important in providing correct genetic information for the affected individual and the family.

ACKNOWLEDGMENTS The authors thank Maria Hordirisky, MD for performing the photo patch testing, and the excellent work of Anne Albers in preparing the manuscript.

REFERENCES 1. McGuire J. Albinism. In: Demis OJ, Dobson RL, McGuire J, eds. Clinical Dermatology. Hagerstown: Harper & Row, 1981 ; Chapter 11-26. 2. Witkop CJ Jr, Quevedo WC Jr, Fitzpatrick TB. Albinism and other disorders of pigment metabolism. In: Stanbury JB, Wyngaarden JB, Fredrickson OS, et ai, eds. The Metabolic Basis of Inherited DiSease, 5th ed. New York: McGraw-Hili, 1983; 301-45. 3. King RA, Olds DP. Hairbulb tyrosinase activity in oculocutaneous albinism: suggestions for pathway control and block location. Am' J Med Genet 1985; 20:49-55. 4. King RA, Creel 0, Cervenka J, et al. Albinism in Nigeria with delineation of new recessive oculocutaneous type . Clin Genet 1980; 17:259-70. 5. King RA, Witkop CJ Jr. Hairbulb tyrosinase activity in oculocutaneous albinism. Nature 1976; 263:69-71. 6. King RA, Olds DP, Witkop CJ. Characterization of human hairbulb tyrosinase: properties of normal and albino enzyme. JInvest Dermatol 1978; 71 :136-9. 7. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues . Anal Biochem 1969; 27:502-22. 8. Hansson C, Agrup G, Rorsman H, et al. Analysis of cysteinyldopas, dopa, dopamine, noradrenaline and adrenaline in serum and urine using high-performance liquid chromatography and electrochemical detection. J Chromatogr 1979; 162:7-22. 9. Toda K, Pathak MA, Parrish JA, et al. Alteration of racial differences in melanosome distribution in human epidermis after exposure to ultraviolet light. Nature [New Bioi) 1972; 236:143-5. 10. Jimbow K, Takeuchi T. Ultrastructural comparison of pheo-melanogenesis and eumelanogenesis in anirrials. In: Klaus SN, ed. Pigment Cell. vol. 4: BiologiC Basis of Pigmentation; Proceedings of the 10th International Conference, Cambridge, Mass., 1977. Basel: Karger, 1979; 308-17 .

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11 . Ortonne JP, Mosher DB, Fitzpatrick TB. Vitiligo and Other Hypomelanoses of Hair and Skin. New York: Plenum, 1983; 11. 12. Lourenco PE, Fishman GA, Anderson RJ. Color vision in albino subjects. Doc Ophthalmol1983; 55:341-50. 13. Creel D, Witkop CJ Jr, King RA. Asymm!'ltric visually evoked potentials in human albinos: evidence for visual system anomalies. Invest Ophthalmol1974; 13:430-40. 14. Carroll WM, Jay BS, McDonald WI, Halliday AM. Pattern evoked potentials in human albinism; evidence for two different topographical asymmetries reflecting abnormai retino-cortical projections. J Neurol Sci 1980; 48:265-86. 15. Prota G. Recent advances in the chemistry of melanogenesis in mammals. J Invest DermatoI1980; 75:122-7. 16. Zelickson AS. Ultrastructure of Normal and Abnormal Skin. Philadelphia: Lea and Febiger, 1967; 163. 17. Szabo G. Photobiology of melanogenesis: cytological aspects with

special reference to differences in racial coloration. Adv Bioi Skin 1967; 8:379-96. 18. Rosdahll, Szabo G. Ultrastructure of the human melanocyte system in the newborn, with special reference to "racial" differences. In: Riley V, ed. Pigment Cell. vol. 3: Unique Properties of Melanocytes; Proceedings of the 9th International Conference, Part II, Houston, TX, 1975. Basel: Karger, 1976; 1-12. 19. Szabo G, Gerald A!3, Pathak MA, Fitzpatrick TB. The ultrastructure of racial color differences in rnan . ln: Riley V, ed. Pigrnentation; Its Genesis and Biologic Control ; Proceedings of the 7th International Pigrnent Ceil Conference, Seattle, Wash, 1969. New York: Appleton-CenturyCrofts, 1972; 23-4. 20. Kinebuchi S, Kobori T, Hori Y. Behavior of melanosomes in melanocytes and keratinocytes of Japanese skin and black hair. In: Kawamura T, Fitzpatrick TB , Seiji M, eds. Biology of Normal and Abnorrnal Melanocytes. Baltirnore: University Park Press, 1971; 195-20.

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