THE JOURNAL 01' I NVESTIGATIVE 0 EI<M A'f0LOGY Vo l. 60, No . 6 Copy r igh t© l973 by The Williams & Wil kins Co. Printed in U.S.A. OPHTHALMOLOGIC, BIOCHEMICAL, PLATELET, AND ULTRASTRUCTURAL DEFECTS IN THE VARIOUS TYPES OF OCULOCUTANEOUS ALBINISM* C ARL J . WITKOP, JR., D.D.S., M.S., CHARLOTTE W. HILL, M.D. t , SUSAN DESNlCK, B.S., J UDlTH K. THIES, HATTIE L. THORN, B.S., MALCOLM JENKINS, PH.D .t, AND JAMES G. WHITE, M.D.§ INTRODUCTION bulbs in cubated in tyrosin e produce pigment (Fig. 4) . M ela nocytes contain early stage III premela no­ Mutations Ca using Generalized Hypopig menta­ somes (Fig. 5), which can be converted to normal­ tion in Man appearing, mature stage IV melanosomes by incu­ Previous studies have demonstrated that at least bation in !-tyros ine or !-dopa (Fig. 6). six mutations affecting the melanin pigment sys­ M arriages of a ty-pos to a ty-neg a lbino indicate tem in man result in recessively inheri ted traits t hat t he genes are not all elic, s ince only norma ll y with features of oculocutaneous a lbinism, i. e., a pigmented offspring have res ul ted from such mat­ gen e r a l reduction of pigment in the skin, hair, and ings (Wi tkop, 1971). eyes w i t h n ystagmus, photophobia, and reduced 3. The yellow mutant (ym) a lbino resembles the visual acui ty (Witkop et al. , 1963; Witkop et a!. , ty-neg albino at birth (Nance et al. , 1970) but by'6 1970; Nance eta!., 1970; Witkop, 1971). In general , mont hs to one year of age has developed yell ow-red these mutations can b e distinguished by t he abili ty hair, a moderate tanning ability, a modera te red of epilated hair bulbs to form pigment when refl ex, nystagmus a nd photophobia, and vi u a l incubated in !-tyros in e, by their clinica l features, acui ty defect. Hair bulbs in cubated in !-tyrosine do and t h e ul t rastructure of melanocytes. Va ri ous not form increased black pigment, but incubation featur es have been described in one or more of in !-tyros ine plus cysteine produces an intensifica­ these conditions, but a systematic study of all t ion of yellow or r ed pheomelanin. Melanocytes types for all of t hese cha racteristics has not been appear to be normally distributed and contain undertaken. unevenly pigmented stage Ill premelanosomes re­ se mbling those seen in red ha ir (Fig. 7). After Characteristics of the Types of Albinism incubation in !-tyrosin e, no increase in pigment is 1. The tyrosin ase-negative (ty-neg) a lbino has seen (Fig. 8). pink s kin, white hair, a pro minent red reflex, Recently, Wa lsh (1971) described " red" a lbinos severe nystagmus, photophobia, and a defect in among New Guinea natives who phenotypica lly visual acuity which d oes not vary with age or r ace. resemble y m American Negro a lbino . Figure 9 is a Hair bulbs incubated in tyrosine do not form photograph of a New Guinea native goldminer pigment (Fig. 1) . Melanocytes are present in nor­ which was sent to us by a geologist a nd probably mal numbers, but no evidence of tyrosinase activ­ represents t he same condition described by Walsh ity is present in cytoplasmic struct ures a nd only (1971). Walsh (1971) reported t hat t he urinary stage II early premelanosomes are present (Fig. 2). chromatograms of the " red" albinos conta ined a After incubation in either !- tyrosine o r !-dopa, the co mpound which stained with ninhydrin with a n prem e la nosomes do not demonstrate in creased Rf va lue s imilar to that of !-dopa. This compound pigmen t ( Fig. 3). was absent o r present o nly in small quantit ies in 2. Tyrosinase-positive (ty-pos) a lbinos have the urine of the black-skin subjects. phenotypic features that vary according to age and 4. Albinism with hemorrhagic diathesis was de­ the degree of pigmentation of the parents. Most scribed by Hermansky a nd Pudlak (1959) in two Ca ucas ian ty-pos a lbinos of a ll ages and infant sisters. A ceroid-li ke pigment was fou nd in the egro a nd Amerindian a lbinos phenotypically re­ reticuloendothelial system, a nd the bleeding disor­ semble ty-neg albinos. Wit h in creasing age small der was attributed to a vascul ar type of h emo­ amounts of pigment accumulate in the iris, skin , philia. Since t hen about 20 similar cases have been and h air and they develop fl axen to yell ow h a ir, reported or a re known (Verl oop et a l. , 1964; Har­ ve ry s lig h t tanning abili ty, pigmented nevi, a loss di sty and Hutton, 1967; Maurer et a l. , 1968; Mills of t he prominent red r eflex , moderate nystagmus and Hardisty, 1970; Muniz et al. , 1970; White et and photophobia, and even brown irides. Hair a !. , 1971; Logan et al. , 1971; White and Witkop, 1972). This investigation was supported by NIH Grants os. The bleeding disorder has now been ascribed to a AMI53 17 -01, HE-11880, AI-05153, DE-00179, the Card i· platelet defect (Mill s a nd Hardisty, 1970; White et avasc ular Clinical Resea rch Centers Program of t he al. , 1971; White a nd Witkop, 1972) with low Division of Resea rch R esources, NIH. take of serotonin, a * From the Di vision of Human and Oral Genetics, in t rinsic levels a nd poor up School of Dentistry, Un ive rsity of Minnesota; t the De­ decreased amount of nonmetabolic adenine nu­ partmen t o f Ophthalmology, School of Medicine, Uni ve r­ cleotide, and by e lectron microscopy a v irtual sity of Minnesota; t t he State Department of Hea lth, of platelet dense bodies (Maurer et al. , Department ofPed iatrics, absence State of Minnesota; and §the concen­ School of Medicine, University of Minnesota, Minneapo­ 1968; White eta!. , 1971) . The addition of lis, Minnesota. trations of aggregatin g agents such as ADP, epi - 44 3 444 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY A B FIG. 1. A. H air bulb from a tyrosin ase-negative albino shows no visible pigment. B. After incubation in !-tyrosine 80 mg/100 ml of phosphate buffer at pH 6.8, for 12 hr there is no pigment formation. · nephrine, thrombin, co ll agen, a nd bacteria to the White and associates (1971). One report described platelet-rich plasma of patients, which normally a large proportion of peripheral lymphocytes with produces a biphasic response, results in a mono­ broken chromosomes in this type of albinism phasic or single wave response instead (White et (Maurer et a!., 1968). al., 1971; White a nd Wit kop, 1972). 5. In addition to these four types of albinism, What has been described as ceroid pigment has two other recessively inherited hypopigmentary been reported in most of the patients examined for disorders manifest a generalized hypopigmenta­ this feature but the pigment was absent in the tion with nystagmus a nd photophobia, the Beguez­ bone marrow of an 18-month-old boy examined by Cesar-Chediak- Higashi syndrome (Beguez-Cesar, OCULOCUTANEOUS ALBINISM 445 F IG. 2 . E lectron photomicrogra ph of a melanocyte from a tyrosinase-negative a lbino shows in te rmediate vesicles and Stage II preme!anosomes but no evid ence of any pigment formation ( X 31,710) . F IG. 3. Electron photomicrograph of premela nosornes from a tyrosin ase- negative a lbino after incubation in !-tyrosine, 80 mg/ 100 ml o f phosphate buffer at pH 6.8, for 12 hours shows that the p1·emelano omes remain depigmented ( >< 74,700) . 1943; Stegma ier and Schneider, 1965) and t he The melanocytes co ntain giant preme\anosomes Cross syndrome (Cross et a!. , 1967) . In t he former, that cannot be passed properly via the melanocyte the defect, which is thought to be in t he mem­ dendrites to the keratinocytes. In addi tion, numer­ branes of lysosomal-like particles, res ults in giant ous polyphagosomes in the melanocyte cytoplasm cy toplasmic granules in granule-producing cells. consist of aggregates of giant melanosomes under- 446 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY A B FIG. 4. A. Ha ir bulb from a tyrosinase-positive albino shows faint yellow pi gment granules. Dark area in hair s haft at left is due to li ght scattering from bubbles in hair. B. After in cubation i n !-tyrosine, 80 mg/ 100 ml of phosphate buffer at pH 6.8, for 12 hours, there is in tense pigmentation. go ing destruction by the surrounding lysosomes vere oligophrenia, and gingival fibromatosis (Wit­ (Windhorst et al. , 1968) . kop, 1971). 6. Children with Cross syndrome are hypopig­ mented with melanocytes in which scanty melano­ Present Study somes respond with increased pigmentation in A study of ty-neg, ty-pos, ym, and albinos with vitro to added ]-tyrosine or 1-dopa. In addition, bleeding tendency was undertaken to determine the children have microphthalmia, athetosis, se- which of the previously described abnormalitie OC ULOCUTANEOUS ALBINISM 447 F tc. 5. M elanocyte from a tyrosinase-pos itive a lbino shows in termediate vesicles, premelanosomes Stage II (a) a nd lightly pig mented premelanosomes Stage Ill (b). Ra rely a re ma ture Stage IV mela nosomes (c) observed ( x 16,500). Ftc .. 6. M elanocyte from a t yrosinase- positive albino prefix ed in 2% g lutar a ld e h~' d e and incubated in 80 mg or 1-tyrosm e/1 00 ml phosph ate bu tTer at pH 6.8 for 12 hours, ref'i xed and stain ed in os mi c acid : g lut a r a ld e h~ · d e shows that most of t h e premelanoso mes have converted t o mature melanosomes S tage IV ( '< 10.250).