- Email: [email protected]
Albinism
8
Albinisrn
Carl J. Witkor, Jr., DDS. MS From the L%ision of Genetics, Department of Oral Pathology and Genetics, University of Minnesota School of Dentistry, Minneapolis, Minnesota.
Albinism includes a group of inherited, congenital, generalized, hypomelanotic conditions in which melanocytes are present in integument and the eyes and are accompanied by specific ocular signs. The ocular changes include congenital nystagmus, hypoplasia of the fovea, hypopigmentation of the fundus, abnormal decussation of the optic neurons at the chiasm, decreased pigment in the irides frequently with photophobia; and decreased visual acuity.1 Traditionally, two major forms of albinism have been recognized, oculocutaneous (OCA) and ocular (OA). OCA was believed to involve the melanogenic system of integument and eye, whereas OA was thought to involve only melanin production in the eye. Present evidence indicates that all forms of albinism are OCA defects with distinct but minor changes in integument in the ocular forms of the condition.2~4 Melanin macroglobules (formerly macromelanosomes) are present in the skin of both males affected with X-linked ocular albinism (NettleshipFalls) (XOAN) and carrier femalessps s-7 Patients with autosomal recessive ocular albinism (AROA) have darkly pigmented hair, but their skin is more lightly pigmented than their unaffected siblings and does not tan or tans only slightly.4 Thus, strictly speaking, these are forms of OCA; however, as the major clinical features are limited to the eye, the distinction of OCA and OA types is retained in a clinical context. As recent publications have reviewed disorders of pigmentation,ilsps this presentation will focus upon procedures useful in providing a diagnosis of types of albinism, evidence from matings for allelism or nonallelism of albinotic phenotypes, and some recent advances in pigment research. Classification of Albino Phenotypes The various phenotypes of OCA and OA and the possible sites of their metabolic defects are shown in Table 8-1.
Supported by NIH Grant GM221 67-12, Albinim, and B RSG DRR-2507-RR-053222L
Diagnostic Feah~es of Albinism Patients with type I forms ofoculocutaneous albinism have marked hypopigmentation of skin, hair, and eyes and do not present major problems in designating these patients as albinos. Problems in diagnosing albinism arise most frequently in those types of OCA and 80
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OA in which the patient has moderate to considerable amounts of pigment in integument or even occasionally in the eyes.2 Nystagmus, Macular Reftex, and Hypoplgtnented Fundi The initial and most important sign that should elicit a suspicion that a patient has some form of albinism is the presence of congenital nystagmus.10 If patients with congenital nystagmus also have absent or a blunted macular reflex and hypopigmentation of the ocular fundus, the probability that they have albinism increases. Good fundal photographs are indicated to document the macular defect. Hypopigmented fundi in albinism have a yellow cast, and not the white color seen in atrophic fundi. Hypopigmentation of fundi may not be obvious in some patients, particularly in blacks with XOAN or brown OCA. Iris Translucency
Patients with nystagmus should be examined for translucent irides. Nearly all albinos have some form of diaphaneous irides varying from diaphaneous slits or mild diffuse transillumination to complete absence of iris pigmentation in the ty-neg OCA patient. The irides of patients should be transilluminated in a dark room.8
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TABLE 8-l. Chdkaih
ol Alblno m
The various phenotypes of OCA and OA and the possible sites of their metabolic defects are shown in Table El. Type I locus A. B. C.
Oculocutaneous Albinism OCA Possible mutations at the tyrosinase Tyrosinase-negative OCA Yellow mutant OCA Platinum OCA
Type II OCA Possible intrinsic defect in the tyrosine-melanin pathway distal to dopachrome Tyrosinase-positive OCA Type III OCA Possible compound albino Minimal pigment OCA Type IV OCA Possible defect in melanosome maturation Brown OCA (may be the same as AROA in Caucasians) Type V OCA Possible defect at the pheomelanin switch point Rufous OCA Type VI OCA Site of gene action extrinsic to the tyrosine-melanin pathway A. Hermansky-Pudlak syndrome B. Chediak-Higashi syndrome Type VII OCA Possible structural defect Autosomal dominant OCA Ocular Albinbm Type I OA X-chromosomal locus A. X-linked ocular albinism, Nettleship (XOAN) B. X-linked ocular albinism and sensorineural deafness, Winship (XOAW)
Tanning Ability
Type II OA Autosomal locus Autosomal recessive ocular albinism (AROA)
The next important clinical feature in patients with any form of albinism is their tanning ability. Albino patients, in general, have a reduced tanning ability. Patients with XOAN and AROA usually have lighter skin pigmentation than their unaffected siblings and only tan with difficulty. This may be difficult to assess in black patients with brown OCA and XOAN. Black patients and darkly pigmented Caucasians with XOAN frequently have a reticulated or spotty pigment pattern of dark and light areas on sun-exposed skin (Fig. 8-l).
Type III OA Possible structural defect Autosomal dominant ocular albinism, lentigines, and deafness, Lewis (ADOAL)
Abnormal Visually Evoked Potentials Indicating Optic Neuronal Decussation Detect If these procedures yield equivocal results and questions remain concerning whether the patient has some form of albinism, the patient should be tested by visually evoked potentials
Clinics in
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C. J. Witkop, Jr.
FIG. 8-l. Mottled pigment pattern of skin characteristic of darkly pigmented patients with XOAN. (Photograph courtesy of Dr. F.E. O’Donnell.)
(VEP) for evidence of asymmetry of the optic tracts, which is present in all forms of albinism.ii~l~ Monocular VEPs are symmetric in normal patients and asymmetric in albinos. Apkarian et al.‘” reported that all albinos tested had asymmetric VEPs. The albino feature was the contralateral latency at 125 rns.16 Patients who have the clinical features of albinism, such as nystagmus, albinotic fundi and hypoplasia of the fovea, but do not have asymmetric optic neuronal pathways do not have albinism. This is the case in the &and eye disease described by Forsius and Eriksson.17 There is no optic neuronal descussation defect in this condition. 18 Aland eye disease is no longer considered a form of ocular albinism.
Diagnosis of Specific Types of Albinism Diagnosis of CHS and HPS Once it is established that a patient has some form of albinism, it should be established whether the patient has ChediakHigashi syndrome (CHS) or HermanskyPudlak syndrome (HPS) because these two
Dermatology
albinotic disorders have the most serious prognosis. Patients with CHS usually have a characteristic history of repeated infections. Examination of neutrophils by light or electron microscopy for the presence of giant, peroxidase positive, secondary lysosomal granules is usually sufficient to establish whether the patient has this disorder.20 Platelets from CHS patients are storage pooldeficient and have a reduced number of dense bodies.“1 HPS is a triad of tyrosinase-positive albinism, a mild hemorrhagic diathesis due to storage pool-deficient platelets lacking dense bodies22 and a ceroid storage disease.1.2:3-25 HPS occurs in diverse ethnic populations.1~z2 It occurs approximately once in 2000 Puerto Rican@ and in isolates in Holland, Switzerland, and Madras, India.1 HPS is a distinct genetic disease.22 With the exception of CHS,26 other types of albinos do not develop massive ceroid storage disease or have storage pool-deficient platelets; however, HPS patients phenotypically may resemble any other type of OCA or 0A.s Some resemble ty-neg oculocutaneous albinos. Most have some pigment in skin, hair, and eyes and resemble ym or ty-pos OCA albinos, whereas others have darkly pigmented skin, hair, and eyes and resemble ocular albinos.* HPS is a ceroid storage disease. The accumulation of yellow, autofluorescent ceroid* in lysosomes of cells throughout the body is agedependent and variable with regard to the particular tissues affected.24~25~27~2* Massive amounts of ceroid have been observed in renal proximal tubular epithelium,sfss urine sediment,“” bone marrow,23 spleen,25 and liver.25 Moderate amounts have been observed in lung,25gastrointestinal mucosa,zsand cardiac muscle.* Patients develop restrictive lung disease,zamz5* 27-29 granulomatous colitis and gingivitis28 resembling Crohn’s disease,27130 kidney failure,8931 and cardiomyopathy.8 HPS is a lysosomal storage disease. Dolichols, which are constituents of lysosomal membranes, are elevated in the urine of those HPS patients who excrete large amounts of ceroid in urine.24 Approximately two-thirds of HPS patients die of causes directly related to
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Albinism
restrictive lung disease, hemorrhage, and granulomatous colitis?* The leading cause of death is restrictive lung disease between 35 and 46 years of age.% The most consistent and diagnostically accurate sign of HPS is lack of platelet dense bodies in an albino patient who does not have CHSE 928(Tables 8-2 and 8-3). Platelet counts are normal in HPS patients in the absence of other thrombopenic conditions. Bleeding time is usually prolonged but is often within the normal range. Nephalometric aggregation studies usually demonstrate that platelets of HPS patients do not aggregate with concentrations of agonists that elicit aggregation in normal platelets. Some HPS patients will have normal aggregation responses, and drugs that inhibit cyclooxygenase, such as acetylsalicylic acid, will give nephalometric responses in normal platelets similar to those of HPS platelets. The most reliable method is to examine platelets by whole mounts or in thin sections of centrifuged buttons of gluteraldehyde-fixed platelet-rich plasma (PRP). A g-ml sample of venous blood is collected in 1 ml of citratecitric acid-dextrose anticoagulant and centrifuged at 100 X g for 20 minutes. For whole mounts, a drop of PRP is collected in a small pipette from the layer above the buffy coat and placed on carbon-stabilized, formvar grids and incubated for 1 minute. Excess PRP is removed by touching the edge of the grid with filter paper. The grid is washed twice with a drop of distilled water and the excess removed by touching the edge of the grid with filter paper. The grid is dried by waving back and forth and observed in the electron
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TABLE 9-Z. Status of Platelet Dense Bodies of Albino Patlenta Tested lnltlally and the Same Patlents Tested Agrin 1 to 15 Year8 Later Initial Test
Repeat Test
Absent 31 Present 16
Absent 31 Absent 0
Present 0 Present 16
microscope. Negative staining is not required because platelets are relatively transparent to the electron beam, whereas dense bodies are electron opaque. Normal platelets have from four to eight dense bodies per platelet (Fig. 8-2A). HPS platelets have no dense bodies, but atypical, unusual electron dense fragments may be evident in rare platelets from HPS patient@ (Fig. 8-2B). If the albino patient lacks dense bodies in platelets and does not have CHS, the patient has HPS. Diagnosis of X-linked Ocular Afbinism (XOAN), X-linked Ocular Albinism wffh Sensorineural Dwfness (XOAW), and Aufosomal Dominant Ocular Albinism wifh Lenfigines and DwfneS (ADOAL) The diagnosis of XOAN or XOAW is usually uncomplicated when there is a history of the condition being inherited as an X-linked trait in the family because XOAN and XOAW are the only X-linked forms of albinism. As X-linked traits may be transmitted through
TABLE 9-3. Dense Body Status 0137 Albino Pmposltl and Their 59 Alblno Relatives Number of Relatives by Dense Body Status Present Absent
Number of Propositi by Dense Body Status
Total Albino Relatives Tested
Absent 26
47
47
Present 11
12
0
0 12
a4
C. J. Witkop. Jr.
Clinics in
Dermatology
FIG. 8-3. Fundus of an obligate heterozygotic woman for XOAN with a tigeroid pattern of pigmented and unpigmented epithelium due to lyonization of genes of the X chromosome.
FIG. 8-2. Transmission electron microscopic appearance of whole mounted platelets. A, Normal platelets containing 11 dense bodies B, HPS platelets lacking dense (bodies. X 24,CKIO).
carrier females for several generations, an Xlinked inheritance is often difficult to establish, especially when an isolated affected male appears in a kindred. Examination of the ocular fundi of mothers of affected males may be helpful. Carrier females frequently show mosaic or tigeroid patterns of lyonization of ocular pigment (Fig. 8-3). Not all carrier females have distinct patterns of lyonization. Melanin macroglobules (formerly macromelanosomes) occur in the skin of both the affected males and carrier females of XOAN of Nettleship, XOAN albinism and sensorineural deafness described by Winship et a1.“2 and in the lentiginous skin of patients with autosomal dominant ocular albinism, lentin-
gines, and deafness described by Lewis”3 (ADOAL). Melanin macroglobules can be identified in hematoxylin and eosin stained sections of skin biopsies (Fig. 8-4) or in electron microscopic sections (Fig. 8-5). Melanin macroglobules are found in the fetal pigment epithelium of fetuses from mothers heterozygous for XOAN (Fig. 8-6). Thus, presumably they are present in the skin of infants at birth. Cortin et al.6 and Szymanski et al.7 found these structures in all hemizygotes and obligate heterozygotes tested. The only instance observed by the author in which obligate heterozygotic XOAN women lacked melanin macroglobules was in the unusual circumstance in which the obligate heterozygotic women also had platinum OCA.35 These women were the offspring of a father with XOAN, and one had a son with XOAN. It appears that in this instance the presence of platinum albinism in these women suppressed the expression of melanin macroglobules. Melanin macroglobules are also found in the clinically normal skin of patients with neurofibromatosis, xeroderma pigmentosum, and nevus spilus, and hence, by themselves, are not pathognomic of XOAN, XOAW, or ADOAL. They have also been reported in the skin of Swiss HPS patients by Frenck and Lattion,sd but they have not been seen in skin biopsies of HPS patients from Puerto Rico.1
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FIO. 8-4. Melanin macroglobules in skin of a patient with XOAN are identified by light microscopy by their dense cores and light rims. Compare with Figure 8-5 (hematoxylin and eosin stain, x 800).
If an albino patient does not have HPS, does not have a dermatologic condition known to be associated with melanin macroglobules, and the mother of the patient, or the patient, has melanin macroglobules, then the patient has either XOAN, XOAW, or ADOAL. If the patient or male relatives of the mother have no evidence of sensorineural hearing loss, then he most likely has XOAN. Winship et al. described late-onset hearing loss in their family. We have seen two similar kindreds in which OCA and sensorineural hearing loss that began around puberty were inherited as an X-linked trait.1 The OCA reported by Lewis33 is inherited as a dominant trait and has melanin macroglobules in the lentiginous skin but not in the normal skin.
Albinism
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FIG. 8-5. Electron photomicrographic appearance of melanin macroglobules. These structures have been identified in the skin of nearly all hemizygotes and heterozygotes of XOAN, XOAW, and in the lentiginous skin of ADOL patients. They have also been seen in some patients with HPS as well as in nonalbinotic patients with neurofibromatosis, xeroderma pigmentosum, and nevus spilus (X SOOO). (From O’Donnell et al.,3 with permission.)
OCA, and ym and darkly pigmented ty-pos OCA may resemble some lightly pigmented AROA patients. Phenotypically, a ty-pos albino should have hair no darker than an African ty-pos albino (Fig. 8-7). If the patient has hair and skin color darker than that
Diagnosis of lyrosinasepositive OCA, AROA, and Brown OCA Ty-pos, brown OCA, and AROA albinos have pigment in irides detectable by transillumination. It accumulates first at the limbus and pupillary borders and later may develop a cartwheel pattern.8 Tyrosinase-positive OCA is the most common form of albinism. Most African and Amerindian albinos have this type of albinism as do many Caucasians. Lightly pigmented Caucasian typos albinos overlap the pigment features of platinum
FIG. S-6. Melanin macroglobules in the retinal pigment epithelium of a fetus from an obligate heterozygotic XOAN mother. These structures appear in the eye early in development and hence are presumably also present in the skin at birth (hematoxylin and eosin stain, X SKI).
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C. J. Witkop. Jr.
shown in Figure 8-7, then the patient most likely has AROA (Fig. 8-8) or brown OCA (Fig. 8-9). Many ty-pos albinos, especially from areas of intense solar radiation, will have numerous freckles and lentigines on sunexposed skin. These are also present in HPS patients from similar environments but are rarely present in brown OCAa6,37 or AROA patients.* Freshly epilated hairbulbs of ty-pos OCA patients have little pigment detectable by light microscopy,s whereas the hairbulbs from AROA and Brown OCA patients are as darkly pigmented, or more so, than hairbulbs from normal blond caucasians.s Electron microscopically, hairbulbs of ty-pos OCA have eumelanosomes up to stage 3.1 After incubation in 80 mg of tyrosine/dl of an 0.1 mol/l phosphate buffer at pH 6.8, they form intense pigment seen by light microscopy,8 and most melanosomes are converted to stage 4 eumelanosomes when examined by electron microsc0py.l Brown OCA has been identified only in black populations.37 They have brown hair, hazel eyes, and light brown skin, which tans slightly (Fig. 8-9). Lentigines are absent or occur on!y as isolated small macules. Nystagmus is present but may be elicited in bright light only after dark adaptation. Melanosomes in hairbulbs are predominantly stage 1 and 2 with few stage 3 and rarely stage 4 melanosomes. Melanosomes from skin are usually round, irregular with a granular pattern rather than the normal banded pattern. Large stage 4 eumelanosomes typical of black skin are absent. Incubation of hairbulbs in tyrosine or dopa has no effect on melanization.ss AROA patients usually have darker hair than typos albinos ranging from light-brown to black (Fig. 8-8). The skin is a light cream color, contains little visible pigment, and usually burns with little tanning (Fitzpatrick grade 1 or 2). Freshly epilated hairbulbs contain pigment. Eumelanosomes occur in all stages of development as seen in brown or black hair. Hairbulbs incubated in tyrosine become deeply pigmented but do not form pigment when incubated in tyrosine-cysteine. The reactions are similar to those seen in
Clinics in Dermatology
normal hair.* It is not known whether AROA in Caucasians is the same or a different condition than brown OCA in blacks. Tyrosinase activities in hairbulbs are normal in AROA and brown OCA albinos and are normal or elevated in ty-pos OCA albinos. The hairbulb incubation reactions8 and the normal tyrosinase activity differentiate typos, AROA, and brown albinos from ty-neg, pt, and ym OCA albinos who have zero to very low tyrosinase activity.’
Diagnosis of Aufosomal Dominant and Rufous OCA Autosomal dominant OCA patients phenotypically most closely resemble ty-pos OCA. Nystagmus is usually about as severe as that in ty-pos albinos, but visual acuities are better from 20130 to 201200. The condition shows an autosomal dominant mode of inheritance in contrast to the autosomal recessive inheritance seen in all other forms of OCA. Rufous albinos have mahogany red hair (Fig. 8-10). In Caucasians the skin is moderately pigmented and in blacks is lighter than the population from which they come. Lentigines are rare and strabismus frequent. Hairbulbs contain red pigment, which increases on incubation in tyrosine and cysteine. Ultrastructurally, the hairbulb melanocytes are crowded with round, pheomelanosomes with heavy spotty pigmentation. Elliptical eumelanosomes are not seen (Fig. 8-11).
Diagnosis of fy-neg, pt, and ym OCA There is no tyrosinase activity in ty-neg OCA albino hairbulbs, and zero to very low activities (up to 0.149 pmol/l20 min) in pt and ym hairbulbs. Clinically, ty-neg albinos have no pigment in hair, skin, or eyes and no pigmented nevi, freckles, or lentigines. They do not tan. No pigment is visible on transillumination of the irides. There is no pigment in freshly epilated hairbulbs, and no pigment is formed on incubation of hairbulbs in tyrosine or tyrosine and cysteine.8 Melanosomes do not develop beyond stage 2
Albinism
FIG. 6-11. Dendrites of hairbulb melanocytes from a rufous albino are crowded with round, densely pigmented spotty pheomelanosomes. Elliptical melanosomes are absent (X 18.000).
unpigmented structures either before or after incubation in tyrosine or dopa. Platinum OCA albinos have platinum or silver colored hair rather than the stark white of the ty-neg albino. They do not tan. They gradually accumulate small amounts of pigment in hair and eyes with age. Before the age of 10 years, they may be difficult to differentiate from ty-neg albinos. By 10 to 14 years of age, small amounts of pigment are seen at the limbus and pupillary border, but spoking or a cartwheel pattern has not been observed. Freshly epilated hairbulbs contain small amounts of pigment best seen in dendrites.8 On incubation in tyrosine, pigment is intensified, but they do not develop the intense black pigmentation seen in normal blond hairbulbs or in ty-pos hairbulbs.sThere is no change in the amount of pigment seen after incubation in tyrosine and cysteine. Hairbulbs contain mostly round or ovoid stage 1 and 2 and a few very early lightly pigmented stage 3 melanosomes with a loose appearing matrix (Fig. 8-12). After incubation in tyrosine there is a slight increase in lightly pigmented round pheomelanosomes of early stage 3 (Fig. 8-13). YM OCA albinos are stark white at birth and resemble ty-neg and pt albinos, Usually by the age of 3 years, the hair gradually develops a bright yellow or yellow-red color. These patients develop a light, but distinct,
FIG. 8-12. Melanosomes from a freshly hairbulb of a pt OCA patient are round to shape with a loosely arranged matrix. occasional melanosome has slight pigment individual matrix lamella (X 16,000).
a7
epilated ovoid in Only an along an
tan. Freshly epilated hairbulbs contain a few lightly pigmented yellow granules. After incubation in tyrosine, there is no increase or a very slight increase in pigmentation. After incubation in tyrosine and cysteine, there is a definite intensification of yellow or yellow-red color.8 Freshly epilated hairbulbs contain up to stage 3 unevenly pigmented small round pheomelanosomes. (Fig. 8-14).% These do not change after incubation in tyrosine. After incubation in tyrosine and cysteine the melanosomes show a spotty pigmentation pattern of small round pheomelanosomes (Fig. 8-15).3s
AlbZnoGeno?ypesand Genetic Loci It is not known whether the various albino phenotypes previously discussed all represent genetically distinct mutations; however, matings of albinos have occurred, which have been informative concerning loci at which mutations occur resulting in albinism. Matings between albinos of different phenotypes are especially valuable in determining whether the different forms of albinism are complementary, as when offspring are normally pigmented, or allelic, as when albino children result from the mating. Table 8-4 are matings of human albinos. Matings
aa
C. J. Witkop, Jr.
Clinics in Dermatology
FIG. S-13. Melanosomes from a pt OCA patient after incubation in tyrosine have an early stage 3 pigment pattern with individual pigmented lamellae discernable. They do not have the homogeneously pigmented matrix of stage 4 melanosomes seen in ty-pos, melanocytes after incubation in tyrosine (X 16,000).
FIG. 8-15. Hairbulb melanocytes from patient in Figure 8-14 after incubation in 40 mg tyrosine and 40 mg cysteine/dl of 0.1 mol/l phosphate buffer pH 6.8 are small round structures with a spotty pigment pattern of pheomelanosomes (X 16,000). (Photograph courtesy of Dr. Funan Hu.)
5-7 would be expected to be complementary because the fathers have an X-linked gene and the mothers’ genes are on autosomal chromosomes. Matings 6 and 7 demonstrate the expected status of the daughters, as all five had mosaic pigment patterns in their ocular fundi and/or melanin macroglobules in skin biopsies. Mating 7 demonstrates that AROA in females is not due to an unusual
lyonization effect in an XOAN carrier female. Matings l-4 and 8 indicate that ty-pos and ty-neg are not allelic, ym and ty-pos are not allelic, ty-pos and HPS are not allelic, and AROA and ty-neg are not allelic. These matings indicate two autosomal loci ty-neg (tyrosinase) and ty-pos and one locus on the X chromosomee at which mutations occur resulting in different types of albinism. It also suggests that a third autosomal locus exists, the HPS locus of which is not allelic with typos. Because HPS has tyrosinase activity and it affects lysosomes and platelet dense bodies, it is doubtful that it is allelic with ty-neg OCA. Allelic matings or matings that suggest allelism are shown in matings 9-14. Mating 9 is shown because both the father and mother were diagnosed prior to marriage as ty-pos albinos and appropriately counseled. This a priori diagnosis demonstrates that the method for diagnosis of a ty-pos albino is reliable and genetically verified in this family. Matings 13 and 14 strongly suggest that ym and pt OCA are due to alleles at the ty-neg locus. Mating 13 is that reported by Hu et al.38 The mother had a first cousin who was a proven ty-neg OCA. The mother’s hairbulb tyrosinase activity was zero as expected for carriers of the ty-neg gene. The
FIG. 8-14. Hairbulb melanosomes from a patient with genotype ym/ty-neg have a ym pattern of round partially pigmented pheomelanosomes. No change in this pattern was observed after incubation in tyrosine (X 16,000). (Photograph courtesy of Dr. Funan Hu.)
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Albinism
father was presumed to carry the ym gene because his hairbulb tyrosinase activity was very low as seen in ym heterozygotes. The daughters had a ym phenotypes and reactions of hairbulbs to substrates and ultrastructure like that of ym albinos (Figs. 8-14 and 8-15). In mating 15, the mother had the phenotype of a platinum albino with near zero tyrosinase activity and lightly pigmented melanosomes. The two daughters were tested ty-neg OCA albinos. The father had very low tyrosinase activity and was presumed to be a carrier for ty-neg OCA. These matings indicate that there are mutations at a minimum of three autosomal loci conditioning different types of OCA, tyneg, ty-pos, and HPS. They further suggest, but do not prove, that ym and pt OCA are due to alleles at the ty-neg locus.
RecentAdvancesin PigmentResearch Roderick and Davidssonss have demonstrated that the c-locus (tyrosinase) in mice is on chromosome ‘7near the beta-globin locus, and O’Brien et al.40 have shown that these two loci are linked on chromosome Dl in the cat. If this linkage group is preserved in the human genome, then the tyrosinase locus (ty-
89
neg OCA) should be near chromosome 11~15.5. Evidence for linkage between human albinism and beta-globin on chromosome 11 has been indicated (Hababan R. personal communications). Yamamoto et al.41 reported the isolation and sequencing of mouse tyrosinase. Kwon et al.42 isolated and sequenced human tyrosinase and developed cDNA probes that map at the mouse c-albino locus. Application of these cDNA probes to human albinism should determine in the near future those types of albinism that are due to alleles at the tyrosinase locus. Work by Schallreuter and Wood*3 on the enzyme thioredoxin reductase suggests that this enzyme, present in keratinocytes and melanocytes, acts through thioredoxin and calcium as a trap for UV-generated free radicals and as a regulator of tyrosinase activity and consequently melanogenesis.43 The activity of thioredoxin reductase correlates with the Fitzpatrick classification of skin type reactions to UV radiation, being lowest in type 1 and highest in type 6 skin. A study of thioredoxin activities in the skin of HPS albinos and their relatives indicates that the method detects persons heterozygous for the HPS gene.**
TABLE 8-4. Types of Matings in Humans Showing Complementation or Allelism Father ty-neg ty-pos ym ty-pos XOAN XOAN XOAN AROA ty-pos HPS HPS het HPS Ym het Ty-neg het
Mother x ty-pos Xym x ty-pos X HPS X ty-neg Xym X AROA X x X X X X X
ty-neg ty-pos HPS HPS HPS het ty-neg het pVty-neg
Nonallelic Complementaw Piamented Daughter normal 2 sons and daughter normal Son and daughter normal Son and daughter normal Son normal 2 daughters XOAN hets 3 daughters XOAN hets, son normal daughter normal -
Allelic Noncomplementary
Albinos
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3 daughters, 2 sons ty-pos 1 daughter, 2 sons HPS 2 sons HPS 1 daughter HPS, 1 daughter HPS het 3 daughters ym/ty-neg 2 daughters ty-neg, 1 son, 1 daughter pigmented hets
C : Witkop.
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‘I 13. et al.
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van UorpDB. Eriksson AW, DellemanJW.etal.,&land rye disease: no albino misrouting. Clin &net. 1985:28:526-531. c 1
Albinism. In: Striver CR, Beaudet AL, Sly WS, et al, eds. The metabolic basis of inherited disease. 6th ed New York: McGraw-Hil!. 1989: (in press). FE Jr, Green WK. Fleischmarr JA. et al X-linked ocular albinism in blacks: ocular albinisnl cum pigmento. Arch Ophthalmol. 1978;96:1189-1192
0’I)onnell FE; Jr, tireen AW, McKuslck VA, et al. Forsius-Eriksson syndrome: its relation to NettleshipFalls X-linked ocular albinism. Clin Genet. 1980:17:403-408.
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FE .Jr. Hambrick GW. (ireen WR. rl ai. ar. oculocutaneouh X-Iinked ocular albinisn: macromelanosomal disorder. Arch Ophthalmol. 1976;94:1883-1892.
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A. Jay BS. Macromelanosomey in X-lrnkel: ocular albinism. Histopathology. 1980;4:24:i-254.
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M, Lemagne JM. X-linked oculat albinism: relative value of skin biopsy, iris transillumination and funduscopl in identifying affected males and carriers. Can J Ophthalmol 1981;16:121-123.
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KA. Baughman JA. Nancr Wk:, el al Genetic studies of ocular albinism in a large Virginia kindred. Ann Ophthalmol. 1984:16:18:~~196.
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CJ Jr. Inherited dlsorderk Clin Dermatol. 1985:3:70-134
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[‘reel I). \? itkog CJ Jr, King RA. Asyninietric \ ~suall> rooked potentials in human albinos, evidence for visua: ;$em anomalies. lnvest Ophthalmol. 1974:13’430
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C’rre! IJ, O’Donnel! FE Jr. U‘ltkopC.1 Jr. l’lsual hystenl anomaiirs in human orular alblnoh. Science 1978:201:93-9:33.
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RR‘, L)koro AN, Wltkop f’d Jr. Abnurma: visual pathways in the brain of a human albino. Brain lies 1475%:171-37; , I,. 1
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16
I-
Kendn T. Breton-Gorius J, Lebret M. et al. Evidence that abnormal platelet functions in human ChediakIllgashi syndrome are the result of a lack of dense bodies. Am d Pathol. 1983;111:307-314. Witkop C.J Jr. Krumwiede M, Sedano I-1, et al. The reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome. Am .J Hematol. 1987;16:305-311. Witkop CJ Jr, White JG, King RA. Oculocutaneous albinism. In: Nyhan WL. ed. Heritable disorders of amino acid metabolism: patterns of clinical expression and genetic variation. New York: John Wiley and Sons. 1!)74:177-216. Wltkop C.J Jr. Wolfe LS, Cat YX. et al. Elevated urinary dolichol excretion in the Hermansky-Pudlak syndrome indicator of Iysosomal dysfunction. Am .I Med. 198i:82:463-470. Schinella RA, Greco MA, Garay SM, elal. Hermanskyl’ud!ak syndrome: a clinicopathologic study. Hum I’wthol. 1985:16:366-376.
Sur>
;1
II
U’hitc, ,J(;. (:lawson Cc’. The Chediak-Higashi syndrome: the nature of the giant neutrophil granules and their interactions with cytoplasm and foreign particulates. Am J Pathol. 1980;98:151-196.
I‘rrel I). Boxrr l,A. Iyauc~ ;1S. \ 1hua1 anti autllLor> dnomalies /I, C:hediak-HIgash syndrome. F:le~~trornce~)hlopr (‘lrn Nruroghysloi l!jk:i:55:252 2.5”.
Wolfe IS, Ivy GO, Witkop CJ Jr. Dolichols, lysosomal membrane turnover and relationship to the accumulation of ceroid and lipofuscin in inherited Iliseases. Alzheimer’s disease and aging. Twelfth Nobel conference: structure, biosynthesis and function IIF lsoprenoid compounds in eucaryotic cells. %Sdergarn. Sweden, May 25-28. 1986. Chemica C‘cripta. 1987:27:79-84. ‘l akahashi A, Tokoyama T. Hermansky-Pudlak
c;aray SM. GardellaJE. I<‘azzini El’,etal. HermanskyPudlak syndrome: pulmonary manifestations of a s,rroid storage disease. Am J Med. 1979:66:737-747. S;chinelia RA. (;rtco MA. (‘oibrrt BL. et al. lierrrlansky-I’udlak syndrome with granuiomatour vfblitl:,. Ann Intern Med 1981);92:20~2:<. ic:rtr!a!>k! .I$. (ireen tJ, (‘arolie t”. 1 Jcutocutaneous l!,:ni>m, plalelc! storage pool disease, and progressive ILlpus nephritis. Arch Intern Med. 1983;143:809-811. :j
\! :nsl~~l: I (;vrlckL G. Beighton I’. X-linked inheri Iiincr of ocular albinism with late-onset sensorineural lrafness. Am .J Med Genet. 1984;19:797-803.
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33. LRwis
Albinism
RA. Ocular albinism and deafness Am J Hum Genet. 1978;30:57.
34. Frenck
disorder syndrome.
(abstract).
E, Lattion F. The melanin pigmentary in a family with Hermansky-Pudlak J Invest Dermatol. 1982;78:141-143.
35. Witkop CJ Jr, King RA, Townsend D. Human albinism and animal models of albinism. Pigment Cell Res. Suppl I:&100. 36. King
RA, Creel D, Cervenka J. et al. Albinism in Nigeria with delineation of a new recessive oculocutaneous type. Clin Genet. 1980;17:259-270.
37. King RA, Lewis RA, Townsend oculocutaneous albinism: clinical, and biochemical characterization. 1985;92:1496-1505.
D. et al. Brown ophthalmological, Ophthalmology.
38. Hu F, Hanifin JM, Prescott GH, et al. Yellow mutant albinism: cytochemical, ultrastructural, and genetic characterization suggesting multiple allelism. Am J Hum Genet. 1980;32:387-395. 39. Roderick TH, Davidsson MT. Linkage map of the mouse (Mus musculus). In: O’Brien SD, ed. Genetic
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maps 1984: a compilation of linkage and restriction maps of genetically studied organisms. Vol. 3, New York: Cold Spring Harbor Laboratory, 1984:344. 40, O’Brien SJ, Haskins ME, Winkler CA, et al. Chromosomal mapping of beta-globin and albino loci in the domestic cat. J Hered. 1986;77:374-378. 41. Yamamoto
H, Takeuchi S, Kudo T, et al. Cloning and sequencing of mouse tyrosinase cDNA. Jpn J Genet. 1987;62:271-274,
SH, et al. Isolation 42. Kwon BS, Haq AK, Pomerantz and sequence of a putative cDNA clone for human tyrosinase that maps at the mouse c-albino locus. Proc Nat1 Acad Sci USA. 1987;84:7473-7477. 43. Schallreuter KU, Wood JM. Thioredoxin reductase and its clinical significance in control of the pigmentary system. Clin Dermatol 1989;7:74-85. KU, Witkop CJ. Thioredoxin reductase 44. Schallreuter activity in Hermansky-Pudlak syndrome: a method for identification of putative heterozygotes. J Invest Dermatol. 1988;90:372-377.
Address for correspondence: Carl J. Witkop, Jr., DDS, MS, MOOS HST 16-662, University of Minnesota, 515 Delaware S.E., Minneapolis, MN 55455.
Albinisrn
Carl J. Witkor, Jr., DDS. MS From the L%ision of Genetics, Department of Oral Pathology and Genetics, University of Minnesota School of Dentistry, Minneapolis, Minnesota.
Albinism includes a group of inherited, congenital, generalized, hypomelanotic conditions in which melanocytes are present in integument and the eyes and are accompanied by specific ocular signs. The ocular changes include congenital nystagmus, hypoplasia of the fovea, hypopigmentation of the fundus, abnormal decussation of the optic neurons at the chiasm, decreased pigment in the irides frequently with photophobia; and decreased visual acuity.1 Traditionally, two major forms of albinism have been recognized, oculocutaneous (OCA) and ocular (OA). OCA was believed to involve the melanogenic system of integument and eye, whereas OA was thought to involve only melanin production in the eye. Present evidence indicates that all forms of albinism are OCA defects with distinct but minor changes in integument in the ocular forms of the condition.2~4 Melanin macroglobules (formerly macromelanosomes) are present in the skin of both males affected with X-linked ocular albinism (NettleshipFalls) (XOAN) and carrier femalessps s-7 Patients with autosomal recessive ocular albinism (AROA) have darkly pigmented hair, but their skin is more lightly pigmented than their unaffected siblings and does not tan or tans only slightly.4 Thus, strictly speaking, these are forms of OCA; however, as the major clinical features are limited to the eye, the distinction of OCA and OA types is retained in a clinical context. As recent publications have reviewed disorders of pigmentation,ilsps this presentation will focus upon procedures useful in providing a diagnosis of types of albinism, evidence from matings for allelism or nonallelism of albinotic phenotypes, and some recent advances in pigment research. Classification of Albino Phenotypes The various phenotypes of OCA and OA and the possible sites of their metabolic defects are shown in Table 8-1.
Supported by NIH Grant GM221 67-12, Albinim, and B RSG DRR-2507-RR-053222L
Diagnostic Feah~es of Albinism Patients with type I forms ofoculocutaneous albinism have marked hypopigmentation of skin, hair, and eyes and do not present major problems in designating these patients as albinos. Problems in diagnosing albinism arise most frequently in those types of OCA and 80
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OA in which the patient has moderate to considerable amounts of pigment in integument or even occasionally in the eyes.2 Nystagmus, Macular Reftex, and Hypoplgtnented Fundi The initial and most important sign that should elicit a suspicion that a patient has some form of albinism is the presence of congenital nystagmus.10 If patients with congenital nystagmus also have absent or a blunted macular reflex and hypopigmentation of the ocular fundus, the probability that they have albinism increases. Good fundal photographs are indicated to document the macular defect. Hypopigmented fundi in albinism have a yellow cast, and not the white color seen in atrophic fundi. Hypopigmentation of fundi may not be obvious in some patients, particularly in blacks with XOAN or brown OCA. Iris Translucency
Patients with nystagmus should be examined for translucent irides. Nearly all albinos have some form of diaphaneous irides varying from diaphaneous slits or mild diffuse transillumination to complete absence of iris pigmentation in the ty-neg OCA patient. The irides of patients should be transilluminated in a dark room.8
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TABLE 8-l. Chdkaih
ol Alblno m
The various phenotypes of OCA and OA and the possible sites of their metabolic defects are shown in Table El. Type I locus A. B. C.
Oculocutaneous Albinism OCA Possible mutations at the tyrosinase Tyrosinase-negative OCA Yellow mutant OCA Platinum OCA
Type II OCA Possible intrinsic defect in the tyrosine-melanin pathway distal to dopachrome Tyrosinase-positive OCA Type III OCA Possible compound albino Minimal pigment OCA Type IV OCA Possible defect in melanosome maturation Brown OCA (may be the same as AROA in Caucasians) Type V OCA Possible defect at the pheomelanin switch point Rufous OCA Type VI OCA Site of gene action extrinsic to the tyrosine-melanin pathway A. Hermansky-Pudlak syndrome B. Chediak-Higashi syndrome Type VII OCA Possible structural defect Autosomal dominant OCA Ocular Albinbm Type I OA X-chromosomal locus A. X-linked ocular albinism, Nettleship (XOAN) B. X-linked ocular albinism and sensorineural deafness, Winship (XOAW)
Tanning Ability
Type II OA Autosomal locus Autosomal recessive ocular albinism (AROA)
The next important clinical feature in patients with any form of albinism is their tanning ability. Albino patients, in general, have a reduced tanning ability. Patients with XOAN and AROA usually have lighter skin pigmentation than their unaffected siblings and only tan with difficulty. This may be difficult to assess in black patients with brown OCA and XOAN. Black patients and darkly pigmented Caucasians with XOAN frequently have a reticulated or spotty pigment pattern of dark and light areas on sun-exposed skin (Fig. 8-l).
Type III OA Possible structural defect Autosomal dominant ocular albinism, lentigines, and deafness, Lewis (ADOAL)
Abnormal Visually Evoked Potentials Indicating Optic Neuronal Decussation Detect If these procedures yield equivocal results and questions remain concerning whether the patient has some form of albinism, the patient should be tested by visually evoked potentials
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FIG. 8-l. Mottled pigment pattern of skin characteristic of darkly pigmented patients with XOAN. (Photograph courtesy of Dr. F.E. O’Donnell.)
(VEP) for evidence of asymmetry of the optic tracts, which is present in all forms of albinism.ii~l~ Monocular VEPs are symmetric in normal patients and asymmetric in albinos. Apkarian et al.‘” reported that all albinos tested had asymmetric VEPs. The albino feature was the contralateral latency at 125 rns.16 Patients who have the clinical features of albinism, such as nystagmus, albinotic fundi and hypoplasia of the fovea, but do not have asymmetric optic neuronal pathways do not have albinism. This is the case in the &and eye disease described by Forsius and Eriksson.17 There is no optic neuronal descussation defect in this condition. 18 Aland eye disease is no longer considered a form of ocular albinism.
Diagnosis of Specific Types of Albinism Diagnosis of CHS and HPS Once it is established that a patient has some form of albinism, it should be established whether the patient has ChediakHigashi syndrome (CHS) or HermanskyPudlak syndrome (HPS) because these two
Dermatology
albinotic disorders have the most serious prognosis. Patients with CHS usually have a characteristic history of repeated infections. Examination of neutrophils by light or electron microscopy for the presence of giant, peroxidase positive, secondary lysosomal granules is usually sufficient to establish whether the patient has this disorder.20 Platelets from CHS patients are storage pooldeficient and have a reduced number of dense bodies.“1 HPS is a triad of tyrosinase-positive albinism, a mild hemorrhagic diathesis due to storage pool-deficient platelets lacking dense bodies22 and a ceroid storage disease.1.2:3-25 HPS occurs in diverse ethnic populations.1~z2 It occurs approximately once in 2000 Puerto Rican@ and in isolates in Holland, Switzerland, and Madras, India.1 HPS is a distinct genetic disease.22 With the exception of CHS,26 other types of albinos do not develop massive ceroid storage disease or have storage pool-deficient platelets; however, HPS patients phenotypically may resemble any other type of OCA or 0A.s Some resemble ty-neg oculocutaneous albinos. Most have some pigment in skin, hair, and eyes and resemble ym or ty-pos OCA albinos, whereas others have darkly pigmented skin, hair, and eyes and resemble ocular albinos.* HPS is a ceroid storage disease. The accumulation of yellow, autofluorescent ceroid* in lysosomes of cells throughout the body is agedependent and variable with regard to the particular tissues affected.24~25~27~2* Massive amounts of ceroid have been observed in renal proximal tubular epithelium,sfss urine sediment,“” bone marrow,23 spleen,25 and liver.25 Moderate amounts have been observed in lung,25gastrointestinal mucosa,zsand cardiac muscle.* Patients develop restrictive lung disease,zamz5* 27-29 granulomatous colitis and gingivitis28 resembling Crohn’s disease,27130 kidney failure,8931 and cardiomyopathy.8 HPS is a lysosomal storage disease. Dolichols, which are constituents of lysosomal membranes, are elevated in the urine of those HPS patients who excrete large amounts of ceroid in urine.24 Approximately two-thirds of HPS patients die of causes directly related to
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Albinism
restrictive lung disease, hemorrhage, and granulomatous colitis?* The leading cause of death is restrictive lung disease between 35 and 46 years of age.% The most consistent and diagnostically accurate sign of HPS is lack of platelet dense bodies in an albino patient who does not have CHSE 928(Tables 8-2 and 8-3). Platelet counts are normal in HPS patients in the absence of other thrombopenic conditions. Bleeding time is usually prolonged but is often within the normal range. Nephalometric aggregation studies usually demonstrate that platelets of HPS patients do not aggregate with concentrations of agonists that elicit aggregation in normal platelets. Some HPS patients will have normal aggregation responses, and drugs that inhibit cyclooxygenase, such as acetylsalicylic acid, will give nephalometric responses in normal platelets similar to those of HPS platelets. The most reliable method is to examine platelets by whole mounts or in thin sections of centrifuged buttons of gluteraldehyde-fixed platelet-rich plasma (PRP). A g-ml sample of venous blood is collected in 1 ml of citratecitric acid-dextrose anticoagulant and centrifuged at 100 X g for 20 minutes. For whole mounts, a drop of PRP is collected in a small pipette from the layer above the buffy coat and placed on carbon-stabilized, formvar grids and incubated for 1 minute. Excess PRP is removed by touching the edge of the grid with filter paper. The grid is washed twice with a drop of distilled water and the excess removed by touching the edge of the grid with filter paper. The grid is dried by waving back and forth and observed in the electron
83
TABLE 9-Z. Status of Platelet Dense Bodies of Albino Patlenta Tested lnltlally and the Same Patlents Tested Agrin 1 to 15 Year8 Later Initial Test
Repeat Test
Absent 31 Present 16
Absent 31 Absent 0
Present 0 Present 16
microscope. Negative staining is not required because platelets are relatively transparent to the electron beam, whereas dense bodies are electron opaque. Normal platelets have from four to eight dense bodies per platelet (Fig. 8-2A). HPS platelets have no dense bodies, but atypical, unusual electron dense fragments may be evident in rare platelets from HPS patient@ (Fig. 8-2B). If the albino patient lacks dense bodies in platelets and does not have CHS, the patient has HPS. Diagnosis of X-linked Ocular Afbinism (XOAN), X-linked Ocular Albinism wffh Sensorineural Dwfness (XOAW), and Aufosomal Dominant Ocular Albinism wifh Lenfigines and DwfneS (ADOAL) The diagnosis of XOAN or XOAW is usually uncomplicated when there is a history of the condition being inherited as an X-linked trait in the family because XOAN and XOAW are the only X-linked forms of albinism. As X-linked traits may be transmitted through
TABLE 9-3. Dense Body Status 0137 Albino Pmposltl and Their 59 Alblno Relatives Number of Relatives by Dense Body Status Present Absent
Number of Propositi by Dense Body Status
Total Albino Relatives Tested
Absent 26
47
47
Present 11
12
0
0 12
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C. J. Witkop. Jr.
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Dermatology
FIG. 8-3. Fundus of an obligate heterozygotic woman for XOAN with a tigeroid pattern of pigmented and unpigmented epithelium due to lyonization of genes of the X chromosome.
FIG. 8-2. Transmission electron microscopic appearance of whole mounted platelets. A, Normal platelets containing 11 dense bodies B, HPS platelets lacking dense (bodies. X 24,CKIO).
carrier females for several generations, an Xlinked inheritance is often difficult to establish, especially when an isolated affected male appears in a kindred. Examination of the ocular fundi of mothers of affected males may be helpful. Carrier females frequently show mosaic or tigeroid patterns of lyonization of ocular pigment (Fig. 8-3). Not all carrier females have distinct patterns of lyonization. Melanin macroglobules (formerly macromelanosomes) occur in the skin of both the affected males and carrier females of XOAN of Nettleship, XOAN albinism and sensorineural deafness described by Winship et a1.“2 and in the lentiginous skin of patients with autosomal dominant ocular albinism, lentin-
gines, and deafness described by Lewis”3 (ADOAL). Melanin macroglobules can be identified in hematoxylin and eosin stained sections of skin biopsies (Fig. 8-4) or in electron microscopic sections (Fig. 8-5). Melanin macroglobules are found in the fetal pigment epithelium of fetuses from mothers heterozygous for XOAN (Fig. 8-6). Thus, presumably they are present in the skin of infants at birth. Cortin et al.6 and Szymanski et al.7 found these structures in all hemizygotes and obligate heterozygotes tested. The only instance observed by the author in which obligate heterozygotic XOAN women lacked melanin macroglobules was in the unusual circumstance in which the obligate heterozygotic women also had platinum OCA.35 These women were the offspring of a father with XOAN, and one had a son with XOAN. It appears that in this instance the presence of platinum albinism in these women suppressed the expression of melanin macroglobules. Melanin macroglobules are also found in the clinically normal skin of patients with neurofibromatosis, xeroderma pigmentosum, and nevus spilus, and hence, by themselves, are not pathognomic of XOAN, XOAW, or ADOAL. They have also been reported in the skin of Swiss HPS patients by Frenck and Lattion,sd but they have not been seen in skin biopsies of HPS patients from Puerto Rico.1
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FIO. 8-4. Melanin macroglobules in skin of a patient with XOAN are identified by light microscopy by their dense cores and light rims. Compare with Figure 8-5 (hematoxylin and eosin stain, x 800).
If an albino patient does not have HPS, does not have a dermatologic condition known to be associated with melanin macroglobules, and the mother of the patient, or the patient, has melanin macroglobules, then the patient has either XOAN, XOAW, or ADOAL. If the patient or male relatives of the mother have no evidence of sensorineural hearing loss, then he most likely has XOAN. Winship et al. described late-onset hearing loss in their family. We have seen two similar kindreds in which OCA and sensorineural hearing loss that began around puberty were inherited as an X-linked trait.1 The OCA reported by Lewis33 is inherited as a dominant trait and has melanin macroglobules in the lentiginous skin but not in the normal skin.
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FIG. 8-5. Electron photomicrographic appearance of melanin macroglobules. These structures have been identified in the skin of nearly all hemizygotes and heterozygotes of XOAN, XOAW, and in the lentiginous skin of ADOL patients. They have also been seen in some patients with HPS as well as in nonalbinotic patients with neurofibromatosis, xeroderma pigmentosum, and nevus spilus (X SOOO). (From O’Donnell et al.,3 with permission.)
OCA, and ym and darkly pigmented ty-pos OCA may resemble some lightly pigmented AROA patients. Phenotypically, a ty-pos albino should have hair no darker than an African ty-pos albino (Fig. 8-7). If the patient has hair and skin color darker than that
Diagnosis of lyrosinasepositive OCA, AROA, and Brown OCA Ty-pos, brown OCA, and AROA albinos have pigment in irides detectable by transillumination. It accumulates first at the limbus and pupillary borders and later may develop a cartwheel pattern.8 Tyrosinase-positive OCA is the most common form of albinism. Most African and Amerindian albinos have this type of albinism as do many Caucasians. Lightly pigmented Caucasian typos albinos overlap the pigment features of platinum
FIG. S-6. Melanin macroglobules in the retinal pigment epithelium of a fetus from an obligate heterozygotic XOAN mother. These structures appear in the eye early in development and hence are presumably also present in the skin at birth (hematoxylin and eosin stain, X SKI).
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C. J. Witkop. Jr.
shown in Figure 8-7, then the patient most likely has AROA (Fig. 8-8) or brown OCA (Fig. 8-9). Many ty-pos albinos, especially from areas of intense solar radiation, will have numerous freckles and lentigines on sunexposed skin. These are also present in HPS patients from similar environments but are rarely present in brown OCAa6,37 or AROA patients.* Freshly epilated hairbulbs of ty-pos OCA patients have little pigment detectable by light microscopy,s whereas the hairbulbs from AROA and Brown OCA patients are as darkly pigmented, or more so, than hairbulbs from normal blond caucasians.s Electron microscopically, hairbulbs of ty-pos OCA have eumelanosomes up to stage 3.1 After incubation in 80 mg of tyrosine/dl of an 0.1 mol/l phosphate buffer at pH 6.8, they form intense pigment seen by light microscopy,8 and most melanosomes are converted to stage 4 eumelanosomes when examined by electron microsc0py.l Brown OCA has been identified only in black populations.37 They have brown hair, hazel eyes, and light brown skin, which tans slightly (Fig. 8-9). Lentigines are absent or occur on!y as isolated small macules. Nystagmus is present but may be elicited in bright light only after dark adaptation. Melanosomes in hairbulbs are predominantly stage 1 and 2 with few stage 3 and rarely stage 4 melanosomes. Melanosomes from skin are usually round, irregular with a granular pattern rather than the normal banded pattern. Large stage 4 eumelanosomes typical of black skin are absent. Incubation of hairbulbs in tyrosine or dopa has no effect on melanization.ss AROA patients usually have darker hair than typos albinos ranging from light-brown to black (Fig. 8-8). The skin is a light cream color, contains little visible pigment, and usually burns with little tanning (Fitzpatrick grade 1 or 2). Freshly epilated hairbulbs contain pigment. Eumelanosomes occur in all stages of development as seen in brown or black hair. Hairbulbs incubated in tyrosine become deeply pigmented but do not form pigment when incubated in tyrosine-cysteine. The reactions are similar to those seen in
Clinics in Dermatology
normal hair.* It is not known whether AROA in Caucasians is the same or a different condition than brown OCA in blacks. Tyrosinase activities in hairbulbs are normal in AROA and brown OCA albinos and are normal or elevated in ty-pos OCA albinos. The hairbulb incubation reactions8 and the normal tyrosinase activity differentiate typos, AROA, and brown albinos from ty-neg, pt, and ym OCA albinos who have zero to very low tyrosinase activity.’
Diagnosis of Aufosomal Dominant and Rufous OCA Autosomal dominant OCA patients phenotypically most closely resemble ty-pos OCA. Nystagmus is usually about as severe as that in ty-pos albinos, but visual acuities are better from 20130 to 201200. The condition shows an autosomal dominant mode of inheritance in contrast to the autosomal recessive inheritance seen in all other forms of OCA. Rufous albinos have mahogany red hair (Fig. 8-10). In Caucasians the skin is moderately pigmented and in blacks is lighter than the population from which they come. Lentigines are rare and strabismus frequent. Hairbulbs contain red pigment, which increases on incubation in tyrosine and cysteine. Ultrastructurally, the hairbulb melanocytes are crowded with round, pheomelanosomes with heavy spotty pigmentation. Elliptical eumelanosomes are not seen (Fig. 8-11).
Diagnosis of fy-neg, pt, and ym OCA There is no tyrosinase activity in ty-neg OCA albino hairbulbs, and zero to very low activities (up to 0.149 pmol/l20 min) in pt and ym hairbulbs. Clinically, ty-neg albinos have no pigment in hair, skin, or eyes and no pigmented nevi, freckles, or lentigines. They do not tan. No pigment is visible on transillumination of the irides. There is no pigment in freshly epilated hairbulbs, and no pigment is formed on incubation of hairbulbs in tyrosine or tyrosine and cysteine.8 Melanosomes do not develop beyond stage 2
Albinism
FIG. 6-11. Dendrites of hairbulb melanocytes from a rufous albino are crowded with round, densely pigmented spotty pheomelanosomes. Elliptical melanosomes are absent (X 18.000).
unpigmented structures either before or after incubation in tyrosine or dopa. Platinum OCA albinos have platinum or silver colored hair rather than the stark white of the ty-neg albino. They do not tan. They gradually accumulate small amounts of pigment in hair and eyes with age. Before the age of 10 years, they may be difficult to differentiate from ty-neg albinos. By 10 to 14 years of age, small amounts of pigment are seen at the limbus and pupillary border, but spoking or a cartwheel pattern has not been observed. Freshly epilated hairbulbs contain small amounts of pigment best seen in dendrites.8 On incubation in tyrosine, pigment is intensified, but they do not develop the intense black pigmentation seen in normal blond hairbulbs or in ty-pos hairbulbs.sThere is no change in the amount of pigment seen after incubation in tyrosine and cysteine. Hairbulbs contain mostly round or ovoid stage 1 and 2 and a few very early lightly pigmented stage 3 melanosomes with a loose appearing matrix (Fig. 8-12). After incubation in tyrosine there is a slight increase in lightly pigmented round pheomelanosomes of early stage 3 (Fig. 8-13). YM OCA albinos are stark white at birth and resemble ty-neg and pt albinos, Usually by the age of 3 years, the hair gradually develops a bright yellow or yellow-red color. These patients develop a light, but distinct,
FIG. 8-12. Melanosomes from a freshly hairbulb of a pt OCA patient are round to shape with a loosely arranged matrix. occasional melanosome has slight pigment individual matrix lamella (X 16,000).
a7
epilated ovoid in Only an along an
tan. Freshly epilated hairbulbs contain a few lightly pigmented yellow granules. After incubation in tyrosine, there is no increase or a very slight increase in pigmentation. After incubation in tyrosine and cysteine, there is a definite intensification of yellow or yellow-red color.8 Freshly epilated hairbulbs contain up to stage 3 unevenly pigmented small round pheomelanosomes. (Fig. 8-14).% These do not change after incubation in tyrosine. After incubation in tyrosine and cysteine the melanosomes show a spotty pigmentation pattern of small round pheomelanosomes (Fig. 8-15).3s
AlbZnoGeno?ypesand Genetic Loci It is not known whether the various albino phenotypes previously discussed all represent genetically distinct mutations; however, matings of albinos have occurred, which have been informative concerning loci at which mutations occur resulting in albinism. Matings between albinos of different phenotypes are especially valuable in determining whether the different forms of albinism are complementary, as when offspring are normally pigmented, or allelic, as when albino children result from the mating. Table 8-4 are matings of human albinos. Matings
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C. J. Witkop, Jr.
Clinics in Dermatology
FIG. S-13. Melanosomes from a pt OCA patient after incubation in tyrosine have an early stage 3 pigment pattern with individual pigmented lamellae discernable. They do not have the homogeneously pigmented matrix of stage 4 melanosomes seen in ty-pos, melanocytes after incubation in tyrosine (X 16,000).
FIG. 8-15. Hairbulb melanocytes from patient in Figure 8-14 after incubation in 40 mg tyrosine and 40 mg cysteine/dl of 0.1 mol/l phosphate buffer pH 6.8 are small round structures with a spotty pigment pattern of pheomelanosomes (X 16,000). (Photograph courtesy of Dr. Funan Hu.)
5-7 would be expected to be complementary because the fathers have an X-linked gene and the mothers’ genes are on autosomal chromosomes. Matings 6 and 7 demonstrate the expected status of the daughters, as all five had mosaic pigment patterns in their ocular fundi and/or melanin macroglobules in skin biopsies. Mating 7 demonstrates that AROA in females is not due to an unusual
lyonization effect in an XOAN carrier female. Matings l-4 and 8 indicate that ty-pos and ty-neg are not allelic, ym and ty-pos are not allelic, ty-pos and HPS are not allelic, and AROA and ty-neg are not allelic. These matings indicate two autosomal loci ty-neg (tyrosinase) and ty-pos and one locus on the X chromosomee at which mutations occur resulting in different types of albinism. It also suggests that a third autosomal locus exists, the HPS locus of which is not allelic with typos. Because HPS has tyrosinase activity and it affects lysosomes and platelet dense bodies, it is doubtful that it is allelic with ty-neg OCA. Allelic matings or matings that suggest allelism are shown in matings 9-14. Mating 9 is shown because both the father and mother were diagnosed prior to marriage as ty-pos albinos and appropriately counseled. This a priori diagnosis demonstrates that the method for diagnosis of a ty-pos albino is reliable and genetically verified in this family. Matings 13 and 14 strongly suggest that ym and pt OCA are due to alleles at the ty-neg locus. Mating 13 is that reported by Hu et al.38 The mother had a first cousin who was a proven ty-neg OCA. The mother’s hairbulb tyrosinase activity was zero as expected for carriers of the ty-neg gene. The
FIG. 8-14. Hairbulb melanosomes from a patient with genotype ym/ty-neg have a ym pattern of round partially pigmented pheomelanosomes. No change in this pattern was observed after incubation in tyrosine (X 16,000). (Photograph courtesy of Dr. Funan Hu.)
April-June 1989 Volume 7 Number 2
Albinism
father was presumed to carry the ym gene because his hairbulb tyrosinase activity was very low as seen in ym heterozygotes. The daughters had a ym phenotypes and reactions of hairbulbs to substrates and ultrastructure like that of ym albinos (Figs. 8-14 and 8-15). In mating 15, the mother had the phenotype of a platinum albino with near zero tyrosinase activity and lightly pigmented melanosomes. The two daughters were tested ty-neg OCA albinos. The father had very low tyrosinase activity and was presumed to be a carrier for ty-neg OCA. These matings indicate that there are mutations at a minimum of three autosomal loci conditioning different types of OCA, tyneg, ty-pos, and HPS. They further suggest, but do not prove, that ym and pt OCA are due to alleles at the ty-neg locus.
RecentAdvancesin PigmentResearch Roderick and Davidssonss have demonstrated that the c-locus (tyrosinase) in mice is on chromosome ‘7near the beta-globin locus, and O’Brien et al.40 have shown that these two loci are linked on chromosome Dl in the cat. If this linkage group is preserved in the human genome, then the tyrosinase locus (ty-
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neg OCA) should be near chromosome 11~15.5. Evidence for linkage between human albinism and beta-globin on chromosome 11 has been indicated (Hababan R. personal communications). Yamamoto et al.41 reported the isolation and sequencing of mouse tyrosinase. Kwon et al.42 isolated and sequenced human tyrosinase and developed cDNA probes that map at the mouse c-albino locus. Application of these cDNA probes to human albinism should determine in the near future those types of albinism that are due to alleles at the tyrosinase locus. Work by Schallreuter and Wood*3 on the enzyme thioredoxin reductase suggests that this enzyme, present in keratinocytes and melanocytes, acts through thioredoxin and calcium as a trap for UV-generated free radicals and as a regulator of tyrosinase activity and consequently melanogenesis.43 The activity of thioredoxin reductase correlates with the Fitzpatrick classification of skin type reactions to UV radiation, being lowest in type 1 and highest in type 6 skin. A study of thioredoxin activities in the skin of HPS albinos and their relatives indicates that the method detects persons heterozygous for the HPS gene.**
TABLE 8-4. Types of Matings in Humans Showing Complementation or Allelism Father ty-neg ty-pos ym ty-pos XOAN XOAN XOAN AROA ty-pos HPS HPS het HPS Ym het Ty-neg het
Mother x ty-pos Xym x ty-pos X HPS X ty-neg Xym X AROA X x X X X X X
ty-neg ty-pos HPS HPS HPS het ty-neg het pVty-neg
Nonallelic Complementaw Piamented Daughter normal 2 sons and daughter normal Son and daughter normal Son and daughter normal Son normal 2 daughters XOAN hets 3 daughters XOAN hets, son normal daughter normal -
Allelic Noncomplementary
Albinos
-
3 daughters, 2 sons ty-pos 1 daughter, 2 sons HPS 2 sons HPS 1 daughter HPS, 1 daughter HPS het 3 daughters ym/ty-neg 2 daughters ty-neg, 1 son, 1 daughter pigmented hets
C : Witkop.
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Wolfe IS, Ivy GO, Witkop CJ Jr. Dolichols, lysosomal membrane turnover and relationship to the accumulation of ceroid and lipofuscin in inherited Iliseases. Alzheimer’s disease and aging. Twelfth Nobel conference: structure, biosynthesis and function IIF lsoprenoid compounds in eucaryotic cells. %Sdergarn. Sweden, May 25-28. 1986. Chemica C‘cripta. 1987:27:79-84. ‘l akahashi A, Tokoyama T. Hermansky-Pudlak
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RA, Creel D, Cervenka J. et al. Albinism in Nigeria with delineation of a new recessive oculocutaneous type. Clin Genet. 1980;17:259-270.
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maps 1984: a compilation of linkage and restriction maps of genetically studied organisms. Vol. 3, New York: Cold Spring Harbor Laboratory, 1984:344. 40, O’Brien SJ, Haskins ME, Winkler CA, et al. Chromosomal mapping of beta-globin and albino loci in the domestic cat. J Hered. 1986;77:374-378. 41. Yamamoto
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SH, et al. Isolation 42. Kwon BS, Haq AK, Pomerantz and sequence of a putative cDNA clone for human tyrosinase that maps at the mouse c-albino locus. Proc Nat1 Acad Sci USA. 1987;84:7473-7477. 43. Schallreuter KU, Wood JM. Thioredoxin reductase and its clinical significance in control of the pigmentary system. Clin Dermatol 1989;7:74-85. KU, Witkop CJ. Thioredoxin reductase 44. Schallreuter activity in Hermansky-Pudlak syndrome: a method for identification of putative heterozygotes. J Invest Dermatol. 1988;90:372-377.
Address for correspondence: Carl J. Witkop, Jr., DDS, MS, MOOS HST 16-662, University of Minnesota, 515 Delaware S.E., Minneapolis, MN 55455.