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Other entities represented in this entry:
SNOMEDCT: 82342003; ORPHA: 352731, 352737, 79434; DO: 0070095;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q14.3 | Albinism, oculocutaneous, type IB | 606952 | Autosomal recessive | 3 | TYR | 606933 |
A number sign (#) is used with this entry because oculocutaneous albinism type IB (OCA1B) is caused by homozygous or compound heterozygous mutation in the tyrosinase gene (TYR; 606933) on chromosome 11q14.
For a discussion of genetic heterogeneity of OCA, see OCA1A (203100).
Oculocutaneous albinism type I is an autosomal recessive disorder characterized by absence of pigment in hair, skin, and eyes, and does not vary with race or age. Severe nystagmus, photophobia, and reduced visual acuity are common features. OCA type I is divided into 2 types: type IA, characterized by complete lack of tyrosinase activity due to production of an inactive enzyme, and type IB, characterized by reduced activity of tyrosinase.
Although OCA caused by mutations in the TYR gene was classically known as 'tyrosinase-negative' OCA, Tripathi et al. (1992) noted that some patients with 'tyrosinase-positive' OCA may indeed have TYR mutations resulting in residual enzyme activity. These patients can be classified as having OCA1B.
Witkop (1971) suggested that the 'yellow mutant' (ym) form of albinism first observed among the Amish (Nance et al., 1970) and later observed in non-Amish families (Witkop et al., 1971) may be distinct from both tyrosinase-positive and tyrosinase-negative albinism. As in type II albinism (203200), the homozygote is 'dead white' at birth, with serious ocular abnormalities, but rather rapidly develops normal skin pigmentation and yellow hair. The condition differs from albinism II in the yellow hair and the fact that incubation with L-tyrosine or L-DOPA yields equivocal results.
Hu et al. (1980) described 3 sisters, including monozygotic twins, with clinical, ultrastructural, and histochemical features typical of yellow mutant albinism. Classic tyrosinase-negative albinism was found in a maternal cousin of the probands. The authors suggested that the probands are genetic compounds for the yellow mutant allele and the classic albinism allele.
King et al. (1986) reported 3 families in which affected individuals had white hair and no skin or eye pigment at birth, but developed minimal amounts of pigment in the iris in the first decade of life. They had no measurable hairbulb tyrosinase activity. The authors referred to this as 'minimal pigment' type albinism. In each of the families, one parent had normal tyrosinase activity and the other abnormally low activity. King et al. (2001) stated that early descriptions of 'minimal pigment' and 'platinum'-type albinism are now considered likely to be part of the OCA1B spectrum. While most affected individuals with OCA1B have blue eyes at birth, they can develop visible light tan or brown pigment over time.
King et al. (2001) discussed changes in the optic system common to all individuals affected with oculocutaneous albinism. Melanin in the retinal pigment epithelium (RPE) is greatly reduced or absent, making the retina transparent; as a result, the choroidal blood vessels may be seen on ophthalmoscopic examination. Foveal hypoplasia results in reduced visual acuity, and correction of refractive errors (myopia, hyperopia, or astigmatism), which are common and significant, often improves acuity modestly. The most striking optic system change in albinism is the abnormal decussation and misrouting of the optic fibers at the chiasm, resulting in loss of stereoscopic depth perception. Asymmetric visual evoked potential, which is evidence of misrouting, is diagnostic for albinism.
Albinism is associated with a variety of ophthalmologic signs, including iris transillumination, nystagmus, strabismus, high refractive errors, foveal dysgenesis, chorioretinal hypopigmentation, and the 'albinotic' optic disc. Brodsky and Fray (2004) reported that a positive angle kappa, with the appearance of exotropia but no fixation shift on alternate cover test, is also associated with albinism in patients with congenital nystagmus. The authors suggested that this association might be related to the anomalous decussation of the optic axons that characterizes the albinotic visual system.
Temperature-Sensitive Phenotype
King et al. (1991) reported a patient with white hair in the warmer areas (scalp and axilla) and progressively darker hair in the cooler areas (extremities) of her body. Tyrosinase assay demonstrated a loss of activity above 35-37 degrees C. The authors noted that the pattern of peripheral pigmentation is analogous to the Siamese cat and the Himalayan mouse.
Ocular Albinism with Waardenburg Syndrome Type 2A
Lewis (1978) found 7 affected males and 5 affected females in 3 consecutive generations of a Caucasian kindred. As in the X-linked Nettleship-Falls form of ocular albinism (300500), the patients showed reduced visual acuity, photophobia, nystagmus, translucent irides, strabismus, hypermetropic refractive errors, and albinotic fundus with foveal hypoplasia. The skin lesions showed macromelanosomes as in X-linked ocular albinism. Deafness, which was accompanied by vestibular hypofunction, lentigines even in unexposed areas, optic nerve dysplasia, and dominant inheritance distinguished this form of ocular albinism. (In the LEOPARD syndrome (151100) vestibular function is normal.)
Bard (1978) described a kindred that was atypical of Waardenburg syndrome (see 193510) in several ways. Although the nasal root was prominent, one affected person had dystopia of the inner canthi or lower puncta. The face in some showed striking freckling of pale skin. Symptomatic vestibular disturbance was another unusual feature. Lewis (1989) expressed the opinion that the family reported by Bard (1978) as an instance of Waardenburg syndrome in fact had this disorder. Lewis (1989) had also been told of 2 other small families with the syndrome. Goldberg (1966) described a Waardenburg syndrome family with apparent ocular albinism.
Morell et al. (1997) presented an update of the clinical findings in the family of Bard (1978). The deafness was sensorineural and congenital. Heterochromia iridis was a prominent feature in 1 sibship in which both segmental iris bicolor and complete heterochromia occurred. Most of the affected individuals showed transillumination defects of the iris. Hypopigmentation of the fundus was mild in some, moderate in others, and severe in yet others. Almost all affected individuals had strabismus and visual acuity defects. One individual with a prominent white forelock, characteristic of Waardenburg syndrome, was pictured. In this family, Morell et al. (1997) identified digenic inheritance of Waardenburg syndrome and oculocutaneous albinism; see MOLECULAR GENETICS.
Nance et al. (1970) stated that abundant pheomelanin but little eumelanin was found naturally in the Amish patients who were referred to as representing the yellow mutant form. Hu et al. (1980) pointed out that the yellow form of albinism is clinically similar to the tyrosinase-positive albinism, but that the hair bulbs show organelles similar to the pheomelanosomes of red hair and absence of tyrosinase activity. Unlike OCA1A, the melanosomes in OCA1B contain residual amounts of melanin and may include the more developed stage III premelanosomes and stage IV melanosomes (Hu et al., 1980; King et al., 2001).
The transmission pattern of OCA1B in the family reported by Chiang et al. (2008) was consistent with autosomal recessive inheritance.
Witkop et al. (1989) concluded, mainly on the basis of the family reported by Hu et al. (1980), that yellow albinism is probably allelic to tyrosinase-negative albinism. Hu et al. (1980) supported the view that the yellow mutant locus is homologous to the c-locus in the mouse and should be so designated in man. Hu et al. (1981) gave a revised (and corrected) table of proposed genotypes of oculocutaneous albinism involving the c-locus.
In a patient with yellow OCA, Spritz et al. (1989) identified a pro81-to-leu substitution that may interfere with the normal folding of the tyrosinase polypeptide; see 606933.0002. In a patient with the yellow form of oculocutaneous albinism Giebel et al. (1990) found compound heterozygosity in the tyrosinase gene for the pro81-to-leu mutation (606933.0002) and a novel val275-to-phe mutation (606933.0007).
Temperature-Sensitive Phenotype
King et al. (1991) found that the R402Q mutation in the tyrosinase gene (606933.0009) was responsible for a temperature-sensitive enzyme that resulted in peripheral pigmentation. In a patient with temperature-sensitive albinism, Giebel et al. (1991) identified a substitution in the tyrosinase gene (R422Q; 606933.0012) that resulted in thermosensitivity of the enzyme.
Ocular Albinism with Waardenburg Syndrome Type 2A, Digenic
Studying the family reported by Bard (1978), Morell et al. (1997) demonstrated apparent digenic inheritance resulting from a combination of heterozygosity for a 1-bp deletion in exon 8 of the MITF gene (156845.0005) and homozygosity or heterozygosity for the R402Q polymorphism of the tyrosinase gene (606933.0009), a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity. Morell et al. (1997) proposed that the WS2-OA phenotype results from digenic interaction between a gene for a transcription factor, MITF, and a gene that it regulates, TYR.
Chiang et al. (2008) reported a Hispanic family in which 2 sibs had variable manifestations of OCA1B. A 6-year-old boy had nystagmus, decreased vision, light hair, light skin color, and foveal hypoplasia. His sister had exotropia, blonde hair, light skin color, and brown irides with no history of nystagmus, foveal hypoplasia or decreased vision. Genetic analysis identified compound heterozygosity for 2 variants in the TYR gene: a pathogenic mutation (G47D; 606933.0024) and the hypomorphic allele R402Q (606933.0009). Each unaffected parent was heterozygous for 1 of the variants. Chiang et al. (2008) postulated that the clinical spectrum of OCA depends on a pigmentation threshold of the affected individual, and that OCA is a quantitative trait disorder with phenotypic variation in individuals of different ethnic background.
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Brodsky, M. C., Fray, K. J. Positive angle kappa: a sign of albinism in patients with congenital nystagmus. Am. J. Ophthal. 137: 625-629, 2004. [PubMed: 15059699] [Full Text: https://doi.org/10.1016/j.ajo.2003.11.066]
Chiang, P.-W., Drautz, J. M., Tsai, A. C.-H., Spector, E., Clericuzio, C. L. A new hypothesis of OCA1B. (Letter) Am. J. Med. Genet. 146A: 2968-2970, 2008. [PubMed: 18925668] [Full Text: https://doi.org/10.1002/ajmg.a.32539]
Giebel, L. B., Musarella, M. A., Spritz, R. A. A nonsense mutation in the tyrosinase gene of Afghan patients with tyrosinase negative (type IA) oculocutaneous albinism. J. Med. Genet. 28: 464-467, 1991. [PubMed: 1832718] [Full Text: https://doi.org/10.1136/jmg.28.7.464]
Giebel, L. B., Strunk, K. M., King, R. A., Hanifin, J. M., Spritz, R. A. A frequent tyrosinase gene mutation in classic, tyrosinase-negative (type IA) oculocutaneous albinism. Proc. Nat. Acad. Sci. 87: 3255-3258, 1990. [PubMed: 1970634] [Full Text: https://doi.org/10.1073/pnas.87.9.3255]
Goldberg, M. F. Waardenburg's syndrome with fundus and other anomalies. Arch. Ophthal. 76: 797-810, 1966. [PubMed: 4958935] [Full Text: https://doi.org/10.1001/archopht.1966.03850010799005]
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King, R. A., Townsend, D., Oetting, W., Summers, C. G., Olds, D. P., White, J. G., Spritz, R. A. Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism. J. Clin. Invest. 87: 1046-1053, 1991. [PubMed: 1900307] [Full Text: https://doi.org/10.1172/JCI115064]
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Nance, W. E., Jackson, C. E., Witkop, C. J., Jr. Amish albinism: a distinctive autosomal recessive phenotype. Am. J. Hum. Genet. 22: 579-586, 1970. [PubMed: 5516239]
Spritz, R. A., Strunk, K., King, R. A. Molecular analyses of the tyrosinase gene in patients with tyrosinase-deficient oculocutaneous albinism. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A221, 1989.
Tripathi, R. K., Droetto, S., Spritz, R. A. Many patients with 'tyrosinase-positive' oculocutaneous albinism have tyrosinase gene mutations. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A179, 1992.
Witkop, C. J., Jr., Quevedo, W. C., Jr., Fitzpatrick, T. B., King, R. A. Albinism. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic Basis of Inherited Disease. Vol. II. (6th ed.) New York: McGraw-Hill (pub.) 1989. Pp. 2905-2947.
Witkop, C. J., Jr., White, J. G., Nance, W. E., Jackson, C. E., Desnick, S. Classification of albinism in man. Birth Defects Orig. Art. Ser. VII(8): 13-25, 1971.
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