Classification of Albinism
Oculocutaneous albinism is the most common inherited disorder of generalized hypopigmentation, with an estimated frequency of 1:20,000 in most populations.1,3 The estimated prevalence for different albinism types in various populations is given in Table 220-3. OCA has been described in all ethnic groups and in all animal species, making it one of the most widely distributed genetic abnormalities in the animal kingdom. The different types of albinism, based on the genetic locus involved, are given in Table 220-4 and the clinical features of each type of OCA are given in Table 220-5. All types of OCA are autosomal recessive in inheritance. Mutations of the genes responsible for the different types of albinism are available at the HUGO Mutation Database Initiative affiliated Web site on albinism
Table 220-3: Estimated Prevalence of Albinism |Favorite Table|Download (.pdf) Table 220-3: Estimated Prevalence of Albinism
|Population ||Type ||Prevalence ||Reference |
|World Survey ||All types ||1:10–20,000 ||494 |
|United States || || || |
|Caucasian || || || |
| ||All OCA ||1:18,000 ||3 |
| ||OCA1 ||1:28,000 ||3 |
| ||OCA2 ||1:10,000 ||3 |
|African-American || || || |
| ||All OCA ||1:10,000 ||3 |
| ||OCA1 ||1:28,000 ||3 |
| ||OCA2 ||1:10,000 ||3 |
|Amerindian || || || |
|Hopi ||OCA2 ||1:227 ||495 |
|Zuni ||OCA2 ||1:240 ||496 |
|General || || || |
| ||OA1 ||1:50,000–150,000 ||497 |
|Africa || || ||948 |
|Cameroon ||OCA2 ||1:7900 ||499 |
|South Africa ||OCA1 ||Rare ||500 |
| ||OCA2 ||1:3900 ||500 |
| ||OCA3 ||1:8500 ||411 |
|Tanzania ||OCA2 ||1:1429 ||373 |
|Zimbabwe ||OCA2 ||1:2833 ||375 |
Table 220-4: Genetic Classification of Oculocutaneous and Ocular Albinism |Favorite Table|Download (.pdf) Table 220-4: Genetic Classification of Oculocutaneous and Ocular Albinism
|Type ||Subtype ||Gene Locus ||Includes ||Mechanism for Albinism |
|OCA1 ||OCA1A ||TYR ||Tyrosinase-negative OCA ||Inactive/missing tyrosinase |
| ||OCA1B ||TYR ||Minimal pigment OCA ||Partially active tyrosinase |
| || || ||Platinum OCA || |
| || || ||Yellow OCA || |
| || || ||Temperature-sensitive OCA || |
| || || ||Autosomal recessive OA (some) || |
|OCA2 ||?OCA2A ||P ||Tyrosinase-positive OCA ||? Intramelanosomal pH |
| ||?OCA2B ||P ||Brown OCA || |
| || || ||Autosomal recessive OA (some) || |
|OCA3 || ||TYRP1 ||Rufous/red OCA ||Unknown |
|HPS || ||HPS1 ||Hermansky-Pudlak syndrome ||? Vesicular transport |
|HPS || ||ADTB3A ||Hermansky-Pudlak syndrome ||Vesicular transport |
|CHS || ||CHS1 ||Chedlak-Higashi syndrome ||Unknown |
|OA1 || ||OA1 ||X-linked OA ||Unknown |
Table 220-5: Clinical Characteristics of the Different Types of Albinism |Favorite Table|Download (.pdf) Table 220-5: Clinical Characteristics of the Different Types of Albinism
| ||OCA1 || || || || || |
| || || || || || || |
|Characteristic ||OCA1A ||OCA1B ||OCA2 ||OCA3 ||HPS ||CHS ||OA1 |
|Hair Color || || || || || || || |
|At birth ||White ||White ||Pigmented ||Pigmented ||Pigmented ||Pigmented ||Pigmented |
|Mature ||White ||Light blond to brown* ||Yellow to blond to brown* ||Ginger to brown ||Yellow to blond to brown ||Blond ||Normal |
|Skin Color || || || || || || || |
|General ||Milky white ||White ||White to brown ||Reddish brown ||White ||White ||Normal |
| ||Pink as baby || || || || || || |
|Tan ||No ||Possible ||No ||Possible ||No ||Unknown ||Normal |
|Pigmented nevi and freckles ||No ||Yes ||Yes ||Yes ||Yes ||Yes ||Normal |
|Iris || || || || || || || |
|Color ||Blue to gray ||Blue/tan ||Blue/tan ||Hazel/brown ||Blue/tan ||Blue/brown ||Blue/brown |
|Translucency ||++++ ||+to++++ ||+to++++ ||0to+++ ||+to++++ ||++to+++ ||0to++ |
|Nystagmus ||Yes ||Yes ||Yes ||Not always ||Yes ||Not always ||Yes |
|Visual acuity ||Reduced ||Reduced ||Reduced ||Normal/reduced ||Reduced ||Unknown ||Reduced |
|Retinal pigment ||Absent ||0to++ ||0to++ ||+++to++++ ||0to++ ||0to+++ ||Absent |
|Foveal hypoplasia ||Yes ||Yes ||Yes ||No ||Yes || ||Yes |
|Optic tract misrouting ||Yes ||Yes ||Yes ||Absent or present ||Yes ||Unknown ||Yes |
|Life span ||Normal ||Normal ||Normal ||Unknown ||Can be reduced ||Reduced ||Normal |
203100): Tyrosinase-Related Oculocutaneous Albinism
One of the two most common types of albinism is tyrosinase-related OCA (also known as tyrosinase-deficient OCA352), produced by loss of function of the melanocytic enzyme tyrosinase resulting from mutations of the tyrosinase gene. Classic OCA, with a total absence of melanin in the skin, hair, and eyes is the most obvious type of OCA1, but a wide phenotypic spectrum of OCA1 has been identified with tyrosinase gene mutations. This correlates to some degree with the well-characterized allelic series of mutations at the c-locus (tyrosinase locus) in the mouse.219 The different phenotypes of OCA1 are dependent on the amount or type of residual enzyme produced by the mutant alleles, as well as the constitutional pigment background of the family. The range in the phenotype extends from total absence to near normal skin, hair and iris pigmentation, but the presence of the ocular changes always identify an individual as having albinism.
An important clinical characteristic of OCA1 that helps distinguish individuals with OCA1 from those with OCA2 is the presence of marked hypopigmentation at birth in OCA1. Most individuals affected with OCA1 have white hair, milky white skin, and blue eyes at birth. During the first and second decade of life, some individuals with OCA1 develop hair, skin, and eye pigment (OCA1B), while others do not develop any pigment (OCA1A).
The ultrastructural architecture of the skin and hairbulb melanocyte is normal in OCA1.1,3 The structure, including the internal matrix, of the melanosome is normal. In OCA1A, there is no melanin within the melanocyte, and all melanosomes are stage I or II premelanosomes. No melanin forms after DOPA or tyrosine incubation. In OCA1B, the melanosomes contain melanin and are a mixture of partially melanized stage III premelanosomes and fully melanized stage IV melanosomes, depending on the amount of pigment that has formed.
Individuals with OCA1A or the classic tyrosinase-negative OCA do not synthesize melanin in their skin, hair, or eyes at any time during their life, resulting in a characteristic phenotype, as shown in Fig. 220-8. They are born with white hair and skin, and blue eyes, and there is no change as they mature.1 They never develop melanin in these tissues. The phenotype is the same in all ethnic groups and at all ages. With time, the hair may develop a more intense rather than a translucent white or a slight yellow tint, but this appears to be denaturing of the hair protein related to sun exposure or to the use of different shampoos. The irides are translucent, appear pink early in life, and often turn a gray-blue color with time. No pigmented lesions develop in the skin, although amelanotic nevi can be present.
Young female with OCA1A. No melanin pigment is present. This is the classic tyrosinase-negative OCA phenotype. See Color Plate 13.
The OCA1B phenotype is produced by mutations that result in enzyme with residual activity (leaky or hypomorphic alleles) rather than a total loss of activity (null alleles). The variation in the phenotype of OCA1B is broad and extends from very little cutaneous pigment to nearly normal skin and hair pigment.340 Fig. 220-9 shows the phenotypic range of OCA1A and OCA1B in relation to normal pigmentation. Previous editions of this book have included clinical and biochemical descriptions of yellow, minimal pigment, platinum, and temperature-sensitive OCA as separate and/or distinct entities, but it is now accepted that these are part of the OCA1B spectrum. OCA1B also includes some individuals who were previously classified as having autosomal recessive ocular albinism. Mutations coding for enzyme with differing amounts of residual activity are the primary cause of this variation, and a moderate amount of residual activity can lead to near normal cutaneous pigmentation and the mistaken diagnosis of ocular albinism. Ethnic and family pigment patterns can also influence the phenotype, and hair color can light red or brown in some families where this is the predominant pigment pattern.
Phenotypic range of OCA1, based on tyrosinase activity. Individuals with 50 percent
(heterozygous) to 100 percent (homozygous normal) of normal activity have normal cutaneous pigmentation. Individuals with no enzyme activity (OCA1A; homozygous for one or compound heterozygous for two null alleles) are unable to synthesize melanin. Individuals with one
(compound heterozygous with homologous null allele) or two (homozygous for one or compound heterozygous for two) residual-activity alleles form minimal to nearly normal amounts of cutaneous pigment.
The original OCA1B phenotype was called yellow albinism (or yellow mutant albinism) because of the color of the hair of affected individuals.1 The hair color is the result of pheomelanin synthesis, and the predominance of this type of melanin reflects the reduced function of tyrosinase leading to reduced amounts of dopaquinone associated with the high affinity of dopaquinone for sulfhydryl compounds resulting in cysteinyldopa and pheomelanin formation. Individuals who had less hair and eye pigment were classified as minimal pigment or platinum OCA, while those who had peripheral but little central pigment were classified as temperature-sensitive OCA.1
The majority of individuals with OCA1B have very little or no pigment at birth and are born with white hair. They develop varying amounts of melanin in the hair and the skin in the first or second decade, as shown in Fig. 220-10. In some cases, the melanin develops within the first year or even the first months of life. The hair color changes from white to light yellow, light blond or golden blond first, and eventually can turn dark blond or brown in the adolescent and the adult. In comparison to the pale blond or yellow hair with many individuals with OCA2, the blond hair color in OCA1B often has a distinct golden quality. The irides can develop visible light tan or brown pigment, sometimes limited to the inner third of the iris, while iris pigment may be seen with globe transillumination when the iris appear blue. Some degree of iris translucency, as demonstrated by slit-lamp examination, is usually present. Many individuals with OCA1B will tan with sun exposure. Pigmented
(melanotic) and pink (amelanotic) nevi and freckles on exposed areas can develop with time.
Young female with OCA1B. The hair was white at birth. This patient now has golden blond hair, dark eyelashes, blue irides, and white skin that tans with sun exposure. See Color Plate 14.
One of the more interesting variations of OCA1B is the temperature-sensitive phenotype.1 The pigmentation that develops after birth has an unusual distribution that is dependent on temperature. Axillary and scalp hair is white, while pigmented arm and leg hair develop. The irides remain blue. This type of OCA1B is analogous to the Siamese cat and the Himalayan mouse, and results from a mutation that makes the tyrosinase enzyme sensitive to higher temperature. Melanin synthesis occurs in the cooler but not the warmer areas of the body, such as the arms and legs, in a pattern similar to the Siamese cat.
Molecular Pathogenesis of OCA1
Mutations of the tyrosinase gene on chromosome 11q are responsible for OCA1.1,228,239,340, 352–367 At present 88 missense, 57 missense, 13 nonsense, 15 frameshift mutations, 2 splice-site mutations, and an entire gene deletion that have been reported in the tyrosinase gene associated with OCA1 (Fig.
220-11).362 A listing of all known mutations of the human tyrosinase gene with the appropriate references is available
(www.cbc.umn.edu/tad).362 The majority of these mutations have been found in individuals with OCA1A. The mutant alleles in OCA1A are thought to be associated with a complete lack of tyrosinase activity due to production of an inactive tyrosinase enzyme, and expression studies of some of these mutations have exhibited null enzymatic activity.171 Many individuals with OCA1A are compound heterozygotes with different maternal and paternal mutations and affected individuals have been found with all combinations of missense, nonsense, and frameshift mutations. Approximately 20 percent of all individuals in which the entire coding region was sequenced as well as flanking intron sequences have shown only one mutation. In all instances, the correct nucleotide is present on the homologous allele showing that these individuals are compound heterozygotes. The second mutation could be within a regulatory region not sequenced, or within the intron sequences where it produces a cryptic splice site or affects an intronic transcriptional regulator.
Location of the mutations of the TYR gene associated with OCA1. The coding region of the TYR gene (529 amino acids) is shown. Striped region is the signal peptide; CuA and CuB are the copper-binding regions; the checkered box is the trans-membrane region. Black circles are the location of cysteine residues and the EGF is an epidermal growth factor-like region. Missense mutations are on indicated on the top and nonsense, frameshift, and splice site mutations are indicated on the bottom. (From Oetting et al.362 Used by permission of John Wiley and Sons, Inc.)
The majority of these mutations are found in Caucasian individuals but mutations unique to other racial groups have been identified. Two frequent mutations in the Japanese population include a missense mutation at codon 77 (R77Q) resulting in an arginine to glutamine substitution and a single base insertion of a cytosine at codon 310 (929insC) resulting in a premature termination at codon 316.368 Mutations have also been reported in African-Americans, Afghans, Pakistanis, Moroccans, Koreans, Hmongs, and Chinese populations.362
Several different mutations have been found in individuals who have OCA1B.1 This type of OCA was first described in the Amish and analysis of the original families have shown that the affected individuals in this population are homozygous for a codon 406 missense mutation resulting in a proline to leucine substitution (P406L). Because the OCA1B phenotype varies in families containing individuals homozygous for the P406L mutation as well as in individuals who are compound heterozygotes, it appears that other familial pigment genes can influence the effect these mutations have on pigmentation. Expression studies of the P406L mutation in HeLa cells showed tyrosinase enzymatic activity was greatly reduced.171,369 One mutation, an arginine to glutamic acid substitution at codon 422
(R422Q), results in a temperature-sensitive enzyme.1 Expression studies using both hairbulb tyrosinase and transfected cells with the R422Q mutation showed a tyrosinase molecule that was inactivated by temperatures above 35°C.
Analysis of the distribution of the in the tyrosinase gene found that the missense mutations cluster in four areas, as shown in Fig. 220-11. Two of these clusters are found in the putative copper A and copper B binding regions. The third cluster is in the amino terminal end of the enzyme in exon I, and the fourth cluster is in exon IV next to the copper B binding region. It is thought that the clusters define functional areas of the tyrosinase enzyme.1
There are several mechanisms on how these mutations may cause a loss of enzymatic activity. Mutations in the putative copper A or copper B binding region could alter binding of this metal to the enzyme, leading to loss of activity. The A206T mutation in the copper A binding site affects a highly conserved motif
(Pro-X-Phe-X-X-X-His), substituting a threonine for an alanine located between the proline and phenylalanine residues. The mutation F176I in the copper A binding region affects a phenylalanine in a motif (Phe-X-X-X-His) that is conserved in the copper binding centers found in tyrosinase and hemocyanin.233,370 Computer modeling of the secondary structure of the copper B binding region has shown that mutations in this area (N371T, T373K, N382K, and D383N) affect a loop structure between the two α-helix regions responsible for correct orientation of the histidine ligands and the copper atoms.371 Missense mutations at these locations alter the predicted secondary structure, especially within the α-helical domains.371 Studies directly analyzing copper binding by tyrosinase show that the A206T mutation in the copper A binding site and the T373K mutation in the copper B binding site interfere with copper binding in the enzyme.186 This is also true of any of the three histidine ligands of the copper B binding region thought to be involved in the binding of the copper atom. The juxtaposition of the two copper atoms is critical because of the need to form a peroxide with dioxygen, which is necessary for catalytic function. Any alteration of the histidine location that would affect the copper-to-copper distance is likely to render the enzyme inactive.
A second possible mechanism is that these mutations may disrupt substrate-binding domains and again reduce or eliminate enzyme function.1 Analysis of the missense mutations H390A and P406L revealed normal to supernormal copper binding, but the mutant protein still lacked enzymatic activity, showing that amino acid residues involved in other aspects of the catalytic site, such as substrate binding, are also critical for normal enzymatic activity.186 The binding of tyrosine or DOPA would have to occur next to the copper atoms, and if these amino acids are involved in this function, even a slight change in the chemical nature of an amino acid side chain in this region might alter substrate binding, reducing enzymatic activity. This may be the case with the cluster at the amino terminal of the enzyme (codons 42 to 89). One mutation in this cluster, R77Q, results in the removal of a positively charged amino acid (arginine) and is substituted by an uncharged amino acid (glutamine). The role of arginine in the active site as an anionic binding site has been reported in over 100 enzymes, and chemical modification of this residue results in inactivation of the enzyme. Removal of the arginine at codon 77 (and the charged group of this amino acid) may disrupt the interaction of the tyrosine substrate or dopa cofactor at the active site, resulting in an inactive enzyme. At present, there is only one mutation within the Epidermal Growth Factor
(EGF)-like region, and this may suggest that this region is not critically important in the biology of tyrosinase.
Several of these missense mutations occur at CpG dinucleotides. The CpG dinucleotide is a mutational hot spot caused by methylation-mediated deamination of 5-methyl cytosine and is responsible for 35 percent of all single base pair substitutions causing human genetic disease. Most of the nucleotide substitutions occur at guanidine residues with the second highest percentage occurring at cytosine residues.1 This distribution of nucleotide substitutions is identical to that found in other genes associated with human genetic disease.
Fifteen different frameshift mutations have been identified in OCA1, and analysis of the flanking sequences shows that many of these mutations are within repetitive sequences suggesting the mechanism of their formation. Streisinger and others have shown that frameshift mutations occur with high frequency in regions that contain repeated base sequences.1 In areas of repetitive nucleotides where L (the length of the paired but misaligned stretch of bases) is equal to or greater than 4, deletion mutations have been found to be two to four times more likely than addition mutations.
203200): P-Related Oculocutaneous Albinism
Individuals with albinism who have pigmented hair and eyes have long been identified, particularly in the African and African-American population, but not well characterized.1 The first major insight into the separation of OCA into different types was provided by the hairbulb incubation test.372 The presence of normally pigmented offspring from a mating between two individuals with OCA (now classified as OCA1 and OCA2) provided evidence for genetic heterogeneity and complementation at two independent pigment loci.
As a generalization that helps separate OCA2 from OCA1, individuals with OCA2 have some hair pigment at birth and iris pigment at birth or early in life. The hair pigment may be difficult to discern in a young child who has little hair, and it may not be possible to distinguish between truly white hair and very light yellow/blond hair without taking a hair cutting and observing the hair color against a dark background (not all parents are willing to have hair removed when there is very little). As with OCA1B, localized (nevi, freckles, and lentigines) skin pigment can develop, often in sun-exposed regions of the skin, but tanning is usually absent. It has been suggested that the ethnic and constitutional pigment background of an affected individual has a greater effect on the variation in pigmentation in OCA2 than in OCA1, but this does not appear to be true now that the phenotypic range of OCA1B can be appreciated. Both OCA1B and OCA2 have a broad phenotypic range that, in part, reflects the constitutional pigment background of the affected individual. There may be some accumulation of pigment in the hair with age in OCA2, but this is much less pronounced than in OCA1B, and many individuals with OCA2 have the same hair color throughout life. OCA2 is the most common type of OCA in the world, primarily because of the high frequency in equatorial Africa.373–377 The diagnosis of “tyrosinase-positive” OCA is often used for individuals with OCA2, but this term fits best with the common OCA2 presentation in African and African-American individuals.
In Caucasian individuals, the hair can be very lightly pigmented at birth, having a light yellow or blond color, or more pigmented with a definite blond, golden blond, or even red color. The normal delayed maturation of the pigment system (i.e., very blond or towheaded as a child with later development of dark blond or brown hair) and lack of hair in many normally pigmented northern European children, can make it difficult to distinguish OCA1 from OCA2 in the first few months of life; the skin is white, does not appear to have generalized pigment, and does not usually tan with sun exposure. The iris color is blue-gray or lighted pigmented, and the degree of translucency on globe transillumination correlates with the amount of iris pigment present. With time, pigmented nevi and pigmented dendritic freckles may be seen in exposed areas with repeated sun exposure. The hair in Caucasian individuals may slowly turn darker through the first two or more decades of life
Young male with OCA2. Hair was light yellow at birth. This individual has yellow/blond scalp and eyelash hair, white skin, and blue irides. The skin does not tan. See Color Plate 15.
The classic tyrosinase-positive OCA phenotype is a distinctive OCA2 phenotype in African-American and African individuals, which may, in part, result from the existence of a single common deletion mutation throughout many parts of sub-Sahara Africa.1, 373–377 The hair is yellow at birth and remains yellow through life, although the color may turn darker
(Fig. 220-13). Interestingly, the hair can turn lighter in older individuals, and this probably represents the normal graying with age. The skin is creamy white at birth and changes little with time, and generalized pigment does not appear to be present in the skin. Pigmented nevi, lentigines, and freckles develop in some individuals,378 but the skin usually does not tan. The development of well-demarcated pigmented lesions (called dendritic freckles, lentigines, or ephelides), usually on sun-exposed areas of the skin, may reflect a separate genetic susceptibility as these lesions only appear to develop in some OCA2 families and not in others.295,378,379 The presence of pigmented freckles is associated with a lower risk of skin cancer in South African individuals, and may reflect the presence of photoprotective melanin in the skin.378,379 The irides in this classic type of OCA2 are blue/gray or lightly pigmented (usually a hazel or tan color, and often with the majority of the pigment forming on the inner third of the iris).
Young Nigerian male with classic tyrosinase-positive OCA phenotype. Scalp and eyelash hair are yellow. The skin is white and does not tan. See Color Plate 16.
Phenotypic Variation in OCA2.
Molecular studies are now helping to define the characteristics of the OCA2 phenotype. The pigmentation pattern in African-Americans includes more than the classic “tyrosinase-positive” phenotype in that some individuals with OCA2 (defined as having pigmented hair at birth and the ocular features of albinism) have brown, ginger, auburn, or red hair. Some of this variation may reflect genetic admixture in this population, and some may reflect allelic heterogeneity resulting from differential effects of P gene mutations on the function of the P protein. One African-American individual with OCA2 was reported with a mild phenotype similar to that expected for autosomal recessive ocular albinism,380 suggesting that this is part of the phenotypic range of OCA2, as well as OCA1B. “Autosomal recessive ocular albinism” is most likely not a distinct type of albinism but rather a part of the phenotypic range of the different types of OCA.
The product of the P gene plays a role in ion transport into the melanosome and maintenance of the intramelanosomal acidic pH,204,381 and studies of human albinism and coat color changes in the mouse suggest that the P gene product has its primary function in the formation of eumelanin.142,382 Mutations of the P gene, as seen in the classic “tyrosinase-positive” phenotype in human OCA2 are associated with the development of pheomelanin and a deficiency in eumelanin. Another type of OCA called “Brown OCA” has been described in the African and African-American populations in which the amount of eumelanin in the skin and hair is reduced but not absent.1,383 Early studies in Nigeria suggested the “brown OCA” segregated as a single gene and did not appear to be part of the spectrum of the more common “tyrosinase-positive OCA” in that population,384 but recent studies in South Africa show that “brown OCA” maps to the OCA2 locus and is part of the phenotypic spectrum of this type of albinism. Ramsay and coworkers carried out linkage analysis on five families containing individuals with “brown OCA” and found linkage to the P gene on chromosome 15q.383 As with OCA1B, the brown phenotype may arise from a mutation of the P gene that reduces but does not extinguish the function of the P protein (i.e., a leaky mutation).
In African and African-American individuals with the “brown OCA” phenotype, the hair and skin color are light brown, and the irides are gray to tan at birth (Fig. 220-14).1 With time there is little change in skin color, but the hair may turn darker and the irides may accumulate more tan pigment. The skin does not burn and will tan on sun exposure. Affected individuals are recognized as having albinism because they have all of the ocular features of albinism. The iris has punctate and radial translucency, and moderate retinal pigment is present. Visual acuity ranges from 20/60 to 20/150. The phenotype is not well defined in Caucasian individuals, but most likely includes moderate amounts of skin, hair, and eye pigmentation associated with the ocular features of albinism in an individual who was born with moderate amounts of pigment in these tissues.
Young Nigerian female with Brown OCA. Hair, skin, and irides are light brown. See Color Plate 17.
Prader-Willi Syndrome (MIM
There is an association between the hypopigmentation found with Prader-Willi and Angelman syndromes and OCA2. Prader-Willi syndrome is a developmental syndrome that includes neonatal hypotonia, hyperphagia and obesity, hypogonadism, small hands and feet, and mental retardation associated with characteristic behavior (reviewed in references385 and 386). Approximately 70 percent of individuals with Prader-Willi syndrome have an interstitial de novo microdeletion of chromosome 15q11-13, and most of those without a deletion of the paternal chromosome 15 have uniparental disomy for the maternal chromosome 15 or an imprinting defect.387,388
Approximately 50 percent or more of individuals with Prader-Willi syndrome (PWS) are hypopigmented but do not have the typical ocular features of albinism, while a smaller number have OCA and PWS.385,389-393 For those without obvious OCA, hair and skin are lighter than unaffected family members, and childhood nystagmus and strabismus are common but often transient.1 The irides are pigmented with some translucency on globe transillumination, and retinal pigment is reduced in amount. Although funduscopic examination does not show classic changes of foveal hypoplasia, the fovea may not appear entirely normal. Visual evoked potential studies revealed optic tract misrouting similar to that found in albinism in some individuals with Prader-Willi syndrome and hypopigmentation,394 but this has not been universally found.320,395 Part of the discrepancy may arise from the technique used, but part may be an effect of biologic differences in individuals with Prader-Willi syndrome.319 The presence of hypopigmentation correlates with the presence of the 15q deletion, but the mechanism responsible for the reduction in melanin is unknown.390,391,393,396
Some individuals with Prader-Willi syndrome have OCA2 with cutaneous hypopigmentation associated with all of the typical ocular features of albinism.389-391 These individuals have been found to have a deletion mutation on the paternal chromosome 15 (accounting for their Prader-Willi syndrome and for their paternal P gene mutation) and a maternal P gene mutation, making them compound heterozygotes for P gene mutations.
Angelman Syndrome (MIM
Hypopigmentation is present in more than 50 percent of individuals with Angelman syndrome.396-399 Angelman syndrome is a complex developmental disorder that includes developmental delay and severe mental retardation, microcephaly, neonatal hypotonia, ataxic movements, and inappropriate laughter. The majority of individuals with Angelman syndrome have an interstitial deletion of chromosome
15q11-13, with the remainder having a single gene abnormality, an imprinting defect, or uniparental disomy for the paternal chromosome 15.387 In Angelman syndrome, the hypopigmentation is characterized by light skin and hair. There may be a history of nystagmus or strabismus, and iris translucency and reduced retinal pigment may be present. No analysis of the optic tract organization is available. It is expected that individuals with Angelman syndrome having OCA2 will be described because of the location of the P gene in the Prader-Willi/Angelman syndrome region of chromosome 15. The presence of hypopigmentation in Angelman syndrome correlates with the presence of a 15q deletion.396,399,400
Molecular Pathogenesis of OCA2
The most prevalent mutation of the P gene associated with OCA2 is a deletion of exon 7. This is a 2.7-kb deletion that includes the entire coding sequence of exon 7 and the flanking intronic sequences, and is thought to be of African origin.374 This deletion is most common among the Bantu-speaking people of southern Africa with an allele frequency of 77 percent in individuals with OCA2 from Tanzania, 92 percent in Zimbabwe, 79 percent in Zambia, 33 percent in Central African Republic, and 65 percent in Cameroon.373–375, 401–404 The allele frequency among southern African Bantu-speaking people is estimated to be 1.3 percent,404 while the frequency among African-Americans is estimated to be between 0.5 percent and
0.2 percent.401 Haplotype analysis suggests that the 2.7-kb deletion mutation is old and arose before the Bantu-speaking people of southern Africa diverged from the middle Benue Valley between Nigeria and Cameroon approximately 3000 years age.404
Other reported mutations include 23 missense mutations, 4 frameshift mutations, 3 splice-site mutations, and 2 inframe deletions.362,373,380,402,405,406 The locations of these mutations are shown in Fig. 220-15. The missense mutations of the P gene, unlike tyrosinase, do not cluster in defined regions. Most of the missense mutations are between or at the border of the transmembrane domains in the central region of the protein. The P gene has 36 reported polymorphisms,
20 of which are in the coding region and 6 result in amino acid substitutions.203,362 This is a much greater number than that found in the tyrosinase gene, with its six reported polymorphisms. There is no functional assay of the P protein and the differentiation between pathogenic mutations and polymorphisms at present can only be accomplished by a transfection assay of p-deficient mouse melanocytes.407
Location of the mutations of the P gene associated with OCA2. The coding region of the P gene (838 amino acids) is shown. The checked boxes are the putative trans-membrane domains. Missense mutations are indicated on the top and nonsense, frameshift, and splice-site mutations are indicated on the bottom.
(From Oetting et al.362 Used by permission of John Wiley and Sons, Inc.)
203290): TYRP1-Related Oculocutaneous Albinism
The characterization of the human phenotype associated with mutations of the TYRP1 gene is new and evolving (and surprising). The Tyrp1 gene maps to the brown locus in the mouse, and mutations at this locus change the mouse coat color from black to brown (see above). The DHICA oxidase function in the eumelanin pathway of the melanocyte is tentatively assigned to TYRP1,174,197,408 and it has been shown that Tyrp1 cDNA transfection to melanocytes derived from the brown mouse can induce the formation of black/dark brown melanin.174,197,408
The first evidence that variations in human pigmentation are related TYRP1 gene mutations came from studies of an African-American twin boy who had light brown skin, light brown hair, and blue-gray irides as a newborn, while his fraternal twin brother had normal pigmentation.282 The affected twin had nystagmus and it was felt that the clinical presentation was consistent with “brown OCA” as described above. Biochemical and molecular studies showed that melanocytes from the affected twin contained no TYRP1 mRNA, produced reduced amounts of insoluble melanin, and appeared brown rather than the black color found in control melanocytes in culture.282 The affected twin was found to be homozygous for a single base deletion in codon 368 of the TYRP1 gene (1104delA) on chromosome 9p281 and the authors concluded that mutations of this gene produced a third type of OCA. This family was unfortunately lost to follow-up and the phenotype of this boy could not be followed.
The phenotype associated with mutations of the TYRP1 gene became more obvious when another type of OCA known as “rufous” or “red OCA” was mapped to the TYRP1 locus on chromosome 9p in the South African population, and the same deletion mutation
(1104delA) of the TYRP1 gene was found to account for 50 percent of the mutations in the study population
(19 of 38 affected chromosomes).283 Rufous or red OCA is now classified as OCA3 and this OCA type has only been partially characterized. Individuals with OCA who have red hair and reddish-brown pigmented skin have been reported in Africa and in New Guinea,283,409,410 but clinical descriptions are incomplete, little biochemical data are available, and similar phenotypes in the U.S. population have not been identified and reported. The cases are described in the literature as “red,” “rufous,” or “xanthous” albinism. Individuals with OCA1 or OCA2 who have red hair are also recognized, but the reddish-brown skin pigment is usually not present, and they should not be confused with OCA3.
The phenotype of OCA3 in South African individuals includes red or reddish brown skin, ginger or reddish hair, and hazel or brown irides.410 All of the ocular features of albinism are not always present, however, as many do not have iris translucency, nystagmus, strabismus, or foveal hypoplasia. This is similar to the hypopigmentation in Prader-Willi syndrome and Angelman syndrome associated with the P gene (see above). No misrouting of the optic nerves has been demonstrated by a visual evoked potential, suggesting either that this is not a true type of albinism as defined in this chapter, or that the hypopigmentation is not sufficient to consistently alter optic nerve development.410 The ultrastructural analysis of hairbulb and skin melanocytes show eumelanosomes and pheomelanosomes in various stages of melanization, suggesting that the red color results from pheomelanin synthesis, as pheomelanosomes are absent in normally pigmented black skin and hairbulbs.410 In New Guinea, the described phenotype includes reddish-brown skin, deep mahogany hair, reddish brown to brown irides with some translucency, and normal retinal pigment and foveal development.409 Congenital nystagmus is present in this population but does not segregate specifically with the red phenotype. At this time, the phenotype for TYRP1-related OCA in the Caucasian and the Asian populations is unknown.
Molecular Pathogenesis of OCA3
Two mutations in the TYRP1 gene have been found in OCA3, S166X, and 1104delA, and both are truncating mutations (Fig. 220-16).282,411 The 1104delA mutation accounted for 50 percent and the S116X mutation accounted for 45 percent of the OCA3 mutations in this sample of 19 individuals with rufous OCA3. Individuals homozygous for each of the mutations, as well as individuals who were compound heterozygotes for both, were identified. Because the loss of TYRP1 enzymatic activity in the mouse does not lead to a loss, but only a change in the amount or biochemical character of eumelanin, it is expected that mutations in the TYRP1 gene will result in a less-severe phenotype than those related to null mutations of the tyrosinase or the P gene. Four polymorphisms in the TYRP1 gene have also been reported. Two of the polymorphisms are within the coding region, but do not result in changes in the amino acid sequence.411
Location of the mutations of the TYRP1 gene associated with OCA3. The coding region of the TYRP1 gene (537 amino acids) is shown. Striped region is the signal peptide; black regions are putative metal binding regions; the checkered box is the trans-membrane region. Black circles are the location of cysteine residues conserved in the family of tyrosinase-related proteins and the EGF is a epidermal growth factor-like region. Nonsense and frameshift mutations are indicated on the bottom.
(From Oetting et al.362 Used by permission of John Wiley and Sons, Inc.)
The study population in South Africa also included three individuals with a phenotype that was not typical for brown OCA2 or red OCA3.411 Two sibs had skin similar to rufous OCA3 but lighter in color, and “straw-yellow” scalp hair more typical of OCA2.411 Most interestingly, the sibs were compound heterozygotes for TYRP1 gene mutations (S166X/1104delA) and heterozygous for the common 2.7-kb deletion mutation of the P gene (see above), suggesting that altered function of the P protein may modify the pigment phenotype in the presence of TYRP1 gene mutations.
Hermansky-Pudlak syndrome is a complex autosomal recessive disorder that includes the triad of OCA, a mild bleeding diathesis resulting from storage-pool-deficient platelets, and a ceroid storage disease affecting primarily the lungs and the gut. The manifestation of OCA in HPS is similar to OCA1B or OCA2, as described above. Hermansky and Pudlak first described this condition in two Czechoslovakian individuals in
1959, and it has subsequently been recognized throughout the world, with the majority of affected individuals in the Puerto Rican population.1,3 HPS is not common, except in the latter population, and does not constitute a major type of OCA in most populations. In Puerto Rico, however, the frequency is approximately 1:1800.59 HPS is not found at an increased frequency on other Caribbean islands.
HPS is not a single entity but a phenotypic description for a collection of disorders that include the combination of OCA, storage-pool-deficient platelets, and ceroid production, the latter likely a reflection of abnormal lysosomal metabolism. There are 14 loci in the mouse that give a murine HPS phenotype of coat color reduction, storage-pool-deficient platelets, and lysosomal dysfunction, and it is expected that mutations of many of these loci will be associated with the HPS phenotype in humans.300 Mutations of two of these loci have already been identified (pale ear 64,412, pearl 302) and a further locus has been associated with Chediak-Higashi syndrome (beige 413,414). Individuals with HPS have also been identified who do not have mutations of any of the identified loci to date.301,415
The OCA in HPS is associated with the formation of cutaneous and ocular pigment, but the amount is variable. Some affected individuals have marked cutaneous hypopigmentation similar to that of OCA1A, others have white skin and yellow or blond hair similar to OCA1B or OCA2, and others have only moderate cutaneous hypopigmentation, suggesting OA rather than OCA. The variation can be seen within families as well as between families. Affected individuals in Puerto Rico have hair color that varies from white to yellow to brown.1,415 Skin color is creamy white and definitely lighter than normally pigmented individuals in this population. Freckles are often present in the sun-exposed regions
(face, neck, arms, and hands), often coalescing into large areas that look like normal dark-skin pigment, but tanning does not occur. Pigmented nevi are common. Iris translucency is present and correlates with iris color which varies from blue to brown,416 and all of the ocular features of albinism (i.e., nystagmus, alternating strabismus, reduced acuity, foveal hypoplasia) are present. Visual acuity ranges from 20/50 to 20/400.315,415,416 The presence of OCA may not be obvious in a Puerto Rican individual with brown hair, skin pigment in exposed areas, and brown eyes unless the cutaneous pigmentation is compared to unaffected family members (who are generally darker in pigment) and unless the ocular features of albinism are recognized. Affected individuals have been identified in other populations infrequently, and the phenotype shows the same degree of variation in pigmentation as is found in Puerto Rico.60,417,418 Hair color varies from white to brown, and this correlates with the ethnic group. The skin is white and does not tan. Eye color varies from blue to pigmented. Excellent clinical photographs are available in several recent references.415,419
The bleeding diathesis in HPS is related to a deficiency of storage granules in the platelets (i.e., storage-pool-deficient platelets), as shown in Fig. 220-17. The storage granules or dense bodies are reduced in number or are absent, and this is associated with a deficiency of serotonin, adenine nucleotides, and calcium in the platelet.1,3 As a result, HPS platelets do not show irreversible secondary aggregation when stimulated with agents that normally produce this response. This deficiency produces mild hemorrhagic episodes in many affected individuals, including easy brusibility, epistaxis, hemoptysis, gingival bleeding with brushing or dental extraction, and postpartum bleeding.415 Major bleeding events do occur, can be life-threatening, and may require transfusions, or treatment with desmopressin or cautery.415
Platelet whole mounts. A, Platelets from a normal individual left in contact with a form var-coated grid for 1 min and air-dried, showing 23 dense bodies. On average, four to eight dense bodies per platelet can be visualized in normal platelets with this method. B, Platelets from an individual with HPS using the same technique, showing no dense bodies. ×15,000. (From Witkop et al.489 Used by permission of the American Journal of Hematology.)
The third part of the HPS triad is the production of autofluorescent ceroid material.3 This is a yellow waxy material that can be found in urine of affected individuals, and is present in many tissues throughout the body when analyzed at autopsy.420 The origin of the ceroid is unknown. Chemical analysis suggests that it arises from lipid peroxidation, and may be a manifestation of lysosomal dysfunction in humans.3,420,421 The accumulation of ceroid in the lungs and gastrointestinal tract is associated with the clinical manifestations involving these tissues, and an obvious hypothesis is that ceroid leads to the manifestations of disease in these tissues, but this has not been proven. Ceroid is also present in the kidneys and the heart, but renal and cardiac functions are normal.415,420
The most severe clinical manifestations of HPS are related to the pulmonary and gastrointestinal changes. Interstitial pulmonary fibrosis has been described in many individuals with HPS, although the actual prevalence is unknown.1,3,415,422 The fibrosis results in moderate to severe restrictive lung disease, and this is a frequent cause of death. A recent study of 49 individuals with HPS (28 Puerto Rican,
21 non-Puerto Rican) shows that homozygosity for the common 16-bp duplication mutation (described below) of the HPS1 gene in individuals from Puerto Rico is associated with an increased frequency of clinically significant restrictive lung disease, as measured by pulmonary function tests and high-resolution computed tomography of the lungs.415 Analysis of bronchoalveolar lavage fluid has shown the presence of PDGF (platelet derived growth factor) in affected and obligate heterozygotes, suggesting that this growth factor could be responsible for the development of the fibrosis.422 The development of granulomatous colitis, presenting with abdominal pain and bloody diarrhea in a child or an adult, has also been described in many individuals with HPS.1 The etiology of the colitis is unknown, and immunologic studies do not show an abnormality. The presence of ceroid material in the epithelial cells of the gut suggests that this material may be involved in the development of the colitis, but this has not been proven.
Molecular Pathogenesis of HPS
Two loci are associated with human HPS: HPS1 on chromosome 10q, and HPS2 on chromosome 5q. The murine homologue to HPS1 is pale ear (ep), and for HPS2 it is pearl (pe).300 Eleven mutations in the HPS1 gene have been identified (Fig.
220-18). Nine of the mutations result in a truncated protein product. The other two mutations consist of a deletion of an isoleucine at codon 55 (I55del) and a splice-site mutation (IVS5 +
5G→A).362 All but one (E133X) of the truncating mutations are in the unique sequence of the long transcript and none have been identified in the unique sequence of the short transcript. The most common mutation is a 16-bp duplication in exon 15 found in affected individuals in the northwestern region of Puerto Rico.63 All individuals from Puerto Rico with mutations in the HPS1 gene are homozygous for this mutation.415
Location of the mutations of the HPS1 gene associated with Hermansky-Pudlak syndrome. Both of the HPS1 gene transcripts that result from alternative splicing
(black line) are shown. The nonfilled region represents the common coding sequences for both transcripts. The black region represents the coding region unique to the short transcript (1.5 kb). The stippled region represents the coding region unique to the large transcript (3.6 kb). Striped regions represent the 3′ untranslated region
(UTR) of the transcripts. Missense mutations are indicated on the top and nonsense; frameshift, and splice-site mutations are indicated on the bottom. (From Oetting et al.362 Used by permission of John Wiley and Sons, Inc.)
Three frameshift mutations cluster in a mutational “hot spot” in exon 11 at codons 321 to 322.423 This region consists of two sets of repeats, a sequence of six guanines, and eight cytosines divided by an CA dinucleotide. The frameshift mutations lie either within the run of guanines or cytosines. One frameshift mutation, 974insC, is the most common non-Puerto Rican mutation.423 Haplotype analysis shows that this mutation has occurred on at least two separate occasions.63 The individual with the I55del mutation was homozygous for this mutation and had a very mild phenotype, whereas the individual with the IVS5+5G→A mutation had a more typical HPS phenotype.63 It has been hypothesized that the location of the truncating mutation correlates with the clinical severity of the HPS.63 Mutations that lead to a longer protein that can be inserted into a membrane may disrupt structure or function of the tissue more than mutations that lead to a smaller protein that is lost and not inserted into a membrane.63,419 The HPS1 gene has 23 identified polymorphisms. Nine of these are within the coding region, four of which result in amino acid substitutions.
To date, mutations of the HPS2 gene, the human homologue of the murine pearl gene, have been reported for two brothers.302 The brothers had reduced skin and hair pigmentation, ocular features of albinism, absent platelet dense bodies, as well as persistent neutropenia associated with frequent respiratory tract infections and otitis media. The β3A subunit of the adaptor complex-3 (AP-3) is part of the mechanism facilitating vesicle budding from the trans-Golgi, indicating a primary role for vesicular transport dysfunction in HPS.302,419,424 The putative location of the HPS2 gene is on chromosome 5q.300
Chediak-Higashi Syndrome (CHS) (MIM
Chediak-Higashi syndrome is a rare autosomal recessive syndrome that consists of increased susceptibility to bacterial (primarily staphylococcal and streptococcal) infections, immune defects, hypopigmentation, neurologic abnormalities, and the presence of giant peroxidase-positive lysosomal granules in peripheral blood granulocytes.425 As with HPS, the hypopigmentation is the result of a primary defect that affects many cell types, including the melanocyte. The skin, hair, and eye pigment is reduced or diluted in CHS, but the affected individuals often do not have obvious albinism and the hypopigmentation may only be noted when compared to other family members. Hair color is light brown to blond, and the hair has a metallic silver-gray sheen. The skin is creamy white to slate gray. Iris pigment is present and nystagmus and photophobia may be present or absent.1 Histologic studies of the eye in CHS show reduced iris pigment, a marked reduction in retinal pigment granules, and infiltration of the choroid with reticuloendothelial cells. Visual evoked potential studies show misrouting of the optic fibers. Bone marrow transplantation has been used to correct the hematologic manifestations of CHS, but this has no effect on the pigmentation.426
The primary defect in CHS is unknown. The susceptibility to bacterial infections appears to be the result of the abnormal granules in the neutrophils and other cells.1,65 The hypopigmentation also arises from the formation of abnormal granules. Giant melanosomes form in the melanocyte and are unable to be transferred to the surrounding keratinocytes, leading to abnormal melanosome distribution and hypopigmentation. The pigment granules in the hair shaft are large and irregular in comparison to normally pigmented hair from an unaffected individual, and this pathologic change has been used to make a prenatal diagnosis of CHS.427 The beige (bg) mouse is the murine model of CHS.56,303,304,428,429 The CHS1 gene encodes a protein with homology to a number of anonymous open reading frames and it has been suggested that the function of the beige/CHS protein is involved in vesicular transport,56 which explains the defective vesicular transport to and from lysosomes and the aberrant compartmentalization of lysosomal and granular enzymes in this condition.56
Molecular Pathogenesis of CHS
Eight mutations have been identified in the CHS1 gene associated with Chediak-Higashi syndrome, including five frameshift and four nonsense mutations. There were also two patients that had unknown mutations that resulted in a reduction of mRNA levels.430 Unlike the mutations of the HPS1 gene, all but one of the CHS1 gene mutations, 9590delA, were found in the common region of the two CHS1 gene transcripts
(Fig. 220-19). The
9590delA mutation in the long transcript is associated with a typical CHS phenotype similar to that seen with truncating mutations in the common region, suggesting that mutations of the large transcript product may be all that is required for the CHS clinical phenotype.414
Location of the mutations of the CHS1 gene associated with Chediak-Higashi syndrome. This figure shows both of the CHS1 gene transcripts that result from alternative splicing (black line). The nonfilled region represents the common coding sequences for both transcripts. The black region represents the coding region unique to the short transcript (6 kb; codes for 1990 amino acids). The stippled region represents the coding region unique to the large transcript (13 kb; codes for 3801 amino acids). Striped regions represent the 3′ untranslated region
(UTR) of the transcripts. Missense mutations are indicated on the top and nonsense; frameshift and splice-site mutations are indicated on the bottom. (From Oetting et al.362 Used by permission of Wiley, Inc.)