Chapter 73. Albinism and Other Genetic Disorders of Pigmentation

Epidemiology of Albinism

Oculocutaneous albinism (OCA) is the most common inherited disorder of generalized hypopigmentation, with an estimated frequency of 1 in 20,000 in most populations. Four different types of OCA have been described. OCA1 and OCA2 are the most frequent types and account for approximately 40% and 50%, respectively, of OCA worldwide. OCA2 occurs in approximately 1 in 30,000 to 1 in 36,000 Caucasians and 1 in 10,000 to 1 in 17,000 blacks in the United States,1–3 but is reported at higher frequencies ranging from 1 in 1,400 to 1 in 7,000 in Sub-Saharan Africa4,5 and even as high as 1 in 170 individuals in the Kuna population of the Panama coast.6 OCA3 and OCA4 are far less frequent, although the rufous OCA phenotype, described later, associated with OCA3 in South African blacks has been reported at an incidence of approximately 1/8,500,7 while OCA4 accounts for 27% of all cases of OCA in Japan.8

Hermansky–Pudlak syndrome (HPS) is rare except in the Caribbean island of Puerto Rico, particularly in the northwestern region where the majority of patients are found, with an incidence of 1 in 1,800.9 Chediak–Higashi syndrome is also quite rare.

Epidemiology of Congenital Disorders of Pigmentation

Waardenburg syndrome (WS) is probably less frequent than OCA. The highest reported incidence is 1/20,000 in Kenya, although most estimates of its incidence in the Netherlands where it was originally reported are in the range of 1/40,000. The incidence of WS with deafness is lower, ranging between 1/50,000 and 1/212,000. WS has been described occurring in a range of frequencies in the congenitally deaf, ranging from 0.9%–2.8% to 2%–5% in different reports. The incidence of piebaldism is estimated to be less than 1/20,000.10,11

Awareness of the biologic basis of the distinction between congenital disorders of pigmentation, which are disorders of melanocyte development, and the varieties of albinism, which are disorders of melanocyte differentiation, is important for fully understanding their clinical manifestations. Albinism results from the dysfunction of a normal complement of pigment cells, which results in complete or partial loss of cutaneous pigmentation. The forms of albinism, including the subtypes of OCA as well as albinism syndromes with systemic manifestations, result either from enzymatic defects in the biosynthesis of melanin, from melanosomal defects that interfere with melanin formation, or from problems in the intracellular transport and localization of proteins essential for melanin biosynthesis (Table 73-1; see Chapter 72). Congenital disorders of pigmentation usually result from mutations in genes critical for melanocyte development during embryogenesis. These disorders can also be associated with other systemic problems because of the requirement for these gene products in the development of cell types other than melanocytes. More accurate descriptors of these disorders could be congenital (or genetic) disorders of melanocyte differentiation and congenital (or genetic) disorders of melanocyte development, to reflecting the fact that both categories of conditions, albinism and developmental pigmentary syndromes, are generally inherited but result from different mechanisms of disease (Fig. 73-1).

Etiology, Pathogenesis, and Clinical Features of Albinism

Although the pigmentary abnormalities associated with types of albinism can vary widely, common to all types of albinism is reduced visual acuity and ocular nystagmus, a result of misrouting of the optic nerve at the optic chiasm and foveal hypoplasia. This has been described not only in humans12 but also in other albino mammals.13 Experiments using the tyrosinase promoter to express both tyrosinase and tyrosine hydroxylase in albino transgenic mice suggest that the tyrosine hydroxylase activity of tyrosinase is particularly important for ensuring the proper routing of retinal projections at the optic chiasm during development.14,15 The ocular manifestations of albinism can vary greatly, ranging from severe (20/400) to nearly undetectable, but is often close to 20/80.16 They also include a reduction in iris pigment, a reduction in retinal pigment, and alternating strabismus.

Oculocutaneous Albinism Type 1

OCA1 [Online Mendelian Inheritance in Man (OMIM) #203100] is caused by loss of function of the melanocytic enzyme tyrosinase resulting from mutations of the TYR gene.17–19 Null mutations are associated with a total loss of function and no pigment formation (OCA1A), whereas “leaky” mutations result in an enzyme that retains some function and is associated with some pigment formation (OCA1B). OCA1 appears to be the most common type of albinism in non-Hispanic Caucasian patients.20

Analyses of DNA from individuals with OCA1A have shown a large number of different mutations in the TYR gene. These mutations include missense, nonsense, frameshift, splice site, and deletion mutations. Most individuals with OCA1 are compound heterozygotes with different mutant maternal and paternal alleles.7 Missense mutations in the TYR gene are distributed among distinct regions of the coding sequence, which suggests that the encoded protein has multiple functional domains. Two of the clusters are in the copper-binding regions, with a third near the amino-terminus of the mature protein, in the extramelanosomal domain of tyrosinase shown to require phosphorylation for enzyme activation.21,22 Clustering of mutations in discrete regions of the coding sequence is consistent with these regions’ importance either for the melanogenic activity of tyrosinase or for functions related to its maturation or processing.7,22 Missense mutations at the signal peptide cleavage site23,24 implicate this cleavage event as an important step in the development of tyrosinase activity. Frameshift mutations near the C-terminus of the coding region25,26 indicate that the cytoplasmic domain of tyrosinase is also important for full activity, possibly because of the presence of protein kinase C-β-dependent phosphorylation sites that have been identified at its extreme C-terminus.22

All nonsense and frameshift mutations are associated with a complete loss of tyrosinase activity, presumably because of the subsequent production of a truncated protein. With missense mutations the picture is more complicated. A set of missense mutations that were associated with OCA1 patients accumulating pigment with age in either OCA1B or temperature-sensitive OCA (OCA1TS) patients27 were shown to have residual enzymatic activity. Hence, it is likely that a subset of TYR missense mutations are responsible for the OCA1B and OCA1TS phenotypes because of the reduced, rather than absent, tyrosinase activity in their melanocytes.7 However, other missense mutations resulting in the OCA1A and OCA1TS phenotypes result in defective intracellular processing of tyrosinase and retention of the mutant tyrosinase proteins in the endoplasmic reticulum, which suggests that some molecular variants of OCA1 represent an endoplasmic reticulum retention disease.28–30 Thus, the residual enzymatic activity of a missense tyrosinase mutant cannot fully predict its phenotype, because other, presumably conformational, determinants of nascent mutant proteins may lead to their retention in the endoplasmic reticulum, block transport to the melanosome, and cause a more severe pigmentary phenotype.

In OCA1A, or the classic tyrosinase-negative OCA, there is a complete inability to synthesize melanin in skin, hair, and eyes, resulting in the characteristic “albino” phenotype. Affected individuals are born with white hair and skin and blue eyes, and there are no changes as they mature. The phenotype is the same in all ethnic groups and at all ages (Fig. 73-2). The hair may develop a slight yellow tint due to denaturing of the hair protein due to sun exposure and/or shampoo use. 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. The architecture of skin and hair bulb melanocytes is normal. The melanosomes show a normal melanosomal membrane, and normal internal matrix formation is observed in stage 1 and 2 melanosomes.

The phenotype of OCA1B can range from minimal hair pigment to skin and hair pigmentation approaching the normal pigmentary phenotype for the individual's genetic composition and continental ancestry. Most individuals with OCA1B have very little or no pigment at birth and develop varying amounts of melanin in the hair and skin in the first or second decade of life (Fig. 73-3). In some cases the melanin develops within the first year. The hair color changes to light yellow, light blond, or golden blond first, as a result of residual pheomelanin synthesis, and eventually can turn dark blond or brown in adolescents and adults. The irides can develop light-tan or brown pigment, sometimes limited to the inner third of the iris, and iris pigment can be present on globe transillumination. However, some degree of iris translucency, as demonstrated by slit lamp examination, is usually present. Many individuals with OCA1B will tan with sun exposure, although it is more common to burn without tanning. Pigmented lesions (nevi, freckles, lentigines) develop in the skin of individuals who have developed pigmented hair and skin. In some patients, the moderate amount of residual tyrosinase activity can lead to near-normal cutaneous pigmentation, so that the clinician may overlook subtle cutaneous pigmentary abnormalities and render instead the mistaken diagnosis of ocular albinism (OA).

One variation of OCA1B is the temperature-sensitive phenotype. In this variation, scalp and axillary hair remain white or slightly yellow, but arm and leg hair pigments. The skin remains white and does not tan. The retention of melanin synthesis in the cooler areas of the body, such as the arms and legs, but not the warmer areas, such as the trunk and the scalp, is associated with a temperature-sensitive mutation in tyrosinase, which loses activity above 35°C.27 Similar tyrosinase mutations have been described in the Himalayan mouse31 and in the Siamese cat with dark “points” at the tips of the ears and on the paws.32

Oculocutaneous Albinism Type 2

Mutations of the OCA2 (P) gene, which maps to chromosome arm 15q, are responsible for OCA2 (OMIM #203200).33 OCA2 occurs worldwide, though somewhat more frequently in the African, African-American, and certain Native American populations. Historically, affected individuals have benefited from limiting their sun exposure, especially in desert and equatorial climates. Interesting anthropological studies have described how various societies have differed in their treatment of members with OCA2. For example, the Cuna Indians of Panama actively forbade marriage between female and male albinos, and infanticide against albino infants was common in the early twentieth century. In contrast, no marriage discrimination was practiced in Hopi tribes, whose albinos were not expected to participate in farming activities requiring substantial exposure to sunlight.34 From the standpoint of melanin synthesis, the defect in OCA2 appears to involve a reduction in eumelanin synthesis primarily, with less effect on pheomelanin synthesis. The predicted structure of the OCA2 gene, a melanosomal protein, includes 12 transmembrane domains.35,36 As expected, a number of mutations of the human OCA2 gene are associated with human OCA2.37,38

In Sub-Saharan Africa, a single 2.7-kb deletion allele accounts for 60%–90% of mutant OCA2 alleles and is associated with a common haplotype, suggesting a common founder.5,38–40 It has been estimated that this single mutation is associated with 25%–50% of all mutant OCA2 alleles in African-Americans.5,38–44 However, other diverse mutant alleles have been described in this population and in Africans. The Brandywine, Maryland, isolate affects an inbred American population, originally located in a rural area east of Washington, DC, that has been studied extensively for its prevalence of albinism, dentinogenesis imperfecta, and other inherited recessive and dominant conditions, with mixed Caucasian, African, and possibly Native American ancestry.45 In this population, 1 in 85 individuals has OCA245,46 and is homozygous for the 2.7-kb deletion allele of OCA2.38 Thus, it is likely that this 2.7-kb deletion allele accounts for the distinct OCA2 phenotype in Africans and African-Americans.47

OCA2 also has been reported at relatively high frequencies ranging from 1 in 28 to 1 in 6,500 in specific Native American groups, including those populations in the southwest United States (Hopi population), southern Mexico, eastern Panama (Kuna population), and southwest Brazil.34 In the Navajo population, a homozygous 122.5-kb deletion has been described in members with OCA2. This mutations results in the loss of exons 10 to 20 of OCA2, corresponding to a region containing seven of the transmembrane domains, and appears to be specific for OCA2 within the Navajo population.48 On the other hand, OCA2 in the Kuna population is caused by a splice site mutation in intron 17 of OCA2.49 Unlike the mutations in TYR, the missense mutations described to date in OCA2 do not seem to cluster in any specific region.

Regarding OCA2 gene product function, it has been shown that melanosomes from P protein-deficient melanocytes have an abnormal pH. Melanosomes in cultured melanocytes derived from wild-type mice are typically acidic, whereas melanosomes from P protein-deficient mice are nonacidic.50 Hence, it is likely that the P protein regulates the pH of melanosomes, perhaps by functioning as an anion cotransporter in conjunction with a distinct proton pump on the melanosomal membrane. An alternate possibility is that the acidic conditions mediated by the P protein favor the normal biogenesis of melanosomes, including the correct targeting of other melanosomal proteins such as tyrosinase.51 Single nucleotide polymorphisms in the first intron of OCA2 are the major determinant of brown versus blue iris color,52 and a germ line polymorphism of the OCA2 gene is associated with favorable survival of estrogen receptor-negative breast cancer.53 Conceivably this finding may be related to the previously reported enhanced sensitivity of cells overexpressing P protein to cytotoxic agents.54

In African and African-American individuals, there is a distinct OCA2 phenotype (Fig. 73-4). Hair is yellow at birth and remains so throughout life, although the color may turn darker. Hair color 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. No generalized skin pigment is present, and no tan develops with sun exposure, but pigmented nevi, lentigines, and freckles often develop, since the cutaneous melanocytes in these individuals both remain susceptible to ultraviolet (UV)-induced changes early in life and retain some ability to synthesize melanin later. The irides are blue–gray or light tan or brown. The development of lentigines or ephelides, well-demarcated pigmented patches usually on sun-exposed areas of the skin, may be evidence of a separate genetic susceptibility because these lesions only develop in some OCA2 families and not in others. The presence versus absence of ephelides is associated with a lower risk of skin cancer in South African albinos,55 probably because the ability to produce ephelides by albinos in that environment also signifies a greater ability to produce pigment and thus demonstrate increased protection from UV radiation.

Brown OCA

In Caucasian individuals with OCA2, the amount of hair pigment present at birth or developing with time varies from minimal in northern Europeans (particularly Scandinavians) to moderate in southern European or Mediterranean 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 skin is creamy white and does not tan. The iris color is blue–gray or lightly pigmented, and the amount of translucency correlates with the development of iris pigment. With time, pigmented nevi and lentigines may develop, and freckles are seen in areas with repeated sun exposure. The hair in Caucasian individuals may slowly turn darker through the first two or more decades of life.

The normal delayed maturation of the pigment system and sparse hair early in life can make it difficult to recognize albinism early in northern European individuals. For all types of OCA in northern European families, the cutaneous hypopigmentation at birth or early in life is often similar to that of the parents and relatives, and the first concern is raised when it appears that the child is not tracking well or has developed nystagmus.

Prader–Willi and Angelman Syndromes

Prader–Willi and Angelman syndromes often are associated with hypopigmentation.57,58 The intragenic deletion encompassing one P allele in these patients59,60 suggests that the observed pigmentary phenotype is related to OCA2 and the P gene, even if the details of this association are not fully understood.47

Etiology

Clinical Features

Oculocutaneous Albinism Type 3

Mutations in the TYRP1 gene result in OCA3 (OMIM #203290). The first described mutation was in an African-American newborn twin initially classified clinically as brown OCA. Mutation analysis revealed a single-base deletion at codon 368 producing a frameshift and premature stop codon in exon 6 and a slightly truncated TYRP1 molecule.63 This mutation is shared by a substantial proportion of the rufous (“red”) OCA population in southern Africa.64 Rufous OCA is a distinct OCA phenotype in which the skin color is a mahogany brown with a slight reddish hue, and the hair color varies from deep mahogany to sandy red.2,64 Additional OCA3-associated TYRP1 mutations include a single-base substitution at codon 166, resulting in the alteration of a serine to a premature stop codon in exon 3 and a truncated TYRP1 molecule,64 also identified in the rufous OCA population; and, in a Pakistani kindred, individuals homozygous for a distinct premature termination mutation.65 A Caucasian male was compound heterozygous for a missense mutation in TYRP1 located in the second copper-binding domain, inherited from the patient's mother, and a stop codon, which apparently occurred spontaneously.66 Interestingly, the p.S166X mutation in TYRP1 previously associated with rufous OCA64 was found to modify an OCA2 phenotype to a red-haired variant.67

OCA3 has presented with both the brown OCA and the rufous OCA phenotypes in the African and African-American populations. In the two cases of individuals with OCA3 mutations only, not of African descent, the phenotype has been that of a tyrosinase-positive albinism, such as OCA1B or OCA2. As additional examples of OCA3 are characterized, genotype–phenotype correlation should become clearer.

Oculocutaneous Albinism Type 4

Hermansky–Pudlak Syndrome

Mutations in eight different genes to date have been associated with types of HPS.70 Currently, our understanding about the function of their gene products varies greatly. However, a common theme is their functional involvement in trafficking cell type-specific products in cells containing lysosome-related organelles (LROs), including melanosomes in melanocytes.

HPS patients have OCA, with variable hypopigmentation of the skin, hair, and irides, and ocular abnormalities (see Fig. 73-5 and eFigs. 73-4.1, 73-5.1, 73-5.2, and 73-5.3). In addition, they lack platelet dense bodies and demonstrate a prolonged bleeding time, mucous membrane bleeding, a predisposition to epistaxis, easy bruising, and metromenorrhagia.75 Whole-mount electron microscopy is used to provide a definitive determination of the absence of platelet dense bodies.76

The greatest clinical experience exists with patients with HPS1 (OMIM #604982), HPS3 (OMIM #606118), and HPS4 (OMIM #606118). Pulmonary fibrosis is a common and severe manifestation of HPS1 and HPS4, generally causing death between the fourth and sixth decades of life.70,77 However, pulmonary fibrosis appears not to be associated with HPS3, which also features less severe pigmentary abnormalities.78–80 Among HPS1 and HPS4 patients, a granulomatous colitis is associated, occurring in approximately 15%.81,77 Ceroid lipofuscin, a complex lipid-protein material, has been reported to accumulate in the cells of HPS patients, predominantly those with HPS1.75

Infrequent HPS Types

Mutations in distinct genes, rather than clinical phenotypes, define the various types of HPS. For example, more than two dozen distinct mutations have been found in HPS1 that cause disease.76–78 The most common, found in over 400 Puerto Rican individuals, is a 16-base pair (bp) frameshift duplication in exon 15.79,80 Although the precise function of HPS1 protein is not yet known, HPS1 associates with HPS4 in the 200 kDa BLOC-3 (biogenesis of LROs complex-3) complex81 and has also been found in association with HPS4 in a larger, 500-kDa complex in melanoma cells and fibroblasts.82–84 In melanocytes cultured from the skin of HPS1 patients, the melanogenic enzymes TYR, TYRP1, and DCT/TYRP2 are found in large vesicular structures in the cell body and dendrites, instead of in the granular pattern typically associated with melanosomal localization,85,86 suggesting a role in the control of protein trafficking to the melanosome. Mutations in HPS4 have been described in 15 patients,76 although its exact cellular role is not yet known. Functionally, the ATP-dependent pump MRP4 (ABCC4), normally localized to platelet granules and the plasma membrane, was found to be greatly reduced in HPS4 platelets.87

Mutations or deficiencies in the AP3B1 gene, encoding the β3A subunit of adaptor complex 3 (AP-3), one of the four known APs, cause HPS2 disease.88 AP-3 interacts with tyrosinase, which is not targeted properly to melanosomes in AP3B1-deficient melanocytes. Hence, AP-3 protein is required for the trafficking of tyrosinase, and possibly other melanosomal proteins, from an intracellular site to melanosomes. Interestingly, the subcellular distribution of TYRP1 is unchanged in HPS2 melanocytes, suggesting that TYRP1 transport, in contrast to tyrosinase, is not entirely dependent upon the AP-3 mechanism.89 The respiratory infections associated with HPS2 may be due to the abnormal movement of lytic granules in cytotoxic T lymphocytes (CTLs) to the immunologic synapse, leading to impairment of microbial killing.90

The most commonly described mutation in HPS3 is a 3904-bp deletion mutation that includes the entire first exon, found in a Puerto Rican population, which is distinct from the HPS1 Puerto Rican mutation.72 In addition, a splice site mutation has been described in Ashkenazi Jews with HPS3 who are either homozygous for this mutation or compound heterozygous for this mutation and other, nonconserved mutations.73 The HPS3 protein associates with the HPS5 and HPS6 proteins in the 340-kDa BLOC-2 complex.91,92 Melanocytes from HPS3 patients exhibit defective localization of tyrosinase and TYRP1 in later stage melanosomes, whereas proteins normally incorporated into early-stage melanosomes, such as silver/Pmel17/gp100 and melan-a/MART1, are unaffected.85,93 These melanocytes exhibited lower levels of melanin than control melanocytes, suggesting that the trafficking defect in tyrosinase, and perhaps also TYRP1, is responsible for the pigmentary dilution that can be observed in these patients.

Griscelli Syndrome

Griscelli syndrome is discussed in Chapter 75.

Chediak–Higashi Syndrome Chs (OMIM #214500)

CHS is a rare autosomal recessive disorder characterized by severe immunologic defects, hypopigmentation, bleeding tendency due to absent or reduced platelet dense bodies,94 progressive neurologic dysfunction, and the presence of giant peroxidase-positive lysosomal granules in peripheral blood granulocytes.95,96 Mutations in the LYST (lysosomal regulator trafficking) gene have been associated with Chediak–Higashi syndrome.97 Although the precise role of the LYST product is not known, structural comparisons and inferences from the cell biology of LYST mutant cells suggest it may be important for membrane fusion during vesicular transport from the trans-Golgi network to late endosomes and multivesicular structures.96,97

Most patients with CHS have a severe form of the disease, childhood CHS,98 with early onset of the so-called accelerated phase, characterized by fever, anemia, and neutropenia, including a lymphoproliferative syndrome with hemophagocytosis and benign infiltration of most tissues by activated T lymphocytes. This form of the disease is uniformly fatal unless patients undergo allogenic bone marrow transplantation. However, this treatment does not prevent future neurologic complications.69 Ten percent to 15% of patients exhibit a much milder clinical disease, adult CHS,98 surviving to adulthood but developing progressive and often fatal neurologic dysfunction in middle age. Very rare patients exhibit the intermediate adolescent CHS phenotype,98 which presents with severe infections in early childhood but has a milder course by adolescence and no accelerated phase. Interestingly, mutation analysis of patients with the childhood, adolescent, and adult forms of CHS showed that patients with severe childhood CHS had only functionally null mutant LYST alleles, whereas patients with the adolescent and adult forms of CHS tended to exhibit missense mutant alleles that likely encode LYST polypeptides with partial function. Furthermore, some patients with the CHS phenotype do not have LYST mutations detectable with established techniques.98

The hypopigmentation phenotype of CHS is variable and can be quite mild. Hair color is light brown to blond, and commonly has a silvery or metallic sheen.96 Iris pigment is present, and nystagmus and photophobia may be present or absent. Histologic studies of the eye in CHS have shown reduced iris pigment, a marked reduction in retinal pigment granules, and infiltration of the choroid with reticuloendothelial cells.99 Cutaneous hypopigmentation is probably a consequence of both the giant, hypopigmented melanosomes clustered around the nucleus within CHS melanocytes, and their inefficient transfer to keratinocytes.100 Pigment granules in the hair shaft are large and have an irregular shape.101

The giant, peroxidase-positive lysosomal granules in neutrophils are a hallmark of the disease. These granules appear to inhibit neutrophil function, which along with neutropenia commonly observed is a likely determinant of the recurrent bacterial infections.96 CHS natural killer (NK) cells have defective lytic granule secretion,102 and defective cytotoxic T lymphocyte-associated antigen 4 function has been proposed as a potential mechanism for the accelerated, lymphoproliferative stage of the disease.103 A reduced number of irregular platelet dense granules in CHS is responsible for the bleeding diathesis component.69,96

Etiology, Pathogenesis, and Clinical Features of Congenital Disorders of Pigmentation

Waardenburg Syndrome

WS, described by the Dutch physician Petrus Waardenburg in 1951,104 is the prototypic congenital disorder of pigmentation. Although it was originally described as a syndrome combining pigmentary defects of the hair (poliosis or white forelock) and iris, congenital deafness, and developmental craniofacial abnormalities, it was subsequently realized that additional phenotypic manifestations could be part of the same syndrome. Four types of WS, WS1 through WS4, have been described.105–110 The discovery of molecular mutations accounting for the different types of WS has helped to explain its wide variety of manifestations as well as to illuminate the importance of specific genes for the development of different tissues and organs (Table 73-2). While practically all cases of WS1 and WS3 show mutated PAX3,105,109,110 WS4 individuals either have homozygous mutations in EDN3 (the endothelin-3 gene)111–113 or EDNRB (the endothelin-B receptor gene)114 or heterozygous mutations in SOX10.115 On the other hand, WS2 appears to arise more heterogeneously, as a mutation in MITF has been shown in only a small fraction of WS2 patients.107,108

Waardenburg Syndrome Type 1

Individuals with WS1 (OMIM #193500) are usually heterozygous for mutations in PAX3; hence, WS1 is autosomal dominant in inheritance. Although many different mutations in PAX3 have been associated with WS1, these mutations are thought either to be functionally null alleles or to abrogate the interactions of PAX3 with DNA.116

Individuals with WS1 have pigmentation abnormalities associated with craniofacial abnormalities (see Fig. 73-6). Dystopia canthorum, which is lateral displacement of the medial canthi of the eyes, is the hallmark craniofacial defect found in virtually all cases of WS1. A broadening of the nasal root, the presence of hypoplastic alae nasi, and synophrys are other craniofacial abnormalities associated with WS1. Poliosis, such as the presence of a white forelock, is the most common pigmentation abnormality associated with WS1. Depigmented white spots on the skin occur less commonly, but are often located at the ventral midline reflecting the compromised migration of dysfunctional melanocyte precursors from their origin in the dorsal neural crest. Pigmentary abnormalities of the iris, including complete heterochromia irides (differently colored irises), partial heterochromia irides (variations of color within an iris), or hypoplastic blue irides, can also be associated with WS1. Premature graying may also be observed in WS1. Congenital deafness is present in 57% of cases.117

The importance of PAX3 for the expression of MITF,118,119 with consequent effects upon melanocyte survival during development, is likely to account for the pigmentary defects of WS1. A role for PAX3 in governing the development of neural crest derivatives that contribute to bony and cartilaginous structures of the face,120 particularly those contributing to the formation of the frontal bone, explain the craniofacial anomalies observed in WS1. Sensorineural deafness, observed with incomplete penetrance in WS1, results from the variable failure of melanoblasts to migrate to or to survive in the stria vascularis in the lateral wall of the cochlea.121,122

Waardenburg Syndrome Type 2

Linkage analysis of families with WS2 (OMIM #193510, 608890, 600193, 606662) identifed the MITF locus as a candidate locus for the disease gene. At least nine different of mutations have been found in the coding region of the MITF gene in WS2 families.107,123 However, MITF mutations account for only a minor portion (15%) of WS2 cases. A mutation in the transcription factor gene SLUG/SNAI2 has also been associated with WS2,124 as have heterozygous deletion mutations in SOX10,125 but mutations in other, as yet undefined genes are likely to be implicated in the future. WS2 is inherited in an autosomal dominant pattern. Since most of the known MITF mutations in WS2 compromise the HLHZip region, thereby interfering with dimerization of mutant MITF with wild-type MITF,126 the pigmentary developmental pathology in most cases of WS2 probably occurs through haploinsufficiency (reduced gene dosage, expression, or protein activity) rather than through dominant-negative effects.123 Tietz syndrome, described later, is likely to result from dominant-negative effects of mutant MITF.

That mutations in MITF cause a subtype of WS is mechanistically attractive because of the crucial importance of MITF in melanocyte survival during development. An epistatic relationship exists between PAX3 and SOX10 and MITF in melanocyte development during embryogenesis. PAX3 and SOX10, as transcription factors, synergically transactivate MITF.33,34 Since mutations of PAX3 and SOX10 also cause auditory-pigmentary symptoms in other types of WS, it is likely that failure of MITF transactivation is the main determinant of pigment cell developmental dysfunction in these other subtypes as well. SLUG/SNAI2, as a transcriptional target of MITF,35 may act in the same pathway as an important downstream MITF effector in melanocytes whose activity is inhibited in SLUG-associated WS2.

Although all types of WS have skin, hair, and iris pigmentation anomalies and the possibility of hearing loss, WS2 is notable for featuring only these auditory-pigmentary symptoms. Diagnostic criteria for WS2 have previously been defined.116 Individuals fulfilling two of the following four criteria, in the absence of dystopia canthorum, limb deformity, or Hirschsprung disease, should be counted as affected:

1. Congenital sensorineural hearing loss

2. Pigmentary disturbance of iris

   1. Complete heterochromia irides (two eyes of different color)

   2. Partial or segmental heterochromia (segments of blue or brown pigmentation in one or both eyes)

   3. Hypoplastic blue irides (characteristic brilliant blue, with thin iris stroma, in both eyes)

3. Pigmentary disturbance of the hair

   1. White forelock from birth or in teens

   2. Premature graying before age 30 years

4. A first- or second-degree relative with two or more of criteria 1–3

A survey of 124 cases of WS2 and 270 cases of WS1 revealed differences of phenotypic penetrance between WS2 and WS1: congenital sensorineural hearing loss occurred in 77% and 57%, respectively; heterochromia irides in 48% and 27%, respectively; hypoplastic blue eye in 9% and 17%, respectively; white forelock in 9% and 17%, respectively; early graying in 23% and 26%, respectively; and white skin patches in 6% and 31%, respectively. The higher incidence of hearing loss in WS2 may be due to the difficulty of diagnosing WS2 in individuals without hearing loss. The hearing loss is congenital, sensorineural, and nonprogressive, showing marked variation between and within families. Among 81 WS2 cases in one series, 84% of patients reported bilateral hearing loss; 40% of patients noted profound loss, whether unilateral or bilateral.117

Waardenburg Syndrome Type 3

WS3 (OMIM #148820), also known as Klein–Waardenburg syndrome, is regarded as a variant of WS1. Most affected persons are heterozygous for a mutation in PAX3, although a few severely affected homozygotes have been described.109 No specific mutations in PAX3, with the possible exception of a missense mutation at Asp47, have been correlated with the WS3 phenotype rather than the WS1 phenotype, although individuals with either homozygous or compound heterozygous mutations in PAX3 may tend to exhibit a severe WS3 phenotype instead of WS1.127 In addition to the features of WS1, WS3 patients have musculoskeletal abnormalities, manifested as limb contractures and hypoplasia of the limb musculature. The WS3 phenotype is consistent with the previously described role of PAX3 in the activation of transcription factors that govern muscle and limb development,128 distinct from its role regulating development of neural crest derivatives.

Waardenburg Syndrome Type 4

WS4 (OMIM #277580), also known as Shah–Waardenburg syndrome, is caused by heterozygous mutations in the transcription factor gene SOX10, or by homozygous mutations in the gene encoding the peptide ligand endothelin-3, EDN3, or its receptor, EDNRB.129 In addition to governing aspects of melanocyte development, these genes are important determinants of the development of the distal aspect of enteric nervous system cells, also neural crest derived, that innervate the distal part of the colon, which explains the association with Hirschsprung's disease or congenital aganglionosis of the colon. WS4 is the combination of the WS1 phenotype with Hirschsprung's disease.

Tietz Syndrome

Tietz syndrome130 (OMIM #103500) is a hypopigmentation–deafness syndrome resulting, like WS2, from mutations in MITF. Tietz syndrome has been described in three families to date. In each case, the mutation is found in the region of the MITF gene encoding the DNA-binding domain. In two cases,131,132 an in-frame deletion mutation (DelR217) has been described, which affects the DNA-binding basic domain of MITF, leaving the dimerization HLHZip domain intact and functional. In these heterozygous Tietz syndrome individuals, it is likely that DelR217-MITF binds with wild-type MITF and interferes with the ability of the dimer to bind to DNA, a dominant-negative effect. Indeed, the identical mutation in mice133 causing a semidominant phenotype, a phenotype that is incomplete in the heterozygous state, in vivo with a mild heterozygous spotting phenotype, but a prominent homozygous phenotype with early embryonic loss of all melanocyte precursors,134 was shown to have a dominant-negative effect in vitro.126 In addition, another mutation described in the family originally reported with the syndrome is predicted to exhibit an Asn210Lys substitution in the basic region.135 The localization of this mutation to the DNA-binding region also suggests that it has dominant-negative effects.

Although sometimes regarded as a variant of WS2A (MITF-associated WS2),136 Tietz syndrome individuals exhibit generalized cutaneous hypopigmentation similar to that found in OCA2, rather than distinct depigmented patches. Reduced melanosomes in keratinocytes found in one affected individual132 may account for the generalized hypopigmentation that is observed. Affected individuals invariably exhibit profound hearing loss. Interestingly, a child with a deletion on chromosome arm 3p encompassing the entire MITF locus not only exhibits generalized hypopigmentation reminiscent of Tietz syndrome but also mild craniofacial anomalies and retention of some hearing function, as can be seen in types of WS.137

Piebaldism

Piebaldism (OMIM #17280) is caused by mutations in the KIT proto-oncogene.138 Stimulation of the KIT receptor tyrosine kinase by its ligand, stem cell factor (SCF)/KIT ligand, results in the phosphorylation of MITF and potentiation of MITF activity.139 This relationship between the KIT receptor and MITF, as a final common effector of melanocyte survival during development, is likely to explain the developmental patchy loss of melanocytes occurring in human piebaldism when KIT receptor function is compromised.

Patients with piebaldism generally have depigmented patches on the ventral or lateral trunk and/or the mid-extremities, sparing the hands and feet. Poliosis is a common feature. The depigmented patches tend to be larger than those observed in WS. Typically, piebaldism is not associated with deafness, although piebaldism with deafness, otherwise referred to as Woolf syndrome, has been molecularly confirmed.140

Dyschromatosis Symmetrica Hereditaria

Dyschromatosis symmetrica hereditaria (DSH; OMIM #127400), an autosomal dominant condition, was recently shown to be caused by mutations in ADAR1, formerly known as DSRAD, encoding adenosine deaminase acting on RNA 1, an RNA-editing enzyme.141,142 It is not known how reduced activity of this enzyme results in pigmentary loss at acral sites. Patients exhibit speckled hypopigmentation, which is limited to the dorsa of the hands and feet.

Differential Diagnosis of Albinism and Congenital Disorders of Pigmentation (eFig. 73-6.1)

The complications of albinism revolve around the impact of the reduced visual acuity and hypopigmentation upon the affected individual. The primary medical complications are the early appearance of skin tumors in individuals with inadequate sun protection in equatorial climates. Delayed recognition and management of squamous cell carcinoma and melanoma in this setting can lead to metastasis and early death.

The complications of congenital disorders of pigmentation are more likely to relate to their associated manifestations, such as deafness or aganglionic megacolon, than the pigmentary loss.

With the exception of individuals with OCA1A, patients with OCA can realize gradual pigmentation of the skin and hair over the course of their lives, and develop melanocytic nevi.

As long as the life-threatening aganglionic megacolon of WS4 is recognized at birth and corrected surgically, the prognosis of congenital disorders of pigmentation is favorable, with minor long-term health consequences. Spontaneous repigmentation of both the white forelock and white spots has been reported, as has contraction of the white spots.

All individuals with albinism should be under the care of an ophthalmologist and should have annual examinations until adult life. Most are hyperopic or myopic, and many have significant astigmatism; refractive correction aids in their visual attentiveness and performance.

Proper dermatologic care and protection from UV radiation of the sun and care by a dermatologist are strongly advised for individuals with OCA. Precautions include the use of sunscreens, hats, and long sleeves, as well as sun avoidance.

For HPS patients, topical control of bleeding can be achieved with thrombin and Gelfoam. In advance of dental procedures or biopsies, intravenous infusion of 1-desamino-8-d-arginine vasopressin can be used prophylactically.69 The accelerated phase of CHS is managed initially with multimodal immunomodulatory therapy and maintenance cyclosporine followed by allogeneic hematopoietic cell transplantation.143

No treatment has been reported for the pigmentary loss associated with congenital disorders of pigmentation. However, melanocyte grafting, either with epidermal grafts or epidermal cell suspensions as used for the treatment of stable vitiligo,144–146 might be an option to consider. Cochlear implants in the pediatric population with WS have led to positive outcomes.147 It is important to recognize the hearing defect early so that proper management, including proper social and mental development and schooling, can be implemented.

Genetic counseling can help affected individuals assess their chances of transmitting the disorder to their progeny.