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Chapter 73

Albinism and Other


Genetic Disorders of
Pigmentation
Thomas J. Hornyak

ETIOLOGY, PATHOGENESIS, AND


CLINICAL FEATURES
ETIOLOGY, PATHOGENESIS, AND
CLINICAL FEATURES OF aLBINISM
BROWN OCA
The brown OCA phenotype is a distinct OCA2 phenotype, which has been described in the African
and African-American populations. In this clinically
less severe phenotype,56 the hair and skin color are
light brown and the irides are gray-to-tan at birth
(eFigure 73-6.1). 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
generally does not burn but may darken with sun
exposure. Affected individuals are recognized as
having albinism rather than a variation in normal
pigmentation because of the ocular changes present. The iris has punctate and radial translucency,
and moderate retinal pigment is present. Visual
acuity ranges from 20/60 to 20/150. In brown OCA,
the amount of eumelanin in the skin and hair is
reduced but not absent. Recent studies have shown
that brown OCA is associated with heterozygosity
for P gene alleles, one of which is null and the other
having partial function.56

PRADERWILLI AND ANGELMAN


SYNDROMES
eTIOLOGY
PraderWilli and Angelman syndromes, whose clinical manifestations are described later but which can
include cutaneous hypopigmentation, are associated with paternal or maternal, respectively, deletions
of regions of the long arm of chromosome 15 containing a portion of the P gene. Hypopigmentation
in these patients, who remain hemizygous for the P
gene in the context of their large 15q deletion, suggests that there may be other genetic determinants

of pigmentation in the chromosome 15 region


of the P gene. Less commonly, these syndromes
are associated with chromosome 15q uniparental
disomy, or the exclusive presence of two copies of
15q from one parent, with maternal disomy associated with PraderWillis syndrome and paternal
disomy associated with Angelmans syndrome.3 In
addition, PraderWillis syndrome or Angelmans
syndrome patients with OCA2 have been described
with a typical deletion of one homolog of the P
gene in the context of PraderWillis syndrome or
Angelmans syndrome and inheritance of a mutation on the another homolog.61

Clinical Features
PraderWillis syndrome is a developmental syndrome that includes neonatal hypotonia, hyperphagia and obesity, hypogonadism, small hands and
feet, and mental retardation associated with characteristic behavior. Many individuals with PraderWillis syndrome are hypopigmented but do not have
the typical ocular features of albinism; however,
individuals with PraderWillis syndrome can have
typical features of OCA. For those without OCA, the
hypopigmentation is characterized by hair and skin
that are lighter than unaffected family members.
Childhood nystagmus and strabismus are common
but often do not persist into adult life. The irides
are pigmented with some translucency on globe
transillumination, and retinal pigment is reduced
in amount. Foveal hypoplasia usually is not present, but the fovea may not appear entirely normal.
Visual evoked potential studies have revealed optic
tract misrouting similar to that found in albinism in
some individuals with PraderWillis syndrome and
hypopigmentation, but this is not a universal finding. Some individuals with PraderWillis syndrome
have typical OCA2 with cutaneous hypopigmentation and all ocular features of albinism.
Angelmans syndrome is a complex developmental disorder with developmental delay and severe
mental retardation, microcephaly, neonatal hypotonia, ataxic movements, and inappropriate laughter.
In Angelmans syndrome, the hypopigmentation
is characterized by light skin and hair. Nystagmus
or strabismus may be present early in life, and iris
translucency and reduced retinal pigment may be
present. No analysis of optic nerve formation is
available. As in PraderWillis syndrome, individuals
with Angelmans syndrome who have typical OCA2
features have been described.62

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72

Chapter 73:

Albinism and Other Genetic Disorders of Pigmentation

PATHOGENESIS OF OCA3
The pathogenesis of OCA3 remains poorly understood because the normal function of Tyrp1 in human melanocytes is still being clarified. In murine
melanocytes, Tyrp1 protein appears to function as
DHICA oxidase (Kobayashi et al, 1994). However,
this enzymatic activity has not been observed for
human Tyrp1 protein.68,69 Clearly Tyrp1 is important
for melanosomal melanization, not only because of
the phenotype of the brown mouse, with a TYRP1
mutation and accompanying coat color dilution,
but also because of the pigmentary phenotypes of
patients with OCA3 due to TYRP1 mutations. TYRP1
and tyrosinase reciprocally stabilize each other
through associations in the endoplasmic reticulum,
with mutations in either of them resulting in the
retention and degradation of both in the endoplasmic reticulum, thus reducing their transport to melanosomes.70 This suggests that abnormal trafficking and/or reduced stability of wild-type tyrosinase
elicited by mutant Tyrp1 could be an important
etiologic factor of OCA3.
OCULOCUTANEOUS ALBINISM TYPE 4.
OCA4 (OMIM #606574) is a form of oculocutaneous
albinism (OCA) that may be rather rare worldwide,
but relatively common as a type of albinism in East
Asian populations. A variety of mutations, including a splice-acceptor-site mutation and missense
mutations, have been found in a gene called
MATP (membrane-associated transporter protein),
located on chromosome 5p, in OCA4.71,73 OCA4 can
have a variable phenotype, ranging from absence
of pigmentation to some pigmentation with brown
irides. Pigment darkening during the first decade of
life has been reported.73
The protein product of the MATP gene is predicted
to be a membrane protein spanning the membrane 12 times, and containing a conserved sucrose
transporter signature sequence, suggesting an
important functional role for this motif.72 In addition, melanosome anomalies have been observed
in the medaka fish and in the mouse homologs of
OCA4.72,74 These data indicate that MATP/Matp plays
a critical role in vertebrate pigmentation and suggest that MATP/Matp may be a component of the
melanosomal membrane, presumably mediating
the transport of a molecule required for melanogenesis or for another melanosome function.

INFREQUENT HPS TYPES


Among the infrequent HPS types, reported symptoms vary. Patients with HPS2 (OMIM #603401)
display characteristic clinical findings. The limited
number of cases described88,90154156 are distinguished by the presence of severe neutropenia
together with mild OCA, a mild bleeding diathesis,
and a susceptibility to recurrent respiratory infections. Pulmonary function tests are borderline low.
The six patients with HPS5 (OMIM #607521) that
have been described have not been reported to
have significant pulmonary symptoms or colitis.157159, Patients reported to date with HPS6 (OMIM
#607522),158,160 including members of a consanguineous Israeli family with prominent cutaneous
hypopigmentation,160 exhibit variable bleeding
tendencies without pulmonary or gastrointestinal
complications. The single patient reported with
HPS7 (OMIM #607145) who was homozygous for a
mutation in DTNBP1 complained of some exertional
dyspnea, but had objectively normal pulmonary
findings in association with a bleeding tendency,161
whereas the members of a Pakistani kindred with
HPS8 (OMIM #609762) exhibit only OCA and a
bleeding tendency to date.162

MOLECULAR BASIS OF
HPS-5, -6, -7, AND -8 DEFECTS
As members of the BLOC-2 complex,91,92 defects
in HPS5 and HPS6 might be expected to result in
similar cellular dysfunction as mutations in HPS3,
perhaps reflecting the more benign clinical course
of these HPS types. Eight distinct HPS5 mutations
have been found to be associated with HPS5, with
two missense mutations occurring as compound
heterozygous mutations in siblings, rendering it
difficult to determine whether each mutation is
pathogenic or whether one is a polymorphism.157,159
In HPS5 fibroblasts, the distribution of the LAMP-3/
CD63 lysosomal marker was exclusively noted in
the perinuclear region, instead of also being present in the periphery as in normal cells.157
Mutations in DTNBP1, encoding the dysbindin protein, are responsible for HPS7. Dysbindin, together
with proteins palladin, muted, cappuccino, and
BLOC1S3, is a member of the BLOC-1 complex.161
Although dysbindin associates with the - and
-dystrobrevins,163 which are binding partners of

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Chapter 73:

Albinism and Other Genetic Disorders of Pigmentation 73

the Duchenne muscular dystrophy gene product


dystrophin,164 it appears that physiologically dysbindin incorporation into BLOC-1 precludes interaction with dystrobrevins,165 perhaps explaining why
Duchenne muscular dystrophy and pigmentation
do not appear to be linked. A mutation in another
BLOC-1 protein, encoded by the BLOC1S3 gene,166,167
is responsible for the HPS8 phenotype.162

ETIOLOGY, PATHOGENESIS, AND


CLINICAL FEATURES of Congenital
Disorders of Pigmentation
DIFFERENTIAL DIAGNOSIS OF ALBINISM
AND CONGENITAL DISORDERS OF
PIGMENTATION (eFig. 73-6.1).
The differential diagnosis of albinism (OCA14)
(Box 73-1) includes HermanskyPudlak syndrome,
Griscelli syndrome, ChediakHigashi syndrome,
ocular albinism (OA), currently unrecognized forms
of albinism, and Tietz syndrome. Other considerations include extensive vitiligo, the Ziprkowski
Margolis syndrome, Cross syndrome (oculocerebral
syndrome with hypopigmentation), and phenylketonuria. ZiprkowskiMargolis syndrome168,169 is
an X-linked recessive disorder described in a large
Israeli kindred characterized by congenital deafness, cutaneous hypopigmentation, and heterochromia irides. Pigmented macules develop on the
skin later in life (eFig. 73-6.2). The etiology is not
known.170 Cross (CrossMcCusickBreen) syndrome
171
combines features of albinism, including hypopigmentation and nystagmus, with psychomotor retardation, spasticity, and growth retardation.
More severe ocular abnormalities such as blindness
and microphthalmia have been reported in association with this syndrome. Some patients exhibit an
admixture of black and white hairs on the scalp and
in the eyebrows. Inheritance is thought to be autosomal recessive, and the etiology is unknown.172

The differential diagnosis of congenital disorders


of pigmentation (Box 73-2) not only includes the
subtypes of Waardenburg syndrome (WS), WS14,
Tietz syndrome, and piebaldism, but also includes
those acquired disorders of pigmentation featuring patchy pigmentary loss. Hence, the differential
diagnosis may include generalized vitiligo, segmental vitiligo, VogtKoyanagiHarada syndrome, and
chemical leukoderma as well as tuberous sclerosis.
Individuals with VogtKoyanagiHarada syndrome
can have depigmented patches and auditory dysfunction, but this disorder is acquired, not inherited. A careful personal and family history should
confirm the congenital nature of either WS, Tietz
syndrome, or piebaldism. Patients with piebaldism
tend to have larger, more symmetrical depigmented patches on the ventral trunk or extremities, and
generally are not deaf. The presence of craniofacial
abnormalities, limb abnormalities, or megacolon
can be used to distinguish between the subtypes
of WS.

Among the forms of OCA, OCA1A is distinctive


because of the complete absence of pigmentation,
both at birth and with continued development.
If hair pigment is present at birth, then the most
likely diagnosis is OCA2. The presence of systemic
features should permit distinguishing between HPS,
Griscelli syndrome, and CHS and the types of OCA.

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74

Chapter 73:

Albinism and Other Genetic Disorders of Pigmentation

Copyright McGraw-Hill Companies, Inc. All rights reserved.