7. Defects of pigmentation

MIM

203100 (OCA1); 203200 (OCA2)

Non-identical twins with oculocutaneous albinism.

Clinical features

OCA is a group of autosomal recessive disorders affecting melanin

synthesis characterized by hypopigmentation of skin, hair and eyes.

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Oculocutaneous albinism

Defects of pigmentation

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Age of onset

Congenital

Epidemiology

OCA1

Prevalence of around 1:40,000 in most populations with a carrier

rate of around 1:100.

OCA2

The most prevalent type of albinism with an estimated frequency in

the USA of approximately 1:36,000. More common in sub-Saharan

indigenous African populations and African-Americans.

Rufous OCA

This has been described amongst southern African blacks only;

in this population there is a frequency of approximately 1:8500.

Brown OCA

Brown OCA is a distinct phenotype in southern Africa characterized

by cream/light tan skin, beige/brown hair and blue-green to brown

irides. The ocular phenotype is of OCA.

Inheritance

Autosomal recessive

Chromosomal location

Disease

Locus

Gene

OCA1

11q14–q21

TYR

OCA2/OCA4

15q11.2–q12

P gene

OCA3

9p23

TRP1

OCA4

5p

MATP

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Oculocutaneous albinism

Gene

Tyrosinase (TYR), OCA1: a transmembrane copper-containing

enzyme that catalyzes the first two steps in melanin synthesis.

Pink-eye (P) gene, OCA2 and OCA4: a transmembrane protein found

within the melanosomes. The function of the P gene is not yet defined.

Tyrosine-related protein 1 (TRP1), OCA3: this regulates the formation

of insoluble melanin and acts late in the melanin production pathway.

Membrane-associated transporter protein (MATP), OCA4; this gene,

whose orthologue underlies the murine underwhite phenotype,

encodes a membrane transporter protein of unknown function.

Mutational spectrum

OCA1

In OCA1A, the majority of TYR mutations are missense mutations that

abolish catalytic activity (TYR null mutations). However, deletion,

nonsense and splicing mutations have also been described. Those

associated with OCA1B retain some enzyme activity. Sequencing of

the coding sequence defines around 50% of mutations.

OCA2

In OCA2 the majority of mutations are missense mutations, although

both frameshift and splicing mutations have been described.

Patients with brown OCA have also been found to carry mutations

in the P gene. The majority is heterozygous for a small deletion of

2.7 kb within the P gene and it is assumed that they carry a milder

mutation on the other allele.

OCA3

Only two mutations have been described within OCA3: S166X (serine

to stop) and a frameshift mutation in patients with rufous OCA.

OCA4

A single splicing mutation has been identified in the MATP gene that

is presumed to result in an in-frame deletion.

Defects of pigmentation

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Diagnosis

Clinical evaluation. Often children with OCA have visual inattention

for some weeks after birth, which can lead some parents and

relatives to believe that the baby is blind. It is important to give

reassurance that vision will improve over the first year of life. The

majority of children with OCA will be able to cope with mainstream

schooling, albeit with additional help.

Ocular and oculocutaneous albinism are frequently missed and a

high index of suspicion should be aroused by the coincidence of

developmental nystagmus and delayed visual maturation in the

absence of other obvious causes.

In general, individuals with OCA have no tanning ability. It is

essential to ensure effective protection from the sun by use of

high-factor sun blocks.

Previously, the formal diagnosis of OCA1 or OCA2 was based on

detection of levels of tyrosinase activity. Diagnosis is more easily made

using molecular genetic analysis, generally available on a research

basis only. This does not alter disease management but can be used

for prenatal diagnosis although this is not commonly requested.

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Oculocutaneous albinism

(also known as: CHS1)

MIM

214500

Clinical features

CHS1 is a form of syndromic OCA.

Ocular

The ocular features are similar to those seen in patients with other

forms of OCA. Children with CHS1 usually present with OCA.

Extraocular

There is partial hypopigmentation of the skin and hair—hair color

varies from blond to dark brown.

Abnormal susceptibility to infection occurs as a result of the

absence of natural killer and cytolytic T cell function. There are

large perinuclear eosinophilic, peroxidase-positive inclusion bodies

in myeloblasts and promyelocytes of bone marrow. A predisposition

to a lymphoproliferative disorder is observed – the so-called

‘accelerated phase’. Viral infection (e.g. Epstein Barr virus) may

initiate a lymphoma-like condition incorporating fever, generalized

lymphadenopathy, hepatosplenomegaly, pancytopenia and sepsis.

Patients often die before the age of 10 years.

Age of onset

Congenital

Inheritance

Autosomal recessive

Chromosomal location

1q42.1–q42.2

Gene

Lysosomal trafficking regulator (LYST)

Mutational spectrum

To date, all mutations in LYST have resulted in premature

termination of the protein.

Defects of pigmentation

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Effect of mutation

LYST is involved in membrane targeting of the proteins present in

secretory lysosomes. Mutations are associated with loss of function.

Diagnosis

Clinical evaluation and hematological investigation. DNA diagnosis

is now possible on a research basis and mutation testing can be

performed both by conventional methods and by the use of protein

truncation testing.

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Chediak-Higashi syndrome

MIM

203300; 604982 (HPS gene); 603401 (AP3B1)

Clinical features

HPS is multisystem disorder characterized by OCA, a bleeding

diathesis and, in some patients, pulmonary fibrosis.

Ocular

The ocular features are similar to those of OCA.

Extraocular

There is hypopigmentation of the skin and hair. In addition, HPS is

characterized by a bleeding disorder that results in easy bruising,

frequent epistaxis and variable bleeding associated with surgery.

Ceroid deposition in a number of tissues results in pulmonary

fibrosis, the major cause of death after 1 year of age, and

granulomatous colitis.

Epidemiology

HPS is rare in most regions of the world with an estimated

prevalence of 1:500,000–1,000,000. However, in Puerto Rico

the frequency is about 1:1800; the origin of this increase has

been traced to southern Spain.

Age of onset

Congenital

Inheritance

Autosomal recessive

Chromosomal location

10q23.1–q23.3 (HPS gene); 5q13 (adaptin beta-3a, AP3B1)

and genes

Mutational spectrum

To date, mutations in the HPS gene have resulted in premature

protein truncation. Both protein truncation and missense mutations

have been described in AP3B1.

Defects of pigmentation

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Effect of mutation

The HPS gene encodes two transcripts. The gene product is thought

to be a transmembrane protein that is a component of cytoplasmic

organelles and is important for their normal development and

function. Expression has been demonstrated in normal human

melanocytes.

AP3B1 mutations result in drastically reduced levels of AP-3, which

is involved in the formation of intracellular vesicles (e.g. lysosomes

and melanosomes). The AP-3 deficiency results in altered trafficking

of integral lysosomal membrane proteins, which show increased

expression on the cell surface.

Diagnosis

Clinical evaluation and hematological investigation showing absent

dense bodies on electron microscopy of platelets. Molecular genetic

testing of HPS is available for patients of Puerto Rican heritage on a

clinical basis, while genetic testing of the AP3B1 gene is available

on a research basis only.

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Hermansky-Pudlak syndrome

MIM

300500

Clinical features

OA1 is an X-linked recessive disorder affecting melanin synthesis,

characterized by hypopigmentation of the eyes with virtually no

signs in the skin and hair. Males with OA1 have ocular features

indistinguishable from that of OCA. Vision ranges from 6/6 to 6/60,

although over 70% can read better than 6/36. Boys with OA1 are

often blond but pigmentation is within the normal range and tanning

in response to UV light is normal.

Females are invariably asymptomatic; ocular examination in OA1

kindreds is helpful in definition of carrier status in 80–90% of cases.

There is significant iris transillumination and fundoscopy reveals a

peripheral ‘mud-splattered’ appearance. Skin biopsy reveals

macromelanosomes in the majority of patients, although this is

rarely indicated.

Age of onset

Congenital

Epidemiology

Unknown, although it is estimated to be around 1:60,000 in

Denmark.

Inheritance

X-linked recessive

Chromosomal location

Xp22.3

Gene

OA1

Mutational spectrum

Over 20 OA1 mutations have been described. Of these, more

than 50% are missense mutations clustered in the central coding

region; deletions, insertions and frameshift mutations have also

been described.

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211

Effect of mutation

The function of OA1 is unclear. Recent evidence suggests that the

protein acts as a G protein-coupled receptor (GPCR), GPCRs are

involved in the common signal transduction systems located at the

plasma membrane. The OA1 gene appears to be a pigment cell-

specific member of the GPCR superfamily found on melanosomes.

There is no evidence as yet for genotype-phenotype correlation—the

number of reported missense mutations is small and it is, therefore,

difficult to determine whether their position in the gene is important

in defining phenotypic outcome.

Diagnosis and

Clinical evaluation. Definition of carrier status can be difficult

counselling issues

although careful ophthalmic evaluation is usually sufficient. Carrier

status may have been defined before the birth of the first child. It is

important therefore, to prepare parents-to-be without creating

unnecessary concern.

As in OCA, children often have visual inattention for some weeks

after birth and reassurance should be given that vision will improve.

The majority of boys with OA1 cope with mainstream schooling.

DNA testing is now available and, according to one study, will

detect an abnormality in over 75% of cases. This may be helpful

in confirming diagnosis and defining carrier status. Parents do not

request prenatal diagnosis very often.

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Ocular albinism type 1