albinism

Coloboma, Microphthalmia, Albinism, and Deafness

Clinical Characteristics
Ocular Features: 

A 5 year old male has been described with uveal colobomas in microphthalmic eyes plus small corneas with a pannus, dense cataracts, translucent irides, and hypopigmentation of the skin, hair and eyes.  A brain MRI showed hypoplasia of the optic nerves and chiasm.   

A 9 month old female from another family had severe microphthalmia and small optic nerves.  The internal ocular features were not reported.

Systemic Features: 

The complete phenotype is uncertain since it is based on only two reported and unrelated individuals.  The head circumference one one patient was consistent with macrocephaly accompanied by frontal bossing, shallow orbits, preauricular pits and posteriorly rotated ears.  A skeletal survey revealed evidence for osteopetrosis.  He had a sensorineural hearing deficit said to be congenital in onset.

The other patient, a 9 month old female, belonged to another nonconsanguineous family, and had similar skeletal and craniofacial features with the addition of micrognathia and hypotonia.  Congenital neurosensory hearing loss and general lack of pigmentation were noted.

All four parents have congenital sensorineural hearing loss, blue irides and fair skin with premature graying of hair.  Four sibs in the two families have phenotypes similar to that of the parents.  Only one child, a female, had no features of the phenotype.

Genetics

This condition, so far reported only in a male and a female in unrelated families, is the result of doubly heterozygous mutations in the MITF gene (3p13).  One mutation that causes Waardenburg syndrome 2  (WS2A) (193510) is combined with a dominant-negative allele (c.952_954delAGA [p.Arg318del]) to produce the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Albinism, Oculocutaneous, Type V

Clinical Characteristics
Ocular Features: 

The phenotype in the two families studied includes photophobia, nystagmus, foveal hypoplasia and decreased visual acuity.  The fundus is hypopigmented.

Systemic Features: 

The hair is golden-colored and the skin is described as white. 

Genetics

The specific gene causing this form of oculocutaneous albinism has not been identified.  However, an area of homozygosity in the region of 4q24 has been identified in 6 members in two families belonging to a large consanguineous Pakistani pedigree in which it segregates with the OCA5 phenotype. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for oculocutaneous albinism but appropriately tinted glasses could be beneficial.

References
Article Title: 

Increasing the complexity: new genes and new types of albinism

Montoliu L, Gronskov K, Wei AH, Martinez-Garcia M, Fernandez A, Arveiler B, Morice-Picard F, Riazuddin S, Suzuki T, Ahmed ZM, Rosenberg T, Li W. Increasing the complexity: new genes and new types of albinism. Pigment Cell Melanoma Res. 2014 Jan;27(1):11-18. Review.

PubMed ID: 
24066960

Albinism, Oculocutaneous, Type VII

Clinical Characteristics
Ocular Features: 

Nystagmus and iris transillumination are present in all family members studied.  VEP studies show asymmetric decussation of axons in the chiasm.  The peripheral retina may have striking hypopigmentation. OCT reveals hypoplasia of the foveal region.   Photophobia is not a significant problem. Visual acuity is mildly to moderately reduced.

Systemic Features: 

Homozygous individuals are lighter in complexion than other family members. Hair color ranges from pale blond to dark brown.

Genetics

Homozygous mutations in the C10orf11 gene (10q22.2-q22.3) are responsible for the phenotype of this autosomal recessive condition.  The gene is active in melanocyte differentiation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the hypopigmentation has been reported.  Visual function might be improved with low vision aids.

References
Article Title: 

Increasing the complexity: new genes and new types of albinism

Montoliu L, Gronskov K, Wei AH, Martinez-Garcia M, Fernandez A, Arveiler B, Morice-Picard F, Riazuddin S, Suzuki T, Ahmed ZM, Rosenberg T, Li W. Increasing the complexity: new genes and new types of albinism. Pigment Cell Melanoma Res. 2014 Jan;27(1):11-18. Review.

PubMed ID: 
24066960

Hermansky-Pudlak Syndrome

Clinical Characteristics
Ocular Features: 

Oculocutaneous hypopigmentation is common to all types of HPS.  The ocular manifestations are similar to that of other types of albinism.  Iris transillumination defects, nystagmus, and strabismus are common features.   Visual acuity is usually stable in the range of 20/40-20/300 and often accompanied by photophobia.  Foveal hypoplasia and fundus hypopigmentation are present similar to that found in other hypopigmentation disorders.  The same is true of excessive decussation of retinal neuron axons at the chiasm.  Many patients have significant refractive errors. 

Systemic Features: 

In addition to decreased hair, ocular, and skin pigmentation, HPS patients suffer from bleeding diathesis, platelet deficiencies, and accumulation of ceroid material in lysosomes.  Pigment can be found in large amounts in reticuloendothelial cells and in the walls of small blood vessels.  Some of the same features are found in Chediak-Higashi  syndrome (214500) which, however, has additional qualitative changes in leukocytes.   HPS2 differs from other forms of HPS in having immunodeficiency and congenital neutropenia.  Some patients, especially those with HPS1 and HPS4 mutations, have restrictive lung disease secondary to pulmonary fibrosis often causing symptoms in the third and fourth decades of life.  Others have granulomatous colitis, kidney failure, and cardiomyopathy.  Solar skin damage is a risk with actinic keratosis, nevi, lentigines and basal cell carcinoma seen in many patients.

Bleeding time is prolonged secondary to an impairment of the normal aggregation response of platelets.  Easy bruising, epistaxis, prolonged bleeding during menstruation, after tooth extraction, and after minor surgical procedures are often reported.  Platelets lack the normal number of 'dense bodies'.  Coagulation factor activity and platelet counts are normal.

The amount of hair and skin pigmentation is highly variable.  Some patients are so lightly pigmented that they are misdiagnosed as having tyrosinase-negative albinism while others have yellow to brown hair with irides blue to hazel.  Some darkening of hair is common. 

Genetics

This is an autosomal recessive genetically heterogeneous condition resulting from mutations in at least 12 loci: HPS1 (203300) at 10q23.1-q23.2, AP3B1 causing HPS2 (608233) at 5q14.1, and AP3D1 (617050) at 19p13.3 causing HPS 10, whereas in types HPS3 (606118) at 3q24, HPS4 (606682) at 22q11.2-q12.2, HPS5 (607521) at 11p15-p13, HPS6 (607522) at 10q24.32 the mutations themselves have not been characterized.  HPS7 is caused by mutations in the DTNBP1 gene (607145) located at locus 6p22.3 and HPS8 by mutations in the BLOC1S3 gene (609762) at 19q13.  The nature of the mutations is variable and often unique to the population in which they are found. 

Chediak-Higashi  syndrome (214500) is a somewhat similar disorder but with leukocyte abnormalities and results from a different gene mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

It has been suggested that any patients with pigmentation disorders should be asked about bleeding problems to rule out HPS.  A hematologic consultation should be obtained if necessary, especially before elective surgery, to avoid bleeding complications through the use of appropriate preoperative measures.   Low vision aids can be helpful.  The skin should be protected from sunburn.  Lifelong surveillance is required for ocular and systemic problems.  The use of aspirin and indomethacin should be avoided. 

References
Article Title: 

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

Ammann S, Schulz A, Krageloh-Mann I, Dieckmann NM, Niethammer K, Fuchs S, Eckl KM, Plank R, Werner R, Altmuller J, Thiele H, Nurnberg P, Bank J, Strauss A, von Bernuth H, Zur Stadt U, Grieve S, Griffiths GM, Lehmberg K, Hennies HC, Ehl S. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016 Feb 25;127(8):997-1006.

PubMed ID: 
26744459

Albinism, Oculocutaneous, Type I

Clinical Characteristics
Ocular Features: 

Oculocutaneous albinism is a genetically and clinically heterogeneous condition.  It is congenital in origin and the combination of foveal hypoplasia and anomalous decussation of neuronal axons in the chiasm results in a permanent reduction of vision in the range of 20/50-20/200.  Most individuals have nystagmus, photophobia, and strabismus.  The iris usually is light blue and transmits light.  The retina lacks pigmentation as well.  The ocular features are similar in types IA and IB.  The iris may darken with age in type IB (606952 ). 

Systemic Features: 

There are generally no systemic abnormalities in these pigmentation disorders with the exception of sensorineural hearing loss in some, and, of course, complete absence of pigment in skin and hair.  Anomalous decussation of axons in the auditory system has been demonstrated in such cases and otic pigment is lacking in albinos.  The skin contains amelanic melanocytes but these cells contain granules similar to those of normal cells.   Some patients with residual tyrosinase activity (type 1B, 606952 ) develop some pigmentation of hair and skin, especially in cooler areas of the body such as the extremities. 

Genetics

This type of oculocutaneous albinism is caused by mutations in the TYR gene (11q14-q21) and inherited in an autosomal recessive pattern. 

Type IA (OCA1A) has no demonstrable tyrosinase activity while type IB (OCA1B, 606952) has a reduction in enzyme activity.  Yet other patients with mutations in TYR have a variant called 'yellow albinism' in which tyrosinase activity resembles that found in type IB.  To explain the difference in skin color, it has been suggested that an individual's background ethnicity may impact the pigmentation phenotype.

Other types also transmitted as autosomal recessive conditions are OCA2 (203200), OCA3 (203290), AND OCA4 (606574). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the basic disease but low vision aids may be helpful for some patients.  Dark glasses provide comfort for photophobic individuals.  The skin should be protected against sunburn. 

References
Article Title: 

A new hypothesis of OCA1B

Chiang PW, Drautz JM, Tsai AC, Spector E, Clericuzio CL. A new hypothesis of OCA1B. Am J Med Genet A. 2008 Nov 15;146A(22):2968-70.

PubMed ID: 
18925668

Oculocutaneous albinism

Gronskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. Review.

PubMed ID: 
17980020

Chédiak-Higashi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular hypopigmentation and visual function deficits in Chediak-Higashi syndrome resembles that of other types of albinism.  The iris has transillumination defects and the retina is hypopigmented.  Patients are photophobic and often have nystagmus.  Due to the early mortality of many patients, vision is difficult to measure, but is said to range from normal to near normal.  Hair bulb incubations studies show normal pigmentation.

A  subset of patients with later onset of disease has been reported to have optic atrophy, thinning of the nerve fiber layer, and a central scotoma.

Systemic Features: 

This is a form of albinism with other systemic features such as adenopathy, hepatosplenomegaly, neutropenia, and susceptibility to infection (especially gram positive organisms).  The hypopigmentation is evident at birth but may be patchy.  The hair has been described as having a blue-green metallic sheen.  It may also be sparse.  Patients have an increased risk of leukemia and lymphoma-like disease.  Peripheral sensory-motor neuropathy and ataxia are common in older individuals.  Thrombocytopenia can lead to easy bruising and extensive bleeding.  Neutrophils are often few in number and deficient in chemotactic and bacterial activity.  Pyoderma and peridontitis can be severe.  Survival without treatment is between 3 and 4 years but those who survive eventually develop lymphohistiocytic infiltration of major organs, bone marrow and peripheral nerves as young adults.

Giant peroxidase-positive inclusions in white blood cells are diagnostic.

Genetics

This is an autosomal recessive disorder caused by mutations in the LYST gene (1q42.1-q42.2) causing defects in vesicle trafficking.

Hermansky-Pudlak syndrome (214500) is another form of hypopigmentation with serious systemic manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Bone marrow transplantation can prolong life but neurologic symptoms often develop in those who survive.  Low-vision aids can be helpful.  Infections, of course, should be promptly and vigorously treated.

References
Article Title: 

Optic neuropathy in late-onset neurodegenerative Chédiak-Higashi syndrome

Desai N, Weisfeld-Adams JD, Brodie SE, Cho C, Curcio CA, Lublin F, Rucker JC. Optic neuropathy in late-onset neurodegenerative Chediak-Higashi syndrome. Br J Ophthalmol. 2015 Aug 25. pii: bjophthalmol-2015-307012. doi: 10.1136/bjophthalmol-2015-307012. [Epub ahead of print].

PubMed ID: 
26307451

Chédiak-Higashi syndrome

Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. 2008 Jan;15(1):22-9. Review. PubMed PMID: 18043242.

PubMed ID: 
18043242

Albinism, Ocular Type 1

Clinical Characteristics
Ocular Features: 

Signs in ocular albinism include hypopigmentation of the fundus with clearly visible choroidal vessels, foveal hypoplasia, and hypopigmentation of the iris. Strabismus, nystagmus, photophobia, absent stereoacuity and high refractive errors including hypermetropia are other common features.  Vision may be near normal but usually worse, in the range of 20/100 to 20/300.  In at least some patients with ocular albinism, concentric macular rings have been identified using infrared reflectance images.

In ocular albinism there is a nearly complete crossing of nerve fibers in the optic chiasm as well as a decreased number of photoreceptors.  MRI imaging of the optic chiasm in humans with albinism reveals it to be smaller with a wider angle between optic tracts, reflecting the atypical crossing of nerve fibers.

This is an X-linked recessive disorder and affects mainly men. In 80% of female carriers a mosaic of pigmentary changes can be observed in the fundus, especially in the periphery as a result of lyonization.  A few female heterozygotes have ocular changes of albinism including nystagmus and reduced visual acuity, likely as a result of unequal X-chromosome inactivation.  Perhaps three-quarters of carrier females have transillumination defects in the iris.

Hearing loss is often associated with pigmentation disorders and one large family with X-linked ocular albinism has been reported with a late onset sensorineural deafness (300650).  The ocular findings are typical but deafness is not significant until late midlife.

Systemic Features: 

In ocular albinism, pigmentation is normal except in the eye.  Hearing loss has been reported in a single family but this may be a unique disorder since the genotype was not determined.

Genetics

Ocular albinism (OA1) is a recessive X-linked disorder, caused by mutations in the GPR143 gene, located at Xp22.3.  The protein product, a G protein-coupled receptor, is localized on the membrane of melanosomes in pigmented cells in the eye.  The same gene is mutated in congenital nystagmus 6 (300814).  Ocular albinism with late onset sensorineural deafness (300650) results from mutations in the Xp22.3 region as well and may or may not be the same condition.

It has been reported that mutations in GNA13 (17q24.1), activated by OA1, can also result in the ocular albinism phenotype.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Treatment for the ocular symptoms is targeted toward specific problems. Refractive errors are treated with corrective glasses with tinted lenses recommended for the photophobia. Low vision aids and special education may be required.

References
Article Title: 

Oculocerebral Syndrome with Hypopigmentation

Clinical Characteristics
Ocular Features: 

Patients have severe ocular malformations which so far lack full characterization.  Nearly complete scleralization of the cornea prevents internal evaluation in most cases.  There may be extensive neovascularization of corneal clouding.  Anterior synechiae and cataracts have been described.  Other patients presumed to have the same disorder have normal fundi or diffuse pigmentary changes.  No limbal landmarks can be seen.  The central cornea can be more transparent but no iris can be visualized.  The eyes are microphthalmic as well.  Slow, wandering eye movements are constant.  Spastic ectropion of the lower lids is present. Lashes and eyebrows have minimal pigmentation and like the scalp hair have a slight yellowish tinge.  There is no response to bright light in severe cases whereas in other more mildly affected individuals presumed to have this disorder there is only hypoplasia of the fovea with diffuse retinal pigmentary changes.

Systemic Features: 

Individuals have severe mental retardation from birth and never respond to environmental cues beyond having a marked startle response to auditory stimuli.  Grasp and sucking responses persist at least into the second decade.  The developmental delay persists from birth and patients never achieve normal milestones.  Athetoid, writhing movements are prominent.  The limbs are spastic, and deep tendon reflexes are hyperactive. Contractures are common.  Hypodontia, diastema, and gingival hyperplasia are usually present and the hard palate is highly arched.  The skin is hypopigmented but pigmented nevi may be present and the distribution of melanocytes is uneven microscopically. Cerebellar hypoplasia has been reported in some patients.

Genetics

This is a presumed autosomal recessive disorder based on its familial occurrence and parental consanguinity in some families.  An interstitial deletion [del(3)(q27.1-1q29)] has been identified in the paternal chromosome of a 4-year-old female but the molecular defect remains unknown. 

Clinically heterogeneous cases from Africa, Germany, Italy, Great Britain, and Belgium may not all have the same disorder and evidence for a distinctive phenotype remains elusive.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None available

References
Article Title: 

Oculocerebral syndrome with hypopigmentation (Cross

De Jong G, Fryns JP. Oculocerebral syndrome with hypopigmentation (Cross syndrome): the mixed pattern of hair pigmentation as an important diagnostic sign. Genet Couns. 1991;2(3):151-5.

PubMed ID: 
1801851
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