fundus hypopigmentation

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

Waardenburg Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Waardenburg syndrome is a disorder of pigmentation, sensorineural deafness, and a characteristic facial (nasal root) morphology.  Some have neural tube defects.  Based on clinical criteria, the syndrome has been divided into types 1, 2, 3, and 4, with subtypes of 2 and 4.  Types 1 and 3 are caused by mutations in the same gene.

Patients often have a white forelock and iris heterochromia.  The latter may be partial in individual irides, or the entire iris in one eye with the fundus hypopigmentation often matching the iris pattern.  The fundus may also have segmental areas of pigmentary changes corresponding to the iris heterochromia. The hypopigmented portion of the iris is often a brilliant blue.  Dystopia canthorum is a prominent and nearly constant (>95%) feature of type 1, and together with the prominent nasal root and increased intercanthal distance may suggest hypertelorism.  Synophrys is often present and the medial portions of the eyebrows can be exceptionally bushy.  Sometimes the poliosis involves the lashes and eyebrows.

Systemic Features: 

Congenital sensorineural deafness is an important feature.  Individuals with type 1 often have a white forelock (29%), premature graying (44%), and hypopigmented skin patches (55%).  A few patients have cleft palate and/or lip. Neural tube defects have also been reported. The considerably more rare type 3 is caused by mutations in the same gene as type 1, but it is claimed by some to be a separate disorder because of the association of limb anomalies. 

Genetics

Autosomal dominant inheritance is typical for the Waardenburg syndrome.  Types 1 and 3 are caused by mutations in the PAX3 gene (2q35) and, of these, type 1 is far more common.  Type 1 is caused by a heterozygous mutation whereas type 3 may result from either a heterozygous, compound heterozygous, or homozygous mutation.  Both types have been reported to occur in the same pedigree.  PAX genes act as transcription factors that attach to specific sections of DNA and regulate protein production.  PAX3 gene products, among other things, specifically influence neural crest cells important to the development of cranialfacial bones and melanocytes.  Paternal age plays a role in new mutations which probably account for many sporadic cases.

Waardenburg syndrome is an excellant example of genetic heterogeneity as types 1 (193500), 2 (193510), 3 (148820  and 4 (277580) can all result from mutations in different genes.  In addition, types 2 and 4 are each caused by mutations in several different genes. 

A child has been reported who was doubly heterozygous for mutations involving both MITF and PAX3. Hypopigmentation in the scalp hair, eyebrows and eyelashes was more severe than usually seen in patients with single mutations. In addition the face showed marked patchy pigmentation. One parent contributed the MITF mutation and the other added the mutation in PAX3.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No ocular treatment is necessary.  Patients may benefit from cochlear implants.

References
Article Title: 

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

Focal Dermal Hypoplasia

Clinical Characteristics
Ocular Features: 

Features have considerable heterogeneity and few patients have all of them.  Some ocular abnormalities are found in 40% of patients.  Microphthalmia is common and many patients (30%) have colobomas of the iris and choroid.  Some patients have dislocated lenses.  Distinctive peripheral corneal lesions consisting of discrete vascularized subepithelial opacities have been described.  Occasional patients have conjunctival or lid margin papillomas.  Strabismus and nystagmus are common.

Systemic Features: 

This disorder has a wide variety of clinical features and many occur in only a few patients.  The skin has focal areas of hypoplasia with hypopigmentation, often appearing in a streak or linear pattern.  These areas may be present at birth and contain bullae or urticarial lesions with signs of inflammation.  Telangiectases and herniated fat may appear in these areas.   Oral, esophageal, and laryngeal fibrovascular papillomas occur but they may also be seen in the perineal, vulvar, and perianal areas.  These may be large, friable, and recurrent.  The teeth erupt late and are usually hypoplastic.  The nails are often dysplastic and the hands and feet may be 'split' with syndactyly of the third and fourth fingers giving a 'lobster claw' appearance.  Polydactyly may be present.  Most have thin 'protruding' ears.  A variety of skeletal anomalies have been reported including absence of metatarsals and metacarpals.  A considerable number of patients have mild to moderate mental deficits.  Severely affected females may die in infancy.

Genetics

This is considered an X-linked dominant disorder with lethality in males.  However, numerous affected males (>30) and rare instances of father-to-daughter transmission have been reported and it has been suggested that half-chromatid mutations or postzygotic somatic mosaicism in these males might be responsible.  Mutations in the PORCN gene (Xp11.23) have been associated with FDH.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

Surgery may be required for the papillomas if they are obstructive.

References
Article Title: 

Waardenburg Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

This type of Waardenburg syndrome is distinguished from type 1 and 3 (193500) by the fact that it is caused by mutations in a different gene and in the absence of dystopia canthorum.  It has been claimed that hearing loss is more common and severe in type 2 (77%) as is heterochromia of the iris (47%) while skin and hair hypopigmentation are less common.

Families with WS2A may have the full spectrum of eye findings seen in X-linked ocular albinism I (300500) including decreased acuity, photophobia, nystagmus, translucent irides, hypermetropia, and albinotic fundi with foveal hypoplasia.  Indeed, such families have been considered to have 'albinism, ocular, with sensorineural deafness' (103470).  Such families might be considered to have an autosomal dominant form of ocular albinism.

Systemic Features: 

Congenital sensorineural hearing loss is an important and common feature.  Also characteristic are the white forelock, poliosis, and hypopigmented skin patches.

Genetics

Waardenburg syndrome is an excellent example of genetic heterogeneity as types 1 and 3 (193500, 148820), 2 (193510), and 4 (277580) are all caused by mutations in different genes. 

Type 2 described here is a genetically heterogeneous autosomal dominant disorder.  WS2A is caused by a mutation in MITF (microphthalmia-associated transcription factor) (3p14.1-p12.3).  This is the same disorder described as 'Albinism, ocular, with sensorineural deafness' in OMIM (103470)  (WS2-OA).

A locus at 1p21-p13.3 is associated with WS2B (600193) and WS2C (606662) maps to 8p23.  In addition, homozygous SNAI2 mutations at 8q11 have been found in several patients with WS2D (608890) suggesting autosomal recessive inheritance but the normal parents were not studied.  Recent evidence suggests that SOX10 mutations can also play a role via MITF promoter modulation (WS2E) (611584).

Type 4 is also the result of mutations in at last three genes.

A child has been reported who was doubly heterozygous for mutations involving both MITF and PAX3.  Hypopigmentation in the scalp hair, eyebrows and eyelashes was more severe than usually seen in patients with single mutations.  In addition the face showed marked patchy pigmentation.  One parent contributed the MITF mutation and the other added the mutation in PAX3.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No ocular treatment is necessary but assistive hearing devices can be helpful.

References
Article Title: 

Aland Island Eye Disease

Clinical Characteristics
Ocular Features: 

This is an X-linked disorder in which males have a variety of ocular defects.  The fundus is hypopigmented and the fovea is incompletely developed.  The hypopigmentation is most pronounced in the posterior pole and peripapillary region.  Variable degrees of iris transillumination have also been noted.  Progressive axial myopia, nystagmus, astigmatism, defective night vision, and a protan color vision defect are additional cardinal features.  Females may be mildly affected with subtle nystagmus and color vision defects.  It is sometimes mislabeled as X-linked albinism (OA1, #300500) but differs importantly from that disorder by the lack of misrouting of optic nerve axons.  The eponymic label 'Forsius-Eriksson type ocular albinism' further adds to the confusion with ocular albinism. 

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an X-linked disorder resulting from a mutation in the CACNA1F gene located at Xp11.23.  Molecular DNA studies suggest that there may be some heterogeneity in the causative mutations but in the original family reported by Forsius and Eriksson, a 425-bp deletion in the CACNA1F gene has been found to segregate as expected in the phenotypes.  The highly variable and subtle nature of clinical manifestations in females limits their usefulness in determination of carrier status and genotyping is necessary.

The CSNB2A type of congenital stationary night blindness (300071) is caused by mutations in the same gene suggesting allelism of the two disorders.  Aland Island eye disease shares some clinical features such as night blindness and occasionally mild color vision defects but differs in the presence of progressive myopia and an abnormal fovea. 

CORDX3 (300476), a cone-rod dystrophy, is also allelic.

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

No treatment is available except for correction of the myopia.

References
Article Title: 

A novel CACNA1F gene mutation causes Aland Island eye disease

Jalkanen R, Bech-Hansen NT, Tobias R, Sankila EM, M?SSntyj?SSrvi M, Forsius H, de la Chapelle A, Alitalo T. A novel CACNA1F gene mutation causes Aland Island eye disease. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2498-502. PubMed PMID:17525176.

PubMed ID: 
17525176
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