choroidal thickening

Nanophthalmos Plus Syndrome

Clinical Characteristics
Ocular Features: 

This is a recently described type of nanophthalmos with characteristic clinical features plus retinal degeneration and optic disc drusen.  Hyperopia is common and, like another recessive form of nanophthalmos (267760), patients have a progressive retinal dystrophy beginning with granular and mottled RPE changes and progressing to a bone spicule pattern resembling retinitis pigmentosa.  No synechiae have been reported in this syndrome however.  Macular retinoschisis and cystic changes with reduced foveal reflexes are commonly present.  The anterior chamber and angles are narrow but no reported cases have had angle closure glaucoma such as frequently occurs in other forms of nanophthalmos (267760, 609549, 600165, 611897).  Drusen of the optic nerve head can be demonstrated by ultrasound.  Scleral and choroidal thickening are usually present.  There is progressive deterioration of photoreceptors beginning with rod dysfunction and eventually involving cones as documented on ERG recordings.  Nyctalopia and visual difficulties begin in childhood and the visual field is concentrically constricted.  Visual acuity is in the range of 20/100 to 20/200.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder caused by mutations in the membrane frizzled-related protein coding gene MFRP (11q23) expressed in retinal tissue.  Both homozygous and compound heterozygous mutations have been described.  It seems to be allelic to another nanophthalmos condition without retinal pigmentary degeneration which is caused by different mutations in MFRP (NNO2 609549).  However, there is considerable clinical overlap of the several nanophthalmos conditions and it is possible that this is simply clinical heterogeneity within the same disease.

A syndromic form (MCOP5) of autosomal recessive microphthalmia with retinitis pigmentosa (611040) is also caused by mutations in MFRP and may be the same disorder.

For other forms of nanophthalmos see:  267760, 609549, 600165, 611897.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Angle closure glaucoma is a constant threat in some nanophthalmic conditions but has not been reported in this disorder.  Nevertheless, it may be prudent to consider prophylactic iridotomies in high risk cases.

References
Article Title: 

Nanophthalmos with Retinopathy

Clinical Characteristics
Ocular Features: 

This is a rare syndrome consisting of a pigmentary degeneration of the retina in association with nanophthalmos.  The globe is small with a thickened choroid and sclera and the macula becomes atrophic later in life. Some patients have cystic macular changes early without fluorescein leakage.  The anterior chamber is shallow, the angle is narrow, and the cornea may be small leading to angle closure glaucoma in most patients.  Extensive anterior and posterior synechiae can be seen.  The retina has a postequatorial bone spicule pattern of pigmentation with narrowing of arterial vessels.  Hyperopia is usually present and nightblindness may be noted in the first decade of life.  The ERG early shows loss of rod function and progression of the retinal disease subsequently leads to extinction of all rod and cone responses by midlife.  The EOG may be subnormal and visual fields are severely constricted.  Pallor and crowding of the optic nerve are common.  The vitreous may contain prominent fibrils and fine white granules.  Visual acuity is often 20/200 or worse.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is likely an autosomal recessive disorder based on frequent parental consanguinity and sibships with multiple affected individuals of both sexes.  However, the first reported family in 1958 with 13 affected individuals in 4 generations suggested autosomal dominant inheritance. No molecular defect has been identified.

This may be the same disorder as microphthalmia with retinitis pigmentosa (611040) in which so far no molecular mutation has been identified. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Narrow angles with shallow anterior chamber depth should be treated with prophylactic iridotomies.

References
Article Title: 

Nanophthalmos 2

Clinical Characteristics
Ocular Features: 

In this condition the axial length of the globe is often only 14-16 mm (normal >20 mm) resulting in extreme hyperopia of +8-25 diopters.  Corrected vision is usually 20/40 to 20/80 but 20/200 is not uncommon.  The choroid and sclera are thickened in nanophthalmos to a greater degree than seen in common mild hyperopia.  While all ocular structures are small in microphthalmia, in nanophthalmos the lens dimensions are generally normal.  In a small globe this causes ‘crowding’ of the anterior chamber angles and angle closure glaucoma is a major risk.

Folds in the choroid and retina are common.  Choroidal effusions, retinal edema and retinal detachments are not uncommon.  The retinal pigment epithelial may have mild window defects.  Hypoplasia, cysts, yellowish discoloration, and horizontal striae of the macula have been reported.  The foveal reflex is frequently absent corresponding to the lack of a normal foveal pit as revealed by OCT.  The foveal avascular zone may be small or absent.  The disks often appear crowded.  ERGs and VEPs are usually normal.   Scleral collagen is abnormal and thickened, leading to the postulation that this interferes with suprachoroidal drainage resulting in effusion and non-rhegmatogenous retinal detachments.

Systemic Features: 

No systemic disease has been consistently associated with simple nanophthalmos. Individuals with Kenny’s syndrome, Hallerman-Streiff-Francois (234100) syndrome and oculodentodigital dysplasia syndrome (164200) with nanophthalmos have been reported.

Genetics

Nanophthalmos may result from several mutations. Most cases occur sporadically but familial cases suggesting autosomal recessive inheritance (NNO2, 609549) have been reported. The mutation is a frameshift insertion, 1143C, in the MFRP gene on chromosome 11 (11q23.3) and has been found in the homozygous configuration in several families. The protein product has a domain that may be related to the Frizzled family of transmembrane  cell-cell signaling molecules responsible for regulation of growth and differentiation. In this connection, it is of interest that this gene is highly expressed in the retinal pigment epithelium.

It seems that at least two dominant mutations can also cause nanophthalmos. One (NNO3, 611897), located on chromosome 2 (2q11-q14), has been identified in a large Chinese pedigree although the molecular mutation remains unknown. Another, NNO1, (600165), has also been mapped to chromosome 11 but at 11p.  The molecular mutations also remain unknown.

Homozygous mutations in serine protease PR2258 have also been reported in several families with nanophthalmos.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Prophylactic iridotomies should be considered.
 

References
Article Title: 

Familial nanophthalmos

Cross HE, Yoder F. Familial nanophthalmos. Am J Ophthalmol. 1976 81(3):300-6.

PubMed ID: 
1258954

The nanophthalmic macula

Serrano JC, Hodgkins PR, Taylor DS, Gole GA, Kriss A. The nanophthalmic macula. Br J Ophthalmol. 1998 Mar;82(3):276-9.

PubMed ID: 
9602624

Mutations in a novel serine protease PRSS56 in families with nanophthalmos

Orr A, Dub?(c) MP, Zenteno JC, Jiang H, Asselin G, Evans SC, Caqueret A, Lakosha H, Letourneau L, Marcadier J, Matsuoka M, Macgillivray C, Nightingale M, Papillon-Cavanagh S, Perry S, Provost S, Ludman M, Guernsey DL, Samuels ME. Mutations in a novel serine protease PRSS56 in families with nanophthalmos. Mol Vis. 2011;17:1850-61.  PubMed PMID: 21850159.

PubMed ID: 
21850159
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