angle closure glaucoma

Nanophthalmos 1

Clinical Characteristics
Ocular Features: 

The axial length ranges from 17.55 to 19.28 mm with a mean of 18.13 mm.  The mean refractive error was +9.88 in one reported family but ranged from +7.25 to +13.00.  More than half of reported patients have developed angle closure glaucoma.  Patients are at risk for strabismus and amblyopia.  Choroidal detachments are often seen in nanophthalmic eyes.

Histological studies on full thickness sclerotomy tissue from a nanophthalmic eye showed frayed and split collagen fibrils with lightly stained cores predominantly in the sclera and episcleral regions which may contribute to the anatomical changes.

Systemic Features: 

None have been reported.

Genetics

No mutation has been described but this autosomal dominant condition maps to 11p.

Another type of autosomal dominant nanophthalmos (NNO3) (611897) maps to 2q22-q14, and yet another, nanophthalmos AD, results from mutations in TMEM98.

Nanophthalmos may also be inherited in an autosomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lifelong monitoring is required because of the risk of angle closure.  Intraocular surgery such as lens extractions carries a high risk of complications.

References
Article Title: 

Nanophthalmos AD

Clinical Characteristics
Ocular Features: 

In the family reported, vision ranged from NLP to 20/20.  Refractive errors ranged from +8.25 to +15.50 D (mean +11.8 D).  Axial length ranged from 16.90 to 18.46 mm with a mean of 17.6 mm.  Angle closure glaucoma was diagnosed in 6 of 16 (37%) patients. Thickened sclera with prominent scleral vessels was described in affected family members.  Optic nerve drusen are often present and increased tortuosity of the retinal vessels has been described.

Systemic Features: 

No systemic abnormalities have been reported in spite of the fact that the TMEM98 gene is widely expressed in body tissues. 

Genetics

This is an autosomal dominant disorder resulting from a missense mutation in exon 8 of the TMEM98 (17p12-q12) gene.  The mutation has been reported in a single Australian family.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens removal may be considered in individuals with shallow anterior chambers and narrow angles but frequent postoperative macular edema and choroidal effusions have been seen and the visual prognosis is guarded.

References
Article Title: 

Vitreoretinochoroidopathy

Clinical Characteristics
Ocular Features: 

Clinical features are variable in this ocular disorder. Small corneas and shallow anterior chambers have been described in some patients.  Chronic narrow angle glaucoma or frank angle closure glaucoma attacks may occur.  Microphthalmia has been reported but nanophthalmos has not been documented.  Presenile cataracts, nystagmus, and strabismus are sometimes present.  Some patients have normal vision but others have a severe reduction in acuity, even blindness.

The vitreous is often liquefied and some patients have a fibrillary vitreous with pleocytosis.  Preretinal white dots and neovascularization are often seen, even in children.  Peripapillary atrophy may extend to the macula which may have cystic edema.  Peripherally in annular fashion there is often a pigmentary retinopathy extending to an equatorial demarcation line at the posterior border.  The ERG is usually moderately abnormal with evidence of rod and cone dystrophy generally in older patients in which some degree of dyschromatopsia is often present.  Some patients demonstrate a concentric reduction in visual field that progresses with age.  A reduced light/dark ratio has also been documented in several families.  Retinal detachment is a risk.  A posterior staphylomas has been noted in a few patients. 

Systemic Features: 

No systemic abnormalities have been reported. 

Genetics

This is an autosomal dominant disorder resulting from mutations in BEST1 (11q13), which is also responsible for Best vitelliform macular dystrophy (153700). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No prophylactic treatment has been reported but patients need lifelong monitoring to detect and treat glaucoma, retinal neovascularization, and detachments. 

References
Article Title: 

Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC)

Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B, Messiaen LM, Perveen R, Reddy MA, Bhattacharya SS, Traboulsi E, Baralle D, De Laey JJ, Puech B, Kestelyn P, Moore AT, Manson FD, Black GC. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3683-9.

PubMed ID: 
15452077

Weill-Marchesani Syndrome 1

Clinical Characteristics
Ocular Features: 

The Weill-Marchesani phenotype is a rare connective tissue disorder manifested by short stature, brachydactyly, spherophakia and stiff joints.   As many as 94% have spherophakia and 64% have dislocated lenses.  The central corneal thickness is increased.  The small, abnormally shaped lens can migrate anteriorly causing pupillary block glaucoma and sometimes dislocates into the anterior chamber.  This may occur spontaneously or following pharmacologic mydriasis which is sometimes done to relieve the pupillary block.

Systemic Features: 

Short stature in the range of 155 cm in height for men and 145 cm for women is common.  Brachydactyly and stiff joints prevent patients from making a tight fist.   A few patients (13%) have some mild mental deficit but most have normal intelligence.  Cardiac defects include patent ductus arteriosis, pulmonary stenosis, prolonged QT interval mitral valve stenosis, and mitral valve prolapse.  Some heterozygous carriers also are short in stature and may have joint stiffness.

Genetics

Homozygous mutations in the ADAMTS10 gene (19p13.3-p13.2) cause this disorder.  Homozygous mutations in LTBP2 (14q24.3) have also been found in WMS1 and in the Weill-Marchesani-Like syndrome (613195).

Weill-Marchesani syndrome 2 (608328) is a clinically similar syndrome but results from heterozygous mutations in FBN1. Homozygous mutations in ADAMTS17 cause the Weill-Marchesani-Like syndrome (613195) .  It is not always possible to distinguish between the AR and AD forms of the disease using clinical criteria alone.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Dislocated lenses should be removed if they are interfering with vision or migrate into the anterior chamber.  A peripheral iridotomy should be considered in cases where pupillary block glaucoma occurs.  Long-term mydriasis is not recommended because of the risk of lens dislocation into the anterior chamber.  Chronic open angle glaucoma is a threat and life-long monitoring is recommended.  Measurements of the intraocular pressure should take the increased central corneal thickness into account.  Trabeculectomy should be considered when the pressure cannot be medically controlled.

References
Article Title: 

LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix

Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH, Yazdani S, Nilforushan N, Fan JB, Klotzle B, Mahmoudi MJ, Ebrahimian MJ, Chelich N, Taghiabadi E, Kamyab K, Boileau C, Paisan-Ruiz C, Ronaghi M, Elahi E. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat. 2012 Apr 26. doi: 10.1002/humu.22105. [Epub ahead of print] PubMed PMID: 22539340.

PubMed ID: 
22539340

Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome

Faivre L, Dollfus H, Lyonnet S, Alembik Y, M?(c)garban?(c) A, Samples J, Gorlin RJ, Alswaid A, Feingold J, Le Merrer M, Munnich A, Cormier-Daire V. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A. 2003 Dec 1;123A(2):204-7. Review.

PubMed ID: 
14598350

Macular Dystrophy, Vitelliform 2

Clinical Characteristics
Ocular Features: 

Best disease primarily affects the macular and paramacular areas.  The classical lesion resembles an egg yolk centered on the fovea.  Most patients, however, never exhibit the typical vitelliform lesion and may instead have normal maculae, or irregular yellowish deposits that may even be extrafoveal.  Histologically the RPE contains increased amounts of lipofuscin.  The ‘egg yolk’ is located beneath the neurosensory retina and the overlying retinal circulation often remains intact.  It can evolve into a ‘scrambled egg’ appearance and an apparent fluid level may be evident.  Some patients exhibit only RPE changes including hyper-  or hypopigmentation throughout the macula.  Choroidal neovasculariztion with hemorrhage leading to scarring and gliosis are uncommon but present a serious risk to vision.  The common end point for symptomatic patients is some degree of photoreceptor damage.

Until recently, most reports of Best macular dystrophy did not include genotypic data.  It is therefore difficult to classify families with variants of the disease, such as adult-onset or atypical vitelliform dystrophy but these at least suggest that this may be a heterogeneous disorder.  At the present time, the diagnosis should be reserved for those with an abnormal light-to-dark (Arden) ratio on electro-oculography and a mutation in the BEST1 gene. 

Visual function varies widely and has considerable fluctuation.   As many as 7-9 percent of patients are asymptomatic throughout life and few have vision loss to 20/200.  Many individuals maintain vision of 20/40 or better throughout life.  Some experience episodic acute vision loss to 20/80 or worse but often recover to at least 20/30.  It has been reported that as many as 76 per cent under the age of 40 retain 20/40 and 30 per cent retain this level of vision into the 5th and 6th decade of life.

Other ocular manifestations include hyperopia, esotropia, and, rarely, shallow anterior chambers with angle closure glaucoma.

Systemic Features: 

None have been reported.

Genetics

A mutation in the bestrophin gene (BEST1) located on chromosome 11 (11q13) is responsible for the disease in most patients.  Best disease is usually transmitted in an autosomal dominant pattern from parent to offspring.  A large number of mutations have been found in the BEST1 gene but so far no correlation with severity of disease is possible.  In fact, there is a great deal of clinical variation within families having identical mutations resembling that of the variation found among different mutations.

Several families have also been reported with autosomal recessive inheritance.  Affected offspring had homozygous mutations in the bestrophin gene with reduced light/dark responses and vision loss.  Some have atypical vitelliform retinal and sometimes multifocal lesions.  They may develop angle closure glaucoma.  Their heterozygous parents  have either normal or abnormal EOGs and no visible fundus disease.  So far no families with presumed recessive inheritance of Best macular dystrophy have demonstrated parent-to-child transmission of typical vitelliform lesions.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease described here we know of at least four more variants and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 (608161) due to mutations in the PRPH2 gene, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Autosomal dominant vitreoretinochoroidopathy (193220) is an allelic disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

None known for disease.  Subretinal neovascularization may benefit from ablation treatments.

References
Article Title: 

Mutations in IMPG1 Cause Vitelliform Macular Dystrophies. Am

Manes G, Meunier I, Avila-Fern?degndez A, Banfi S, Le Meur G, Zanlonghi X, Corton M, Simonelli F, Brabet P, Labesse G, Audo I, Mohand-Said S, Zeitz C, Sahel JA, Weber M, Dollfus H, Dhaenens CM, Allorge D, De Baere E, Koenekoop RK, Kohl S, Cremers FP, Hollyfield JG, S?(c)n?(c)chal A, Hebrard M, Bocquet B, Garc??a CA, Hamel CP. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies. Am J Hum Genet. 2013 Aug 29. [Epub ahead of print] PubMed PMID: 23993198.

PubMed ID: 
23993198

Biallelic mutation of BEST1 causes a distinct retinopathy in humans

Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008 Jan;82(1):19-31. PubMed PMID: 18179881

PubMed ID: 
18179881

Identification of the gene responsible for Best macular dystrophy

Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C. Identification of the gene responsible for Best macular dystrophy. Nat Genet. 1998 Jul;19(3):241-7.

PubMed ID: 
9662395

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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