ectopia lentis

Kniest Dysplasia

Clinical Characteristics
Ocular Features: 

High myopia and vitreoretinal degeneration are characteristic ocular features in this disorder.   The myopia is in the range of -7.5 to -15.25 with most patients having about -11 diopters.  Acuity may be normal but inoperable retinal detachments can lead to blindness.  The vitreous demonstrates liquefaction and syneresis and often detaches posteriorly forming a retrolental curtain.  About half of affected eyes have perivascular lattice degeneration and the same proportion of patients at some point develop a retinal detachment.  Giant tears and retinal dialysis are commonly the cause.  The lens is often dislocated and cataracts are common.

Systemic Features: 

Short stature, cleft palate, stiff joints, and conductive hearing loss are characteristic extraocular features of Kniest dysplasia.  Some patients develop frank joint contractures and many are unable to make a tight fist due to inflexibility of the interphalangeal joints.  Lumber kyphoscoliosis is common.  Epiphyseal cartilage has a 'Swiss cheese appearance' with prominent lacunae.  The facies are round and the midface is underdeveloped with a flat nasal bridge.  Mild psychomotor retardation is sometimes seen.  

High levels of keratin sulfate are found in the urine.

Genetics

Mutations in the COL2A1 gene (12q13.11-q13.2) coding for type II collagen is responsible for this autosomal dominant disorder. This is one of a number of disorders known as type II collagenopathies (see Stickler syndrome I [609508]).  The clinical features arise from a defect in type II procollagen.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the dysplasia.  Displaced lenses can be removed but the myopia and degenerated vitreous require a cautious approach.  Rhegmatogenous detachments demand prompt attention.

References
Article Title: 

Ophthalmic and molecular genetic findings in Kniest dysplasia

Sergouniotis PI, Fincham GS, McNinch AM, Spickett C, Poulson AV, Richards AJ, Snead MP. Ophthalmic and molecular genetic findings in Kniest dysplasia. Eye (Lond). 2015 Jan 16. doi: 10.1038/eye.2014.334. [Epub ahead of print].

PubMed ID: 
25592122

The Kniest syndrome

Siggers CD, Rimoin DL, Dorst JP, Doty SB, Williams BR, Hollister DW, Silberberg R, Cranley RE, Kaufman RL, McKusick VA. The Kniest syndrome. Birth Defects Orig Artic Ser. 1974;10(9):193-208.

PubMed ID: 
4214536

Weill-Marchesani Syndrome 2

Clinical Characteristics
Ocular Features: 

Glaucoma may have an infantile onset and pupillary block glaucoma is a lifelong risk.  The lenses dislocate inferiorly but may migrate into the anterior chamber.  Spherophakia occurs in 74% of patients.  Extreme myopia in the range of -13 D may be present.  There is an increased risk of retinal detachment.

Systemic Features: 

One patient had mitral valve insufficiency.  Midface hypoplasia with a protruding lower lip was found in two patients.  The elbow and perhaps other large joints have limited mobility and the interphalangeal joints are thickened with difficulty in full extension of the fingers.  Patients are short in stature and the digits are often short and stubby.  The skin is tanned and thickened in places.  Cardiac anomalies are present in 13% of patients.

Genetics

This is an autosomal dominant disorder resulting from heterozygous mutations in FBN1 (15q21.1).  It is thus allelic to the Marfan syndrome (154700).  Weill-Marchesani syndrome 1 (277600) is a clinically similar syndrome but results from homozygous mutations in ADAMTS10. Homozygous mutations in ADAMTS17 cause the Weill-Marchesani-Like syndrome (613195).

Some individuals with isolated autosomal dominant ectopia lentis (129600) have mutations in FBN1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Patients should be monitored for the occurrence of glaucoma and treated appropriately.  Frequent refractive checks are recommended.  Lens extraction may be indicated when the visual axis is obstructed by a displaced lens or when lens-induced glaucoma occurs.

References
Article Title: 

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

Sulfite Oxidase Deficiency

Clinical Characteristics
Ocular Features: 

Dislocated lenses are the only significant ocular features of this disorder.  In one patient the lenses were said to be in normal position at 5.5 months of age but mild nasal subluxation of both lenses was present at 11 months.  In a series of 22 patients, 10 had dislocated lenses and one had spherophakia.  Lens dislocations occur early and maybe even congenitally in some cases as the diagnosis has been made in seven children before one year of age.  On the other hand it is not a consistent sign since the lenses were not dislocated in seven individuals who were examined specifically for this sign.

Systemic Features: 

Outside of the eye, the main features of this disorder are secondary to neurological damage.  Symptoms of irritability, poor feeding, ataxia, and language development may be seen in the first year or two of life.  Respiratory distress can be a feature in neonates.  Hypotonia, dystonia and choreoathetosis may be seen as well.  Seizures (sometimes with opisthotonus) often occur in the first days or weeks of life.  Later, generalized hypertonia and hyperactive reflexes are present.  Global developmental delays occur in nearly 80% of patients.  However, some patients also have a later onset with a milder course indicating that the full range of clinical expression remains to be determined.

Genetics

A number of mutations in the SUOX gene on chromosome 12 (12q13.13) cause this rare autosomal recessive disorder.  Less than 50 cases have been reported worldwide.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Not enough patients have been evaluated for long enough to determine the optimum treatment but low protein diets and restriction of sulfur containing amino acids have been tried with mixed results.

References
Article Title: 

Isolated sulfite oxidase deficiency

Claerhout H, Witters P, Regal L, Jansen K, Van Hoestenberghe MR, Breckpot J, Vermeersch P. Isolated sulfite oxidase deficiency. J Inherit Metab Dis. 2017 Oct 4. doi: 10.1007/s10545-017-0089-4. [Epub ahead of print].

PubMed ID: 
28980090

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

Marfan Syndrome

Clinical Characteristics
Ocular Features: 

Marfan syndrome typically has skeletal, ocular and cardiovascular abnormalities.  The globe is elongated creating an axial myopia and increasing the risk of rhegmatogenous retinal detachments.  Ectopia lentis is, of course, the classical ocular feature and is often if not always congenital with some progression.  The lenses most frequently dislocate superiorly and temporally and dilating the pupils often reveals broken and retracted lens zonules.  Phacodenesis and iridodenesis are commonly present even in the absence of evident lens dislocations. Cataracts develop several decades earlier than in unaffected individuals. The cornea is generally several diopters flatter than normal and there is an increased risk of open angle glaucoma.  There is considerable clinical variation among patients.

Systemic Features: 

Patients with the Marfan phenotype are usually tall with disproportionately long limbs (dolichostenomelia) and digits (arachnodactyly).   Patients frequently have scoliosis or kyphoscoliosis.  The joints are lax and hyperflexible although contractures can also occur.  The sternum is often deformed, either as a pectus excavatum, or sometimes pectus carinatum.  The hard palate is high and narrow resulting in crowding of the teeth and maloccclusion.  The defect in fibrillin is responsible for the weakness in connective tissue that leads to frequent cardiac valve malfunction, especially insufficiency of the aortic valve resulting from aortic dilatation, tear, and rupture.  The latter is often life-threatening as aortic dissection can be fatal.  Mitral valve prolapse is seen as well.  Cardiovascular disease is primarily responsible for the shortened life expectancy in this disease, more pronounced among males.

Genetics

As many as 25% of cases are caused by new mutations, but familial cases usually follow an autosomal dominant pattern of inheritance.  Autosomal recessive inheritance is claimed for several individuals in a consanguineous Turkish family.  Mutations in the fibrillin-1 gene (FBN1) on chromosome 15 (15q21.1) are considered responsible for the typical phenotype.  The exact nature of the fibrillin defect is unknown but the result is a generalized weakness in connective tissue.

The same gene is mutant in the autosomal dominant form of the Weill-Marchesani syndrome (608328) which is allelic to the Marfan syndrome.

Mutations in FBN1 have also been found in cases with isolated autosomal dominant ectopia lentis (129600).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Isometric exercises such as weight lifting should be avoided as should contact sports in which blunt trauma to the chest may occur because of the weakened aortic wall due to cystic changes that predispose the athlete to aortic dissection.  A dislocated and/or cataractous lens may need to be removed from the visual axis, and, of course, periodic retinal examinations for retinal holes and retinal detachments should be made.   Beta-adrenergic blockade reduces the risk of aortic dilatation and improves survival.

Pravastatin has been reported to reduce aortic dilation in marfan mice.

References
Article Title: 

Pravastatin reduces marfan aortic dilation

McLoughlin D, McGuinness J, Byrne J, Terzo E, Huuskonen V, McAllister H, Black A, Kearney S, Kay E, Hill AD, Dietz HC, Redmond JM. Pravastatin reduces marfan aortic dilation. Circulation. 2011 Sep 13;124(11 Suppl):S168-73.

PubMed ID: 
21911808

Cohen Syndrome

Clinical Characteristics
Ocular Features: 

Patients have early onset night blindness with defective dark adaptation and corresponding ERG abnormalities.  Visual fields are constricted peripherally and central visual acuity is variably reduced.  A pigmentary retinopathy is often associated with a bull’s eye maculopathy. The retinopathy is progressive as is high myopia.  The eyebrows and eyelashes are long and thick and the eyelids are highly arched and often ‘wave-shaped’.  Congenital ptosis, optic atrophy, and ectopia lentis have also been reported.

Systemic Features: 

Affected individuals have a characteristic facial dysmorphism in which ocular features play a role.  They have a low hairline, a prominent nasal root, and a short philtrum.  The tip of the nose appears bulbous. The head circumference is usually normal at birth but lags behind in growth so that older individuals appear microcephalic.  Delays in developmental milestones are noticeable in the first year of life.  Mild to moderate mental retardation is characteristic but does not progress.  Hypotonia is common early, and many individuals are short in stature.  Low white counts and frank neutropenia are often seen and some patients have frequent infections, especially of the oral mucosa and the respiratory tract.  A cheerful disposition is said to be characteristic.

Genetics

This is an autosomal recessive disorder caused by a mutation in the COH1 (VPS13B) gene on chromosome 8 (8q22-q23).  However, a variety of mutations have been reported including deletions and missense substitutions and, since these are scattered throughout the gene, complete sequencing is necessary before a negative result can be confirmed.

There is evidence of significant clinical heterogeneity between cohorts descended from different founder mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Corrective lenses for myopia can be helpful.  For patients with sufficient vision, low vision aids can be helpful.  Selected individuals may benefit from vocational and speech therapy.  Infections should be treated promptly.

References
Article Title: 

Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport

Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003 Jun;72(6):1359-69.

PubMed ID: 
12730828

Ectopia Lentis et Pupillae

Clinical Characteristics
Ocular Features: 

This disorder is generally considered to consist of simple displacement of the pupil and dislocation of the lens (usually in opposite directions).  However, other abnormalities are often present such as persistent pupillary membrane (87%), iridohyaloid adhesions, increased corneal thickness, enlarged corneal diameters, and axial myopia.  The iris may transilluminate (67%) and the pupils dilate poorly.  Iridodenesis is common (85%).  The lens is often malformed and in some cases frankly microspherophakic.  The lens displacement can progress and cataracts seem to form at a relatively young age.  Visual acuity is highly variable, ranging from 20/20 to light perception depending upon the density of cataracts which often develop at a relatively young age. Prominent iris processes into the anterior chamber angle have been reported and glaucoma, both acute and chronic, is sometimes seen.  Retinal detachment is a risk.

Studies in families with ectopia lentis et papillae have revealed that as many as 50% of individuals with dislocated lenses do not have ectopic pupils.

Systemic Features: 

None reported

Genetics

This disorder is usually inherited in an autosomal recessive pattern.  Multiple affected sibs have been born to consanquineous matings.  However, other families in which detailed ophthalmological examinations were done have suggested dominant inheritance based upon the presence of more subtle ocular signs in relatives.  This is likely a more clinically heterogeneous disorder than has been appreciated.

In five Norwegian families a homozygous 20 bp deletion has been found in the gene ADAMTSL4 on chromosome 1 (c.767_786del20) (1q21.3) producing a frameshift and the introduction of a stop codon leading to truncation of the protein product.  Mutations in the same gene have also been found in the autosomal recessive form of isolated ectopia lentis (225100).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma, retinal detachments, and cataracts may require surgery.

References
Article Title: 

Aniridia 1

Clinical Characteristics
Ocular Features: 

Aniridia is the name of both a disorder and a group of disorders.  This because aniridia is both an isolated ocular disease and a feature of several malformation syndromes.  Absence of the iris was first reported in the early 19th century.  The hallmark of the disease is bilateral iris hypoplasia which may consist of minimal loss of iris tissue with simple radial clefts, colobomas, pseudopolycoria, and correctopia, to nearly complete absence.  Goniosocopy may be required to visualize tags of iris root when no iris is visible externally.  Glaucoma is frequently present (~67%) and often difficult to treat.  It is responsible for blindness in a significant number of patients.  About 15% of patients are diagnosed with glaucoma in each decade of life but this rises to 35% among individuals 40-49 years of age.  Hypoplasia and dysplasia of the fovea are likely responsible for the poor vision in many individuals.  Nystagmus is frequently present.  The ciliary body may also be hypoplastic. 

Visual acuity varies widely.  In many families it is less than 20/60 in all members and the majority have less than 20/200.  Photophobia can be incapacitating.  Posterior segment OCT changes suggest that outer retinal damage suggestive of a phototoxic retinopathy may also be a factor in the reduced acuity.  Cataracts (congenital in >75%), ectopia lentis (bilateral in >26%), optic nerve hypoplasia, variable degrees of corneal clouding with or without a vascularized pannus, and dysgenesis of the anterior chamber angle are frequently present. 

Increased corneal thickness (>600 microns) has been found in some series and should be considered when IOP measurements are made.  In early stages of the disease, focal opacities are present in the basal epithelium, associated with sub-basal nerves.  Dendritic cells can infiltrate the central epithelium and normal limbal palisade architecture is absent. 

Meibomian gland anomalies also contribute to the corneal disease.  The glands may be decreased in number and smaller in size contributing to deficiencies of the tear film and unstable surface wetting.

Systemic Features: 

In addition to 'pure' aniridia in which no systemic features are found, at least six disorders have been reported in which systemic anomalies do occur.  Three of these have associated renal anomalies, including Wilms tumor with other genitourinary anomalies and mental retardation, sometimes called WAGR (194072) syndrome, another (612469) with similar features plus obesity sometime called WAGRO (612469) syndrome reported in isolated patients, and yet another with partial aniridia (206750) and unilateral renal agenesis and psychomotor retardation reported in a single family.  Aniridia with dysplastic or absent patella (106220) has been reported in a single three generation family.  Cerebellar ataxia and mental retardation with motor deficits (Gillespie syndrome; 206700) have been found in other families with anirdia.  Another 3 generation family has been reported in which aniridia, microcornea and spontaneously resorbed cataracts occured (106230).

About one-third of patients with aniridia also have Wilms tumor and many have some cognitive deficits.

Genetics

The majority of cases have a mutation in the paired box gene (PAX6) complex, or at least include this locus when chromosomal aberrations such as deletions are present in the region (11p13).  This complex (containing at least 9 genes) is multifunctional and important to the tissue regulation of numerous developmental genes.   PAX6 mutations, encoding a highly conserved transcription regulator, generally cause hypoplasia of the iris and foveal hypoplasia but are also important in CNS development.  It has been suggested that PAX6 gene dysfunction may be the only gene defect associated with aniridia.  More than 300 specific mutations, most causing premature truncation of the polypeptide, have been identified.  

AN1 results from mutations in the PAX6 gene.  Two additional forms of aniridia have been reported in which functional alterations in genes that modulate the expression of PAX6 are responsible: AN2 (617141) with mutations in ELP4 and AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Associated abnormalities may be due to a second mutation in the WT1 gene in WAGR (194072) syndrome, a deletion syndrome involving both WT1 and PAX6 genes at 11p13.  The WAGRO syndrome (612469) is caused by a contiguous deletion in chromosome 11 (11p12-p13) involving three genes: WT1, PAX6, and BDNF.  All types are likely inherited as autosomal dominant disorders although nearly one-third of cases occur sporadically.

Mutations in PAX6 associated with aniridia can cause other anterior chamber malformations such as Peters anomaly (604229).

Gillespie syndrome (206700 ) is an allelic disorder with neurological abnormalities including cerebellar ataxia and mental retardation.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at the associated threats to vision such as glaucoma, corneal opacities, and cataracts.  Glaucoma is the most serious threat and is the most difficult to treat. The best results have been reported with glaucoma drainage devices.  All patients should have eye examinations at appropriate intervals throughout life, focused on glaucoma screening.  It is well to keep in mind that foveal maldevelopment often precludes significant improvement in acuity and heroic measures must be carefully evaluated.  Specifically, corneal transplants and glaucoma control measures frequently fail.

Low vision aids are often helpful.  Tinted lenses can minimize photophobia.  Occupational and vocational training should be considered for older individuals.  Surface wetting of the cornea should be periodically evaluated and appropriate topical lubrication used as needed. 

Young children with aniridia should have periodic examinations with renal imaging as recommended by a urologist.

In mice, postnatal topical ocular application of ataluren-based eyedrop formulations can reverse malformations caused by PAX6 mutations.

References
Article Title: 

Familial aniridia with preserved

Elsas FJ, Maumenee IH, Kenyon KR, Yoder F. Familial aniridia with preserved ocular function. Am J Ophthalmol. 1977 May;83(5):718-24.

PubMed ID: 
868970

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