ectopia lentis

Spherophakia and Metaphyseal Dysplasia

Clinical Characteristics
Ocular Features: 

The corneas and anterior chambers were normal in the son but the lenses were small and spherical and had colobomatous defects.  The father developed a retinal detachment in one eye and elevated intraocular pressure. The morphology of the lenses in the father is unknown.

Systemic Features: 

The diaphyses of the long bones are thickened with relative sparing of the small bones in the extremities.  The epiphyses become more irregular later in life.  The vertebrae are deformed with flattening.  The result is brachymelia and moderately severe dwarfism.  Pigeon breast deformity can be present.

Genetics

A father and son have been reported with this combination of findings suggesting autosomal dominant inheritance.  No locus or mutation has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Unknown.

References
Article Title: 

Megalocornea, Ectopia Lentis, and Spherophakia

Clinical Characteristics
Ocular Features: 

Patients have megalocornea and mobile lenses.  Corneal diameters are at least 13 mm in diameter.  Some lenses are spherophakic (refractive errors may be in the +11-12 diopter range) and sometimes displace into the anterior chamber or cause pupillary block glaucoma.  The clinical picture often resembles congenital glaucoma in young children but the elevated pressure is usually secondary to hypermobility of the lens and/or its spherical shape.  Haab striae are not present but cloudy corneas have been reported in a few patients.

Many patients develop phthisis or have severe reductions in vision.

Systemic Features: 

Some but not all patients have several physical features of the Marfan syndrome (154700) such as high arched palate, tall stature, and narrow face but those tested do not have mutations in the FBN1 gene.

Genetics

This is an autosomal recessive disorder.  Parental consanguinity is common.  Homozygous mutations in the LTBP2 gene (14q24.3) are found in affected individuals.

LTBP2 competes with LTBP1 (ADAMTSL2) for binding to the gene product of FBN1 in which mutations are associated with the Marfan syndrome (154700) and may account for the variable skeletal signs sometimes found in patients with this megalocornea syndrome.  Both gene products are important to the structure of the extracellular matrix proteins of the ciliary processes, lens capsule, and lens epithelial layer.  The different modes of inheritance and the unique mutations, of course, argue for separateness of the two disorders.

Mutations in LTBP2 have also been found in a family with microspherophakia and ectopia lentis but corneal diameters were described as normal suggesting clinical heterogeneity.

This is a unique disorder which previously has been classified as Glaucoma, Congenital Primary D (613086).  The usual occurrence of ectopia lentis,  the sometimes spherophakic nature of the lenses, the congenital presence of megalocornea without corneal edema in the absence of elevated intraocular pressure, and the lack of breaks in the Descemet membrane strongly suggest that this is not a primary congenital glaucoma.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Urgent lensectomy is necessary for lenses that migrate into the anterior chamber.  Patients have to be monitored as lens dislocations can occur at any age.

References
Article Title: 

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

Microphthalmia, AR

Clinical Characteristics
Ocular Features: 

The most consistent feature associated with mutations in the VSX2 gene is, of course, microphthalmia/anophthalmia.  Other anomalies include dysplasia of the retina, cataracts and/or dislocated lenses, and iris anomalies ranging from hypoplasia to colobomas and absence of the pupils. Colobomas may also involve the posterior uveal tract as well as the optic nerve. The majority of patients are blind.   

Systemic Features: 

No systemic features are associated.

Genetics

This is an autosomal recessive disorder resulting from mutations in the VSX2 (formerly CHX10) gene located at 14q24.3.  The gene is expressed in progenitor cells of the developing neuroretina and in inner nuclear cells of the adult retina.   Most parents are consanguineous.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None other than rehabilitation.

References
Article Title: 

Ectopia lentis, Isolated AD

Clinical Characteristics
Ocular Features: 

Ectopia lentis as an isolated finding has been known for many years although early reports did not rule out features of the Marfan syndrome (154700).  In more recent reports clinical evidence of the Marfan syndrome has been absent in a number of families and there seems little doubt that mutations in the FBN1 can be responsible for isolated ectopia lentis.  Iridodenesis may be noted at birth but the dislocated lens may not be diagnosed until late adulthood in mild cases.  Vision can be normal but nystagmus and strabismus have been noted in other patients. The lenses may be dislocated superiorly and may contain opacities.  Areas of missing zonules have been observed in some patients while others have posterior synechiae.

Systemic Features: 

Related family members have been observed to have polydactyly and craniosynostosis but without dislocated lenses.  It is important to rule out skeletal and cardiac manifestations of the Marfan syndrome because of the prognostic implications.

Genetics

This is an autosomal dominant disorder attributed to mutations in FBN1 (15q21), the same gene that is mutant in the Marfan syndrome (154700).  The dislocated lenses may represent variable expressivity or simply allelism.  The latter seems more likely in view of the fact that numerous thoroughly studied individuals have not had the skeletal or cardiovascular signs of the Marfan syndrome (154700).  However, the revised Ghent nosology now suggests that all patients with the FBN1 mutation and ectopia lentis be designated to have the Marfan syndrome when aortic dilation/dissection is present as well.  This should be extended to include all patients with FBN1 mutations and ectopia lentis plus at least one other phenotypic feature of the Marfan syndrome.

The same gene is mutant in the autosomal dominant form of the Weill-Marchesani 2 syndrome (608328) which is allelic to the Marfan syndrome. 

There is also an autosomal recessive condition of isolated ectopia lentis (225100) which results from homozygous nonsense mutations in ADAMTSL4 (225100). A patient with craniosynostosis and ectopia lentis has been reported in which there was a homozygous 20 bp deletion in the same gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens removal may be indicated when vision cannot otherwise be corrected.

References
Article Title: 

The Revised Ghent Nosology; Reclassifying Isolated Ectopia Lentis

Chandra A, Patel D, Aragon-Martin JA, Pinard A, Collod-Beroud G, Comeglio P, Boileau C, Faivre L, Charteris D, Child AH, Arno G. The Revised Ghent Nosology; Reclassifying Isolated Ectopia Lentis. Clin Genet. 2014 Feb 7. [Epub ahead of print].

PubMed ID: 
24635535

Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion

Faivre L, Collod-Beroud G, Callewaert B, Child A, Loeys BL, Binquet C, Gautier E, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Grasso M, Beroud C, Bonithon-Kopp C, Claustres M, Stheneur C, Bouchot O, Wolf JE, Robinson PN, Ades L, De Backer J, Coucke P, Francke U, De Paepe A, Boileau C, Jondeau G. Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Am J Med Genet A. 2009 May;149A(5):854-60.

PubMed ID: 
19353630

Ectopia lentis phenotypes and the FBN1 gene

Ades LC, Holman KJ, Brett MS, Edwards MJ, Bennetts B. Ectopia lentis phenotypes and the FBN1 gene. Am J Med Genet A. 2004 Apr 30;126A(3):284-9. Review.

PubMed ID: 
15054843

Ectopia lentis, Isolated AR

Clinical Characteristics
Ocular Features: 

Most dislocated lenses of non-traumatic origin are associated with syndromes, particularly those with defective connective tissue.  However, a few families with dislocated lenses have been reported in which no evidence of defective collagen is present.  The lens is most commonly displaced temporally, often creating myopic astigmatism.  The mean age of discovery of the dislocated lenses is about 2 years of age.  The eye is otherwise normally formed, intraocular pressure is normal, and the axial length is in the normal range.  The cornea, pupil, and iris are normal unlike that found in many patients with ectopia lentis et pupillae (225200).

Systemic Features: 

None by definition.

Genetics

Homozygous nonsense mutations in ADAMTSL4 (1q21.3) are responsible for this autosomal recessive condition.  The same gene is mutated in ectopia lentis et pupillae (225200).  A patient has been reported with craniosynostosis and ectopia lentis in which there was a homozygous 20 bp deletion in this gene.

An autosomal dominant condition of isolated dislocated lenses (129600) secondary to a mutation in FBN1 has also been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lens removal may be indicated when vision cannot otherwise be corrected.

References
Article Title: 

Glaucoma, Congenital Primary D

Clinical Characteristics
Ocular Features: 

Evidence of glaucoma can appear in early childhood but may appear much later.  However, typical signs such as enlarged corneas or frank buphthalmos, cloudiness of the corneas, tearing and photophobia are present only when the pressure is elevated due to pupillary block or when the lens migrates into the anterior chamber.  Most patients have additional signs such as ectopia lentis and spherophakia.

Systemic Features: 

Some patients have osteopenia, a high arched palate, and a marfanoid habitus.

Genetics

This form of congenital glaucoma has been described primarily in Middle Eastern and Asian as well as Roma/Gypsy families and is inherited in an autosomal recessive pattern.  The mutations occur in the LTBP2 gene (14q24) which is in close proximity to GLC3C, another putative gene with mutations causing congenital glaucoma. 

Mutations in other genes are also associated with primary congenital glaucoma such as in CYP1B1 causing type A (231300) and in GLC3B causing type B (600975).

THIS IS NOT A PRIMARY GLAUCOMA DISORDER.  Microspherophakia and ectopia lentis are not features of primary congenital glaucoma.  Elevated pressures in these patients are found only when there is a pupillary block or when the lens dislocates into the anterior chamber.  The enlarged cornea is clear and has no breaks in the Descemet membrane.  THIS CONDITION IS THEREFORE RECLASSIFIED AS "MEGALOCORNEA, ECTOPIA LENTIS, AND SPHEROPHAKIA".     

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The usual surgical and pharmacological treatments for glaucoma apply but vision preservation is a challenge.  The spherophakic or dislocated lenses may need to be removed.

References
Article Title: 

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

Azmanov DN, Dimitrova S, Florez L, Cherninkova S, Draganov D, Morar B, Saat R, Juan M, Arostegui JI, Ganguly S, Soodyall H, Chakrabarti S, Padh H, L??pez-Nevot MA, Chernodrinska V, Anguelov B, Majumder P, Angelova L, Kaneva R, Mackey DA, Tournev I, Kalaydjieva L. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Eur J Hum Genet. 2011 Mar;19(3):326-33.

PubMed ID: 
21081970

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

Blepharoptosis, Myopia, Ectopia Lentis

Clinical Characteristics
Ocular Features: 

A mother and 2 daughters with ectopia lentis, myopia, and blepharoptosis have been reported.  The axial length of the globes was increased in the mother and one of the daughters while the myopia in the other daughter with ectopia lentis was presumably lens-induced as the equator bisected the visual axis (axial length approximately 25mm).  The upper lid creases were considered to be abnormally high but levator function was good, consistent with levator aponeurosis disinsertion.  Extraocular movements were normal.  

Systemic Features: 

No systemic abnormalities were present.  More specifically, there was no evidence of Ehlers-Danlos (225400) or Marfan syndrome (154700).

Genetics

The presence of similar findings in a mother and 2 daughters suggests autosomal dominant inheritance but no locus has been identified. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Displaced lenses may need to be removed. 

References
Article Title: 

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: 

Homocystinuria, MTHFR Deficiency

Clinical Characteristics
Ocular Features: 

The ocular signs in MTHFR deficiency are likely similar to those found in beta-synthase deficiency (236200) but no comparative study has been reported.  Ectopia lentis is common and the high mobility of the lens carries a significant risk of pupillary block glaucoma and migration into the anterior chamber.

Systemic Features: 

There is a wide range in clinical disease in MTHFR deficiency but the neurological signs and the progressive of disease seem to be more aggressive than in beta-synthase deficiency (236200) . Neonates may have seizures and failure to thrive but other affected patients may live to adulthood without symptoms.  Early death from neurological complications is more common and the mental retardation is apparently more severe.  There is a serious risk for thromboembolic events which may be life-threatening.  Hyperhomocyteinemia and low plasma methionine are present as is increased homocystine in urine.

Genetics

Mutations in MTHFR (1p36.3) are responsible for this form of homocystinuria.  Another form, beta-synthase deficiency (236200), is caused by a mutation in the CBS  gene (21q22.3).  This is an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Administration of betaine has been reported to reduce the neurological disease but it must be started early before brain damage occurs.  It does not correct hyperhomocysteinemia nor does it correct CNS MTHFR deficiency.  It has also been reported that betaine in combination with folic acid and cobalamin can prevent symptoms.

References
Article Title: 

Mutation Update and Review of Severe MTHFR

Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Gueant JL, Landolt MA,
Kozich V, Fowler B, Baumgartner MR. Mutation Update and Review of Severe MTHFR
Deficiency. Hum Mutat. 2016 Feb 13.

PubMed ID: 
2687264

Homocystinuria, Beta-Synthase Deficiency

Clinical Characteristics
Ocular Features: 

More than half of patients have ectopia lentis by the age of 10 years and the dislocation is progressive.  Ectopia lentis occurs in 90% of patients and 94% of these are noted by the age of 20 years.  The lenses seem to be more mobile than those in Marfan syndrome with a significantly increased risk of lens migration into the anterior chamber (19%) or complete dislocation into the posterior chamber (14%).   Lens surgery is required in homocystinuria about 7 years earlier than in Marfan syndrome with 62% of procedures necessitated by pupillary block glaucoma or displacement into the anterior chamber.  Whereas nearly 70% of lenses dislocate superiorly in Marfan syndrome, only 9% of homocystinuria lenses do so.

Other ocular features include optic atrophy (23%), iris atrophy (21%), anterior staphylomas (13%) and corneal opacities (9%).  Retinal detachments occur in 5-10%.  The majority of patients both pre- and postoperatively have vision of 20/50 or worse.

Systemic Features: 

Arachnodactyly and tall stature in some patients may suggest Marfan syndrome.  Mental deficiencies or behavioral problems are present in a majority of patients (50-60%) with mental functioning higher in the subset of patients who are B6-responsive.  Thromboembolic events (strokes, myocardial infarctions) are a significant risk at any age, especially so after age 20 years, and this is responsible for considerable morbidity and mortality.  The risk is especially high following general anesthesia unless hydration is strictly controlled.  Osteoporosis and seizures are common.  Hypopigmentation is often present but darkening of hair has been noted following pyridoxine treatment.  Serum homocysteine is generally elevated and the urine contains elevated levels of methionine.

Genetics

Classic homocystinuria is an autosomal recessive disorder that results from mutations in the CBS (21q22.3) gene encoding cystathionine beta-synthase.  It is the second most common error of amino acid metabolism.  Numerous mutations have been identified but among the most common ones are I278T which causes a pyridoxine-responsive disorder, and the G3307S mutation which leads to a variant that is not responsive to pyridoxine treatment.

For another more aggressive form of homocystinuria caused by mutations in MTHFR (1p36.3) see Homosystinuria, MTHER Deficiency (236250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Patients with this disorder form two groups: those who respond to pyridoxine (vitamin B6) and those who do not.  Those who do not respond to B6 tend to have more severe disease.  Methionine restriction administered neonatally has been reported to prevent mental retardation and reduce the rate of lens dislocation.  Neonates should be treated with B6 therapy, protein and methionine restriction, betaine, and folate with vitamin B12 supplementation.  Surgical removal of lenses may be required but the rate of vitreous loss is high.

References
Article Title: 

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