spherophakia

Spherophakia, Isolated

Clinical Characteristics
Ocular Features: 

Small, spherical lenses are characteristic of this entity.  Lenticular myopia is usually present but no increased axial length.  Glaucoma has been reported in several individuals and speculated to be due to pupillary block.  No buphthalmos or angle anomalies were present.  The lens may sublux into the vitreous cavity.

Systemic Features: 

No skeletal, cardiovascular or metabolic disease is present.

Genetics

Isolated spherophakia is an autosomal recessive disorder resulting from homozygous mutations in LTBP2 (13q24.1-q32.12).  Parental consanguinity was present in reported families. 

Spherophakia is a clinically and genetically heterogeneous disorder and usually found in association with systemic findings.  It is commonly seen in the Weill-Marchesani syndrome 1 (277600), in Weill Marchesani syndrome 2 (608328), in the Weill-Marchesani-Like syndrome (613195), in a condition known as ‘megalocornea, ectopia lentis, and spherophakia’ (?), another one called 'spherophakia and hernia' (157150), sulfite oxidase deficiency (272300), primary congenital glaucoma D (613086) and in a syndrome known as ‘spherophakia and metaphyseal dysplasia’ (157151).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The lenses may require extraction for secondary glaucoma and/or visual rehabilitation.

References
Article Title: 

Spherophakia with Inguinal Hernia

Clinical Characteristics
Ocular Features: 

Individuals with this condition have small spherical lenses that are usually displaced superiorly.  Myopia, both lenticular and axial, is often present and retinal detachments can occur.  Glaucoma was reported in one patient but this followed surgery for a retinal detachment.  Iridodenesis and nystagmus may be present.  The single report mentions strong zonules that created difficulties during intracapsular lens removal.  None of the spherical lenses were reported to migrate into the anterior chamber nor was lens-induced glaucoma present.

Systemic Features: 

Inguinal hernias are the only systemic manifestation of this disorder.  Four of 11 affected individuals in the family reported required surgery.  Physical examination and skeletal measurements were used to rule out the Marfan and Weill Marchesani syndromes.

Genetics

A single family with 11 affected individuals in 4 generations has been reported.  The four generation pedigree suggested autosomal dominant inheritance but nothing is known regarding the mutation or locus.

Spherophakia is a clinically and genetically heterogeneous disorder and usually found in association with systemic findings.  It is commonly seen in the Weill-Marchesani syndrome 1 (277600), in Weill Marchesani syndrome 2 (608328), in the Weill-Marchesani-Like syndrome (613195), in a condition known as ‘megalocornea, ectopia lentis, and spherophakia’ (?), and in a syndrome known as ‘spherophakia and metaphyseal dysplasia’ (157151).  Autosomal recessive isolated spherophakia (251750) has been found in several families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens extraction may be necessary for vision rehabilitation if it is partially displaced.

References
Article Title: 

Dominant microspherophakia

Johnson VP, Grayson M, Christian JC. Dominant microspherophakia. Arch Ophthalmol. 1971 May;85(5):534-7.

PubMed ID: 
5087595

Weill-Marchesani-Like Syndrome

Clinical Characteristics
Ocular Features: 

Several families have been reported in which the ocular features were similar to Weill-Marchesani syndromes WMS1 and WMS2 but lacked most of the skeletal features.  The ocular abnormalities included: myopia, ectopia lentis, spherophakia, and glaucoma.  Shallow anterior chambers and peripheral iris synechiae are often present. Axial length ranges from 21 to 23 mm.

Systemic Features: 

Short stature is a feature of this syndrome but brachydactyly and decreased joint mobility are not present.  Height is usually below the 25th percentile and often at the third or 5th percentile.

 

Genetics

This is an autosomal recessive disorder resulting from mutations in ADAMTS17 (15q26.3).  See also Weill-Marchesani Syndrome 1 (277600), and Weill-Marchesani Syndrome 2 (608328) for other conditions with clinical similarities but caused by different mutations.

Homozygous mutations in LTBP2 (14q24.3) have also been found in this disorder and in WMS1 (277600).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma requires the usual treatments.  The lens may need to be removed for visual rehabilitation and/or lens induced glaucoma.

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

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

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

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

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
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