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Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations.

Khan AO, Aldahmesh MA, Alkuraya FS - Mol. Vis. (2011)

Bottom Line: One member from each family developed spontaneous complete crystalline lens dislocation into the anterior chamber with associated acute glaucoma during early childhood.LTBP2 sequencing in the third family revealed a third novel homozygous mutation (p.C1438Y [c.4313G>A]).Complete dislocation of the crystalline lens into the anterior chamber during early childhood can occur in young children with this unique phenotype.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. arif.khan@mssm.edu

ABSTRACT

Purpose: To clinically and genetically characterize a distinct phenotype of congenital megalocornea (horizontal corneal diameter ≥13 mm) with secondary glaucoma from spherophakia and/or ectopia lentis during childhood in affected Saudi families.

Methods: Clinical exam, homozygosity scan, and candidate gene analysis.

Results: From 2005 to 2010, eight affected individuals from three consanguineous families were identified. In addition to congenital megalocornea, affected children presented with secondary glaucoma from spherophakia and/or ectopia lentis. One member from each family developed spontaneous complete crystalline lens dislocation into the anterior chamber with associated acute glaucoma during early childhood. Older individuals had phenotypes that would have suggested prior uncontrolled primary congenital/infantile glaucoma had past ophthalmic and/or family histories not been available. Homozygosity mapping performed for the first two families suggested the candidate gene latent transforming growth factor-beta-binding protein 2 (LTBP2), which when sequenced revealed a novel homozgyous mutation that segregated with the phenotype in each family (p.S338PfsX4 [c.1012delT], p.Q1619X[(c.4855C>T]). LTBP2 sequencing in the third family revealed a third novel homozygous mutation (p.C1438Y [c.4313G>A]).

Conclusions: Congenital megalocornea with childhood secondary glaucoma from spherophakia and/or ectopia lentis is a distinct condition caused by recessive LTBP2 mutations that needs to be distinguished from buphthalmos secondary to primary congenital/infantile glaucoma because typical initial surgical treatment is lens removal in the former and angle surgery in the latter. Complete dislocation of the crystalline lens into the anterior chamber during early childhood can occur in young children with this unique phenotype.

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Genetic analysis. A, B, C: Sequencing of LTPB2 revealed a novel homozygous mutation in each family that segregated with the phenotypes.
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f5: Genetic analysis. A, B, C: Sequencing of LTPB2 revealed a novel homozygous mutation in each family that segregated with the phenotypes.

Mentions: LTBP2 was amplified using primers (Table 2) that cover the entire coding region followed by bidirectional sequencing in all eight examined affected individuals from the three families. Three novel homozygous LTBP2 mutations were identified in the eight patients, one in each family: c.1012delT (p.S338PfsX4) in exon 4 for Family 1, c.4855C>T (p.Q1619X) in exon 33 for Family 2, and c.4313G>A (p.C1438Y) in exon 29 for Family 3 (Figure 5). For Family 1 and Family 2, the unaffected parents were confirmed to be heterozygous for the respective mutations. For Family 3, the affected father and paternal aunt were homozygous for the p.C1438Y mutation while the unaffected mother was a carrier. This missense mutation mutation in LTBP2 results in loss at position 1438 of cysteine, a nonpolar hydrophobic amino acid that is important in disulfide bonds and protein folding and is conserved among species (Table 3). It was not present in 100 ethnically-matched normal controls.


Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations.

Khan AO, Aldahmesh MA, Alkuraya FS - Mol. Vis. (2011)

Genetic analysis. A, B, C: Sequencing of LTPB2 revealed a novel homozygous mutation in each family that segregated with the phenotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198484&req=5

f5: Genetic analysis. A, B, C: Sequencing of LTPB2 revealed a novel homozygous mutation in each family that segregated with the phenotypes.
Mentions: LTBP2 was amplified using primers (Table 2) that cover the entire coding region followed by bidirectional sequencing in all eight examined affected individuals from the three families. Three novel homozygous LTBP2 mutations were identified in the eight patients, one in each family: c.1012delT (p.S338PfsX4) in exon 4 for Family 1, c.4855C>T (p.Q1619X) in exon 33 for Family 2, and c.4313G>A (p.C1438Y) in exon 29 for Family 3 (Figure 5). For Family 1 and Family 2, the unaffected parents were confirmed to be heterozygous for the respective mutations. For Family 3, the affected father and paternal aunt were homozygous for the p.C1438Y mutation while the unaffected mother was a carrier. This missense mutation mutation in LTBP2 results in loss at position 1438 of cysteine, a nonpolar hydrophobic amino acid that is important in disulfide bonds and protein folding and is conserved among species (Table 3). It was not present in 100 ethnically-matched normal controls.

Bottom Line: One member from each family developed spontaneous complete crystalline lens dislocation into the anterior chamber with associated acute glaucoma during early childhood.LTBP2 sequencing in the third family revealed a third novel homozygous mutation (p.C1438Y [c.4313G>A]).Complete dislocation of the crystalline lens into the anterior chamber during early childhood can occur in young children with this unique phenotype.

View Article: PubMed Central - PubMed

Affiliation: Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. arif.khan@mssm.edu

ABSTRACT

Purpose: To clinically and genetically characterize a distinct phenotype of congenital megalocornea (horizontal corneal diameter ≥13 mm) with secondary glaucoma from spherophakia and/or ectopia lentis during childhood in affected Saudi families.

Methods: Clinical exam, homozygosity scan, and candidate gene analysis.

Results: From 2005 to 2010, eight affected individuals from three consanguineous families were identified. In addition to congenital megalocornea, affected children presented with secondary glaucoma from spherophakia and/or ectopia lentis. One member from each family developed spontaneous complete crystalline lens dislocation into the anterior chamber with associated acute glaucoma during early childhood. Older individuals had phenotypes that would have suggested prior uncontrolled primary congenital/infantile glaucoma had past ophthalmic and/or family histories not been available. Homozygosity mapping performed for the first two families suggested the candidate gene latent transforming growth factor-beta-binding protein 2 (LTBP2), which when sequenced revealed a novel homozgyous mutation that segregated with the phenotype in each family (p.S338PfsX4 [c.1012delT], p.Q1619X[(c.4855C>T]). LTBP2 sequencing in the third family revealed a third novel homozygous mutation (p.C1438Y [c.4313G>A]).

Conclusions: Congenital megalocornea with childhood secondary glaucoma from spherophakia and/or ectopia lentis is a distinct condition caused by recessive LTBP2 mutations that needs to be distinguished from buphthalmos secondary to primary congenital/infantile glaucoma because typical initial surgical treatment is lens removal in the former and angle surgery in the latter. Complete dislocation of the crystalline lens into the anterior chamber during early childhood can occur in young children with this unique phenotype.

Show MeSH
Related in: MedlinePlus