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

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.

Figure 1

Pedigrees of the families. The pedigrees for Family 1 (A), Family 2 (B), and Family 3 (C) are shown. Pt: patient; by hx: affected by history but not available for the study.

Figure 2

Family 1: cousin of the proband. A: At one year of age, large corneas are evident (14 mm horizontal diameters) but without corneal haze/scarring or Descemet breaks. B: After primary Ahmed valve implantation in both eyes, the crystalline lens dislocated into the posterior chamber and retinal tears developed bilaterally. The right eye is shown.

Figure 3

Family 2: two affected brothers. A: At six years of age, the proband developed right acute pupillary block glaucoma. Complete crystalline lens dislocation into the anterior chamber of the right eye can be seen. In the left eye, inferotemporal crystalline lens subluxation can be appreciated. Both corneas are symmetrically enlarged (14 mm horizontal diameter). B, C: The proband's brother had lens-related pupillary block glaucoma in the left eye for which he had bilateral lensectomy and anterior vitrectomy at four years of age. At ten years of age, glaucomatous cupping in the left eye (C) as opposed to the right eye (B) can be appreciated. Megalocornea (not shown) was symmetric (14 mm horizontal corneal diameters without scars or breaks).

Figure 4

Family 3: two affected brothers, affected paternal aunt. A: At one and one-half year of age, the proband developed left acute pupillary block glaucoma. Complete crystalline lens dislocation into the anterior chamber of the left eye and a large corneal diameter (14 mm horizontally) can be seen. B: The proband's six-month-old brother was tentatively scheduled for primary congenital glaucoma surgery by his physician. Megalocornea is evident (14 mm horizontal diameter without breaks or scarring). The child also had bilateral spherophakia (not shown). C: The paternal aunt of the proband had been diagnosed with glaucoma at ten years of age but never had surgery. At 20 years old, bilateral symmetric megalocornea (14 mm horizontal diameter without breaks or scarring) is evident. Both crystalline lenses were posteriorly dislocated (not shown). She had high intraocular pressure, angle synechiae, and glaucomatous optic nerve damage in her right eye (not shown).

Figure 5

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