What Is Causing Progressive Vision Problems in a 32-Year-Old Woman?

What's behind the progressive lens dislocation that has affected this 32-year-old woman for the past 16 years?

The patient, who was African American, presented with significant vision loss in her left eye, reported Rachel W. Kuchtey, MD, PhD, of Vanderbilt Eye Institute in Nashville, Tennessee, and colleagues in JAMA Ophthalmology.

The patient's long history of vision problems began when she was diagnosed with glaucoma and elevated intraocular pressure (IOP) at age 13. Her medical history included a bilateral trabeculectomy at the time of her original diagnosis.

About 4 years later, at the age of 17, the patient developed significantly elevated IOP in both eyes, along with severe cupping and open iridocorneal angle in both eyes. Examination showed no signs of Haab striae, buphthalmos, or high iris insertion that would suggest that the patient had primary congenital glaucoma (PCG). Ultimately, both the patient's eyes required glaucoma tube shunt implantation.

When the patient presented again with vision problems at age 32, clinicians suspected she had a connective tissue disorder, such as Marfan syndrome, based on a constellation of clinical factors including being considerably taller than her relatives (180.4 cm), her long fingers, and the lens dislocation. Clinicians performed a thorough cardiac and genetic evaluation.

Although there were no abnormalities revealed by a series of echocardiograms, the patient had hypermobility of the shoulders, digits, and knees. Kuchtey and team ordered a comprehensive connective tissue genetic testing panel.

The patient's complete family history did not include any similar findings, they noted. Eye exams of the patient's two children -- ages 4 years and 10 years -- were normal. However, cascade testing determined that one child carried each variant, which Kuchtey and team noted was "consistent with transheterozygous mutations responsible for the patient's predominantly ocular and mild systemic phenotypic manifestations."

Discussion

In their report of juvenile-onset glaucoma and other ocular sequelae as a result of compound heterozygous mutations in LTBP2, Kuchtey and co-authors noted that the gene encoding LTBP2 has been implicated in the development of PCG and other developmental glaucomas.

That LTBP2 mutations leading to PCG have been observed in consanguineous families suggests an autosomal recessive pattern of inheritance. LTBP2 mutations have been associated with various ocular phenotypes, including goniodysgenesis that has caused elevated IOP and glaucomatous optic nerve damage, unstable or dislocated lens, and high myopia (i.e., a measurement of -6.00 diopters or more).

Kuchtey and co-authors explained that LTBP2 is expressed in optic tissues that regulate IOP, such as the trabecular meshwork and ciliary body. Study of a domestic cat population found that homozygous LTBP2 mutations resulted in increased IOP, globe enlargement, and elongated ciliary processes, similar to observations in human PCG, the authors noted. "Subtle lens dislocation with zonular instability was common, though complete ectopia lentis occurred in less than 10% of the animals," they wrote.

Likewise, homozygous LTBP2 mutations in humans have also been associated with megalocornea, ectopia lentis, and myopia. Despite reports of glaucoma and ectopia lentis in people with known LTBP2 mutations, glaucoma is often thought to be due to ectopia lentis, Kuchtey and team said.

"Biallelic mutations in the LTBP2 gene have been associated with microspherophakia and early ectopia lentis in patients with a Marfan-like phenotype (tall stature, high-arched palate, long arm span) and later secondary glaucoma development," they wrote.

This patient's presentation with severe bilateral optic nerve cupping and subtle dislocated lens occurred more than 10 years after gradually progressing lens dislocation was first detected in her left eye. More recently, the team observed the onset of subtle lens dislocation in her right eye.

Despite another report of a young patient with compound heterozygous LTBP2 mutations who developed juvenile open angle glaucoma, the authors said that their long-term observation of the current patient -- who had no systemic symptoms aside from her eye symptoms -- suggests that glaucoma developed independently of dislocated lens.

"Our report highlights the pluripotent functions of LTBP2 in the eye as well as systemically," Kuchtey and colleagues concluded.

Regular observation of patients found to carry these mutations is crucial, they said, both to allow timely detection of ocular and systemic effects, and to provide affected families with screening and genetic counseling.

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