Inherited ectopia lentis or ectopia lentis et pupillae can be either isolated or syndromic and have autosomal dominant or autosomal recessive modes of inheritance.1–4 The most common causes for ectopia lentis and ectopia lentis et pupillae are pathogenic variants in the FBN1 gene causing an autosomal dominant inheritance pattern (both syndromic and isolated) and the ADAMTSL4 gene causing autosomal recessive inheritance pattern (isolated).5,6 The ADAMTSL4 gene belongs to ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs gene family,7 and encodes proteins for cellular adhesion, angiogenesis, nervous system development, and anterior and posterior segment structures, especially the lens epithelium.8 In cell culture, ADAMTSL4 increases fibrillin-1 assembly into microfibrils.8 Abnormal ADAMTSL4 gene function disturbs this process, which results in abnormal stretching of zonular fibers.8,9
Additional genetic causes of inherited ectopia lentis with systemic features10 include: homocystinuria,11 Ehlers-Danlos syndrome,12 Weill-Marchesani syndrome,13 hyperlysinemia,14 and sulfite oxidase deficiency disorder.15 Ectopia lentis can also occur in other ophthalmologic conditions such as high myopia, buphthalmos, anterior uveal tumors, exfoliation syndrome, and hypermature cataracts.10
We describe a 4-year-old girl referred to the genetics clinic by her ophthalmologist with the diagnosis of ectopia lentis et pupillae for evaluation of an underlying inherited syndrome. Her mother was a 22-year-old, otherwise healthy, gravida 1 para 1 woman with an uncomplicated pregnancy and normal spontaneous vaginal delivery. Our proband was healthy with no other significant medical history and no known cardiac abnormalities. Laboratory tests that were performed during an earlier evaluation included a normal urine homocysteine level and a normal gene panel for thoracic aortic aneurysm and dissection, Marfan syndrome, and related disorders.
A three-generation pedigree (Figure 1) was obtained and was negative for ectopia lentis, sudden deaths in the family, tall stature, or cardiac issues. The only significant history was in her paternal grandfather, who was born deaf and had vision loss due to retinitis pigmentosa in his teenage years. His history was suggestive of Usher syndrome and not associated with ectopia lentis.
Three-generation pedigree suggestive of an autosomal recessive pattern of inheritance with the patient being the only affected person with ectopia lentis. Paternal grandfather with likely Usher syndrome given congenital hearing loss and retinitis pigmentosa.
Physical examination with special attention to height, arm span, wrist and thumb sign, and skeletal features of Marfan syndrome was negative. Ophthalmologic examination revealed corrected visual acuity of 20/200 in the right eye and 20/80 in the left eye. Extraocular movements were full and pupillary reflexes were normal in both eyes. Intraocular pressures using the iCare rebound tonometer (Icare USA, Inc., Raleigh, NC) were elevated at 32 mm Hg in the right eye and 27 mm Hg in the left eye. Anterior segment eye examination revealed corectopia in both eyes with mild temporal displacement of a slightly elongated pupil in the right eye and oval elongated pupil with inferotemporal displacement in the left eye with neither iris showing atrophy or transillumination defects.
Gonioscopy was not performed due to lack of patient cooperation. Dilated eye examinations revealed a nasally displaced lens in the right eye (Figure 2A) and a superiorly displaced lens in the left eye (Figure 2B). Dilated fundus examination showed mild thinning of the temporal rim of the optic disc with no other retinal abnormality in the right eye and was within normal limits in the left eye. Cycloplegic refraction performed outside the lens revealed a hyperopic right eye (+9.00 diopters sphere) and over the lens revealed a myopic left eye (−7.50 diopters sphere +3.00 diopters cylinder × 100°).
(A) Nasally displaced lens in the right eye of the patient and (B) superiorly displaced lens in the left eye of the patient.
Heidelberg Spectralis optical coherence tomography (Heidelberg Engineering, Heidelberg, Germany) of the optic nerve and retinal nerve fiber layer was performed and showed a retinal nerve fiber layer thickness within normal limits. Repeat measurement in 7 months showed a stable retinal nerve fiber layer profile. The patient was not taking any medication to lower intraocular pressure at this time.
Given our proband's isolated ocular findings and negative family history suggestive of autosomal recessive isolated ectopia lentis et pupillae, we sent testing for the ADAMTSL4 gene.
Our patient was found to have two heterozygous pathogenic variants in the ADAMTSL4 gene: c.767_786del (a 20 bps microdeletion) and c.208_ delA (p.Arg90Aspfs*43). Parental testing revealed these variants to be in trans (ie, the variants found in the ADAMTSL4 gene were on different chromosomes, inherited one from each parent) and confirmed the autosomal recessive inheritance pattern.
Ophthalmologists are often the first medical specialists to evaluate a patient with ectopia lentis. It is important to obtain a thorough medical history including the family history to evaluate for other systemic associations. Referral to cardiology and an echocardiogram can be helpful if Marfan syndrome or Ehlers-Danlos syndrome is suspected. Detailed physical examination with special attention to skeletal features, dermatologic changes, and distinct facies is helpful in determining syndromic causes of ectopia lentis. Supplemental laboratory studies such as urine homocysteine (eg, elevated in homocysteinuria) and echocardiogram (eg, aortic root dilation in Marfan syndrome) can be paramount in detecting homocystinuria and Marfan syndrome. With autosomal dominant conditions, incomplete penetrance and variable expressivity often may result in the lack of characteristic features, making clinical diagnosis difficult. In these instances, genetic testing helps in obtaining a definitive result. With the advent of next generation sequencing, multiple genes causing ectopia lentis can be tested at once. We propose an algorithm for work-up of a patient with ectopia lentis (Figure 3).
Algorithm for ectopia lentis work-up, which begins with thorough history, head-to-toe physical examination, and ophthalmologic examination. Supplemental studies should be performed, at which point the patient should be referred to a geneticist for genetic testing. MOI = mode of inheritance; AR = autosomal recessive; AD = autosomal dominant
Our 4-year-old patient harbored pathogenic variants in the ADAMTSL4 gene that caused ectopia lentis et pupillae. ADAMTSL4 gene mutations are known to cause ectopia lentis et pupillae and isolated autosomal recessive ectopia lentis.4 The c.767_786del variant has been frequently reported to be pathogenic.9 The c.268delA variant is novel and has not been previously reported in the literature, but is expected to be pathogenic given it results in frameshift and truncated protein. Targeted testing of parents determined that the two variants are in trans. The positive genetic test result helped in appropriate medical treatment of this patient because ADAMTSL4-related conditions are not usually associated with systemic findings and negate the need for routine cardiology evaluations and echocardiogram that is recommended for patients with suspected Marfan syndrome or Ehlers-Danlos syndrome. Furthermore, accurate recurrence risk estimates were provided to the family. ADAMTSL4-related eye disorders are inherited in an autosomal recessive manner. Parents have a 25% chance of having another affected child, a 50% chance of having an asymptomatic carrier, and a 25% chance of having an unaffected child. Unless an individual with an ADAMTSL4-related eye disorder has children with another affected individual or a carrier harboring pathogenic variants in the ADAMTSL4 gene, his or her offspring will be obligate heterozygotes (carriers) and recurrence is rare.
With the decreasing cost of genetic testing and next generation sequencing panels, genetic tests would be the first line of testing for individuals with inherited diseases when the genetic testing option is available; however, pregenetic counseling is essential to prepare families for outcomes of genetic testing. Referral to a genetics clinic for evaluation and appropriate testing should be considered.
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- Ahram D, Sato TS, Kohilan A, et al. A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet. 2009;84:274–278. doi:10.1016/j.ajhg.2009.01.007 [CrossRef]
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