ORPHA: 1885; DO: 0111150;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.1 | Ectopia lentis, familial | 129600 | Autosomal dominant | 3 | FBN1 | 134797 |
A number sign (#) is used with this entry because autosomal dominant isolated ectopia lentis-1 (ECTOL1) is caused by heterozygous mutation in the FBN1 gene (134797) on chromosome 15q21.
Mutation in the same gene causes Marfan syndrome (154700), of which ectopia lentis is a feature.
Ectopia lentis is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene et al., 2010).
Citing the revised Ghent criteria for Marfan syndrome, Loeys et al. (2010) proposed the designation 'ectopia lentis syndrome' (ELS) for patients with ectopia lentis and a mutation in the FBN1 gene who lack aortic involvement, to highlight the systemic nature of the condition and to emphasize the need for assessment of features outside the ocular system (see DIAGNOSIS).
Genetic Heterogeneity of Isolated Ectopia Lentis
An autosomal recessive form of isolated ectopia lentis (ECTOL2; 225100) is caused by mutation in the ADAMTSL4 gene (610113).
McKusick (1972) restudied the family reported by McGavic (1966) as having Weill-Marchesani syndrome (608328) and concluded that they probably suffered from an autosomal dominant form of 'simple' ectopia lentis. Eleven members were affected; all members with or without ectopia lentis were short.
Stevenson et al. (1982) reported 2 families, 1 black and 1 white, in which congenital dislocation of the lenses was associated with joint stiffness and dolichostenomelia but no arachnodactyly or cardiovascular complications typical of Marfan syndrome. In 1 family, 11 persons in 4 generations were affected. By echocardiography, the aortic root measured 3.8 cm in a 55-year-old woman and 4.0 cm in a 52-year-old man, both with ectopia lentis. Molecular genetic studies are necessary in families of this type. Further uncertainty as to whether families with seemingly isolated ectopia lentis represent an entity separate from the Marfan syndrome arose from the findings of Tsipouras et al. (1992): in 2 families, the isolated ectopia lentis was linked to the fibrillin gene (FBN1; 134797) on chromosome 15, the same gene to which Marfan syndrome is linked. The experience with a variety of phenotypes produced by mutations in different parts of the collagen genes and indeed in many other genes suggests that isolated ectopia lentis could be caused by mutation in the FBN1 gene of a different nature or at a different site than those which cause the full-blown Marfan syndrome. Already a considerable range of phenotypes has been observed with FBN1 mutations.
Loeys et al. (2010) reported the establishment of a revised Ghent nosology for the diagnosis of Marfan syndrome (MFS), which emphasizes the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are considered cardinal clinical features that together prove sufficient for an unequivocal diagnosis of MFS. Noting that patients with familial ectopia lentis typically have some skeletal features of MFS and an FBN1 mutation, the authors proposed the designation 'ectopia lentis syndrome' (ELS) to better highlight the systemic nature of the condition and the need for assessment of features outside the ocular system. Loeys et al. (2010) stated that the presence of a personal or family history of aortic aneurysm, or the identification of an FBN1 mutation previously associated with aortic aneurysm, would be sufficient to transition a patient's diagnosis to Marfan syndrome. They also suggested that to ensure vigilance of other organ systems, the diagnosis of ectopia lentis syndrome should not be formally invoked before 20 years of age.
Chandra et al. (2015) reviewed all published cases of FBN1-associated isolated ectopia lentis and found that 57 (46.3%) of 123 such probands were subsequently reclassified as MFS, and that 37 (38.5%) of 96 mutations reported to cause isolated ectopia lentis had also been found in patients with aortic dilation/dissection. The authors suggested that ectopia lentis caused by mutation in the FBN1 gene is actually part of a spectrum of fibrillinopathies with MFS, and that the term 'isolated ectopia lentis' should be avoided in such cases.
Falls and Cotterman (1943) described a family with a large number of affected persons in 5 generations, and Chace (1945) observed affected persons in 3 generations. Autosomal dominant inheritance was suggested.
Jaureguy and Hall (1979) reported isolated congenital ectopia lentis in 6 persons in 3 generations of a family.
Edwards et al. (1994) described a kindred in which ectopia lentis appeared to occur in the absence of clear indications of Marfan syndrome in other systems. Linkage studies demonstrated linkage to FBN1 on chromosome 15q21.
Ades et al. (2004) used denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of the previously elusive FBN1 mutation in the large autosomal dominant ectopia lentis kindred described by Edwards et al. (1994). They presented a 9-year update of the clinical status of the family. They found an arg240-to-cys (R240C) mutation in the FBN1 gene (134797.0042), which had been reported 3 times before: once in a family with classic Marfan syndrome (Loeys et al., 2001), once in 1 member of a multigeneration ectopia lentis kindred (Korkko et al., 2002), and once in an adult from a familial ectopia lentis kindred who had ectopia lentis and involvement of the skin, without cardiovascular involvement (Comeglio et al., 2002). The report of Ades et al. (2004) was the second finding of the R240C mutation in association with isolated ectopia lentis, and supported the previous evidence that the R240C mutation can result in 2 quite distinct, yet related, phenotypes. Presumably modification by the genetic background is involved in the phenotypic differences.
Comeglio et al. (2007) analyzed the FBN1 gene in 38 patients with isolated ectopia lentis and identified mutations in 19 (50%).
Faivre et al. (2009) analyzed the clinical and molecular characteristics of 146 adult probands with known FBN1 mutations who did not fulfill the Ghent criteria for Marfan syndrome. The authors noted that in the 12 patients with isolated ectopia lentis, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature termination were found. They stated that analysis of recurrent mutations and of affected family members of probands with only 1 major clinical criterion argued for a clinical continuum between such phenotypes and classic Marfan syndrome.
Aragon-Martin et al. (2010) analyzed the FBN1 gene in 36 UK patients with ectopia lentis who did not fulfill the Ghent criteria for Marfan syndrome and identified causative mutations in 23 (64%). The authors noted that this represented an improved mutation detection rate over their previous study (Comeglio et al., 2007), due to rescreening of patients who were negative for mutation by SSCA with the more sensitive dHPLC detection method.
Yang et al. (2012) studied a 5-generation Chinese family in which 16 members were affected with isolated ectopia lentis and identified a heterozygous missense mutation in the FBN1 gene (R974C; 134797.0063) that segregated with the disease. Yang et al. (2012) reviewed published reports and stated that 18 FBN1 mutations associated with isolated ectopia lentis had been found, 3 of which had also been found in association with Marfan syndrome in different families; they also noted that 15 of the mutations were cysteine substitutions.
Chandra et al. (2012) studied 16 patients with isolated ectopia lentis and identified homozygous or compound heterozygous mutations in the ADAMTSL4 gene (610113) in 8 patients (see, e.g., 610113.0003) and heterozygous mutations in the FBN1 gene in 4 patients. No mutations were identified in the remaining 4 patients. The median age of diagnosis of ectopia lentis was 35 years in patients with FBN1 mutations versus 2 years in patients with ADAMTSL4 mutations (p less than 0.01). Mean axial length was 22.74 mm in FBN1 patients compared to 27.54 mm in ADAMTSL4 patients (p less than 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups. Chandra et al. (2012) concluded that ADAMTSL4 mutations appear to cause earlier manifestation of ectopia lentis and are associated with increased axial length compared to mutations in FBN1.
Horner (1876) reported persons with ectopia lentis in 3 generations, and Usher (1924) reported 7 affected persons in 3 successive generations. In these early reports one cannot be certain that Marfan syndrome was not present.
Ades, L. C., Holman, K. J., Brett, M. S., Edwards, M. J., Bennetts, B. Ectopia lentis phenotypes and the FBN1 gene. Am. J. Med. Genet. 126A: 284-289, 2004. [PubMed: 15054843] [Full Text: https://doi.org/10.1002/ajmg.a.20605]
Aragon-Martin, J. A., Ahnood, D., Charteris, D. G., Saggar, A., Nischal, K. K., Comeglio, P., Chandra, A., Child, A. H., Amo, G. Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients. Hum. Mutat. 31: E1622, 2010. Note: Electronic Article. [PubMed: 20564469] [Full Text: https://doi.org/10.1002/humu.21305]
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