The revised ghent nosology; reclassifying isolated ectopia lentis

Abstract

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term ‘IEL’ should be avoided in such cases.

ADAMTSL4‐associated isolated ectopia lentis: Further patients, novel mutations and a detailed phenotype description

“…Autosomal dominant EL due to FBN1 mutations [Ades et al, 2004] has been described; however, it remains to be determined whether this truly is isolated EL or whether this resembles minimal manifestation of syndromal ectopia lentis such as homocystinuria or fibrillinopathies [Chandra et al, 2015]. However, it can also be observed as an isolated finding without obvious systemic comorbidities such as aortic root dilatation.…”

“…However, it can also be observed as an isolated finding without obvious systemic comorbidities such as aortic root dilatation. Mutations in this gene, which also harbors a European founder mutation [Neuhann et al, 2011], seem to represent the most frequent cause of isolated EL [Chandra et al, 2012[Chandra et al, , 2015. Autosomal dominant EL due to FBN1 mutations [Ades et al, 2004] has been described; however, it remains to be determined whether this truly is isolated EL or whether this resembles minimal manifestation of syndromal ectopia lentis such as homocystinuria or fibrillinopathies [Chandra et al, 2015].…”

“…The differentiation between syndromic and isolated EL is crucial for the further surveillance, treatment, and counseling of these patients, especially in young children. Autosomal dominant EL due to FBN1 mutations [Ades et al, 2004] has been described; however, it remains to be determined whether this truly is isolated EL or whether this resembles minimal manifestation of syndromal ectopia lentis such as homocystinuria or fibrillinopathies [Chandra et al, 2015]. Mutations in ADAMTSL4 have been associated with autosomal recessive isolated EL [Ahram et al, 2009].…”

Diagnosis and Management (Summary)

“…Rare conditions include rarely congenital contractural arachodactyly [ 3 ], and overgrowth syndromes, for example Sotos syndrome [ 4 ]. Another common overlap syndrome is Ectopia Lentis as an isolated problem [ 5 ]. If the echocardiogram is normal, and a parent is affected with dislocated lenses, then this may still be due to mild fi brillin-1 defi ciency, often with a mutation in the fi rst 15 exons of the gene [ 6 ].…”

“…If the echocardiogram is normal, and a parent is affected with dislocated lenses, then this may still be due to mild fi brillin-1 defi ciency, often with a mutation in the fi rst 15 exons of the gene [ 6 ]. If the child with Ectopia Lentis is the only one in the family and parents are related (consanguineous), this is most likely an autosomal recessive type of Ectopia Lentis due to ADAMTSL4, ADAMTS18, or other gene [ 5 ]. Adolescent idiopathic scoliosis can also be inherited dominantly, and is now being shown to be due to separate genes [ 7 ].…”