FBN1

Marfan Lipodystrophy Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are large resulting in high myopia and apparent proptosis.  The palpebral fissures usually slant downwards and ectopia lentis may be present.  

Systemic Features: 

This syndrome shares many features of Marfan syndrome (154700) such as tall stature, dislocated lenses, myopia, high arched palate, aortic root and valvular anomalies, arachnodactyly, high arched palate, lax and hyperextensible joints, and pectus excavatum.  In addition, MFLS patients have retrognathia, intrauterine growth retardation, scarce or absent subcutaneous fat, a progeroid facies, and sometimes macrocephaly.  Postnatal growth and psychomotor development have been reported to be normal albeit with slow weight gain.

Genetics

This condition is transmitted as an autosomal dominant as the result of heterozygous mutations in FBN1 (15q21.1).  The same gene is mutated in 6 other conditions in this database including Marfan Syndrome (154700) with which it shares some features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual features such as ectopia lentis can be surgically corrected.  Patients with high myopia require frequent evaluation for retinal tears and detachments.  Cardiac monitoring likewise is important to monitor for aortic valve prolapse and dilation of the aortic root.

References
Article Title: 

Ectopia lentis, Isolated AD

Clinical Characteristics
Ocular Features: 

Ectopia lentis as an isolated finding has been known for many years although early reports did not rule out features of the Marfan syndrome (154700).  In more recent reports clinical evidence of the Marfan syndrome has been absent in a number of families and there seems little doubt that mutations in the FBN1 can be responsible for isolated ectopia lentis.  Iridodenesis may be noted at birth but the dislocated lens may not be diagnosed until late adulthood in mild cases.  Vision can be normal but nystagmus and strabismus have been noted in other patients. The lenses may be dislocated superiorly and may contain opacities.  Areas of missing zonules have been observed in some patients while others have posterior synechiae.

Systemic Features: 

Related family members have been observed to have polydactyly and craniosynostosis but without dislocated lenses.  It is important to rule out skeletal and cardiac manifestations of the Marfan syndrome because of the prognostic implications.

Genetics

This is an autosomal dominant disorder attributed to mutations in FBN1 (15q21), the same gene that is mutant in the Marfan syndrome (154700).  The dislocated lenses may represent variable expressivity or simply allelism.  The latter seems more likely in view of the fact that numerous thoroughly studied individuals have not had the skeletal or cardiovascular signs of the Marfan syndrome (154700).  However, the revised Ghent nosology now suggests that all patients with the FBN1 mutation and ectopia lentis be designated to have the Marfan syndrome when aortic dilation/dissection is present as well.  This should be extended to include all patients with FBN1 mutations and ectopia lentis plus at least one other phenotypic feature of the Marfan syndrome.

The same gene is mutant in the autosomal dominant form of the Weill-Marchesani 2 syndrome (608328) which is allelic to the Marfan syndrome. 

There is also an autosomal recessive condition of isolated ectopia lentis (225100) which results from homozygous nonsense mutations in ADAMTSL4 (225100). A patient with craniosynostosis and ectopia lentis has been reported in which there was a homozygous 20 bp deletion in the same gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens removal may be indicated when vision cannot otherwise be corrected.

References
Article Title: 

The Revised Ghent Nosology; Reclassifying Isolated Ectopia Lentis

Chandra A, Patel D, Aragon-Martin JA, Pinard A, Collod-Beroud G, Comeglio P, Boileau C, Faivre L, Charteris D, Child AH, Arno G. The Revised Ghent Nosology; Reclassifying Isolated Ectopia Lentis. Clin Genet. 2014 Feb 7. [Epub ahead of print].

PubMed ID: 
24635535

Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion

Faivre L, Collod-Beroud G, Callewaert B, Child A, Loeys BL, Binquet C, Gautier E, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Grasso M, Beroud C, Bonithon-Kopp C, Claustres M, Stheneur C, Bouchot O, Wolf JE, Robinson PN, Ades L, De Backer J, Coucke P, Francke U, De Paepe A, Boileau C, Jondeau G. Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Am J Med Genet A. 2009 May;149A(5):854-60.

PubMed ID: 
19353630

Ectopia lentis phenotypes and the FBN1 gene

Ades LC, Holman KJ, Brett MS, Edwards MJ, Bennetts B. Ectopia lentis phenotypes and the FBN1 gene. Am J Med Genet A. 2004 Apr 30;126A(3):284-9. Review.

PubMed ID: 
15054843

Weill-Marchesani Syndrome 2

Clinical Characteristics
Ocular Features: 

Glaucoma may have an infantile onset and pupillary block glaucoma is a lifelong risk.  The lenses dislocate inferiorly but may migrate into the anterior chamber.  Spherophakia occurs in 74% of patients.  Extreme myopia in the range of -13 D may be present.  There is an increased risk of retinal detachment.

Systemic Features: 

One patient had mitral valve insufficiency.  Midface hypoplasia with a protruding lower lip was found in two patients.  The elbow and perhaps other large joints have limited mobility and the interphalangeal joints are thickened with difficulty in full extension of the fingers.  Patients are short in stature and the digits are often short and stubby.  The skin is tanned and thickened in places.  Cardiac anomalies are present in 13% of patients.

Genetics

This is an autosomal dominant disorder resulting from heterozygous mutations in FBN1 (15q21.1).  It is thus allelic to the Marfan syndrome (154700).  Weill-Marchesani syndrome 1 (277600) is a clinically similar syndrome but results from homozygous mutations in ADAMTS10. Homozygous mutations in ADAMTS17 cause the Weill-Marchesani-Like syndrome (613195).

Some individuals with isolated autosomal dominant ectopia lentis (129600) have mutations in FBN1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Patients should be monitored for the occurrence of glaucoma and treated appropriately.  Frequent refractive checks are recommended.  Lens extraction may be indicated when the visual axis is obstructed by a displaced lens or when lens-induced glaucoma occurs.

References
Article Title: 

Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome

Faivre L, Dollfus H, Lyonnet S, Alembik Y, M?(c)garban?(c) A, Samples J, Gorlin RJ, Alswaid A, Feingold J, Le Merrer M, Munnich A, Cormier-Daire V. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A. 2003 Dec 1;123A(2):204-7. Review.

PubMed ID: 
14598350
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