How to Cite this Article: Zadeh N, Bernstein J, Niemi AK, Dugan S, Kwan A, Liang D, Hyland JC, Hoyme HE, Hudgins L, Manning MA. 2011. Ectopia lentis as the presenting and primary feature in Marfan syndrome. Am J Med Genet Part A 155: 2661–2668.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with a prevalence of 1 in 3,000–1 in 5,000 individuals. MFS affects multiple systems with primary involvement of the skeletal, cardiovascular, and ocular systems [Loeys et al., 2001]. Diagnosis is usually made clinically in affected individuals by fulfillment of the Ghent criteria [De Paepe et al., 1996], an international diagnostic standard based largely on clinical findings in the various organ systems mentioned above as well as family history. Recently, the Ghent criteria have been revised to decrease the risk of premature or misdiagnosis [Loeys et al., 2010]. The new nosology places more diagnostic weight on two features of MFS (aortic root aneurysm/dissection and ectopia lentis) and removed some of the less specific manifestations in the diagnostic evaluation. The new criteria should aid clinicians in determining a correct diagnosis, as reports in the medical literature have shown that MFS demonstrates a wide phenotypic spectrum in which mildly affected individuals may be overlooked.
Mutations in the Fibrillin-1 (FBN1) gene located on chromosome 15q12 are known to be causative for MFS. FBN1 has epidermal growth factor (EGF)-like domains, transforming growth factor (TGF)-like domains as well as unique hybrid motif domains that resemble both EGF and TGF motifs. FBN1 consists of 65 exons and spans 235 kb of genomic DNA and codes for the 2,871 amino acid protein fibrillin. Fibrillin is a cysteine-rich secreted glycoprotein that is a vital component of the extracellular matrix, specifically the 10 nm microfibril that interacts with elastin in tissues such as the aorta and other ligamentous structures [Booms et al., 1997; Pereira et al., 1993; Hayward and Brock, 1997]. It also has an anchoring function in non-elastic tissues such as ciliary zonules of the eye, bone periosteum, and tendon [Gray and Davies, 1996; Comeglio et al., 2002].
Phenotype–genotype correlation with respect to FBN1 mutations would be helpful in directing appropriate medical management and perhaps aiding in appropriate designation. This is an area of continuing investigation, as there have been more than 1,200 mutations identified in FBN1 which are distributed throughout the gene. Mutation types include nonsense, small deletions/duplications, splice site alterations, mutations affecting highly conserved cysteine residue(s), and mutations involving calcium-binding residues [Faivre et al., 2007; Attansaio et al., 2008]. The majority of mutations are missense, which tend to affect highly conserved cysteine residues [Turner et al., 2009]. Various mutations have been shown to cause a phenotypic continuum: Patients with milder findings such as isolated ectopia lentis (EL) or Ectopia Lentis syndrome (ELS), those with MASS phenotype (Mitral valve prolapse, Aortic dilatation, Skeletal and Skin involvement) and finally patients with MFS that clinically meet the Ghent criteria [Rommel et al., 2005; Turner et al., 2009]. Due to clinical variability within this condition, there have been discussions regarding classification of individuals with only one phenotypic finding and a mutation in FBN1 as “Marfan syndrome” versus “type 1 fibrillinopathy” [Faivre et al., 2009]. Our patient cohort, on initial evaluation did not demonstrate systemic manifestations of MFS and did not satisfy the revised Ghent criteria. We report on these eight patients, who initially presented solely with bilateral EL during early childhood, and all possessed missense mutations in FBN1 that were observed to congregate in the 5′ region of the gene.
All eight patients were evaluated through medical genetics consultation secondary to the presenting feature of EL during early childhood without other systemic features of MFS. Each patient was evaluated by a medical geneticist and genetic counselor. The visit included collection of the patient's past medical history, and family history. A physical examination was performed with appropriate measurements and considerations for skeletal manifestations of the revised Ghent criteria. Subsequently, as all of the patients exhibited bilateral EL without skeletal manifestations of MFS, FBN1 sequencing and an echocardiogram were recommended. Blood was obtained and sent to various commercial laboratories certified to perform clinical testing. Full gene sequencing of FBN1 was performed, which involved genomic DNA isolation, PCR amplification, and forward and reverse sequencing of all 65 exons and exon–intron boundaries. Results were communicated to the ordering medical geneticist via a written laboratory report, which identified the mutation type and location in the FBN1 gene. The written lab report also commented if the mutations had been previously reported (Table III). Genetic counseling and health care recommendations were provided.
This is a retrospective review of eight patients who were seen through medical genetics consultation over the past 10 years. The authors have been involved with the initial evaluation and follow-up visits of particular patients in this cohort. All patients had presenting features of EL during early childhood, which led to referral for medical genetics evaluation. The mean age of EL diagnosis in our patient group was (approximately) 4.75 years. Typically, referral for genetics consultation was made at the time of EL identification on ophthalmology examination.
The patient cohort represents the majority of patients referred for genetics evaluation at our institution for EL over the past 10 years. One patient was not included in our cohort, the sister of Patient 2, as FBN1 sequencing could not be performed secondary to reimbursement issues. Several other patients were referred to our institution for ELS, but possessed easily identifiable skeletal and systemic features of MFS on clinical exam, and/or fulfilled the revised Ghent criteria; thus, these patients were not included in our cohort. Thus, based on our inclusion and exclusion criteria, our patient cohort is an excellent representation of our clinical experience of patients with isolated EL and a disease-causing mutation in FBN1.
Medical genetics evaluation of our patient cohort included a review of the past medical history, family history, as well as a thorough physical examination with consideration for skeletal or other systemic features of MFS. FBN1 sequencing was recommended and ordered by the evaluating medical geneticist. At the time of evaluation, none of the patients satisfied the 1996 Ghent criteria. After the publication of the revised 2010 criteria, reassessment of these cases revealed that none of the cohort fulfilled the 2010 Ghent criteria for a clinical diagnosis of MFS at initial presentation. A summary of all patient findings is outlined in Table I, and a summary of echocardiogram findings is outlined in Table II, which includes measurements at the sinuses of Valsalva and calculated Z-score.
Table I. Location and Type of Mutation, Clinical Features and Family History in our Patient Cohort.
Family history of EL
EL: Ectopia lentis.
Previously described mutation per Attansaio et al. .
Sinus of Valsalva is at the upper limits of normal
AoRt measurements are at upper limits of normal
Aorta has “cloverleaf” appearance.
Normal appearing aortic and mitral valves
Normal appearing aortic and mitral valves.
Mitral prolapse, loss of sinotubular ridge
Normal sized aortic root with loss of the Sinotubular ridge
Minimal mitral valve prolapse, loss of the Sinotubular ridge
Mitral valve prolapse involving anterior leaflet
Normal appearing AoRt
Patient 1 is a female diagnosed with bilateral EL at the age of 2 years which was surgically corrected by age 3. She was seen by genetics shortly afterward with observed physical findings noted to be Sprengel deformity of the right scapula, mild scoliosis without any other skeletal features known to be associated with MFS. Family history was non-contributory. FBN1 sequencing revealed a c.2051G > A mutation in exon 16. This mutation has been previously reported in Attansaio et al.  (Table III). An echocardiogram was recommended at the time of the initial evaluation (at the age of 3 years), which revealed aortic root dilatation at the upper limits of normal. Echocardiograms have been performed annually in this individual, who is now 17 years old, with the most recent findings consisting of mild mitral valve prolapse and regurgitation as well as a dilated aortic root with a maximum diameter of 3.8 cm at the sinuses of Valsalva (Table II).
Table III. Patient Cohort Mutation Location and Type along with Previously Reported Status and Associated Clinical Features.
Amino acid change
Previously reported status
Associated reported features
AD, Aortic root dilatation; DE, Dural ectasia; EL, Ectopia lentis; P, Pes planus; R, Reduced arm span to height ratio.
Patient 2 is a male that initially presented with bilateral EL at 3 years of age. This individual did not have skeletal or dermatological features typical of MFS. The patient's mother and sister both have bilateral lens subluxation and mild musculoskeletal findings; however, neither of these individuals had molecular testing. Mutation analysis was recommended and performed in Patient 2 which revealed a c.368G > A mutation in exon 4 causing a cysteine for tyrosine substitution. This mutation has been previously reported in Attansaio et al.  (Table III). Echocardiogram revealed an aortic root diameter that was considered to be at the upper limits of normal. The patient was started on a beta-blocker to prevent further enlargement of the aortic root. Over the next 3 years, serial cardiac imaging was performed, which demonstrated stable aortic root measurements with trace pulmonic and tricuspid regurgitation (Table II). The sister of Patient 2 was also evaluated; she had an initial normal echocardiogram at the age of 2 years. However, by the age of 4, she was exhibiting aortic diameter of 2.2 cm at the sinuses of Valsalva. It was recommended that Patient 2's mother have cardiac imaging, echocardiograms were reportedly normal. Echocardiogram reports for this individual and Patient 2's sister were not available at the time of this report.
Patient 3 is a male with a history of poor vision noted by his parents during early infancy. At 7 months of age, myopia was diagnosed. Bilateral EL was evident by 4 years of age. He was referred for medical genetics evaluation at 6 years of age. He was evaluated by cardiology shortly after with an echocardiogram that revealed an aortic root measurement of 3.0 cm at the sinuses of Valsalva, which was enlarged compared to other cardiac dimensions (Table II). On short axis view, the aorta had a “cloverleaf” appearance without evidence of mitral valve prolapse or regurgitation, or aortic insufficiency. Patient 3's family history was significant for a paternal first cousin with subluxed lenses and “long-appearing extremities” who never had a formal genetics evaluation or molecular testing. (This individual is currently residing in South America, and it is unknown if cardiac imaging had been performed). Patient 3's father had no history of visual problems or features suggestive of MFS; this individual has not had a formal ophthalmology evaluation or cardiac imaging performed, although given his son and nephew's presentation, this would be recommended. FBN1 sequencing in Patient 3 revealed a c.3513C > G mutation in exon 28. This mutation had been previously reported in the medical literature and was considered to be disease-causing (Table III). Molecular analysis has not been performed on any other family members.
Patient 4 is a male patient diagnosed with bilateral EL and high myopia on ophthalmology evaluation at 8 years of age. Genetics evaluation took place shortly after, with no other features of MFS identified on initial examination. Echocardiogram performed on the proband revealed aortic root measurements at the upper limits of normal. FBN1 sequencing was performed and revealed two sequence variations in exon 4: The first was c.364C > T which has been described in the medical literature; the second mutation was c.370A > G which has not been reported previously and was deemed a variant of uncertain clinical significance by the clinical laboratory. Patient 4's family history was noteworthy for the patient's mother and sister, who were also affected with bilateral EL. These two individuals were examined by our service. Despite our recommendations, Patient 4's mother was not able to have her vision checked; however, Patient 4's sister is followed by an ophthalmologist and was wearing spectacles for vision correction. Molecular testing was performed on the Patient 4's mother and sister, which revealed the same c.364C > T and c.370A > G FBN1 mutations previously identified in the propositus. Cardiovascular imaging was recommended for the propositus' mother and sister, the results of which were unavailable at the time of this report.
Patient 5 is a female diagnosed with EL at 5 years of age and was not evaluated by genetics until the age of 25 years during her first pregnancy. At the time of the consultation, she was considering lens replacement surgery and was wearing gas-permeable contact lenses. Her obstetrician was concerned regarding her ophthalmologic history for a potential underlying connective tissue disorder. She was assessed during mid-pregnancy and other than some mild hyperextensibility of the large joints, did not demonstrate other characteristic features of MFS. However, she was noted to have absence of the uvula. Due to this finding, fluorescence in situ hybridization (FISH) was performed for chromosome 22q11.2 microdeletion, which was negative. Family history was unremarkable. Molecular analysis of FBN1 revealed a c.1948C > T sequence variation in exon 15. The clinical laboratory commented that to their knowledge this exact mutation had not been previously reported; however, similar mutations in this particular gene region had been reported in patients with MFS. Echocardiogram was significant for an aortic root which measured 3.6 cm at the sinuses of Valsalva but otherwise normal appearance to the aortic arch and abdominal aorta. No molecular testing for any other possible connective tissue disorders (i.e., TGFBR1/2) was performed in this patient or her child, Patient 5b.
Patient 5b is a female infant born to Patient 5. This infant was tested for known familial mutation while in the newborn nursery which confirmed the inheritance of c.1948C > T from her mother. Physical examination was unremarkable. Ophthalmology evaluation was performed shortly after birth. Poor eye dilation was achieved despite multiple topical mydriatic administrations, which in the opthalmologist's opinion was consistent with early dysfunction of the ciliary zonules.
Patient 6 is a female patient that was brought to attention when myopia was noted during a school eye examination. She was evaluated by pediatric ophthalmology at age 6 years and found to have bilateral superotemporal lens subluxation. The right lens was removed and replaced with an intraocular lens shortly afterwards. She was subsequently referred for a genetic evaluation shortly afterwards. Initial physical exam revealed tall stature with no other skeletal manifestations of MFS, and thus she did not satisfy the Ghent criteria. Family history was unremarkable. FBN1 sequencing revealed a c.1496G > A sequence variation in exon 12, which has not been previously reported in the medical literature, but was thought to be a disease-causing mutation by the clinical laboratory performing the molecular testing. Initial cardiac imaging was performed at 6 years of age with normal results (the actual echocardiogram report and cardiac measurements from this date were not available at the time of this report). By 8 years of age she had developed mild arachnodactyly with borderline Walker–Murdoch and Steinberg signs. Echocardiogram performed at that time demonstrated a normal sized aortic root with loss of the sinotubular ridge. By age 11 years, there was mild mitral valve prolapse noted (Table II). By this age, (per revised Ghent criteria), this patient still did not satisfy criteria for MFS, mitral valve prolapse syndrome, ELS, or MASS phenotype [Loeys et al., 2010].
Patient 7 is a female with EL first noted at 4 years of age. On eye exam, there was notable upward and outwardly subluxed crystalline lenses. The lenses also appeared to have small diameter, but the anterior chamber otherwise appeared normal. She underwent bilateral cataract extraction with intraocular lens implantation at age 5 years. Patient 7 was 4 years of age at the time of her initial echocardiogram, which revealed mitral valve prolapse involving the anterior leaflet and very mild mitral regurgitation with a normal appearing aortic root. A renal ultrasound was performed secondary to family history of cystic kidneys, which was normal in our patient. FBN1 sequencing revealed a heterozygous 1426T > C nucleotide change predicting an amino acid substitution of cysteine to arginine, which has not been identified previously as a disease causing mutation in other patients, and has not been reported in the medical literature. Unfortunately, none of the other family members had molecular testing, which would be helpful in this case to clarify whether this variant likely is a disease-causing mutation. Patient 7's family history was significant for multiple individuals on the maternal side with poor vision (Fig. 1). The patient's mother had symptomatic EL first noted during adolescence with normal echocardiograms, initially performed during late adolescence and continuing on through her adult life. Patient 7 also has a maternal half-brother (Fig. 1, individual IV-4) with EL, polycystic kidney disease, striae, mild scoliosis, pectus carinatum, and developmental delay. Diagnostic testing was not performed secondary to insurance reasons, and to our knowledge, this individual had a normal echocardiogram performed at 17 years of age. Individual IV-4 is thought to potentially have two different genetic conditions: Polycystic kidney disease and potentially MFS. There are additional maternal uncles who all have visual difficulties. Another maternal uncle died at 13 years of age secondary to an “unknown cardiac problem”; however, this person was believed to have normal vision, and it is not known if he had any renal abnormalities. Maternal grandmother and great-grandmother also had history of EL and renal disease of uncertain etiology. None of these individuals had cardiac imaging to our knowledge. After careful review of the family history, we noted that there are at least two unrelated genetic disorders in this family. We could make the distinction between the likely autosomal dominant polycystic kidney disease and the autosomal connective tissue disorder (likely MFS), which we considered to be two separately segregating disorders both originating on the patient's maternal side of the family. However, without further information on the extended family members, or additional genetic testing, it is impossible to completely ascertain if these conditions are possibly related or segregating separately.
Patient 8 is a 6-year-old female recently brought to medical attention due to poor vision. She was diagnosed with bilateral EL and myopia, and genetics consultation took place soon afterwards. Physical examination was not suggestive of MFS as the patient's clinical exam findings did not fulfill revised Ghent criteria. Echocardiogram was recommended that revealed mild mitral valve prolapse with a normal thoracic aorta (Table II). FBN1 sequencing revealed a c.1379G > A mutation causing a cysteine to tyrosine change in amino acid 460 (Cys460Tyr) in exon 11 which has been previously reported in the Universal Marfan database-FBN1 (UMD-FBN1;http://www.umd.be). Patient 8's parents did not have a history of vision problems, features suggestive of MFS, or tall stature for their family background; neither of these individuals has undergone molecular testing.
EL is the most common ocular abnormality in MFS in which there is displacement of the lens, and the ciliary zonular filaments are stretched or discontinuous with disrupted microfibril bundles seen on transmission electron microscopy. Lenses tend to be bilaterally dislocated upward. EL is associated with conditions other than MFS which include congenital contractural arachnodactyly, sulfite oxidase deficiency, Ehlers–Danlos syndrome, Weill–Marchesani syndrome, and homocystinuria. It can also be present as a familial finding or as an isolated anomaly [Koenig and Mieler, 1996].
Patients with familial EL typically exhibit marfanoid skeletal features, but may lack aortic symptomatology; causing diagnostic difficultly in distinguishing this entity from emerging MFS. For this reason, Loeys et al.  in the revised Ghent criteria proposed the designation “ELS” to emphasize the need for assessment of features outside the ocular system. Per revised Ghent criteria, individuals considered to have ELS are those: (1) With EL with or without systemic manifestations and a FBN1 mutation not known to be associated with aortic disease or (2) EL without an identifiable FBN1 mutation. Accordingly, the presence of personal or family history of aortic aneurysm, and concurrent identification of a disease-causing mutation in FBN1 is sufficient to modify the diagnosis from ELS to MFS [Loeys et al., 2010]. EL along with an FBN1 mutation warrants cardiovascular imaging throughout life. Furthermore, to ensure proper surveillance of at-risk organ systems, the diagnosis of ELS cannot be invoked prior to age 20 years [Loeys et al., 2010].
All patients presented in this report (5 females and 3 males) were diagnosed with bilateral EL during early childhood, with a mean age of diagnosis at 4.75 years of age. Due to patient age, all but one of our cohort would be possibly eligible for a diagnosis of ELS based on the recommendations of the revised Ghent criteria [Loeys et al., 2010]. As a result of this initial ophthalmologic finding, all patients were appropriately referred for genetic evaluation. Complete detailed physical examinations were performed in all patients, with none having skeletal or dermatologic systemic manifestations of MFS. Additionally, four patients had a positive family history of EL (63%). Of those four cases, two had first-degree relatives with isolated EL and normal cardiovascular findings. One case had a second-degree relative with bilateral lens subluxation and mild musculoskeletal findings. The final case had a significant number of first and second degree maternal relatives with EL, cystic kidneys, and mild musculoskeletal findings. This individual's family is thought to have two distinct genetic conditions, polycystic kidney disease and possibly MFS.
Our patients were evaluated prior to the published revision of the Ghent criteria. For the purpose of review, Ghent nosology [De Paepe et al., 1996] consists of “major” and “minor” manifestations in numerous tissues/organ systems of the body. “Major” criteria included EL, aortic root dilatation/dissection, dural ectasia, or a combination of ≥4 out of eight major skeletal features (pectus carinatum, pectus excavatum requiring surgery, reduced upper to lower segment ratio or arm span to height ratio >1.05, wrist and thumb signs, scoliosis of >20° or spondylolisthesis, reduced extension at the elbows (<170°), medial displacement of the medial malleolus causing pes planus, and protrusion acetabulae of any degree) [Loeys et al., 2010]. “Minor” skeletal criteria included pectus excavatum of moderate severity, joint hypermobility, highly arched palate with crowding of teeth, and facial appearance (dolichocephaly, malar hypoplasia, enopthalmos, retrognathia, down-slanting palpebral fissures). Fulfillment of Ghent criteria required at least two major criteria and one minor criterion, (or one major criterion and one minor criterion in the presence of a positive family history), to be present. None of our patients satisfied the Ghent skeletal criteria for MFS.
The 2010 revised Ghent criteria places more weight on cardiovascular manifestations where aortic root aneurysm along with EL are now the cardinal clinical features [Loeys et al., 2010]. Presence of these two clinical features is sufficient for a diagnosis of MFS. In the absence of either EL or aortic root manifestations, the presence of a disease-causing FBN1 mutation or a combination of systemic manifestations is required [Loeys et al., 2010]. The revised criteria provide a scoring scale for systemic features, assigning a numerical value to particular skeletal, craniofacial, cardiovascular, dermatologic, and ocular manifestations, with a maximum score of 20 points with ≥7 indicating systemic involvement [Loeys et al., 2010].
Only four of our patients had nonspecific findings of slightly tall stature with two individuals having long hyperextensible fingers with borderline Walker–Murdoch (wrist) and Steinberg (thumb) signs noted at an older age and not present on initial exam; none earned a score ≥7 on the revised Ghent criteria scoring of systemic features.
Cardiology evaluation, including an echocardiogram, was performed on all eight patients. Z-scores were calculated using Aortic Root Z-score calculator based on Haycock BSA and Boston Children's Hospital echocardiogram normal values (available at: http://marfan.stanford.edu/BCHzscore.htm) using our patient's weight (kg), height (cm), and measurement (cm) at the sinuses of Valsalva. The presence of aortic root dilatation is Z-score ≥2 when standardized to age and body size. Seven patients had dilatation of the aortic root, or at least loss of the sinotubular junction, visualized on imaging and confirmed by Z-score calculation. In Table II, we have illustrated when possible, the cardiovascular progression over time, reiterating our observation and supporting the revised Ghent criteria, that these patients are at increased risk for cardiovascular sequelae.
The revised Ghent nosology comments on criteria for causal FBN1 mutations. These include missense mutations that substitute or create cysteine residues, alter one of the conserved residues important for calcium binding in EGF-like domains, nonsense mutations, inframe and out of frame deletion/insertion, and splice site mutations shown to alter splicing on mRNA/cDNA level [Loeys et al., 2010].
FBN1 sequencing was offered to all patients seen, and all had identifiable mutations thought to be disease causing. Individuals in our patient cohort with mutations previously reported in the literature were all associated with aortic changes. Mutations not reported in the literature were thought to be disease-causing per the experience of the reporting clinical reference lab. All mutations were found to be missense, with four of eight patients having unique mutations. A total of nine mutations are described, with the majority occurring near the 5′ end of the gene. Seven mutations were located within exons 4 through 16, and the remaining patient had a mutation occurring in exon 28. Mutations involving conserved cysteine residues occurred in six patients (67%). Two patient mutations had been previously described according to the Universal Marfan database-FBN1 (UMD-FBN1; http:/www.umd.be) [Collod-Beroud et al., 1998] and another three patients' mutations had been previously published in a review by Attansaio et al.  as well as Robinson et al. . With respect to the 364C > T mutation described by Robinson et al., three of the four patients reported by the authors had late onset cardiovascular manifestations. Attansaio et al. described two mutations (c.368G > A and c.2051G > A), which were both observed with aortic root dilatation along with EL and other systemic features [Attansaio et al., 2008]. The three remaining previously undescribed mutations are thought to be causative because they alter the structure or biochemical characteristics of fibrillin-1. The c.370A > G variant (observed in Patient 4) is thought to be benign, especially as it was observed along with the previously reported c.364C > T mutation in the same patient (Table I) and was not thought to affect gene function.
FBN1 mutations have been associated with a broad spectrum of phenotypes ranging from lethal neonatal MFS to single connective tissue manifestation such as isolated EL [Faivre et al., 2007]. Severe neonatal MFS tend to have mutations in exons 24-32, whereas mutations in exons 26-32 are associated with earlier onset of ascending aortic aneurysms [Schrijver et al., 1999]. In a review by Faivre et al. , patients with EL and at least one minor criterion in another organ system had missense mutations involving cysteine in the vast majority with an overrepresentation of mutations at the 5′ end of the gene. The overall frequency of EL was significantly higher in individuals with this type of mutation. This finding was also reported in the Attansaio et al.  study. The authors observed that the prevalence of EL was higher in patients harboring Cys-missense mutations than those carrying premature termination codons [Attansaio et al., 2008]. The majority of FBN1 mutations associated with isolated EL involve cysteine residues and tend to occur in exons 2, 6, or 13 of the gene [Ades et al., 2004]. All but one of the observed mutations in our cohort occurred between exons 4 and 16 (Table III).
The fibrillin polypeptide chain is composed of 47 EGF-like motifs. These EGF-like domains have six highly conserved cysteine residues which form disulfide bridges creating stable β sheet conformation that aids in calcium binding [Schrijver et al., 1999]. Calcium has been shown to be essential for the maintenance of the rod-like structure of cbEGF domains in fibrillin-1 and microfibrils [Downing et al., 1996]. Mutations involving cysteine substitutions tend to have a detrimental effect on EGF-like domains, disrupt calcium binding and are frequent causes of MFS, specifically with ocular manifestation as one of the most consistent features [Schrijver et al., 1999]. Correct cysteine localization in FBN1 may play an important role in structural integrity of suspensory ligament of the lens [Nemet et al., 2006] and possibly the aorta. This hypothesis is supported by our findings in which 88% of our patients had mutations in exons 4–16 that were all associated with some degree of aortic root dilatation.
In the presence of EL, but absence of aortic root dilatation/dissection, the identification of a disease causing FBN1 mutation is required prior to making a diagnosis of MFS. Three of our patients had unclassified mutations in FBN1, with two of the three having aortic root measurements at the upper limits of normal at the time of diagnosis, which were prior to the age of 8 years (Table I).
The families presented here demonstrate the utility of FBN1 gene testing and the subsequent identification of potentially life-threatening complications. Limitations of this study include a somewhat small number of patients that fit our inclusion criteria of early bilateral EL without other systemic manifestations of MFS (who were later found to have a disease causing mutation in FBN1). A larger sample size may help us trend cardiovascular sequelae as well as provide more accurate genotype–phenotype correlation. We were also unable to obtain all echocardiograms performed for each patient, as several had imaging performed outside our institution.
FBN1 mutation analysis may be helpful in diagnosing MFS in families in which EL appears to be the primary and only presenting feature. The current revised Ghent criteria places more emphasis on the presence of EL and aortic root abnormalities, and our patient experience has demonstrated that the revised criteria work well. We have reaffirmed that due to clinical variability, it is possible that EL in young patients may evolve towards MFS with aging, thus long term follow-up in these patients is necessary [Attansaio et al., 2008]. The particular mutations listed in this paper were mostly located at the 5′ end of the gene, and were associated with bilateral EL and variable cardiovascular involvement. The majority of the mutations described in our patient population involved highly conserved cysteine residues, which are thought to play a role in the structure of suspensory ligaments. Thus, we may speculate this specific type of mutation as a contributing factor of aortic root dilatation seen in the majority of our cohort. Further clarification of genotype/phenotype correlation in MFS through FBN1 mutation analysis will assist in identifying at-risk individuals and help determine appropriate medical management.