Marfan syndrome and the eye clinic: from diagnosis to management

Abstract

Marfan syndrome (MFS) is an autosomal dominantly inherited disorder affecting the cardiovascular, ocular and musculoskeletal systems. Frequently, clinical suspicion and subsequent diagnosis begins in the ophthalmology clinic. Importantly, the ophthalmologist has a responsibility to cater not only to the eye, but also to be involved in a holistic approach for these patients. In this review, we discuss how MFS may present to an eye clinic, including clinical features, ocular morbidity, genetic diagnosis and management. Although this condition is ideally managed by a multidisciplinary team, our focus will be on MFS and the eye, including other conditions which may present with similar phenotypes. The ophthalmologist’s role as the potential first contact for a patient with suspected MFS is crucial in making the proper investigations and referral, with the knowledge that not all ectopia lentis cases are MFS and vice versa. Management of ocular conditions in MFS may range from simple observation to surgical intervention; current options will be discussed.

Plain Language Summary

Eye problems in Marfan Syndrome – A Review

Marfan syndrome (MFS) is an inherited disorder that affects many systems of the body, including the heart, joints, skeleton, skin and eyes. Although the more dangerous problems caused by this are to do with the heart and blood vessels, it is quite often that such patients are first found by eye doctors. They are either seen due to being very short-sighted or with dislocated lenses which can cause major problems in the eye.

Eye problems can be managed by regular observation, although they often require surgery. Because eye doctors are often the first to see these patients, they must involve other doctors of different specialities to help in diagnosing and managing important issues these patients may have, especially affecting the heart and major blood vessels.

Confirmation of diagnosis is done through genetic testing, which has advanced greatly, finding new mutations which may contribute to this disorder. Genetic counselling services can help families in understanding their diagnosis and making better informed decisions about future family planning as well as screening other family members. The eye is just one part of this complex genetic disease. We look in detail at how eye doctors can best approach such patients.

Keywords

ectopia lentis eye genetics management Marfan syndrome

Introduction

Antoine Marfan first described the condition in 1896 that would later be named after him (Marfan syndrome: MFS OMIM 154700).¹ MFS is a multisystem condition, diagnosed according to the revised 2010 Ghent criteria (see Figure 1).² Although a relevant family history is considered a positive indicator of the diagnosis, genetic confirmation adds a layer of certainty and is invaluable. It is inherited in an autosomal dominant manner and caused by mutations in the FBN1 gene, which encodes the protein fibrillin-1. Inheritance of the condition is from one affected parent in around 75% of patients. The remaining are thought to be as a result of sporadic mutations. The population incidence is 2–3 per 10,000.³ Since FBN1 was linked with MFS in 1991,⁴ more than 800 mutations in this gene have been identified.⁵

Figure 1.

Summarised Ghent criteria (2010). A diagnosis of Marfan Syndrome can be made when any ONE criteria is fulfilled. See Appendix 1 for full systemic score.

The major ocular association between ectopia lentis (EL) and MFS is well established. Ocular manifestations are common and best managed with early diagnosis. Frequent associations and their incidence include EL (subluxation or dislocation of the crystalline lens), which has been reported to occur in up to 70% of cases, and rhegmatogenous retinal detachment (RRD) in around one third.^6,7 Other manifestations include glaucoma, myopia and corneal flattening. The prevalence of these in MFS is unclear. Herein, we will discuss in detail the genetic architecture, ocular manifestations, diagnostic criteria and management.

Genetics overview

FBN1, a 66-exon gene located on chromosome 15 (15q21), is the major affected gene in MFS. As described in the Ghent criteria,² a causative FBN1 mutation with either aortic root dilatation or EL immediately diagnoses MFS and is a crucial criterion in the absence of family history (see Figure 1).

EL causing mutations may lead to post-translational folding defects in the protein. Misfolded fibrillin-1 accumulates in the endoplasmic reticulum, thus leading to haploinsufficiency. There is a predominance of missense mutations affecting cysteine residues in up to 70%;⁵ most often resulting in this residue being substituted.⁸ The first 15 exons (5′ end) harbour more EL causing mutations, suggesting that the N-terminus of the protein (encoded by this end of the gene) is particularly significant in the aetiology of EL.⁹ It has even been suggested that there is an inverse relationship between mutations in the distal part of the gene (3′ end) and EL.¹⁰

Overall, the calcium-binding epidermal growth factor (EGF)-like domains of fibrillin-1 are affected the most. Around 10% of mutations are shared between families.¹¹

A recent study of over 1500 patients demonstrated 643 different pathogenic variants.¹² The authors broadly categorised their variants into two categories: premature termination codon (PTC) mutations or ‘in-frame’ mutations. Interestingly, they found that EL was less common in those with PTC variants. Rather, they had more severe aortic phenotype with higher risk of aortic dissection. They also confirmed the association with ‘in-frame’ mutations in which cysteine residues were involved.

Another example of genotype–phenotype correlation was demonstrated by Hernándiz et al.,¹³ in which patients with haploinsufficiency-causing variants had a greater aortic involvement and systemic manifestation. By contrast, dominant-negative mutations, especially including cysteine substitution, more frequently presented with EL.

It has been acknowledged that 25% of disease-causing FBN1 variants are found to be de novo mutations, the remainder unknown. A recent study of 30 families suggested screening for parental somatic mosaicism should be routinely implemented in de novo cases of MFS after they found 2/30 families were found to have somatic mosaicism. It is becoming apparent that parental mosaicism may be more common in MFS than previously thought.^14,15 This can clarify clinical signs and symptoms and help in offering appropriate counselling and surveillance.¹⁶

Many autosomal recessive conditions have been demonstrated to cause EL (see Table 1). The most common recessive mutations affect members of the ADAMTS (A Disintegrin and Metalloproteinase with ThromboSpondin) family of proteins, resulting from a loss-of-function mechanism. This family contains 19 enzymatic members, and 7 ADAMTS-like proteins, which lack the protease domain of the ADAMTS proteins.¹⁷

Table 1.

Genes that cause ectopia lentis.

Gene	Inheritance	Condition	Reference
FBN1	AD	Marfan Syndrome; Incomplete Marfan Syndrome; Dominant Weill Marchesani Syndrome	Dietz et al.⁴ Chandra et al.¹⁰ Faivre et al.¹⁸
ADAMTS10	AR	Weil Marchesani Syndrome	Dagoneau et al.¹⁹
ADAMTS17	AR	Weil Marchesani Like	Morales et al.²⁰
ADAMTSL4	AR	Isolated Ectopia Lentis; Ectopia Lentis & Craniosynostosis; Ectopia Lentis et pupillae	Ahram et al.²¹ Chandra et al.²² Christensen et al.²³
CBS	AR	Homocystinuria	Kraus²⁴
COL18A1	AR	Knobloch	Sertié et al.²⁵
VSX2	AR	High Myopia, EL, cone-rod dystrophy	Khan et al.²⁶
PAX6	AR	Aniridia	Jin et al.²⁷
LTBP2	AR	Weil Marchesani Syndrome; Megalocornea, Spherophakia	Haji-Seyed-Javadi et al.²⁸ Désir et al.²⁹

AD, autosomal dominant; AR, autosomal recessive.

The most relevant of these mutations are in ADAMTSL4, located at chromosome 1q21.2. Mutations in this gene cause isolated ectopia lentis (IEL) and Ectopia Lentis et Pupillae (ELP).²² As the names suggest, these conditions are isolated with no systemic features. The ADAMTSL4 protein has been demonstrated in ocular tissue³⁰ and has been found to co-localise and co-function with fibrillin-1.³¹ Its most relevant role, demonstrated by EL, is likely to be in the structure and function of the ciliary zonule. It has been suggested that ADAMTSL4 has pleiotropic effects,³² but the gene’s true function is not yet known.

Other ADAMTS mutations have been described (see Table 2) to cause syndromes with EL, including ADAMTS10 (19p13), ADAMTS17 (15q26) and ADAMTS18 (16q23.1).^16,33

Table 2.

Recessive mutations in ADAMTS group.

Gene	Ocular phenotype	Reference
ADAMTS10	Weil Marchesani Syndrome 1 (OMIM 277600)	Dagoneau et al.¹⁹ Kutz et al.³⁴ Morales et al.²⁰
ADAMTS17	Weil Marchesani Like (OMIM 613915)	Morales et al.²⁰ Khan et al.³⁵
ADAMTS18	Early-onset retinal dystrophy	Peluso et al.³⁶
	Microcornea, myopic chorioretinal atrophy and telecanthus (MMCAT) (OMIM 615458)	Aldahmesh et al.³⁷
	Microcornea, early-onset cataract, ectopia pupillae	Chandra and Charteris³³
ADAMTSL4	Ectopia lentis and craniosynostosis (OMIM 603595)	Chandra et al.³²
	Ectopia lentis et papillae (OMIM 225200)	Christensen et al.²³ Chandra et al.²² Sharifi et al.³⁸
	Isolated ectopia lentis (OMIM 225100)	Ahram et al.²¹ Greene et al.³⁹ Neuhann et al.⁴⁰ Chandra et al.²² Aragon-Martin et al.⁴¹

Current genetic testing techniques and analysis

Investigation for a FBN1 mutation is a crucial element of confirming MFS. Relying on clinical criteria alone may lead to false negatives.⁴² The Ghent criteria² stipulate that identification of a mutation in FBN1, which is recognised to cause MFS, is a major diagnostic criterion.

Most commonly, DNA is extracted from a saliva or blood sample and quantified using fluorescent quantification. Sanger sequencing was traditionally the gold standard method to investigate for mutations; however, it requires the use of MLPA (multiplex ligation-dependent probe amplification) to study possible large deletions. The arrival of next-generation sequencing (NGS) in the past few years has revolutionised genetic interrogation. Many laboratories use genetic panels,⁴³ while others prefer whole exome sequencing (WES). This investigates the protein coding exons and the intronic/exonic boundaries;^44,45 however, the full intronic sequence is not covered. Deep intronic mutations are recognised in MFS,⁴⁶ hence whole genome sequencing (WGS) is preferred.

As the name suggests, WGS investigates every nucleotide, including intronic and regulatory regions and structural variants such as copy number variants (CNV) or large deletions,⁴⁷ which may be missed with WES. When investigating the whole genome, WGS allows researchers to interrogate mutations outside FBN1, which may cause conditions with very similar phenotypes to MFS. These include ACTA2 in thoracic aortic aneurysm and dissection (TAAD), ADAMTSL4 for IEL or TTLL11 for scoliosis.⁴⁸ This is particularly valuable if a variant of unknown significance is found in FBN1.

The data processing from NGS is time-consuming and requires a great knowledge of bioinformatics. The variants identified are analysed and variant interpretation tools are used to further clarify their significance. Finally, causative variants are confirmed with Sanger sequencing in the proband and preferably in affected family members to confirm co-segregation.

There are thought to be over 1000 mutations in FBN1⁴⁹ associated with MFS. It is important to interpret any FBN1 variants from the ophthalmic clinic in the context of updated curated databases to clarify if these have been described in MFS. More than 1800 different pathogenic variants in the FBN1 gene have been found, with a large variety of phenotypes.⁵⁰ We have previously demonstrated that FBN1 variants causing EL considered insignificant may subsequently become recognised as MFS mutations.¹⁰

The term ‘autosomal dominant isolated ectopia lentis’ has existed for those with FBN1 mutations causing EL without other clinical features of MFS. With this in mind, we showed that 46% of patients described as ‘FBN1 associated autosomal dominant ectopia lentis’ would subsequently be diagnosed as MFS based on their mutation.¹⁰ This suggests that EL caused by novel mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS. Thus, in the context of an FBN1 variant with EL, these patients should have regular cardiovascular review. We recommend the term ‘autosomal dominant isolated ectopia lentis’ be dismissed. Instead, we recommend ‘Incomplete Marfan Syndrome’ to highlight the importance of cardiac monitoring. The term ‘isolated ectopia lentis’ should be reserved for recessively inherited EL, particularly if a genetic mutation is found in a recognised gene such as ADAMTSL4.²²

A major study of 1013 probands with MFS showed that 48% did not have a previous family history, either because related carriers were asymptomatic or the mutation appeared sporadically.⁵ In the Sonalee laboratory (Imperial College London, UK) in 2021, FBN1 mutation was seen in 789/1186 (67%) participants. These mutations were classified as familial in 446 (56.5%) and sporadic in 343 (43.5%). Further analysis of the 393 probands only found 50 (12.7%) familial variants and 343 (87.3%) sporadic. Participants were classified with a sporadic mutation if there was no other family member in the database with the same mutation. Participants were classified with a familial mutation if there were at least one more family member in the database with the same mutation. Therefore, it is important that even in the absence of a family history, those with suggestive phenotypes are considered for genetic investigation. The advances in investigative techniques have led to mutations being discovered in over 90% of clinically suspicious patients with MFS.

Whether fourth-generation sequencing, a method of sequencing nucleic acids directly in fixed cells used in cancers,⁵¹ comes into use in MFS is yet to be considered. It is of the authors’ opinion that screening cells one at a time is more useful in cancer research due to various somatic mutations in different cells. This also aids in assessing tumour extent.

Although FBN1 mutations have been seen in individual exhibiting mosaicism, this arises when some cells do have the mutation in the heterozygote form and other cells show only the wild type. Fourth-generation sequencing of one cell at a time could be beneficial to confirm the mosaicism in a patient with MFS, but would not have a major role in routine screening with WGS [either with short DNA fragments (Illumina Inc., San Diego, USA) or large DNA fragments (Oxford Nanopore® or PacBio®)]. These large DNA fragment tools are also used mainly for CNV (Copy Number Variation), to interrogate large deletions that otherwise would not have been easily traced with WES or Sanger sequencing. It is clear that the role of genetic analysis in MFS is clearly critical and the future is promising.

Clinical overview and diagnostic criteria

MFS exhibits high inter-familial and intra-familial variability. Its broad phenotypic spectrum ranges from mild symptom free clinical features to rapidly progressive neonatal multisystem disease.³ MFS typically affects the cardiovascular, skeletal and ocular systems and can also involve the central nervous system, respiratory system and the skin.²

MFS diagnostic criteria consist of major and minor manifestations in different organ systems (Ghent Criteria).² The main clinical manifestations are EL and aortic root aneurysm/dissection. Other clinical features are less influential in the diagnostic evaluation and only contribute to a systemic score (see Appendix 1) that guides diagnosis in the presence of aortic disease but absence of EL. Genetic testing is crucial as it is also the third major criterion. In the absence of relevant family history, the diagnosis of MFS is made when any two of the following three features are present:

A disease-associated variant in the FBN1 gene;

Ectopia lentis;

Aortic root enlargement (Z-score ⩾2.0).²

The so-called ‘Marfanoid Habitus’ is described as tall, long, slender build⁵² associated with a wide range of skeletal findings including arachnodactyly, chest wall deformities and scoliosis. Facial features include a long, narrow face with deep set eyes, down slanting palpebral fissures, flat cheek bones and a small chin.³

Ocular manifestations

The ocular manifestations of MFS are varied. Visual morbidity is most commonly associated with EL and RRD; these will be discussed in greater detail.

Ectopia lentis

EL is defined as the abnormal location of the crystalline lens as it moves from its natural position. It is described as subluxation if within the pupillary plane or dislocation if the lens moves beyond this into the anterior or posterior segment. Beyond trauma, this condition can be inherited in four major ways:

Isolated Ectopia Lentis (IEL): autosomal recessive inheritance (OMIM # 225100);

Ectopia lentis et pupillae (ELP): autosomal recessive inheritance (OMIM# 225200);

As part of ocular dysgenesis (e.g. aniridia, ADAMTS18 mutations);

As part of systemic syndromes (most commonly MFS: autosomal dominant inheritance OMIM# 154700).³³

The human crystalline lens is held in its natural position behind the iris by the zonular filaments (ZF). Together, they form a ring-like structure between the equatorial lens and the ciliary body. Fibrillins are the major macromolecular component of ZF, the most abundant of which is fibrillin-1.⁵³ Fibrillin-1 is encoded by FBN1, hence mutations in this gene lead to disruption of the structure and function of fibrillin-1 and zonular dysfunction, causing EL.⁵⁴

EL is a hallmark feature (see Figure 2) and is considered an early sign of MFS with most displacements occurring in childhood. However, there is a small risk of developing lens displacement in adulthood.⁵⁵

Figure 2.

Ectopia lentis in MFS, the edge of the lens can be seen temporally within the pupillary plane.

Lens displacement can range from a subtle posterior tilt (often accompanied by iridodonesis) to frank dislocation. It is typically bilateral and symmetrical although unilateral cases have also been described.⁵⁶ Asymmetric zonular deficiency causes the lens to move towards the least affected zonules. Occasionally, only a small notch may be found on careful examination which may be just an incidental finding. If the zonular deficiency is circumferential around the equatorial region of the lens, the result is microspherophakia, which may result in lenticular myopia. If the lens tilts forward, this may cause pupil block, with a subsequent rise in intraocular pressure and accompanying corneal decompensation. Although more common in Weill Marchesani Syndrome, microspherophakia is encountered in other genetic causes of EL.⁵⁴

Classifications of EL have been proposed previously.³⁰ One example is a 5-grade classification by Zech et al.,⁵⁷ which is for EL specific to MFS. Their defined method includes measurement of visual acuity with and without correction, slit-lamp biomicroscopy, retro illumination and a three-mirror lens. The examination must be done in primary and downward gaze.

Grade 2 is described as that in which there is anteroposterior shift with superior displacement in primary gaze and visualisation of the equatorial part of the lens in downgaze. The authors demonstrated a specificity (100%) and positive predictive value (100%) when using it for clinical diagnosis of MFS. Other clinical features can vary depending on the underlying condition and are determined by the genotype-phenotype. IEL is a condition, as the name suggests, which has no features beyond EL. It is caused by mutations in ADAMTSL4 and most commonly presents in early childhood and tends to have a more severe ocular phenotype than MFS.²² Other features such as pupillary membranes might point to the diagnosis of ELP (also caused by mutations in ADAMSTL4).²²

Abnormal location of the crystalline lens may be asymptomatic, particularly if mild and not involving the visual axis. In children, particularly EL may be identified incidentally. Symptoms depend on the anatomy, position, clarity and location of the lens. Ectopic lenses are prone to cataract earlier which may be visually significant.

A subluxated lens can be managed conservatively. Optical correction with appropriate glasses or contact lenses (often to correct around the lens itself in the ‘aphakic’ part of the pupil) may be sufficient.

Surgery may be indicated for the following:⁵⁸

EL is causing the edge of the crystalline lens to interfere with the visual axis;

Required corrected visual acuity is no longer achievable using optical correction;

Intolerance to aphakic correction;

Troublesome fluctuation of vision caused by the instability of the lens;

To prevent amblyopia;

Anterior dislocation of the lens;

Lens-induced glaucoma or uveitis;

Visually significant cataract.

Surgical removal of the ectopic lens has many options. Patients may initially be left aphakic and managed with contact lenses. This is our preferred initial approach. However, in some cases, intraocular lens (IOL) implantation may be required, either as a primary or secondary procedure.⁵⁹

If limited zonular deficiency is found, an anterior approach may be undertaken. The major advantage of this approach would be the possibility of preserving the capsule. Techniques involving Cionni capsular tension rings (CTR) and segments have been reported to have utility in stabilising the capsule for IOL insertion.⁶⁰ However, long-term stability has not been reported. It is possible that gradual loss of zonular function may continue, perhaps exacerbated by the surgery. Therefore, our preferred approach is pars plana lensectomy together with vitrectomy which may offer long-term stability. Management of the aphakia in the absence of capsule then offers its own challenges.

FBN1-deficient capsule, zonules, iris and sclera of patients with MFS results in difficult iris and scleral fixation of IOL. Open-loop anterior chamber lenses have been used in MFS with some success, even in paediatric cases.⁶¹ However, the often very deep anterior chambers in MFS may compromise good anterior chamber intraocular lens (ACIOL) fitting resulting in potentially excessive movement of the IOLs. Artisan (iris claw ACIOL) may also provide good results in terms of improving vision, but high incidence of postoperative complications has been reported.⁶² Concerns have been raised regarding endothelial cell loss with these IOLs and for this reason surgeons may be reluctant to use such IOLs in younger patients. In an attempt to counter this, retro pupillary iris clip IOLs have been used.⁶³ Finally, IOLs may be fixed in the sclera in the posterior chamber either with or without sutures. There are numerous techniques available. Comparisons of different techniques are few, with equivalence being demonstrated in some studies.⁶⁴

Removal of both the lens and the vitreous gel together reduces the chances of secondary retinal detachment, which has been a significant complication of previous forms of surgery for lens dislocation in MFS.⁵⁹ IOL power calculation should be done with caution. Any extreme axial length (AL) can affect the reliability of biometry.⁶⁵

Currently, there is no consensus on which type of IOL is most suitable for these patients; therefore, decisions must be made on individual cases. Our preferred technique involves using GORE-TEX® sutures to fix four haptic IOLs. We report recent success with a partially sighted patient diagnosed with EL secondary to MFS. Their visual acuity was reduced to 6/60. With our technique of pars plana vitrectomy (PPV) and four-point fixation IOL with GORE-TEX® sutures, vision improved to 6/9; sufficient for him to hold a driving licence in the United Kingdom (see Figure 3).

Figure 3.

Partially sighted individual with MFS: (a) preoperative – ectopic lens with inferior displacement (VA 6/60), (b) intraoperative – Akreos® Insertion, four-point fixation of haptics with GORE-TEX®, Black Arrow shows suture threaded through haptic and (c) postoperative – 6 weeks after surgery, VA 6/9.

Refractive error

Myopia is more common in patients with MFS. The Ghent criteria suggest that myopia of greater than −3DS should be a minor criterion.²

However, refraction is a complex phenotype with many influencing endophenotypes, including corneal and lenticular structure; both of which are affected in MFS and other EL conditions. Substantial subluxation or dislocation of the crystalline lens may even render the eye hypermetropic and refraction may be somewhat unstable. Therefore, in addition to the relative prevalence of myopia in the general population, we do not feel that refraction serves any diagnostic utility in MFS.

Increased AL is commonly and consistently associated with EL regardless of the genetic aetiology. AL increases particularly when EL is prominent at a young age as a result of form deprivation myopia (FDM) and lens-induced myopia (LIM).⁵⁴

Corneas of patients with MFS with EL are flatter and have a higher degree of astigmatism. There is also correlation between eyes with longer AL and flatter corneal measurements.⁶⁶ It has even been suggested that corneal curvature may be a useful screening tool for the diagnosis of MFS and shows promising sensitivity and specificity.⁶⁷ Although reports regarding central corneal thickness (CCT) are varied, some studies suggest that this is also reduced significantly.^68,69

Therefore, we recommend that ocular examination, at least in the absence of EL, also should include full biometric measurements when MFS is suspected. AL should be used rather than refraction as the standard assessment, particularly in children. It has been suggested that AL/Total Corneal Refractive Power ratio may be a potential diagnostic factor for MFS and a better comparison with the myopia of greater than −3D model in terms of specificity and sensitivity. These results indicated that the new model had better discrimination than the myopia of greater than −3D model.⁷⁰ Careful examination of the subluxated state of the lens can help clarify the clinical situation and avoid inappropriate prescription.

As with all uncorrected refractive abnormalities, there is the risk of amblyopia. Refractive correction should not be underestimated as a simple and very effective method to manage children with MFS and can be crucial in preventing amblyopia. However, if these measures are insufficient and there is significant progression or once optimal vision is no longer obtainable with refractive correction, early surgical intervention in children with lens subluxation should be considered.⁷¹

Retinal detachment

Posterior segment pathology is reported to be present in 18% of eyes in MFS and the incidence is higher (70%) in patients with a subluxated lens.⁷² Retinal detachment (RD) is the most visually significant potential posterior segment complication. Risk factors for RD in MFS include younger age, EL and aphakia.⁵⁸ We have previously reported that RD in MFS tends to occur bilaterally (30–42% of cases), and women with MFS seem to develop RD earlier than their male counterparts.⁷ This is in contrast to RD affecting those without MFS.

RD can occasionally occur as a complication of surgery to remove a subluxated or dislocated crystalline lens. Although more significant lenticular displacement and high axial myopia are thought to be significant risk factors for RD development after vitreolensectomy,⁷³ this complication is now much less common with modern surgical approaches. What is unclear is whether the apparent risks of RD are in direct relation to the increased axial myopia in the MFS population or an inherent risk of FBN1 mutations. MFS does not present a clear vitreoretinopathy, clinically. Pathology at the vitreoretinal interface has not been demonstrated.

RD repair can involve either scleral buckling or vitrectomy. The choice of which approach is used will be dependent on the age of the patient, the status of the vitreous, clarity of view and surgeon and patient choice.

Glaucoma

Glaucoma is a common ocular finding in patients with MFS, the most common type being primary open angle glaucoma (POAG); in cases accompanying the syndrome, glaucoma is usually diagnosed at a younger age than in the general population.⁷⁴ Microfibril defects could alter elasticity of the trabecular meshwork and episcleral veins, which could impede the pumping action and the pulsatile outflow of aqueous humour, increasing the propensity to ocular hypertension.^75–77 Furthermore, alterations to the compliance of the sclera may have an impact on the lamina cribrosa and thus the vulnerability of the ganglion cells.⁷⁸

Prostaglandin analogues may be preferred for POAG in MFS. Patients may already be taking β blockers, and it is probably advisable therefore to avoid topical supplementation.

Secondary open angle glaucoma may occur due to RD, vitreoretinal or lens extraction surgeries, iritis, or pigment dispersion due to excessive movement of crystalline or intracapsular IOL.^79,80 The latter cause may require peripheral iridotomy.⁸¹

Primary angle closure can result from anterior subluxation of the lens resulting in a pupillary block mechanism. Surgical intervention is therefore often required early in anterior displaced lens. Glaucoma surgery in patients with MFS should be done with caution. Thin sclera and higher risk of hypotony can complicate procedures.⁸¹

Strabismus

Strabismus may present in MFS, and if left uncorrected in children can result in amblyopia. It is suggested to be present in 19% of individuals with MFS, compared to 3–5% in the general population, and may be a presenting sign of the disorder.^82,83 Abnormalities in FBN1 in extraocular muscle pulleys and reduced stability may explain the higher incidence of strabismus in patients with MFS.⁸⁴

Correction of strabismus is done by extraocular muscle surgery. Since many patients have binocular function potential and are young at diagnosis, if good surgical alignment is achieved, favourable visual outcome may be expected.

Summary

MFS is often first identified in an eye clinic. We have demonstrated its importance and relevance to an ophthalmologist as well as the salient features of the eye. Genetic diagnosis, family counselling and using a multidisciplinary approach are vital.

Once diagnosed, ocular manifestations can be monitored for complications and appropriately managed. We have illustrated the most common conditions. EL is a hallmark feature that must not be underestimated and dealt with in a timely manner. A good visual outcome may be obtained with prompt intervention.

Footnotes

Appendix 1

Systemic manifestations scoring chart.

Systemic sign	pts
Wrist AND thumb sign	3
Wrist OR Thumb sign	1
Pectus carinatum deformity	2
Pectus excavatum or chest asymmetry	1
Hindfoot deformity	2
Plain Pes Planus	1
Pneumothorax	2
Dural ectasia	2
Protrusio acetabuli	2
Reduced Upper Segment/Lower Segment ratio AND increased arm/height AND no severe scoliosis	1
Scoliosis or thoracolumbar kyphosis	1
Reduced elbow extension	1
Facial features (3/5) (dolichocephaly, enophthalmos, down slanting palpebral fissures, malar hypoplasia, retrognathia)	1
Skin striae	1
Myopia > 3 diopters	1
Mitral valve prolapse (all types)	1

Score ⩾7 indicates systemic involvement.

(Maximum total possible: 20 points).

Author contributions

Haseeb Akram: data curation, writing: original draft, writing: review and editing.

Jose Antonio Aragon-Martin: data curation, writing: original draft, writing: review and editing, resources

Aman Chandra: conceptualization, data curation, writing: original draft, writing: review and editing, supervision.

Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Haseeb Akram

References

Gott

. Antoine Marfan and his syndrome: one hundred years later. Md Med J 1998; 47: 247–252.

Loeys

Dietz

Braverman

, et al The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010; 47: 476–485.

Judge

Dietz

. Marfan’s syndrome. Lancet 2005; 366: 1965–1976.

Dietz

Cutting

Pyeritz

, et al Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991; 352: 337–339, https://www.nature.com/articles/352337a0 (accessed 5 December 2020).

Faivre

Collod-Beroud

Loeys

, et al Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007; 81: 454–466, https://www.sciencedirect.com/science/article/pii/S0002929707613433 (accessed 26 December 2020).

Wakita

Ryu

Nakayasu

, et al Statistical analysis of Marfan’s syndrome. Nippon Ganka Gakkai Zasshi 1989; 93: 682–690, https://europepmc.org/article/med/2816576 (accessed 6 December 2020).

Chandra

Ekwalla

Child

, et al Prevalence of ectopia lentis and retinal detachment in Marfan syndrome. Acta Ophthalmol 2014; 92: e82–e83.

Faivre

Collod-Beroud

Callewaert

, et al 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; 149A: 854–860.

Turner

CLS

Emery

Collins

, et al Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy. Am J Med Genet A 2009; 149A: 161–170.

10.

Chandra

Patel

Aragon-Martin

, et al The revised Ghent nosology; reclassifying isolated ectopia lentis. Clin Genet 2015; 87: 284–287.

11.

Baetens

van Laer

de Leeneer

, et al Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat 2011; 32: 1053–1062.

12.

Arnaud

Milleron

Hanna

, et al Clinical relevance of genotype–phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants. Genet Med 2021; 23: 1296–1304.

13.

Hernándiz

Zúñiga

Valera

, et al Genotype FBN1/phenotype relationship in a cohort of patients with Marfan syndrome. Clin Genet 2021; 99: 269–280.

14.

Chesneau

Plancke

Rolland

, et al Parental mosaicism in Marfan and Ehlers–Danlos syndromes and related disorders. Eur J Hum Genet 2021; 29: 771–779.

15.

Arnaud

Morel

Milleron

, et al Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome. Genet Med 2021; 23: 865–871.

16.

Fernández-Álvarez

Codina-Sola

Valenzuela

, et al A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome. J Med Genet. Epub ahead of print 28 April 2021. DOI: 10.1136/JMEDGENET-2020-107604.

17.

Tang

. ADAMTS: a novel family of extracellular matrix proteases. Int J Biochem Cell Biol 2001; 33: 33–44.

18.

Faivre

Gorlin

Wirtz

, et al In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet 2003; 40: 34–36.

19.

Dagoneau

Benoist-Lasselin

Huber

, et al ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet 2004; 75: 801–806, https://www.sciencedirect.com/science/article/pii/S0002929707627037 (accessed 6 June 2021).

20.

Morales

Al-Sharif

Khalil

, et al Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet 2009; 85: 558–568, https://www.sciencedirect.com/science/article/pii/S0002929709004078 (accessed 6 June 2021).

21.

Ahram

Sato

Kohilan

, et al A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 2009; 84: 274–278, https://www.sciencedirect.com/science/article/pii/S0002929709000147 (accessed 6 June 2021).

22.

Chandra

Aragon-Martin

Hughes

, et al A genotype-phenotype comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis. Invest Ophthalmol Vis Sci 2012; 53: 4889–4896.

23.

Christensen

Fiskerstrand

Knappskog

, et al A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae. Invest Ophthalmol Vis Sci 2010; 51: 6369–6373.

24.

Kraus

. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis 1994; 17: 383–390.

25.

Sertié

Sossi

Camargo

, et al Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum Mol Genet 2000; 9: 2051–2058, https://academic.oup.com/hmg/article-abstract/9/13/2051/627378 (accessed 6 June 2021).

26.

Khan

Aldahmesh

Noor

, et al Lens subluxation and retinal dysfunction in a girl with homozygous VSX2 mutation. Ophthalmic Genet 2015; 36: 8–13.

27.

Jin

Wang

, et al A recurrent PAX6 mutation is associated with aniridia and congenital progressive cataract in a Chinese family. Mol Vis 2012; 18: 465–470, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291521/ (accessed 6 June 2021).

28.

Haji-Seyed-Javadi

Jelodari-Mamaghani

Paylakhi

, et al LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat 2012; 33: 1182–1187.

29.

Désir

Sznajer

Depasse

, et al LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma. Eur J Hum Genet 2010; 18: 761–767, https://www.nature.com/articles/ejhg201011?free=2 (accessed 6 June 2021).

30.

Chandra

Jones

Cottrill

, et al Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina. Br J Ophthalmol 2013; 97: 1208–1212, https://bjo.bmj.com/content/97/9/1208.short (accessed 26 December 2020).

31.

Gabriel

Wang

Bader

, et al ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest Ophthalmol Vis Sci 2012; 53: 461–469, https://iovs.arvojournals.org/article.aspx?articleid=2127219 (accessed 26 December 2020).

32.

Chandra

Aragon-Martin

Sharif

, et al Craniosynostosis with ectopia lentis and a homozygous 20-base deletion in ADAMTSL4. Ophthalmic Genet 2013; 34: 78–82.

33.

Chandra

Charteris

. Molecular pathogenesis and management strategies of ectopia lentis. Eye 2014; 28: 162–168.

34.

Kutz

Wang

Dagoneau

, et al Functional analysis of an ADAMTS10 signal peptide mutation in Weill-Marchesani syndrome demonstrates a long-range effect on secretion of the full-length enzyme. Hum Mutat 2008; 29: 1425–1434.

35.

Khan

Aldahmesh

Al-Ghadeer

, et al Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation. Ophthalmic Genet 2012; 33: 235–239.

36.

Peluso

Conte

Testa

, et al The ADAMTS18 gene is responsible for autosomal recessive early onset severe retinal dystrophy. Orphanet J Rare Dis 2013; 8: 16.

37.

Aldahmesh

Alshammari

Khan

, et al The syndrome of microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is caused by mutations in ADAMTS18. Hum Mutat 2013; 34: 1195–1199.

38.

Sharifi

Tjon-Fo-Sang

Cruysberg

JRM

, et al Ectopia lentis et pupillae in four generations caused by novel mutations in the ADAMTSL4 gene. Br J Ophthalmol 2013; 97: 583–587.

39.

Greene

Stoetzel

Pelletier

, et al Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis. Ophthalmic Genet 2010; 31: 47–51.

40.

Neuhann

Artelt

Neuhann

, et al A homozygous microdeletion within ADAMTSL4 in patients with isolated ectopia lentis: evidence of a founder mutation. Invest Ophthalmol Vis Sci 2011; 52: 695–700, https://iovs.arvojournals.org/article.aspx?articleid=2126736 (accessed 6 June 2021).

41.

Aragon-Martin

Ahnood

Charteris

, et al Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients. Hum Mutat 2010; 31: E1622–E1631.

42.

Fuchs

Rosenberg

. Congenital ectopia lentis, A Danish national survey. Acta Ophthalmol Scand 1998; 76: 20–26.

43.

Bean

LJH

Funke

Carlston

, et al Diagnostic gene sequencing panels: from design to report – a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2020; 22: 453–461.

44.

Fusco

Morlino

Micale

, et al Characterization of two novel intronic variants affecting splicing in FBN1-related disorders. Genes 2019; 10: 442.

45.

Torrado

Maneiro

Trujillo-Quintero

, et al A novel heterozygous intronic mutation in the FBN1 gene contributes to FBN1 RNA Missplicing events in the Marfan syndrome. Biomed Res Int 2018; 2018: 3536495, https://www.hindawi.com/journals/bmri/2018/3536495/abs/ (accessed 10 January 2021).

46.

Gillis

Kempers

Salemink

, et al

An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an explanation for genetically unsolved cases?

Hum Mutat 2014; 35: 571–574.

47.

Benke

Ágg

Meienberg

, et al Hungarian Marfan family with large FBN1 deletion calls attention to copy number variation detection in the current NGS era. J Thorac Dis 2018; 10: 2456–2460.

48.

Mathieu

Patten

Aragon-Martin

, et al Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family. Sci Rep 2021; 11: 11026, https://www.nature.com/articles/s41598-021-90155-0 (accessed 6 June 2021).

49.

Sakai

Keene

Renard

, et al FBN1: the disease-causing gene for Marfan syndrome and other genetic disorders. Gene 2016; 591: 279–291, https://www.sciencedirect.com/science/article/pii/S0378111916305595 (accessed 22 February 2021).

50.

Collod-Béroud

. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 2003; 22: 199–208.

51.

Mignardi

Hauling

, et al Fourth generation of next-generation sequencing technologies: promise and consequences. Hum Mutat 2016; 37: 1363–1367.

52.

Child

. Non-cardiac manifestations of Marfan syndrome. Ann Cardiothorac Surg 2017; 6: 599–609.

53.

Traboulsi

Whittum-Hudson

Mir

, et al Microfibril abnormalities of the lens capsule in patients with Marfan syndrome and ectopia lentis. Ophthalmic Genet 2000; 21: 9–15.

54.

Black

Ashworth

. Clinical ophthalmic genetics and genomics. Amsterdam: Elsevier Science, 2021, https://books.google.co.uk/books?id=acuEuAEACAAJ

55.

Sandvik

Vanem

Rand-Hendriksen

, et al Ten-year reinvestigation of ocular manifestations in Marfan syndrome. Clin Exp Ophthalmol 2019; 47: 212–218.

56.

Child

. Diagnosis and management of Marfan syndrome. London: Springer, 2016, https://books.google.co.uk/books?id=W8btCwAAQBAJ

57.

Zech

J-C

Putoux

Decullier

, et al Classifying ectopia lentis in Marfan syndrome into five grades of increasing severity. J Clin Med 2020; 9: 721, https://www.mdpi.com/659170 (accessed 7 August 2021).

58.

Esfandiari

Ansari

Mohammad-Rabei

, et al Management strategies of ocular abnormalities in patients with Marfan syndrome: current perspective. J Ophthalmic Vis Res 2019; 14: 71–77.

59.

Hubbard

. Vitreolensectomy in Marfan’s syndrome. Eye 1998; 12: 412–416, https://www.nature.com/articles/eye199897 (accessed 24 February 2021).

60.

Hasanee

Butler

Ahmed

IIE

. Capsular tension rings and related devices: current concepts. Curr Opin Ophthalmol 2006; 17: 31–41, https://journals.lww.com/co-ophthalmology/fulltext/2006/02000/capsular_tension_rings_and_related_devices_.7.aspx (accessed 6 June 2021).

61.

Morrison

Sternberg

Jr Donahue

. Anterior chamber intraocular lens (ACIOL) placement after pars plana lensectomy in pediatric Marfan syndrome. J AAPOS 2005; 9: 240–242, https://www.sciencedirect.com/science/article/pii/S1091853105000522 (accessed 6 June 2021).

62.

Çevik

MÖ

Özmen

. Iris-claw intraocular lens implantation in children with ectopia lentis. Arq Bras Oftalmol 2017; 80: 114–117, https://www.scielo.br/scielo.php?pid=S0004-27492017000200114&script=sci_arttext (accessed 24 February 2021).

63.

Faria

Ferreira

Neto

. Retropupillary iris-claw intraocular lens in ectopia lentis in Marfan syndrome. Int Med Case Rep J 2016; 9: 149–153, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918898/ (accessed 6 June 2021).

64.

Erdogan

Kandemir Besek

Onal Gunay

, et al Outcomes of three surgical approaches for managing ectopia lentis in Marfan syndrome. Eur J Ophthalmol. Epub ahead of print 7 February 2021. DOI: 10.1177/1120672121992950.

65.

Jiménez-Alfaro

Miguélez

Bueno

, et al Clear lens extraction and implantation of negative-power posterior chamber intraocular lenses to correct extreme myopia. J Cataract Refract Surg 1998; 24: 1310–1316, https://www.sciencedirect.com/science/article/pii/S0886335098802204 (accessed 24 February 2021).

66.

Kinori

Wehrli

Kassem

, et al Biometry characteristics in adults and children with Marfan syndrome: from the Marfan Eye Consortium of Chicago. Am J Ophthalmol 2017; 177: 144–149.

67.

Wang

Lian

Zhou

, et al Differential diagnosis of Marfan syndrome based on ocular biologic parameters. Ann Transl Med 2020; 8: 1354–1354.

68.

Heur

Costin

Crowe

, et al The value of keratometry and central corneal thickness measurements in the clinical diagnosis of Marfan syndrome. Am J Ophthalmol 2008; 145: 997–1001.

69.

Salchow

Gehle

. Ocular manifestations of Marfan syndrome in children and adolescents. Eur J Ophthalmol 2019; 29: 38–43.

70.

Chen

Jin

, et al Clinical ocular diagnostic model of Marfan syndrome in patients with congenital ectopia lentis by Pentacam AXL system. Transl Vis Sci Technol 2021; 10: 3, https://arvojournals.org/article.aspx?articleid=2772657 (accessed 7 August 2021).

71.

Romano

Kerr

Hope

. Bilateral ametropic functional amblyopia in genetic ectopia lentis: its relation to the amount of subluxation, an indicator for early surgical management. Binocul Vis Strabismus Q 2002; 17: 235–241, https://europepmc.org/article/med/12171598 (accessed 27 December 2020).

72.

Rahmani

Lyon

Fawzi

, et al Retinal disease in Marfan syndrome: from the Marfan Eye Consortium of Chicago. Ophthalmic Surg Lasers Imaging Retina 2015; 46: 936–941.

73.

Fan

Luo

Liu

, et al Risk factors for postoperative complications in lensectomy-vitrectomy with or without intraocular lens placement in ectopia lentis associated with Marfan syndrome. Br J Ophthalmol 2014; 98: 1338–1342.

74.

Izquierdo

Traboulsi

Enger

, et al Glaucoma in the Marfan syndrome. Trans Am Ophthalmol Soc 1992; 90: 111–117; discussion 118–122.

75.

Kuchtey

. The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure. J Ocul Pharmacol Ther 2014; 30: 170–180.

76.

Sigal

Yang

Roberts

, et al

IOP-induced lamina cribrosa deformation and scleral canal expansion: independent or related?

Invest Ophthalmol Vis Sci 2011; 52: 9023–9032, https://iovs.arvojournals.org/article.aspx?articleid=2187504 (accessed 6 June 2021).

77.

Maumenee

. The eye in the Marfan syndrome. Trans Am Ophthalmol Soc 1981; 79: 684–733.

78.

Burian

Allen

. Histologic study of the chamber angle of patients with Marfan’s syndrome: a discussion of the cases of Theobald, Reeh and Lehman, and Sadí de Buen and Velázquez. Arch Ophthalmol 1961; 65: 323–333.

79.

Chakravarti

Spaeth

. An overlap syndrome of pigment dispersion and pigmentary glaucoma accompanied by Marfan syndrome: case report with literature review. J Curr Glaucoma Pract 2013; 7: 91–95.

80.

Doyle

Hamard

Puech

, et al Asymmetric pigmentary glaucoma in a patient with Marfan’s syndrome. Graefes Arch Clin Exp Ophthalmol 2005; 243: 955–957.

81.

Turaga

Senthil

Jalali

. Recurrent spontaneous scleral rupture in Marfan’s syndrome. BMJ Case Rep 2016; 2016: bcr2016214764, https://casereports.bmj.com/content/2016/bcr-2016-214764.abstract (accessed 6 June 2021).

82.

Izquierdo

Traboulsi

Enger

, et al Strabismus in the Marfan syndrome. Am J Ophthalmol 1994; 117: 632–635, https://www.sciencedirect.com/science/article/pii/S0002939414700698 (accessed 27 December 2020).

83.

Cross

Jensen

. Ocular manifestations in the Marfan syndrome and homocystinuria. Am J Ophthalmol 1973; 75: 405–420.

84.

Clark

Velez

, et al Incomitant strabismus associated with instability of rectus pulleys. Invest Ophthalmol Vis Sci 2002; 43: 2169–2178, http://arvojournals.org/article.aspx?articleID=2122986 (accessed 6 June 2021).