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Clinical science
Ocular morbidity in Marfan syndrome: a nationwide epidemiological study
  1. Sia Kjeldsen1,
  2. Niels Andersen2,
  3. Kristian Groth2,
  4. Dorte Larsen1,
  5. Jesper Hjortdal1,
  6. Agnethe Berglund3,
  7. Claus Gravholt4,5,
  8. Kirstine Stochholm4,6
  1. 1Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark
  2. 2Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
  3. 3Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark
  4. 4Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
  5. 5Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  6. 6Centre of Rare Diseases, Pediatrics, Aarhus University Hospital, Aarhus, Denmark
  1. Correspondence to Dr Sia Kjeldsen, Aarhus University Hospital, Aarhus N 8200, Denmark; siakjeld{at}rm.dk

Abstract

Background Ophthalmic complications are profound in Marfan syndrome (MFS). However, the overall burden is not well described. Our purpose was to evaluate the ocular morbidity in a nationwide perspective.

Methods We identified the ocular morbidity in patients with MFS (n=407) by use of Danish national healthcare registers, using number and timing of hospital contacts related to ophthalmic diagnoses, to ophthalmic surgery and to prescriptions for ophthalmic medication. An age-matched and gender-matched background population (n=40 700) was used as comparator.

Results Among MFS, 56% (226/407) of the patients had at least one registration of an ophthalmic diagnosis as inpatient or outpatient during the study period (HR of 8.0 (95% CI 7.0 to 9.2)). Seven out of 11 main groups of diagnoses were affected, including ‘Lens’, ‘Choroid and retina’, ‘Ocular muscles, binocular movement, accommodation and refraction’, ‘Glaucoma’, Visual disturbances and blindness’, ‘Vitreous body and globe’, and ‘Sclera, cornea, iris and ciliary body’. The number of surgical procedures as well as the use of ophthalmic medication in patients with MFS was significantly increased.

Conclusion This nationwide epidemiological study of ocular morbidity in MFS demonstrates a profound burden and emphasises the need for thorough and experienced ophthalmological surveillance.

  • lens and zonules
  • retina
  • glaucoma
  • cornea
  • genetics

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information. Not applicable.

https://doi.org/10.1136/bjophthalmol-2021-320871

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    Key message

    What is already known in this topic

    • Ophthalmic complications are profound in Marfan syndrome (MFS). Severe myopia and ectopia lentis are key manifestations of MFS.

    What this study adds

    • This nationwide epidemiological study demonstrates an immense ophthalmological burden in patients with MFS with early and increased registrations in almost all areas, including diagnoses, surgery and medication.

    How this study might affect research, practice or policy

    • Thorough ophthalmological surveillance is needed, due to the increased risk of refractive amblyopia, glaucoma and retinal detachment, which are all sight-threatening conditions.

    Introduction

    Marfan syndrome (MFS) is a rare inherited disorder of connective tissue with multisystem involvement1 and a reported prevalence of 6.5 per 100 000.2 Most persons with MFS carry an autosomal mutation in the FBN1 gene3 and thus an affected function of the extracellular matrix protein, fibrillin-1, which contributes to the integrity and function of connective tissue.4

    The burden of ophthalmic morbidity in MFS is profound, and this is also noted in the literature.5–7

    In 1982, a comprehensive review on the eye in MFS described enlargement of the globe, flattened cornea, dislocation of the lens, thin choroid, retinal detachment, increased axial length, increased number of patients with either myopia or hypermetropia, and severely reduced vision in 15 out of 151 patients.5

    At present, severe myopia and ectopia lentis (EL) are key manifestations in the clinical diagnosis of MFS (Ghent criteria).6 Myopia is found in 34%–44% of patients with MFS, compared with 4,8% in the general population.7 EL is one of the main findings in MFS, ranging from 33% to close to 100%.5 8–10

    The exact pathogenesis of the ocular abnormalities of MFS is unknown11; however, mouse models show that disruption of both the elastic fibre and collagen fibril ultrastructure, caused by dysfunctional fibrillin-1 glycoprotein, results in corneal diseases11 and EL.12

    Many case series describing specific eye diseases in MFS are reported.5 8 10 13–17 However, a complete overview in a nationwide setting is lacking. Thus, our purpose was to evaluate the ocular morbidity, using registrations in hospitals, surgery and redeemed prescriptions as indicators, in a nationwide cohort of persons with MFS compared with the background population.

    Materials and methods

    Previously, we identified all patients registered with Ghent II verified MFS in Denmark in 1977 to 20142; in total 412 patients. In brief, we verified the MFS diagnosis after manual evaluation of their medical records and application of the Ghent-II criteria, and listed their civil registration number, given to all Danes at birth2 and time of diagnosis. Four hundred seven patients with MFS (194 women) were included as they were alive at the beginning of the study period or born during the study period.

    We retrieved information from Statistics Denmark, the central authority on Danish statistics, where information from several national registries is available, including the National Patient Registry (NPR). Statistics Denmark registrations are mandatory for all hospitals and pharmacies in Denmark, and is a valuable tool for epidemiological research.18 Hajari et al showed that NPR on retinal detachment has a registration error of 0.36–3%.19

    Statistics Denmark used the civil registration number and identified patients with MFS individually in all relevant registries and ensured identification of 100 controls per patient with MFS matched on age (year of birth), place of living (at diagnosis) and gender.

    Thus, to describe the ocular morbidity in the 407 patients with MFS and their 40 700 controls, we retrieved the following registrations, including dates of contact:

    • Ophthalmic diagnoses, all inpatient and outpatient hospital contacts in Denmark, using International Classification of Diseases (ICD), 10th edition.

    • Ophthalmic surgery, information on all registrations corresponding to the ‘KC’ code, in the Nomesco Classification of Surgical Procedure (NCSP).

    • Ophthalmic medication, information on all redeemed prescriptions using the Anatomical Therapeutic Chemical code (ATC).

    We divided all ophthalmic registrations in the ICD 10 system (table 1), in the NSCP system (table 2), and in the ATC system (table 3) into main groups, and, when relevant, further into subgroups. For all main group and subgroup registrations, we only used the first registration, regardless of time of registration.

    View this table:
    Table 1

    All ophthalmic diagnoses in The International Classification of Diseases, 10th edition (ICD-10), divided in 11 main groups (in bold) and in subgroups

    View this table:
    Table 2

    HRs of all first registrations in The Nomesco Classification of Surgical Procedure (NCSP), in total and divided into 10 main groups

    View this table:
    Table 3

    All registrations of ophthalmic medication in total and in specific areas from the Anatomical Therapeutic Chemical (ATC) code

    Statistics Denmark does not hold information of over-the-counter medicine or of clinical data, for instance on use of tobacco, the use of glasses or similar, or whether one or two eyes were affected. Further, there is no information concerning registrations from general ophthalmologists who cover an estimated 80% of all consultations related to the eye in Denmark. The general ophthalmologists normally perform routine examinations including surveillance and routine operations, whereas the more complicated procedures such as surgical treatment of dislocated crystalline lenses, glaucoma and vitreoretinal surgery take place at department of ophthalmology in public hospitals.

    All persons with MFS were diagnosed from 1977 to 2014 and alive in 1994 or later (table 4).

    View this table:
    Table 4

    Background data on all Danes diagnosed with Marfan syndrome in 1977 to 2014, and alive 1 January 1994 or later

    The registrations from Statistics Denmark were from 1 January 1977 to 31 December 2017.

    Statistics

    Basic epidemiological data are given using median and 95% CIs. Due to the non-parametric data, Kruskall-Wallis was used to describe differences in age at registration. Time to first registration in all main groups and subgroups was analysed using stratified Cox regression, where each person with MFS and his or her matched controls constituting one stratum, reporting a HR. For the overall analyses, time at risk started at birth of the person with MFS or on date of start of registry, which ever came first. Time at risk ended on date of relevant registration, date of death, end of study, or emigration, whichever came first. Less than 10 MFS persons emigrated during the study period.

    Cox regression was also undertaken in all non-operated patients and controls. Thus, all patients and controls were excluded from all calculations if they at any time had a registration of ‘KC’ within the NCSP system, indicating that they had undergone surgery, regardless of date of surgery. Year of birth was applied as covariate on analyses in persons with MFS only. Stata V.16.1 for Windows (StataCorp LP) was used for all calculations.

    Results

    The occurrence of ophthalmic diagnoses (HR: 8.1, CI 7.0 to 9.2), ophthalmic surgery (HR: 8.4, CI 6.9 to 10.2) and ophthalmic medication (1.18, CI 1.05 to 1.31) were significantly increased in MFS compared with controls, caused by increased numbers of registrations generally as well as a younger age at registration. For all above, men and women were equally affected in MFS (no further data shown).

    Ophthalmic diagnoses

    Combined, 56% (226/407) patients with MFS had at least one ophthalmic diagnose registration as inpatient or outpatient during the study period, corresponding to an HR of 8.1 (95% CI 7.0 to 9.2; figure 1).

    Figure 1
    Figure 1

    Kaplan-Meier estimates—time without a registration of an ophthalmic diagnosis at a hospital. Proportion of persons with Marfan syndrome (grey lines) and controls (black lines) without registration of a hospital diagnosis relating to an ophthalmic disease.

    Patients with MFS were significantly younger at first registration (29.4 years, range 0.4–74.8 vs 42.7 years, range 0.1–92.4), p<0.05.

    The HR was significantly increased in 7 out of 11 main groups (table 1), namely in ‘Sclera, cornea, iris and ciliary body’, ‘Lens’, ‘Choroid and retina’, ‘Glaucoma’, " Vitreous body and globe’, ‘Ocular muscles, binocular movement, accommodation and refraction’, and in ‘Visual disturbances and blindness’. The following subgroups were significantly affected: ‘Senile cataract’, ‘Secondary cataract’ and ‘Ectopia lentis’, ‘Retinal detachments’, ‘Vitreous body’, ‘Strabismus’, Hypermetropia’, ‘Myopia’ and ‘Astigmatism’.

    Twenty-eight patients with MFS were registered with one or more ophthalmic diagnoses at least 1 year before their MFS diagnosis; the diagnosis was EL in two of these.

    Ophthalmic surgery

    Combined, 28% (113/407) patients with MFS had at least one registration of ophthalmic surgery during the study period, corresponding to an HR of 8.4 (95% CI 6.9 to 10.1) (figure 2).

    Figure 2
    Figure 2

    Kaplan-Meier estimate—time without a registration of ophthalmic surgery at a hospital. Proportion of persons with Marfan syndrome (grey lines) and controls (black lines) with no registration of ophthalmic surgery.

    Patients with MFS underwent surgery at a younger age (33.9 years, range 3.4–74.3 vs 53.3 years, range 1.0–91.6). In the NCSP system, the surgical registrations in hospital care due to ophthalmic causes were significantly increased in the categories ‘Globe’, ‘Ocular muscles’, ‘Conjunctiva’, ‘Cornea and sclera’, ‘Anterior chamber, anterior chamber angle, iris and ciliary body’, ‘Lens’, and ‘Choroid, vitreous body and retina’ (table 2). Twenty-one per cent (85/407) of patients with MFS had a surgery registration in ‘Lens’ and 16% (64/407) had a registration in ‘Choroid, vitreous body and retina’.

    Scrutinising our data, we found that 49 out of the 58 with MFS, who were registered with retinal detachment surgery (NCSP codes KCKC and KCKD), were registered prior to or concurrently with any kind of lens surgery, emphasising the severely increased additional risk of retinal detachment.

    Fifteen patients with MFS had been registered as undergoing surgery in the anterior chamber of the eye. Twelve out of these 15 persons had another NCSP registration before or simultaneously, indicating that most of the anterior eye chamber surgery is due to complications associated to other ocular surgery.

    Ophthalmic medication

    The use of ophthalmic medication was significantly more frequent in patients with MFS (table 3). The increased use was in the main groups of ‘Glucocorticoids’, ‘Antibiotics and glucocorticoids’, and in ‘Glaucoma’. Excluding patients with previous ophthalmic surgery (corresponding to NCSP ‘KC’), this increase was still present for ‘Glucocorticoids’ and ‘Glaucoma’.

    Discussion

    The present study demonstrates that the ophthalmic morbidity burden is immense in MFS with a significantly increased risk of disease in 7 of 11 main diagnostic groups, significantly increased risk of intervention in 7 of 10 main surgical groups and increased medical treatment in 3 of 4 main drug classes compared with controls. As data mirror the natural history and clinical practise of ocular morbidity in patients with MFS, we consider data highly relevant and valid, regardless of organisation of healthcare system.

    As expected, we found a significantly increased number of patients with MFS with disorders of the lens and with lens surgery. The diagnosis EL was solely registered in patients with MFS, and in a very high number (52 patients with MFS vs 0 controls), which underlines why it is included as a central clinical feature in the Ghent II nosology.6 However, EL is not pathognomonic for persons with MFS, as it is present in other diseases like autosomal dominant EL, autosomal recessive EL, Weill-Marchesani syndrome, homocystinuria and Knobloch syndrome.20

    Registrations of diagnoses related to ‘Choroid and retina’ in MFS was significantly increased compared with controls, primarily due to registrations in the subgroup ‘Retinal detachments and breaks’. Moreover, surgery related to choroid, vitreous body and retina was significantly increased in patients with MFS (64 patients out of the 407) with an HR above 20. The mean axial length is longer in persons with MFS and EL compared with persons with MFS without EL, probably due to scleral stretching,5 8 13 21 which could explain the high risk of retinal detachment once a person with MFS has a dislocated lens.22

    The number of registrations of cataracts in the MFS group was also significantly increased. The exact pathogenesis is not known. As described in earlier reports, cataract surgery is common in persons with MFS although it is typically surgery for a subluxated otherwise clear crystalline lens.23 However, in FBN1 gene knockout mice, it has been shown that a dislocated lens will eventually result in the development of cataract, because of a range of histopathological changes.12

    The increased number of patients with a glaucoma registration could be a true risk of glaucoma in persons with mutations in the FBN1 gene24 or due to transient increased intraocular pressure secondary to intraocular surgery.25 The risk of glaucoma in MFS is debated since Maumenee et al5 did not find glaucoma as a common disease in MFS while others even found that the intraocular pressure was low in MFS.8 14 An apparent low intraocular pressure measurement may, however, be caused by decreased resistance to deformation of the cornea, which has been observed in patients with MFS.26

    Vitreous degeneration and vitreous haemorrhage were also significantly more common in MFS compared with controls. The increased axial length in patients with MFS with a dislocated lens increases the risk of having vitreous degeneration or haemorrhage.27 28 However, vitreous degeneration is a physiological condition, often with few subjective symptoms and optimised ophthalmological surveillance in outpatient clinic settings will undoubtedly result in a higher number of registrations of vitreous degenerations.

    The significantly increased risk of diseases in ‘Sclera, cornea, iris and ciliary body’ in MFS compared with controls is in line with the flatter cornea in persons with MFS with dislocated lenses,8 21 29 30 and with the known iris transillumination defects.5 8 Corneal parameters are not included in the 2010 revised Ghent Nosology for MFS6; however, it has been suggested that corneal parameters should be measured if MFS is suspected.8 29 30 In these patients, measurement of corneal topography could qualify the clinical suspicion.

    Registrations in ‘Ocular muscles, binocular movement, accommodation and refraction’ were also significantly increased in persons with MFS. This corresponds with the much wider distribution of ocular refraction in MFS than in the normal population and a higher proportion of extreme refractive errors.5 The higher occurrence of hypermetropia in MFS could partly be explained by an aphakic refraction caused by a totally dislocated lens or lack of artificial intraocular lens implantation after lens removal. The higher frequency of myopia could be ascribed to enlargement of the globe, one of the most striking ocular abnormalities in persons with MFS.5

    In the ‘Strabismus’ subgroup, we observed a significantly increased risk of disease, in line with previous findings, as it is reported in MFS in 19%–45% (compared with 3%–5% in the general population).22 This might be caused by a poor visual acuity in at least one eye, perhaps as a result of ocular complications, for example, dislocation of the lens or retinal detachment. The diagnosis ‘Strabismus’ is not translated into a high level of ocular muscle surgery.

    Visual disturbances and blindness were significantly more frequent in MFS, however, with a low absolute number. Earlier studies have shown that only a few with MFS are visually impaired.9 13

    Patients with MFS had an overall significantly increased risk of receiving topical ophthalmic medication throughout their lifetime. However, in cases that had no registration of ophthalmic surgery, the difference was solely related to increased use of glucocorticoids and glaucoma medication. This supports the earlier described possibility of a true increased basic risk of glaucoma in patients with MFS. The higher number of patients using corticosteroids could be related to postoperative treatment. However, we have no explanation as to why the group of patients with MFS with no earlier surgery has a higher risk of use of topical corticosteroids.

    Strengths and limitations

    A limitation of the current study is the lack of clinical data, especially data on the use of optical correction, and whether one or two eyes are affected. Further, as MFS is a rare disease with well-established risk of ophthalmological complications, it is highly likely that also patients with minor ophthalmic findings in MFS are referred to hospitals more often than subjects in the control group. As this is an explorative study, we did not perform any testing for multiplicity issues; thus, data should be interpreted with caution. Strengths of this study are the inclusion of a nationally identified cohort of persons with MFS as well as the uniform approach covering all ophthalmic complications in one investigation. Moreover, the possibility to use the registers with cross-linkage, which enables identification of the age-matched controls and the linkage to all hospital contacts, is of paramount importance.

    Conclusions

    Ophthalmic complications severely impact the lives of most patients with MFS with early and increased registrations in almost all areas, including diagnoses, surgery and medication. This emphasises the need for an early MFS diagnosis as well as thorough and experienced ophthalmological surveillance, due to the increased risk of refractive amblyopia, glaucoma and retinal detachment, which are all sight-threatening conditions.

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplemental information. Not applicable.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The Danish Data Protection Authority approved the project with the registration number 2011-41-6986. Data were accessed using a secure remote access to Statistics Denmark. In order to avoid any possibility of personal identification of cases, Statistics Denmark prohibits specification of the exact number of cases with a given condition if less than 4, and we therefore report these as ‘<4’.

    Acknowledgments

    Claus H. Gravholt and Kirstine Stochholm are members of the European Reference Network on Rare Endocrine Conditions (ENDO-ERN), Project ID number 739 543.

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    Footnotes

    • Contributors SK, NA, KG, CG and KS conceptualised and designed the study, designed the data collection, collected data, and carried out all analysis and calculations, drafted the initial manuscript and reviewed and revised the manuscript. DL, JH and AB supervised data collection, contributed to the design of the study and critically reviewed the manuscript. SK acted as guarantor, responsible for the overall content of the study.

    • Funding This study was supported by a grant from Aarhus University. No grant number available.

    • Disclaimer The funding organisation had no role in the design or conduct of this research.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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