The Underlying Relationship between Keratoconus and Down Syndrome
Abstract
:1. Introduction
2. Ophthalmic Manifestations of Down Syndrome
3. Genetics of Keratoconus and Down Syndrome
4. Central Corneal Thickness (CCT) of Keratoconus and Down Syndrome Patients
5. Eye Rubbing in Keratoconus and Down Syndrome Patients
6. Diagnosis/Treatment of Keratoconus in Down Syndrome Patients
7. Mouse Models of DS for KC
8. Summary and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Title of Article | Sample Size | Mean Age/Age Range of DS Patients | Ethnicity | KC Diagnosis and/or Instrument Used | Findings | Reference |
---|---|---|---|---|---|---|
Corneal Morphologic Characteristics in Patients with Down Syndrome | 112 DS patients | 14.88 ± 15.76 years Range: 3 months–60 years | DS group—59% Caucasians, and 41% Arabs | Visual, refractive, anterior, and posterior corneal characteristics were assessed and compared in both groups using Placido disc/Scheimpflug camera topographer (Sirius, CSO) | Patients with DS have steeper, thinner corneas and more corneal aberrations compared to those without genetic alterations. | [30] |
Ophthalmological abnormalities in Down syndrome among Brazilian patients | 1207 DS patients | No mean age reported Range: 0–42 years | Brazilians | Slit-lamp evaluation, corneal pachymetry, and topography were used for KC detection | A prevalence of KC of 27.2 % was observed among 1207 persons with Down syndrome | [65] |
Emmetropisation, axial length, and corneal topography in teenagers with Down’s syndrome | 50 DS patients | 17.4 years Range: 15–22 years | Mancunians | TMS-1 machine was used for corneal topographic mapping. Slit lamp examination was also conducted | Prevalence of KC in this cohort was 2%, but 6% had corneal topography with inferior steepening, which may represent a preclinical keratoconic process. | [66] |
Clinical profile and main comorbidities of Spanish adults with Down syndrome | 144 DS patients | 35 ± 12 years Range: 17–65 years | Spanish | Not mentioned | KC is a prominent ocular feature associated with DS in individuals > 50 years. | [68] |
Corneal thickness measured by Sheimpflug imaging in children with Down syndrome | 27 DS patients | 8.94 ± 2.35 years Range: 5–12 years | Turkish | CCT, TP, and CV were analyzed using Pentacam Scheimpflug imaging system | Corneal thickness was lower in DS children than in healthy control subjects. | [42] |
Prevalence of ocular abnormalities in adults with Down syndrome in Hong Kong | 91 DS patients | 38 years ± 6.5 years Range: 30–56 years | Chinese | Corneal pachymetry was measured using a handheld ultrasound pachymeter | There is a high prevalence of corneal problems (including KC) in Chinese DS patients. | [43] |
The ophthalmic anomalies in children with Down Syndrome in Split-Dalmatian County | 153 DS patients | 11.7 ± 3.2 years Range: 0–18 years | Croatians | Biomicroscopic examination of the anterior eye segment | Though less common than other refractive disorders, KC was observed in patients with DS. | [57] |
Incidence of ocular pathologies in Italian children with Down Syndrome | 157 DS patients | 5.28 years Range: 1 month –18 years | Italians | Slit lamp biomicroscopy | No KC was observed in this cohort of DS patients. | [47] |
Ocular findings in Malaysian children with Down syndrome | 60 DS patients | 6.72 ± 3.38 years Range: 1 month –17 years | Malaysians | Slit lamp biomicroscopy and Placido disc | No KC was observed in this cohort of DS patients. | [59] |
Computerized corneal topography in a pediatric population with Down syndrome | 21 DS patients | 6.9 years Range: 10 months–18 years | Caucasians | Slit-lamp biomicroscopy, scissoring or oil-drop reflex on retinoscopy, corneal topography mapping using using the EyeSys Computer-Assisted Videokeratoscope | Corneal curvature in DS children was significantly steeper than in the control population. | [41] |
Prevalence of ocular diagnoses found on screening 1539 adults with intellectual disabilities | 1539 DS patients | 45.7 years Range: 20.2–88.7 years | Dutch | Slit-lamp biomicroscopy | KC is independently related to DS (OR 7.65, 95% CI, 3.91 to 14.96). | [55] |
Characteristic ocular findings in Asian children with Down syndrome | 123 DS patients | 6.5 years Range: 6 months–14 years | Koreans | Visual acuity assessment, slit-lamp biomicroscopy | KC was not observed in this cohort of Asian DS patients. | [33] |
Biometric measurements of the eyes in teenagers and young adults with Down syndrome | 47 DS patients | 20.0 ± 3.9 years Range: 14–26 years | Norwegians | Retinoscopy reflexes, central corneal thickness and anterior chamber depth were measured with a A Nidek Model EAS-1000 anterior eye segment analysis system. Corneal topography was analyzed with a TechnoMed C-Scan V2.0.0. Corneal curvature was also measured with a hand-held Nidek autokeratometer KM-500 | DS patients have thinner corneas and higher keratometry values compared to control. | [40] |
Ocular abnormalities in Down syndrome: an analysis of 140 Chinese children | 140 DS patients | 3.74 years Range: 3 months–13 years | Chinese | Visual acuity assessment, slit-lamp biomicroscopy | No KC was observed in this DS cohort. | [58] |
Health care concerns and guidelines for adults with Down syndrome | 38 DS patients | 36.2 years for middle aged DS patients Range: 30–43 years old 59.7 years for elderly DS patients Range: 47–68 years old | Canadians | Not mentioned | KC was observed in 15.8% of all DS adults. | [69] |
Corneal ectasia in mothers of Down syndrome children | 77 MDS and 63 MNC controls | Mean age at the time of examination was 48.81 ± 6.93 years in MDS and 48.46 ± 8.35 years in MNC | Iranians | Slit-lamp biomicroscopy, corneal tomography was assessed using Oculus Pentacam HR and corneal biomechanics was also measured using Corneal Visualization Scheimpflug Technology | Mild KC was identified in 30.9% (21 cases) in the MDS in comparison with 14.3% (9 cases) MNC. | [70] |
Prevalence of Keratoconus in Persons with Down Syndrome in a National Registry in Norway | 4342 DS patients | 37.1 years Range: Not reported | Norwegians | Data analysis from International Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes Q90 for Down syndrome and H18.6 for KC from 1 January 2010, to 31 December 2019 | A prevalence of KC of 238 (5.5%) was observed among 4342 DS patients. | [13] |
Keratoconus detection by novel indices in patients with Down syndrome: a cohort population-based study | 250 DS patients | 17.0 ± 4.7 years Range: 10–30 years | Iranians | Slit-lamp examinations, topographic indices were measured by Pentacam HR and corneal biomechanics were examined using the Corvis ST | A prevalence of KC of 28 (12.39%) was observed among the DS patients. | [71] |
Corneal grafting for keratoconus in mentally retarded patients | 33 DS patients | 36.7 ± 10.8 years Range: 18–60 years | Norwegians | Not reported | KC was observed in 33 mentally retarded patients with DS. | [72] |
Title of Paper | Sample Size | Ethnicity | Extract from Study | Reference |
---|---|---|---|---|
Corneal Morphologic Characteristics in Patients with Down Syndrome | 112 DS patients | DS group—59% Caucasians, and 41% Arabs | “Furthermore, it has been reported that patients with DS frequently rub their eyes which is a habit related to keratoconus development owing to the inflammation process and biomechanical alterations linked to eye rubbing habit” | [30] |
Prevalence of ocular abnormalities in adults with Down syndrome in Hong Kong | 91 DS patients | Chinese | “This, together with frequent eye rubbing, may predispose DS patients to keratoconus” | [43] |
The Ocular Features of Down’s Syndrome | 53 DS patients | Caucasians | “The cause of this increased incidence of keratoconus in Down’s syndrome is unknown. Several investigators have suggested eye rubbing as a probable cause” | [145] |
Acute keratoconus with perforation in a patient with Down’s syndrome | 1 DS patient | Austrian | “Habitual eye rubbing, which is frequently observed in patients with Down’s syndrome and other forms of mental deficiency, has been postulated as an important factor not only for the development of keratoconus itself” | [146] |
Posterior corneal features in patients with Down syndrome and their relation with keratoconus | 20 DS patients | Spanish | “Furthermore, patients with DS used to rub their eyes, and it is well known that the eye rubbing habit is an important risk factor for keratoconus development” | [36] |
Computerized corneal topography in a pediatric population with Down syndrome | 21 DS patients | Canadians | “Some authors have attributed the high prevalence of keratoconus in patients with Down syndrome to chronic eye rubbing because of irritation caused by blepharitis, seen in 7–47% of patients with Down syndrome” | [41] |
Keratoconus and corneal morphology in patients with Down syndrome at a pediatric hospital | 31 DS patients | 16 Caucasians, 10 Hispanics, 3 “other” patients, and 1 unreported patient | “Eye rubbing may also play a role in development of keratoconus and eye rubbing is commonly reported in patients with DS” | [38] |
Biometric measurements of the eyes in teenagers and young adults with Down syndrome | 47 DS patients | Norwegians | “A thin cornea must be assumed to be particularly vulnerable to eye rubbing, and together these factors might lead to clinically manifest keratoconus in many Down syndrome patients” | [40] |
Ocular findings in Malaysian children with Down syndrome | 60 DS patients | Malaysians | “However, there has been no established evidence to link genetic abnormality of Down syndrome to keratoconus. It is thought to be due to eye rubbing or underlying structural abnormalities of the cornea” | [59] |
Topographic screening reveals keratoconus to be extremely common in Down syndrome | 48 DS patients | New Zealanders | “Eye rubbing behaviour is also common in DS and may further contribute to the predisposition to keratoconus development” | [147] |
Acute Corneal Hydrops in Down Syndrome | 1 DS patient | Japanese | “Habitual eye rubbing, which is frequently observed in patients with Down syndrome and other forms of mental deficiency, has been postulated as an important factor, not only for the development of keratoconus” | [148] |
Evaluation of early corneal topographic changes in children with Down syndrome | 27 DS patients | Caucasians | “Habitual eye rubbing, which is also frequently observed in patients with DS, has been postulated as a crucial factor either for the development of keratoconus or the progression of the disease” | [149] |
Keratoconus detection by novel indices in patients with Down syndrome: a cohort population-based study | 250 DS patients | Iranians | “Eye rubbing was reported in 18.1% of the healthy individuals, in 13.6% of those with suspected KC, in 19.6% of those with KC, and in 21.1% of those with progressive KC” | [71] |
Severe acute corneal hydrops in a patient with Down syndrome and persistent eye rubbing | 1 DS patient | Turkish | “Eye-rubbing may play a role in the pathogenesis of acute hydrops,” | [150] |
Amniotic membrane transplantation with cauterization for keratoconus complicated by persistent hydrops in mentally retarded patients | 8 DS patients | Polish | “Vigorous eye rubbing is a cause of extensive hydrops in mentally retarded patients with keratoconus” | [151] |
Mouse Model | Description | Clinical Phenotype in DS | Limitation(s) | Reference(s) |
---|---|---|---|---|
Ts16 (Trisomy 16) | First mouse model released in 1980, trisomic for all parts of mouse chromosome 16 in synteny with human chromosome 21 | Early developmental abnormalities | Barely survived to term by dying in utero, syntenic with other regions of human chromosome 3 and human chromosome 8 | [181,182,183,184] |
Ts65Dn | Segmentally trisomic for about 55% of genes on mouse chromosome 16 that are homologous to segment MRP139-ZNF295 on human chromosome 21 | Impaired vision and hearing, congenital heart defects, learning and memory deficits | Difficulty in using model in vision research due to retinal degeneration, male mice are sterile | [181,183,185,186] |
Ts1Cje | Produced from the reciprocal translocation between the distal portion of mouse chromosome 16 and the end of chromosome 12. Trisomic for a shorter region of mouse chromosome 16, which is smaller than that in Ts65Dn mouse spanning from Sod1 to Mx1 genes | Craniofacial abnormalities | Loss of a functional variant of superoxide dismutase1 | [181,183] |
Ts2Cje (Derivative of Ts65Dn) | Developed from Ts65Dn mice by a Robertsonian translocation of the extra chromosome of Ts65Dn mice onto mouse chromosome 12 | Similar features as seen in Ts65Dn mice—congenital heart defects, learning and memory deficits | Although improved compared to the Ts65Dn, males still have moderate fertility | [181,187] |
Tc1 | First transchromosomic (Tc) mouse DS model with a nearly complete fragment of human chromosome 21 including most of the gene orthologs located on mouse chromosome 10, 16, and 17 | Congenital heart defects, learning and memory deficits, motor coordination defects | Mosaic trisomy, where the human chromosome 21 is lost randomly in a large number of cells | [178,188,189] |
TcMAC21 | Humanized DS mouse model containing a clone of the long arm of the human chromosome 21 as an artificial mouse chromosome | Learning and memory deficits, craniofacial abnormalities, heart anomalies | Made up of some deletions that affect about 8% of genes found on the long arm human chromosome 21 | [178,188] |
Ts1Rhr | Segmental trisomic model containing segments of mouse chromosome 16 that are homologous to human chromosome 21. The model is also trisomic for the DS-critical region (DSCR) known to contain genes that may influence mental abnormalities in DS | Learning and memory impairment, craniofacial abnormalities | May not show accurate phenotypic feature in DS due to the inability of the trisomic region for the DSCR to impair hippocampal function in the brain | [190] |
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Akoto, T.; Li, J.J.; Estes, A.J.; Karamichos, D.; Liu, Y. The Underlying Relationship between Keratoconus and Down Syndrome. Int. J. Mol. Sci. 2022, 23, 10796. https://doi.org/10.3390/ijms231810796
Akoto T, Li JJ, Estes AJ, Karamichos D, Liu Y. The Underlying Relationship between Keratoconus and Down Syndrome. International Journal of Molecular Sciences. 2022; 23(18):10796. https://doi.org/10.3390/ijms231810796
Chicago/Turabian StyleAkoto, Theresa, Jiemin J. Li, Amy J. Estes, Dimitrios Karamichos, and Yutao Liu. 2022. "The Underlying Relationship between Keratoconus and Down Syndrome" International Journal of Molecular Sciences 23, no. 18: 10796. https://doi.org/10.3390/ijms231810796