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Original Investigation | Ophthalmic Molecular Genetics

Distinct Ocular Expression in Infants and Children With Down Syndrome in Cairo, Egypt Myopia and Heart Disease FREE

Hanan H. Afifi, MD, PhD1; Amira A. Abdel Azeem, MD2; Hala T. El-Bassyouni, MD, PhD1; Moataz E. Gheith, MD3; Akmal Rizk, MD4; J. Bronwyn Bateman, MD5
[+] Author Affiliations
1Department of Clinical Genetics, National Research Centre, Cairo, Egypt
2Department of Ophthalmogenetics, Research Institute of Ophthalmology, Cairo, Egypt
3Department of Ophthalmology, Research Institute of Ophthalmology, Cairo, Egypt
4Department of Pediatric Ophthalmology, Research Institute of Ophthalmology, Cairo, Egypt
5Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles
JAMA Ophthalmol. 2013;131(8):1057-1066. doi:10.1001/jamaophthalmol.2013.644.
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Published online

Importance  The study establishes the importance of genetic background for the expression of Down syndrome phenotype.

Objective  To define the ocular manifestations of Down syndrome in infants and children in Cairo, Egypt, a historically isolated region, and compare them with systemic features and with findings in other geographic groups.

Design and Participants  We prospectively studied the ocular status and systemic features of 90 infants and children with Down syndrome and monitored all patients for 3 years. The complete ophthalmic examinations were performed along with ultrasonography, if media opacities were evident. Thyroid and cardiac status were assessed. An extensive literature search for comparison was performed.

Setting  Outpatient clinical genetics department at the National Research Centre in Cairo, Egypt.

Main Outcomes and Measures  Ocular and systemic manifestations of Down syndrome in infants and children in Cairo, and comparison of these features with patients with this anomaly from other geographic regions and ethnic populations.

Results  Fifty-two infants or children (58%) had at least 1 abnormal ocular finding identified at the first visit. Significant refractive errors (in 37 [41%] patients) were the most common. Nasolacrimal duct obstruction, blepharoconjuctivitis, or conjunctivitis was found in 18 (20%), strabismus in 13 (14%), cataract in 5 (6%), nystagmus in 3 (3%), and optic nerve dysplasia in 2 (2%). Brushfield spots were not found. Additional ocular features developed over time. Thirty-six patients (40%) had congenital heart defects, and many (31 [86%]) had associated ocular disorders; a statistically significant correlation with myopia was established. Chromosomal translocations were high. The phenotype in Cairo was distinct.

Conclusions and Relevance  More than half of infants and children with Down syndrome in Cairo had ophthalmic abnormalities; myopia was correlated with congenital heart defects. Comparison of the specific ocular features in our population with those in previous worldwide studies shows differences that may be related to overexpression or polymorphisms of key, modifying genes or other mutations in this historically isolated region along the Nile River. Down syndrome is more common in the highly consanguineous and multiparous Middle Eastern populations, and our Cairo findings underscore regional differences.

Down syndrome (triplicate of all or part of chromosome 21 [HSA21]; OMIM 1906851) is a common cause of mental retardation, with a prevalence in Western societies ranging from 0.9 per 1000 live births in the United States2 to 1.4 and 1.7 per 1000 live births in the Netherlands,3 and France,4 respectively; in US second-trimester pregnancies (16-week fetuses), the prevalence is 2.0 per 1000 live births.5 Advanced maternal age6 was identified as the major risk factor before the identification of the normal number of human chromosomes. Subsequently, maternal parity7,8 was established as an additional independent risk factor, and genetic predisposition for chromosomal nondisjunction as a third independent risk factor.4,914 An increased risk for Down syndrome may be the result of an autosomal recessive gene mutation, particularly in the Middle East.1517 The live-birth incidence in the United States varies geographically and by ethnicity, maternal education, and marital status2; as an isolated factor, socioeconomic status does not affect risk.18 The availability of prenatal diagnosis and pregnancy termination as well as ethnic and religious values influence the prevalence of live births for Down syndrome.

In the Middle East, the prevalence of Down syndrome is relatively high, ranging from 1.8 per 1000 live births in Libya19 to 2.0 in Qatar,20 2.3 in Saudi Arabia,21 3.1 in Dubai,8 and up to 3.6 in Kuwait.10 Birth rates and parity in this region are high, and advanced maternal age and consanguinity are common; pregnancy termination is rare. Down syndrome has been correlated with parental consanguinity in Egypt,12,13 Kuwait,13 and Saudi Arabia.22 In Saudi Arabia, a relationship between consanguinity and congenital heart disease (CHD) has been established.14 Although, to our knowledge, population-based studies of the prevalence of live births for Down syndrome in Egypt have not been published, this condition may be more common than in a Western age-matched population.

The phenotype of Down syndrome is caused by triplicate of all or part of chromosome 21, resulting from nondisjunction with 3 complete chromosome 21s and an unbalanced translocation with some or all of chromosome 21 attached to another chromosome; mosaicism may also occur. The ocular and systemic features of Down syndrome are protean, and cardiac malformations are common. Some forms of the CHD found in patients with Down syndrome (ventriculoseptal defect, atrioseptal defect, atrioventricular septal defect, pulmonary stenosis, and pulmonary atresia) may be inherited in an autosomal recessive pattern in Middle Eastern populations,23 complicating the study of associations in consanguineous populations. Although no regional mapping has been performed for the ocular features, the facial features have been mapped to the 21q22 region.24

The ocular features of the disorder, first described by Langdon Down in the mid-19th century, include epicanthus, obliquely positioned and narrow palpebral fissures, and increased interinternal canthal distances (as hypertelorism); reports of decreased interpupillary distance (as hypotelorism) have been published.24 Multiple publications have expanded the ocular phenotype to include common pediatric conditions such as blepharoconjunctivitis, conjunctivitis, nasolacrimal duct obstruction, significant refractive errors, and strabismus; less common diseases, such as glaucoma, cataract, optic nerve hypoplasia or dysplasia, nystagmus, and keratoconus, also have been described.

For millennia, the current Egyptian borders have been subject to invaders from the Mediterranean (including the Greeks, Romans, and Ottomans) in the north (Alexandria and the Southern Mediterranean) and from the south (the Nubian region of modern Southern Egypt and the Northern Sudan). Cairo divides Egypt into Upper Egypt, south to the Sudan border, and Lower Egypt, north to the Mediterranean, including Alexandria. The population in Cairo, although large, has remained relatively isolated along the Nile River with an ancient agricultural heritage, and thus does not have the genetic diversity of Europe, the Americas, some parts of Asia, or some other regions of the Middle East. Therefore, we studied a large population of Egyptian infants and children with Down syndrome from the Cairo region to identify ocular abnormalities and study their associations with systemic disease, comparing our findings with those described in other regions of the world. The study patients were representative of a socioeconomic cross-section of the Cairo region because of readily available public access to the National Research Centre in Cairo, a centralized resource; the widespread, esteemed reputation of this public institution; an extensive Egyptian primary care network; and universal health care coverage. We found major differences among geographic regions worldwide and postulate that the bases for these differences include the underlying genetic background in the Cairo/Nile region and, possibly, autosomal recessive founder effects.

This prospective 3-year study of infants and children with Down syndrome was initiated in 2006 and included all individuals referred to the Clinical Genetics Clinic at the National Research Centre in Cairo with a diagnosis of Down syndrome; all patients were referred for a complete eye examination. The study population is representative of the region (Cairo and surrounding villages) because of referral patterns, easy public access to the site, affiliation of this public institution with the Ministry of Health, an extensive primary care network, and universal health care coverage in Egypt. The investigation was approved by the institutional review board (National Research Centre Ethical Research Committee) of the Egyptian Research Institute of Ophthalmology in Cairo, in compliance with the Declaration of Helsinki; informed consent was obtained from the parent or guardian for each patient. The inclusion criteria were clinical evidence of Down syndrome and cytogenetic confirmation. A parent or guardian of each prospective patient was queried about family history (with a pedigree constructed) as well as the patient’s developmental and medical information. Physical and ocular examinations were performed in each patient; enrollment in an early stimulation and intervention program (Portage program25) was offered. The parent or guardian committed to regular follow-up visits for 3 years.

The physical examination included height and weight measurement; external evaluation of body habitus, including face, ears, hands, and feet; and cardiac auscultation. Each patient underwent cardiac ultrasonographic examination and thyroid testing (free triiodothyronine [T3], free levorotatory thyroxine [T4], and thyrotropin).

Ocular examination was performed by a pediatric ophthalmologist (M.E.G. or A.R.) and included assessment of visual acuity, monocularly if feasible, with figures as targets; pupillary responses; extraocular muscle movement; ocular alignment, assessed using the corneal light reflex test and the cross-cover test (prisms), if feasible; cycloplegic refraction, following the use of 2 drops of cyclopentolate and retinoscopy; and ophthalmoscopy. Uncooperative infants and children were examined while under anesthesia with cycloplegia. Eyeglasses were prescribed for myopia of −1.50 spherical equivalents or less, hyperopia of at least +1.00 spherical equivalent, and astigmatism of more than 1.50 diopters. These criteria were consistent with modifications for developmental delay (American Academy of Ophthalmology Preferred Practice Patterns for the Pediatric Eye Evaluation26). Ocular ultrasonography was performed in patients with significant media opacities. The diagnosis of CHD was based on results of cardiac auscultation and ultrasonography in each patient. G-banding chromosomal analysis was performed in each patient according to standard methods.

Patients were reassessed at least every 3 months with ocular and physical examinations. The follow-up period ranged from 31 to 36 months, with a mean of 33.2 months. The follow-up ocular examination included assessment of visual acuity; cycloplegic refraction was performed at least every 6 months. At each visit, an interim medical history was obtained, and the physical examination included measurement of height, weight, and cardiac auscultation.

Statistical analyses27 were conductedby age group, frequency of ophthalmic disorders, and types of refractive errors. The frequency of heart defects in infants and children with ocular anomalies was calculated, and the association of heart defects with ocular anomalies was assessed by using χ2 and Fisher exact tests.

Ninety infants and children with Down syndrome were included in the study (47 boys and 43 girls); their ages ranged from 3 months to 10 years (mean age, 2.2 years) at initial examination. Parental consanguinity was found in 26 patients (29%). Two children had a family history of Down syndrome; neither proband nor their affected first cousins was the product of a known consanguineous mating. All mothers were 40 years of age or older. The ocular features are summarized in Table 1 and Table 2.

Table Graphic Jump LocationTable 1.  Reported Prevalence or Incidence of Ocular Features or Abnormalities in Down Syndrome in Cairo, Egypt, and Other Countries1
Table Graphic Jump LocationTable 2.  Ophthalmic Features by Age at Last Examination

Fifty-two patients (58%) had ophthalmic disorders at the first visit; refractive errors were the most common followed by nasolacrimal duct obstruction, conjunctivitis, or blepharoconjunctivitis (combined because of clinical overlap); strabismus; infantile or juvenile cataract; nystagmus; and tilted optic disc or optic nerve dysplasia (Tables 1 and 2). Two patients with significant myopia had tilted (dysplastic) optic nerve heads. Twelve additional findings were identified during the monitoring period, including 2 cases of esotropia and 10 of conjunctivitis or blepharoconjunctivitis. All patients had an element of hypertelorism (external observation), epicanthic folds, and upward slanting of palpebral fissures. None had Brushfield spots. Ocular abnormalities increased with age (χ2 = 66.9; P < .001) (Table 2). Hyperopia was the most common type of refractive error (Table 3); differences among refractive errors in different age groups were not statistically significant (χ2 = 0.53; P = .97).

Ultrasonographic results were consistent with refractive errors; no vitreous or retinal abnormalities were identified. Karyotype analyses revealed nondisjunction trisomy 21 in 85 patients (94%); 1 patient had a mosaic trisomy 21 and 4 probands had unique translocations. Thyroid assessment revealed that 5 patients (6%) had thyroid dysfunction (3 were hypothyroid and 2 were hyperthyroid).

Thirty-six patients (40%) had congenital heart defects, the most common being isolated atrioseptal and ventriculoseptal defects. In Table 4, heart defects are analyzed in relation to ocular anomalies. The infants and children with CHD were more likely to have myopia (P = .03) and less likely to have astigmatism (P = .045). There was no statistical correlation between ocular anomalies and the cytogenetic or thyroid findings. Of the 36 infants or children with CHD, 31 (86%) had associated ocular disorders; 2 patients had cataract and none had optic nerve dysplasia.

Table Graphic Jump LocationTable 4.  Heart Defects in Egyptian (Cairo) Children With Down Syndrome and Ocular Anomalies

In this prospective study of 90 Egyptian patients with Down syndrome from the Cairo region, we describe the ocular abnormalities in 52 patients (58%) and compare our results with those in other populations as summarized in Table 1, which is based on searches in MEDLINE (keywords: Down syndrome, eye, and ocular) and citations in reviews,28,29,7679 with a full search of AMED, BMI, EMBASE, HMIC, MEDLINE, PsycINFO, and CINAHL in 200979; sources included English-language publications since the late 1950s, when the chromosomal basis of Down syndrome was identified and loupes and slitlamp biomicroscopy became available. In several studies from the 1950s, some large, the diagnosis was based on clinical criteria, and included ocular manifestations. The studies in Table 1 are observational, with some cross-sectional or retrospective, and categorized by geographic regions to underscore differences with our Cairo population. Comparisons are limited by inconsistent or vague definitions of some features (eg, refractive errors and blepharitis/conjunctivitis/nasolacrimal duct obstruction); lack of cycloplegic refractions for accurate assessment of refractive error; variability with respect to population age range and institutionalization status; descriptions of risk factors for nystagmus (eg, media opacities); differences in examination methods; racial background in countries with diverse populations, such as the United States; and other parameters. We identified inconsistencies and numerical miscalculations within publications, particularly in the early reports (corrected in Table 1).

Characteristic facial features of Down syndrome, such as epicanthus (or mongoloid fold), upward slanting of the palpebral fissures, low-set ears, and protruding tongue, are hallmarks of the condition, and the reported prevalences vary, depending on definitions. Some features, such as refractive error and strabismus, occur in the general population and are associated with developmental delay more commonly, and some, such as glaucoma, can be attributed to Down syndrome. Because genetic background, modifier genes, and environment may influence the ocular manifestations in Down syndrome, it is essential to compare regional and ethnic populations. Systemic diseases were rarely included in Down syndrome reports in the ophthalmologic literature.

Overall, refractive errors or ophthalmic abnormalities commonly occur in at least 1 eye of individuals with Down syndrome, and rates vary considerably within and among geographic regions (Table 1). Thirty-seven (41%) of our patients with Down syndrome had refractive errors, primarily hyperopia, in at least 1 eye at initial examination, and the percentage increased with age. Although many studies do not include refractive details, studies of Europeans,30,31 Americans,32 Koreans,33,34 and Brazilians,35 using cycloplegia, found hyperopia and astigmatism to be most common. Myopia was more common in Malaysia, where the patients were also studied with the use of cycloplegic agents.36 Large refractive errors (some, unspecified number of patients with cycloplegia) was correlated with more profound developmental delay in pediatric patients in Israel37; high myopia is a feature of Down syndrome28 and has been confirmed with the use of cycloplegic agents.38 As we found in our population, Stephen and colleagues,31 in the United Kingdom, reported an increase in refractive errors with age. To our knowledge, no previous study of refractive errors in Middle Eastern individuals with Down syndrome has been published.

Strabismus was seen in 13 (14%) of our patients with Down syndrome at the first visit, and another 2 patients developed esotropia over time, increasing the rate in our population to 17%. This rate is lower than those found in some studies in developed countries, with rates ranging from 36% in Italy30 to 47% in the United Kingdom31 and between 34%39 and 73% (esotropia only)40 in the United States. In emerging countries, the rates of strabismus have been relatively low: 18% in Nigeria,41 22% in Turkey,42 25% in Korea,34 27% in Malaysia,36 and 38% in Brazil.35 Esotropia was more common (12%) than exotropia (4%) in our study population, as has been documented by others35,37,40,43,44; in a large US study, exotropia was more common.45 Significant developmental delay37 and nystagmus40 increase the prevalence of strabismus, which is only partially related to refractive error.46

At the first visit, 9 of our patients with Down syndrome had blepharoconjunctivitis and 9 had nasolacrimal duct obstruction, conditions that are more common in infants (aged 3-12 months) (20%) and may be related to hygiene. Although malformations of the nasolacrimal system have been reported in Down syndrome,80,81 none were evident in our Cairo population; in some of our patients with nasolacrimal duct obstruction, stenosis may have been caused by recurrent infections or the use of irritating antibiotics. In Table 1, blepharitis, blepharoconjunctivitis, conjunctivitis, and nasolacrimal duct obstruction are combined because of symptomatic overlap.

Iris anomalies in Down syndrome include anterior stromal hypoplasia28 and Brushfield spots (normal iris on a background of anterior iris hypoplasia) and do not change with age.47 Although found in the general population, these iris changes are more common in and characteristic of Down syndrome.47 Conclusions based on studies of correlation with iris color have been inconsistent; some studies suggest that there are no differences,47 but others have found these iris anomalies to be more common in individuals with light-colored irides.35,42,48 None of our infants or children from Cairo had Brushfield spots of the iris, similar to findings from large studies in Italy,30 Malaysia,36 Korea,33 and China.49 However, in some large studies of populations with dark irides, these iris anomalies were evident, but with wide variability (with rates of approximately 3% in India,50 36% in Turkey,42 and 52% in Brazil35). Brushfield spots are easily identified without magnification; although iris coloration may be the basis of some differences, we postulate that the large range of findings is related to differences in genetic background.

The development of cataract in the Down syndrome population is an objective feature, relatively common, and age related.29,35,38,51,82 The incidence in our patients younger than 10 years of age was 6%; most of our patients were 1 to 5 years of age, and 1 developed cataract at age 9 years. One infant in our study had CHD, congenital cataract, and high myopia. In what is to our knowledge the only other study in our geographic region, 37% of an Israeli group of slightly older children (aged 5-18 years) were affected.37 In an age-matched US Down syndrome population, 24% had cataracts.29 Igersheimer29 and Igersheimer and Mautner,51,82 using slitlamp biomicroscopy, found cataract in all their US study patients older than 21 years; Jaeger38 did not confirm this rate of cataracts in his large US study population.

The cataract phenotypes were carefully documented by means of slitlamp biomicroscopy before the chromosomal bases of the disease were identified,29 with punctate and cerulean (punctate and flakelike) the most common opacities.29,51,82 Rates of congenital cataract in Down syndrome range from 0.7%4 in Europe, based on a large sample size, to 8% in the United States82 and 13% in Malaysia.36 In a large population of infants and children with Down syndrome undergoing cataract surgery, 76% had congenital cataract.83 As documented in Table 1, the presence of cataract in comparable pediatric age groups ranged from 2%50 in a large Indian population (aged ≤26 years) to 3% in the United States32 (aged ≤19 years), 13% in Brazil (aged ≤19 years),35 and 18% in Scotland31; in the population younger than 5 years, a subset of the heterogeneous Brazilian population studied,35 the prevalence was 1% compared with 6% in our Cairo patients. Although the genetic background, including modifier genes, is the most likely basis for such differences, examination methods or environmental factors may confound the analyses.

At ophthalmoscopy, tilted (dysplastic) optic nerve heads were evident in 2 of our study patients, both with significant myopia. Different forms of optic nerve dysplasia have been reported in Down syndrome, with the most common characterized by a rosy coloration52 and an increase in the number of vessels crossing the margin,38,52,53 a congenital anomaly. Broadly defined, optic nerve dysplasia and vascular anomalies have been found in 4%41 to 38%42 of patients with Down syndrome in emerging countries. Hypoplasia of the optic nerve head also has been reported in the United States.84 A tilted or dysplastic optic nerve, sometimes associated with significant astigmatism and high levels of myopia,85 may be the basis of optic nerve dysplasia in our patients.

Isolated nystagmus in patients with Down syndrome is an objective finding that can be identified without loupes or slitlamp biomicroscopy. Its bases are not known; some affected individuals have near-normal visual acuity,40 and the finding is not generally associated with other mental retardation syndromes. In our study, 2 children (2%; without media opacities) had nystagmus. This rate is lower than those in previous studies, which have ranged from 3% to 33%.33,35,36,41,42,49,50 Although this wide variation may be related to sample size and/or environmental issues, such as nutrition, genetic modifiers are the most likely explanation.

Other reported ocular features in Down syndrome include retinal dystrophy with optic atrophy,42 decreased fundus pigmentation,53 and choroidal sclerosis,53 as well as unrelated ocular findings, such as retinoblastoma and uveitis.36 Retinal detachment also has been described42,53 and may be related to the self-abusive behavior seen in some persons with Down syndrome.

Congenital heart disease was diagnosed in 40% of our study patients, comparable to the 39% rate in a study of patients with Down syndrome from the northern Mediterranean region of Egypt (Alexandria, Lower Egypt).12 Mokhtar and Abdel-Fattah12 established consanguinity as an additional risk factor for CHD in affected individuals in this northern Egyptian geographic region. We found combinations of atrioseptal and ventriculoseptal defects, atrioventicular canal, patent ductus arteriosus and other malformations. In other regions of the Middle East, cardiac malformations in Down syndrome are common. In Qatar, 48% of patients with Down syndrome have congenital heart malformations20; and in Saudi Arabia, 49%.22 By comparison, cardiac malformations have been found in 44% of the US Down syndrome population86 and 46% in a prospective study in Europe,4 but only 18% of Indian patients with Down syndrome in a retrospective study had cardiac disease.50 The prevalence of heart disease in our Egyptian (Cairo/Lower Egypt) patients with Down syndrome was lower than in Western societies, even though consanguinity is relatively common. The low prevalence of cardiac disease in the Indian population may be related to genetic background or ascertainment bias. Because some forms of CHD are inherited in an autosomal recessive Mendelian pattern, the lower prevalence in our study group is probably due to the effects of the genetic background in the region.

We found a positive, statistically significant correlation between myopia and CHD (P = .03) (Table 4); astigmatism was not associated (P = .045). Similarly, Bromham and colleagues87 found an association between myopia and nystagmus in British patients with Down syndrome and cardiac malformations, and da Cunha and Moreira35 identified myopia with heart disease in a large Brazilian study population. The bases for the association of cardiac malformations and myopia in Down syndrome are not clear.

Cardiac malformations are a diverse group and heterozygous (autosomal dominant) mutations of genes encoding the GATA-binding protein 4 (GATA4), (*600576), and zinc finger protein, multitype 2 (ZFPM2), (*603693) proteins have been identified as causative of nonsyndromic cardiac disorders; neither gene is located on human chromosome 21. Consanguinity is a known risk factor for cardiac disease in Middle Eastern patients with Down syndrome, implicating autosomal recessive gene(s) as a component.12,14 Several genes on chromosome 21 have been independently implicated in cardiac malformations and myopia. Co-overexpression of the Down syndrome cell adhesion molecule (DSCAM) (*602523) and the collagen, type VI, alpha-2 (COL6A2) (*120240) genes on chromosome 21q22.3 causes cardiac malformations in mice.88 Mutations of COL6A2 result in recessive and dominant myopathic, multisystem diseases but are not known to cause cardiac malformations; similarly, mutations of collagen, type VI, alpha-1 (COL6A1) (*120220), a gene in the region, cause myopathic diseases. Mutations of the DSCAM gene have not been reported. Although myopia genes have been mapped to many chromosomal regions, only 1 gene, zinc finger protein 644 (ZNF44) (*614159) on chromosome 1, has been demonstrated to cause an autosomal dominant form of high myopia.89 However, mutations of the collagen, type XVIII, alpha-1 gene (COL18A1) (*120328), on chromosome 21, cause myopia in the spectrum of the autosomal recessive Knobloch syndrome, type 1 (KNO1) (*267750), characterized by the ocular features of high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects and/or cardiac malformations. An autosomal dominant myopia susceptibility locus has been mapped to the region of the uromodulinlike 1 gene (UMODL1) (*613859) on chromosome 21q22.3,90 but a mutation has not been reported. Thus, we have established that CHD and myopia are correlated in our Middle Eastern infants and children with Down syndrome and speculate that the bases may include overexpression of genes such as DSCAM and COL6A2, resulting from the trisomy or polymorphisms (DNA sequence variations that are common in the population) of these or other key genes as phenotypic modifiers; alternatively, mutations of genes that result in autosomal recessive cardiac malformations or myopia may be more common in this Cairo population.

We did not find a correlation between karyotype category or thyroid dysfunction and ocular features. In the Cairo region, 94% of patients had trisomy 21 (nondisjunction) and 5% had translocations; 1 case was mosaic. Karyotypic analyses worldwide show wide variation of translocation rates.13,91 Our study population had a rate of nondisjunction similar to those in the northern, Mediterranean region of Egypt (Alexandria, Lower Egypt)13 and Kuwait.92 Our rate of translocations was higher than in Europe,4 Qatar,91 Saudi Arabia,21 the United Arab Emirates,8 and Kuwait,89 but comparable to that in a large US study in Ohio.93 This variability may be related to the specific translocations and/or fetal/newborn demises. Consanguinity was high in our population.

Thyroid function was normal in most (94%) of our pediatric patients; 3 patients had hypothyroidism and 2 had hyperthyroidism. Thyroid dysfunction was documented in 0.1% of newborns with Down syndrome in a large US study94 and in 55% of a broad age range of institutionalized persons with Down syndrome in Kuwait.95 To our knowledge, no other studies of thyroid function in Down syndrome have been published for a population comparable in age to ours.

In conclusion, the incidence of Down syndrome is higher in the Middle East than in Western societies because of more mothers bearing children into their sixth decade of life, higher parity, and higher rates of consanguinity, with at least 1 unknown autosomal recessive gene predisposing to nondisjunction and possibly a second predisposing to cardiac malformations. We found a high rate of consanguinity in the parents of our Cairo patients with Down syndrome, demonstrated a high frequency of ophthalmic disorders, and found no identifiable Brushfield spots. Follow-up of these infants and children showed that refractive errors increased with age and the percentage of strabismus increased over time, despite cycloplegic refractions and the relatively reliable use of corrective eyeglasses. We found a statistically significant relationship between congenital heart defects and myopia. Cairo has a relatively isolated genetic population because this region of the Nile has been an agricultural base for millennia. We attribute the differences between the ocular manifestations in this Cairo pediatric population and both the region and world to modifying genes characteristic of the local population. Egypt has approximately 80 million citizens96; all Egyptian parents have the legal right to genetic information, and primary care clinics are available to all newborns. Thus, this study is of clinical importance in the Middle East in view of the anticipated increase of newborns with Down syndrome in the region and the challenges to the Egyptian health care system during the impending rebuilding of the nation’s infrastructure.

Section Editor: Janey L. Wiggs, MD, PhD

Submitted for Publication: February 24, 2012; final revision received June 5, 2012; accepted August 7, 2012.

Corresponding Author: J. Bronwyn Bateman, MD, 1133 Race St, 17N, Denver, CO 80206 (Bronwyn.bateman@comcast.net).

Published Online: June 13, 2013. doi:10.1001/jamaophthalmol.2013.644.

Author Contributions:Study concept and design: El-Bassyouni.

Acquisition of data: Afifi, Azeem, Gheith, Rizk.

Analysis and interpretation of data: Afifi, Azeem, Bateman.

Drafting of the manuscript: Bateman.

Critical revision of the manuscript for important intellectual content: Afifi, Azeem, El-Bassyouni, Gheith, Rizk.

Administrative, technical, and material support: Afifi, El-Bassyouni.

Study supervision: Afifi, Azeem, Rizk.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study did not have specific financial support aside from professional salaries (Dr Bateman was not salaried).

Additional Contributions: The statistician, Manal H. Abu EL Ela, MD, Public Health Department, Research Institute of Ophthalmology, Cairo, provided assistance.

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PubMed
El Mouzan  MI, Al Salloum  AA, Al Herbish  AS, Qurachi  MM, Al Omar  AA.  Consanguinity and major genetic disorders in Saudi children: a community-based cross-sectional study. Ann Saudi Med. 2008;28(3):169-173.
PubMed   |  Link to Article
Quaife  R, Al Gazali  L.  A case of consanguineous parents with three living trisomy 21 children. Emir Med J. 1994;12:150-153.
Krishna Murthy  DS, Farag  TI.  Recurrent regular trisomy-21 in two Bedouin families: parental mosaicism versus genetic predisposition. Ann Genet. 1995;38(4):217-224.
PubMed
Zlotogora  J, Shalev  SA.  The consequences of consanguinity on the rates of malformations and major medical conditions at birth and in early childhood in inbred populations. Am J Med Genet A. 2010;152A(8):2023-2028.
PubMed   |  Link to Article
Lindsten  J, Marsk  L, Berglund  K,  et al.  Incidence of Down’s syndrome in Sweden during the years 1968-1977. Hum Genet Suppl. 1981;2:195-210.
PubMed
Verma  IC, Mathews  AR, Faquih  A, el-Zouki  AA, Malik  GR, Mohammed  F.  Cytogenetic analysis of Down syndrome in Libya. Indian J Pediatr. 1990;57(2):245-248.
PubMed   |  Link to Article
Wahab  AA, Bener  A, Sandridge  AL, Hoffmann  GF.  The pattern of Down syndrome among children in Qatar: a population-based study. Birth Defects Res A Clin Mol Teratol. 2006;76(8):609-612.
PubMed   |  Link to Article
Amir  IM, Al-Tawil  K, Al-Harbi  A.  Cytogenetics and prevalence of Down syndrome: a study from Saudi Arabia [abstract 1204]. Am J Hum Genet. 2002;71(suppl).
Al-Jarallah  AS.  Down’s syndrome and the pattern of congenital heart disease in a community with high parental consanguinity. Med Sci Monit. 2009;15(8):CR409-CR412.
PubMed
Becker  SM, Al Halees  Z, Molina  C, Paterson  RM.  Consanguinity and congenital heart disease in Saudi Arabia. Am J Med Genet. 2001;99(1):8-13.
PubMed   |  Link to Article
Ronan  A, Fagan  K, Christie  L, Conroy  J, Nowak  NJ, Turner  G.  Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region. J Med Genet. 2007;44(7):448-451.
PubMed   |  Link to Article
Sturmey  P, Thorburn  MJ, Brown  JM, Reed  J, Kaur  J, King  G.  Portage guide to early intervention: cross-cultural aspects and intra-cultural variability. Child Care Health Dev. 1992;18(6):377-394.
PubMed   |  Link to Article
American Academy of Ophthalmology Pediatric Ophthalmology/Strabismus Panel. Preferred Practice Pattern Guidelines. San Francisco, CA: American Academy of Ophthalmology; 2007. http://www.aao.org/ppp. Accessed 2012.
IBM SPSS software, version 10. http://www.SPSS.com. Accessed March 6, 2013.
Lowe  RF.  The eyes in mongolism. Br J Ophthalmol. 1949;33(3):131-174.
PubMed   |  Link to Article
Igersheimer  J.  The relationship of lenticular changes to mongolism [cited in: Trans Am Ophthalmol Soc Otolaryngol Allergy. 1951;49:595-624]. Trans Am Ophthalmol Soc. 1951;49:595-624.
Fimiani  F, Iovine  A, Carelli  R, Pansini  M, Sebastio  G, Magli  A.  Incidence of ocular pathologies in Italian children with Down syndrome. Eur J Ophthalmol. 2007;17(5):817-822.
PubMed
Stephen  E, Dickson  J, Kindley  AD, Scott  CC, Charleton  PM.  Surveillance of vision and ocular disorders in children with Down syndrome. Dev Med Child Neurol. 2007;49(7):513-515.
PubMed   |  Link to Article
Roizen  NJ, Mets  MB, Blondis  TA.  Ophthalmic disorders in children with Down syndrome. Dev Med Child Neurol. 1994;36(7):594-600.
PubMed   |  Link to Article
Kim  JH, Hwang  J-M, Kim  HJ, Yu  YS.  Characteristic ocular findings in Asian children with Down syndrome. Eye (Lond). 2002;16(6):710-714.
PubMed   |  Link to Article
Kim  U, Hwang  JM.  Refractive errors and strabismus in Asian patients with Down syndrome. Eye (Lond). 2009;23(7):1560-1564.
PubMed   |  Link to Article
da Cunha  RP, Moreira  JB.  Ocular findings in Down’s syndrome. Am J Ophthalmol. 1996;122(2):236-244.
PubMed
Liza-Sharmini  AT, Azlan  ZN, Zilfalil  BA.  Ocular findings in Malaysian children with Down syndrome. Singapore Med J. 2006;47(1):14-19.
PubMed
Merrick  J, Koslowe  K.  Refractive errors and visual anomalies in Down's syndrome. Down Syndr Res Pract. 2001;6(3):131-133.
Link to Article
Jaeger  EA.  Ocular findings in Down’s syndrome. Trans Am Ophthalmol Soc. 1980;78:808-845.
PubMed
Hiles  DA, Hoyme  SH, McFarlane  F.  Down’s syndrome and strabismus. Am Orthopt J. 1974;24:63-68.
PubMed
Wagner  RS, Caputo  AR, Reynolds  RD.  Nystagmus in Down’s syndrome. Ophthalmology. 1990;97(11):1439-1444.
PubMed
Ebeigbe  JA, Akpalaba  R.  Ocular health status of subjects with Down’s syndrome in Benin City, Nigeria. Afr J Med Med Sci. 2006;35(3):365-368.
PubMed
Berk  AT, Saatci  AO, Erçal  MD, Tunç  M, Ergin  M.  Ocular findings in 55 patients with Down’s syndrome. Ophthalmic Genet. 1996;17(1):15-19.
PubMed   |  Link to Article
Caputo  AR, Wagner  RS, Reynolds  DR, Guo  SQ, Goel  AK.  Down syndrome: clinical review of ocular features. Clin Pediatr (Phila). 1989;28(8):355-358.
PubMed   |  Link to Article
Yurdakul  NS, Ugurlu  S, Maden  A.  Strabismus in Down syndrome. J Pediatr Ophthalmol Strabismus. 2006;43(1):27-30.
PubMed
Eissler  R, Longenecker  LP.  The common eye findings in mongolism. Am J Ophthalmol. 1962;54(9):398-406.
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Cregg  M, Woodhouse  JM, Stewart  RE,  et al.  Development of refractive error and strabismus in children with Down syndrome. Invest Ophthalmol Vis Sci. 2003;44(3):1023-1030.
PubMed   |  Link to Article
Donaldson  D.  The significance of spotting of the iris in mongoloids: Brushfield’s spots. Arch Ophthalmol. 1961;65(1):26-31.
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Wong  V, Ho  D.  Ocular abnormalities in Down syndrome: an analysis of 140 Chinese children. Pediatr Neurol. 1997;16(4):311-314.
PubMed   |  Link to Article
Kava  MP, Tullu  MS, Muranjan  MN, Girisha  KM.  Down syndrome: clinical profile from India. Arch Med Res. 2004;35(1):31-35.
PubMed   |  Link to Article
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Williams  EJ, McCormick  AQ, Tischler  B.  Retinal vessels in Down’s syndrome. Arch Ophthalmol. 1973;89(4):269-271.
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Ahmad  A, Pruett  RC.  The fundus in mongolism. Arch Ophthalmol. 1960;94(5):772-776.
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Levinson  A, Friedman  A, Stamps  F.  Variability of mongolism. Pediatrics. 1955;16(1):43-54.
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Wagner  HR.  Mongolism in orientals. Am J Dis Child. 1962;103(5):706-714.
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Cullen  JF, Butler  HG.  Mongolism (Down’s syndrome) and keratoconus. Br J Ophthalmol. 1963;47(6):321-330.
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Lyle  WM, Woodruff  ME, Zuccaro  VS.  A review of the literature on Down’s syndrome and an optometrical survey of 44 patients with the syndrome. Am J Optom Arch Am Acad Optom. 1972;49(9):715-727.
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Peterson  RA. Ophthalmological manifestations. In: Pueschel  SM, ed. The Young Child With Down Syndrome. New York, NY: Human Sciences Press. 1984;343-349.
Shapiro  MB, France  TD.  The ocular features of Down’s syndrome. Am J Ophthalmol. 1985;99(6):659-663.
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Wesson  MD, Maino  DM. Oculovisual findings in children with Down syndrome, cerebral palsy, and mental retardation without specific etiology. In: Maino  DM, ed. Diagnosis and Management of Special Problems. St Louis, MO: Mosby; 1995:17-54.
Tsiaras  WG, Pueschel  S, Keller  C, Curran  R, Giesswein  S.  Amblyopia and visual acuity in children with Down’s syndrome. Br J Ophthalmol. 1999;83(10):1112-1114.
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Wallis  HR.  The significance of Brushfield’s spots in the diagnosis of mongolism in infancy. Arch Dis Child. 1951;26(130):495-500.
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Gardiner  PA.  Visual defects in cases of Down’s syndrome and in other mentally handicapped children. Br J Ophthalmol. 1967;51(7):469-474.
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Gaynon  MW, Schimek  RA.  Down’s syndrome: a ten-year group study. Ann Ophthalmol. 1977;9(12):1493-1497.
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Cregg  M, Woodhouse  JM, Pakeman  VH,  et al.  Accommodation and refractive error in children with Down syndrome: cross-sectional and longitudinal studies. Invest Ophthalmol Vis Sci. 2001;42(1):55-63.
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Skeller  E, Øster  J.  Eye symptoms in mongolism. Acta Ophthalmol (Copenh). 1951;29(2):149-161.
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Walsh  SZ.  Keratoconus and blindness in 469 institutionalised subjects with Down syndrome and other causes of mental retardation. J Ment Defic Res. 1981;25(pt 4):243-251.
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Hestnes  A, Sand  T, Fostad  K.  Ocular findings in Down’s syndrome. J Ment Defic Res. 1991;35(pt 3):194-203.
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Pérez-Carpinell  J, de Fez  MD, Climent  V.  Vision evaluation in people with Down’s syndrome. Ophthalmic Physiol Opt. 1994;14(2):115-121.
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Castañe  M, Peris  E, Sanchez  E.  Ocular dysfunction associated with mental handicap. Ophthalmic Physiol Opt. 1995;15(5):489-492.
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Källén  B, Mastroiacovo  P, Robert  E.  Major congenital malformations in Down syndrome. Am J Med Genet. 1996;65(2):160-166.
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Haugen  OH, Høvding  G, Lundström  I.  Refractive development in children with Down’s syndrome: a population based, longitudinal study. Br J Ophthalmol. 2001;85(6):714-719.
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Haargaard  B, Fledelius  HC.  Down’s syndrome and early cataract. Br J Ophthalmol. 2006;90(8):1024-1027.
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Fanning  GS.  Vision in children with Down’s syndrome. Aust J Optom. 1971;54(3):74-82.
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Falls  H.  Ocular changes of mongolism. Ann N Y Acad Sci. 1970;171(2):627-636.
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Pueschel  SM. Ophthalmology. In: Pueschel  SM, Rynders  JE, eds. Down’s Syndrome: Advances in Biomedicine and Behavioral Sciences. Cambridge, MA: Ware Press; 1982:190-196.
Catalano  RA. Ophthalmologic concerns. In: Pueschel  SM, Pueschel  JK, Paul  H, eds. Biomedical Concerns in Persons With Down Syndrome. Baltimore, MD: Brookes Publishing; 1992:59-68.
Creavin  AL, Brown  RD.  Ophthalmic abnormalities in children with Down syndrome. J Pediatr Ophthalmol Strabismus. 2009;46(2):76-82.
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Clark  RA.  Dilation probing as primary treatment for congenital nasolacrimal duct obstruction. J AAPOS. 2002;6(6):364-367.
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Coats  DK, McCreery  KM, Plager  DA, Bohra  L, Kim  DS, Paysse  EA.  Nasolacrimal outflow drainage anomalies in Down’s syndrome. Ophthalmology. 2003;110(7):1437-1441.
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Igersheimer  J, Mautner  H.  About the significance of lenticular changes in mongolism. Ann Paediatr. 1953;181(1):34-44.
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Gardiner  C, Lanigan  B, O’Keefe  M.  Postcataract surgery outcome in a series of infants and children with Down syndrome. Br J Ophthalmol. 2008;92(8):1112-1116.
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Awan  KJ.  Uncommon ocular changes in Down’s syndrome (mongolism). J Pediatr Ophthalmol. 1977;14(4):215-216.
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Vongphanit  J, Mitchell  P, Wang  JJ.  Population prevalence of tilted optic disks and the relationship of this sign to refractive error. Am J Ophthalmol. 2002;133(5):679-685.
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Freeman  SB, Taft  LF, Dooley  KJ,  et al.  Population-based study of congenital heart defects in Down syndrome. Am J Med Genet. 1998;80(3):213-217.
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Bromham  NR, Woodhouse  JM, Cregg  M, Webb  E, Fraser  WI.  Heart defects and ocular anomalies in children with Down’s syndrome. Br J Ophthalmol. 2002;86(12):1367-1368.
PubMed   |  Link to Article
Grossman  TR, Gamliel  A, Wessells  RJ,  et al.  Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects. PLoS Genet. 2011;7(11):e1002344. doi:10.1371/journal.pgen.1002344.
PubMed   |  Link to Article
Shi  Y, Li  Y, Zhang  D,  et al.  Exome sequencing identifies ZNF644 mutations in high myopia. PLoS Genet. 2011;7(6):e1002084. doi:10.1371/journal.pgen.1002084.
PubMed   |  Link to Article
Nishizaki  R, Ota  M, Inoko  H,  et al.  New susceptibility locus for high myopia is linked to the uromodulin-like 1 (UMODL1) gene region on chromosome 21q22.3. Eye (Lond). 2009;23(1):222-229.
PubMed   |  Link to Article
Wahab  AA, Bener  A, Teebi  AS.  The incidence patterns of Down syndrome in Qatar. Clin Genet. 2006;69(4):360-362.
PubMed   |  Link to Article
al-Awadi  SA, Farag  TI, Teebi  AS, Naguib  KK, Sundareshan  TS, Murthy  DS.  Down syndrome in Kuwait. Am J Med Genet Suppl. 1990;7:87-88.
PubMed
Pulliam  LH, Huether  CA.  Translocation Down syndrome in Ohio 1970-1981: epidemiologic and cytogenetic factors and mutation rate estimates. Am J Hum Genet. 1986;39(3):361-370.
PubMed
Fort  P, Lifshitz  F, Bellisario  R,  et al.  Abnormalities of thyroid function in infants with Down syndrome. J Pediatr. 1984;104(4):545-549.
PubMed   |  Link to Article
Ali  FE, Bayoumy  HA, Mohammad  AS, Al-Busairi  WA, Al-Othman  AN.  Thyroid function in Kuwaiti subjects with Down’s syndrome. Med Princ Pract. 2002;11(4):206-209.
PubMed   |  Link to Article
World Health Organization. Eastern Mediterranean Region (EMRO), 2008. http://rho.emro.who.int/rhodata. Accessed March 14, 2011.

Figures

Tables

Table Graphic Jump LocationTable 1.  Reported Prevalence or Incidence of Ocular Features or Abnormalities in Down Syndrome in Cairo, Egypt, and Other Countries1
Table Graphic Jump LocationTable 2.  Ophthalmic Features by Age at Last Examination
Table Graphic Jump LocationTable 4.  Heart Defects in Egyptian (Cairo) Children With Down Syndrome and Ocular Anomalies

References

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Mokhtar  MM, Abdel-Fattah  M.  Major birth defects among infants with Down syndrome in Alexandria, Egypt (1995-2000): trends and risk factors. East Mediterr Health J. 2001;7(3):441-451.
PubMed
Mokhtar  MM, Abd el-Aziz  AM, Nazmy  NA, Mahrous  HS.  Cytogenetic profile of Down syndrome in Alexandria, Egypt. East Mediterr Health J. 2003;9(1-2):37-44.
PubMed
El Mouzan  MI, Al Salloum  AA, Al Herbish  AS, Qurachi  MM, Al Omar  AA.  Consanguinity and major genetic disorders in Saudi children: a community-based cross-sectional study. Ann Saudi Med. 2008;28(3):169-173.
PubMed   |  Link to Article
Quaife  R, Al Gazali  L.  A case of consanguineous parents with three living trisomy 21 children. Emir Med J. 1994;12:150-153.
Krishna Murthy  DS, Farag  TI.  Recurrent regular trisomy-21 in two Bedouin families: parental mosaicism versus genetic predisposition. Ann Genet. 1995;38(4):217-224.
PubMed
Zlotogora  J, Shalev  SA.  The consequences of consanguinity on the rates of malformations and major medical conditions at birth and in early childhood in inbred populations. Am J Med Genet A. 2010;152A(8):2023-2028.
PubMed   |  Link to Article
Lindsten  J, Marsk  L, Berglund  K,  et al.  Incidence of Down’s syndrome in Sweden during the years 1968-1977. Hum Genet Suppl. 1981;2:195-210.
PubMed
Verma  IC, Mathews  AR, Faquih  A, el-Zouki  AA, Malik  GR, Mohammed  F.  Cytogenetic analysis of Down syndrome in Libya. Indian J Pediatr. 1990;57(2):245-248.
PubMed   |  Link to Article
Wahab  AA, Bener  A, Sandridge  AL, Hoffmann  GF.  The pattern of Down syndrome among children in Qatar: a population-based study. Birth Defects Res A Clin Mol Teratol. 2006;76(8):609-612.
PubMed   |  Link to Article
Amir  IM, Al-Tawil  K, Al-Harbi  A.  Cytogenetics and prevalence of Down syndrome: a study from Saudi Arabia [abstract 1204]. Am J Hum Genet. 2002;71(suppl).
Al-Jarallah  AS.  Down’s syndrome and the pattern of congenital heart disease in a community with high parental consanguinity. Med Sci Monit. 2009;15(8):CR409-CR412.
PubMed
Becker  SM, Al Halees  Z, Molina  C, Paterson  RM.  Consanguinity and congenital heart disease in Saudi Arabia. Am J Med Genet. 2001;99(1):8-13.
PubMed   |  Link to Article
Ronan  A, Fagan  K, Christie  L, Conroy  J, Nowak  NJ, Turner  G.  Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region. J Med Genet. 2007;44(7):448-451.
PubMed   |  Link to Article
Sturmey  P, Thorburn  MJ, Brown  JM, Reed  J, Kaur  J, King  G.  Portage guide to early intervention: cross-cultural aspects and intra-cultural variability. Child Care Health Dev. 1992;18(6):377-394.
PubMed   |  Link to Article
American Academy of Ophthalmology Pediatric Ophthalmology/Strabismus Panel. Preferred Practice Pattern Guidelines. San Francisco, CA: American Academy of Ophthalmology; 2007. http://www.aao.org/ppp. Accessed 2012.
IBM SPSS software, version 10. http://www.SPSS.com. Accessed March 6, 2013.
Lowe  RF.  The eyes in mongolism. Br J Ophthalmol. 1949;33(3):131-174.
PubMed   |  Link to Article
Igersheimer  J.  The relationship of lenticular changes to mongolism [cited in: Trans Am Ophthalmol Soc Otolaryngol Allergy. 1951;49:595-624]. Trans Am Ophthalmol Soc. 1951;49:595-624.
Fimiani  F, Iovine  A, Carelli  R, Pansini  M, Sebastio  G, Magli  A.  Incidence of ocular pathologies in Italian children with Down syndrome. Eur J Ophthalmol. 2007;17(5):817-822.
PubMed
Stephen  E, Dickson  J, Kindley  AD, Scott  CC, Charleton  PM.  Surveillance of vision and ocular disorders in children with Down syndrome. Dev Med Child Neurol. 2007;49(7):513-515.
PubMed   |  Link to Article
Roizen  NJ, Mets  MB, Blondis  TA.  Ophthalmic disorders in children with Down syndrome. Dev Med Child Neurol. 1994;36(7):594-600.
PubMed   |  Link to Article
Kim  JH, Hwang  J-M, Kim  HJ, Yu  YS.  Characteristic ocular findings in Asian children with Down syndrome. Eye (Lond). 2002;16(6):710-714.
PubMed   |  Link to Article
Kim  U, Hwang  JM.  Refractive errors and strabismus in Asian patients with Down syndrome. Eye (Lond). 2009;23(7):1560-1564.
PubMed   |  Link to Article
da Cunha  RP, Moreira  JB.  Ocular findings in Down’s syndrome. Am J Ophthalmol. 1996;122(2):236-244.
PubMed
Liza-Sharmini  AT, Azlan  ZN, Zilfalil  BA.  Ocular findings in Malaysian children with Down syndrome. Singapore Med J. 2006;47(1):14-19.
PubMed
Merrick  J, Koslowe  K.  Refractive errors and visual anomalies in Down's syndrome. Down Syndr Res Pract. 2001;6(3):131-133.
Link to Article
Jaeger  EA.  Ocular findings in Down’s syndrome. Trans Am Ophthalmol Soc. 1980;78:808-845.
PubMed
Hiles  DA, Hoyme  SH, McFarlane  F.  Down’s syndrome and strabismus. Am Orthopt J. 1974;24:63-68.
PubMed
Wagner  RS, Caputo  AR, Reynolds  RD.  Nystagmus in Down’s syndrome. Ophthalmology. 1990;97(11):1439-1444.
PubMed
Ebeigbe  JA, Akpalaba  R.  Ocular health status of subjects with Down’s syndrome in Benin City, Nigeria. Afr J Med Med Sci. 2006;35(3):365-368.
PubMed
Berk  AT, Saatci  AO, Erçal  MD, Tunç  M, Ergin  M.  Ocular findings in 55 patients with Down’s syndrome. Ophthalmic Genet. 1996;17(1):15-19.
PubMed   |  Link to Article
Caputo  AR, Wagner  RS, Reynolds  DR, Guo  SQ, Goel  AK.  Down syndrome: clinical review of ocular features. Clin Pediatr (Phila). 1989;28(8):355-358.
PubMed   |  Link to Article
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