Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom.

Overall, approximately one-quarter of patients with genetic eye diseases will receive a molecular diagnosis. Patients with developmental eye disorders face a number of diagnostic challenges including phenotypic heterogeneity with significant asymmetry, coexisting ocular and systemic disease, limited understanding of human eye development and the associated genetic repertoire, and lack of access to next generation sequencing as regarded not to impact on patient outcomes/management with cost implications. Herein, we report our real world experience from a pediatric ocular genetics service over a 12 month period with 72 consecutive patients from 62 families, and that from a cohort of 322 patients undergoing whole genome sequencing (WGS) through the Genomics England 100,000 Genomes Project; encompassing microphthalmia, anophthalmia, ocular coloboma (MAC), anterior segment dysgenesis anomalies (ASDA), primary congenital glaucoma, congenital cataract, infantile nystagmus, and albinism. Overall molecular diagnostic rates reached 24.9% for those recruited to the 100,000 Genomes Project (73/293 families were solved), but up to 33.9% in the clinic setting (20/59 families). WGS was able to improve genetic diagnosis for MAC patients (15.7%), but not for ASDA (15.0%) and congenital cataracts (44.7%). Increased sample sizes and accurate human phenotype ontology (HPO) terms are required to improve diagnostic accuracy. The significant mixed complex ocular phenotypes distort these rates and lead to missed variants if the correct gene panel is not applied. Increased molecular diagnoses will help to explain the genotype-phenotype relationships of these developmental eye disorders. In turn, this will lead to improved integrated care pathways, understanding of disease, and future therapeutic development.

Clinical and histological features and outcomes of upper eyelid colobomas in the Saudi population.

PURPOSE: To study the clinical features, histopathology, and management of congenital upper eyelid coloboma (CEC) in the Saudi population. METHODS: A retrospective review of health records evaluated the demographics, histopathology, and surgical outcomes of patients with CEC. RESULTS: Thirty-nine eyelids of 27 patients were included in this study. CEC was bilateral in 12 (44.4%) patients, isolated in 17 (62.9%), and as part of a syndrome in 10 (37.1%) patients. CEC was commonly located in the medial upper lid (22 lids, 56.4%) and mostly involved the full thickness of the lid (27 lids, 69.2%). Corneal adhesion (18 eyes, 46.1%) and poorly formed eyebrows (21 eyebrows, 53.8%) were the most common ocular/adnexa associations. Histopathology was similar in all cases and the main features were scarred dermis, atrophic orbicularis oculi, and atrophic or absent tarsus. Visual acuity at the final follow-up was 20/50 or better in 13 (33.3%) eyes. Complete lid closure without lagophthalmos after one or more surgical procedures was achieved in 11 (40.7%) cases. CONCLUSIONS: CEC features in Saudi patients are similar to those described in the literature. Dermal scarring and defective orbicularis muscles are common. Achieving cosmetic and functional success after management remains challenging.

Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities.

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.

Congenital upper eyelid coloboma: embryologic, nomenclatorial, nosologic, etiologic, pathogenetic, epidemiologic, clinical, and management perspectives.

PURPOSE: To review the recent literature and describe the authors' experience with congenital upper eyelid coloboma. METHODS: In this review, we will summarize the embryologic and etiopathogenetic bases of congenital upper eyelid coloboma, and study the published clinical reports. We will also attempt to briefly shed some light on the rarer syndromic curiosities associated with upper eyelid coloboma. RESULTS: Congenital upper eyelid colobomas are one of the few nontraumatic oculoplastic emergencies that may occasionally present in the first few days of life with a corneal ulcer and may even present with impending perforation. They can present with or without corneopalpebral adhesions, may be isolated findings or a part of a larger spectrum of congenital anomalies as in the case of Fraser syndrome or Goldenhar syndrome, or could be associated with other rare curiosities that could challenge the clinician with a huge diagnostic dilemma. CONCLUSIONS: Existing literature dealing with congenital colobomas of the upper eyelid is fraught with nosologic problems, confusing etiologies, and overlapping clinical features. We attempted to clarify the salient clinical features, outline the management principles, and until a time in the not-so-distant future where advances in molecular genetic testing would help redefine the etiology and the diverse clinical spectrum of genetic diseases associated with upper eyelid colobomas, we propose a simplified classification scheme based on the relation of the coloboma to the cornea, the presence or absence of systemic features, and all the syndromic and nonsyndromic associations of congenital coloboma of the upper eyelid known today.

Anophthalmos, microphthalmos, and Coloboma in the United kingdom: clinical features, results of investigations, and early management.

PURPOSE: To describe the clinical features of children with anophthalmos, microphthalmos, and typical coloboma (AMC). DESIGN: Descriptive, observational, cross-sectional study of the United Kingdom. PARTICIPANTS: A total of 135 children with AMC newly diagnosed over an 18-month period beginning in October 2006. METHODS: Cases were identified using active surveillance through an established ophthalmic surveillance system. Eligible cases were followed up 6 months after first notification. MAIN OUTCOME MEASURES: Phenotypic characteristics, both ocular and systemic, clinical investigations, causes, and interventions. RESULTS: A total of 210 eyes (of 135 children) were affected by AMC, of which 153 had isolated coloboma or coloboma with microphthalmos. The most common colobomatous anomaly was a chorioretinal defect present in 109 eyes (71.2%). Some 44% of children were bilaterally visually impaired. Systemic abnormalities were present in 59.7% of children, with craniofacial anomalies being the most common. Children with bilateral disease had a 2.7 times higher odds (95% confidence interval, 1.3-5.5, P = 0.006) of having systemic involvement than unilaterally affected children. Neurologic imaging was the most frequent investigation (58.5%) performed. Less than one third (30.3%) of the children with microphthalmos had ocular axial lengths measured. Eight children had confirmed genetic mutations. Approximately half (49.2%) of the children required ocular intervention. CONCLUSIONS: Colobomatous defects were the most common phenotype within this spectrum of anomalies in the United Kingdom. The high frequency of posterior segment colobomatous involvement means that a dilated fundal examination should be made in all cases. The significant visual and systemic morbidity in affected children underlines the importance of a multidisciplinary approach to management.

Clinical and Demographic Profile of Uveal Coloboma: A Hospital-Based Study of 14,371 Eyes of 9557 Indian Patients.

OBJECTIVE: To describe the demographics and clinical profile of uveal coloboma in patients presenting to a multi-tier ophthalmology hospital network in India. DESIGN: Cross-sectional hospital-based study. METHODS: This cross-sectional, hospital-based study included 2,817,766 new patients presenting between August 2010 and May 2021. Patients with a clinical diagnosis of uveal coloboma in at least 1 eye were included as cases. Data were collected using an electronic medical record system. RESULTS: Overall, 9557 patients (0.34%) were diagnosed with uveal coloboma. Just over half of the patients were male (51.82%) and were affected bilaterally (50.37%). The most common age group at presentation was individuals in the second decade of life, comprising 2198 patients (23%). The overall prevalence was higher in patients of lower socio-economic status (0.53%) and from rural areas (0.39%). The most common type was retino-choroidal coloboma in 8049 patients (84.22%), followed by iris coloboma in 2129 patients (22.28%). The most common Ida Mann classification in the eyes with retino-choroidal coloboma was type 4 in 7049 eyes (57.23%), followed by type 2 in 3685 eyes (29.92%). Of the 14,371 eyes, 5696 eyes (39.64%) had a visual impairment of blindness (>20/400), followed by mild or no visual impairment (<20/70) in 2875 eyes (20.01%). In the 2228 eyes (15.5%) that required a surgical/ laser intervention, cataract surgery was performed in 951 eyes (6.62%), vitreo-retinal surgery in 661 eyes (4.6%), followed by laser photocoagulation in 357 eyes (2.48%). CONCLUSION: Uveal coloboma is more common in male individuals and is predominantly bilateral in the population studied. It is more commonly found in patients from lower socio-economic strata and from a rural background. The most common type is retino-choroidal coloboma, and more than one-third of the eyes are affected by blindness.

Clinical spectrum of non-syndromic microphthalmos, anophthalmos and coloboma in the paediatric population: a multicentric study from North India.

AIMS: To describe the clinical features, visual acuity and causes of ocular morbidity in children (0-18 years) with microphthalmos, anophthalmos, and coloboma (MAC) from North India. METHODS: A retrospective study conducted between October 2017 and September 2018 in three tertiary eye institutes, part of the Bodhya Eye Consortium with consensus led common pro formas. Children with complete clinical data and without syndromic/systemic involvement were included. The clinical phenotype was divided into isolated ocular coloboma (CB), coloboma with microcornea (CBMC), colobomatous microphthalmos (CBMO), non-colobomatous microphthalmos (MO) and anophthalmos (AO). RESULTS: A total of 532 children with MAC were examined. Seventeen records were excluded due to incomplete data (0.2%). 515 children (845 eyes) were included: 54.4% males and 45.6% females. MAC was unilateral in 36% and bilateral in 64%. CB, CBMC, CBMO, MO and AO were seen in 26.4%, 31%, 22%, 8% and 12.5% of eyes, respectively. Nystagmus was found in 40%, strabismus in 23%, cataract in 18.7% and retinal detachment in 15%. Best-corrected visual acuity (BCVA) of <3/60 was seen in 62.4% eyes. Blindness (BCVA <3/60 in better eye) was seen in 42.8% of bilateral patients. Those with microcornea or microphthalmos with coloboma had worse BCVA (p<0.001). There were regional differences in the type of MAC phenotype presenting to the three institutes. CONCLUSION: The MAC group of disorders cause significant ocular morbidity. The presence of microcornea or microphthalmos with coloboma predicts worse BCVA. The variation of the MAC phenotype with the district of origin of the patient raises questions of aetiology and is subject to further studies.

Collie Eye Anomaly in Switzerland.

In this retrospective study, the results of 3'527 eye examinations in 6 different breeds affected with Collie Eye Anomaly (CEA) over a period of 8 years (1999 - 2007) are described. CEA was divided into three main ophthalmoscopic features, a) choroidal hypoplasia (CRH), b) CRH and coloboma and c) coloboma alone. Of the 101 Smooth Collies 8.9 % showed signs of CRH, whereas 36.9 % of Rough Collies were affected with CRH, 2.8 % with CRH and coloboma and 0.38 % with coloboma alone. Choroidal hypoplasia was present in 13.1 %, CRH and coloboma in 1.8 % and coloboma alone in 0.2 % of the Shetland Sheepdogs. Only one Australian Shepherd dog had CRH, while 0.7 % of the Border Collies were affected with CRH. None of the Nova Scotia Duck Tolling Retrievers were affected with CEA. There were no statistically significant differences in the occurrence of CEA between males and females, nor was there any relation between coat colors. Significant differences could be shown between dogs younger or older than 8 weeks at first examination. CEA was more often diagnosed in dogs younger than 8 weeks within the Rough Collie and Shetland Sheepdog.

Coloboma and CHARGE association in Puerto Rico.

INTRODUCTION: Previous studies have reported that patients with the CHARGE association have congenital anomalies including: Coloboma; heart defects; choanal atresia, retarded growth and development; genital hypoplasia; and ear anomalies. Ocular findings in patients with the association include: poor visual acuity; anisometropia; myopic astigmatism; strabismus; microcornea; cataracts; staphyloma; and reduced stereopsis. METHODS: We conducted a non-concurrent prospective study of 13 patients with coloboma from Puerto Rico. RESULTS: Seven patients out of the 13 patients (53.8%) had the CHARGE association. Age ranged from 10 to 84 (mean = 38 years). Ocular findings in all the patients with coloboma include: nystagmus; strabismus; poor visual acuity; refractive errors; microcornea; cataracts; glaucoma; and dry eyes. Patients in our study had systemic findings such as: heart defects; ear anomalies; and endocrine problems. CONCLUSIONS: To our knowledge this is the first case series of patients with Coloboma and the CHARGE association reported in Puerto Rico and the Caribbean basin.

Optic Disc Coloboma in children - prevalence, clinical characteristics and associated morbidity.

PURPOSE: The aim of the study was to report prevalence, ocular outcome, neurological characteristics, cognitive and behavioural problems in children with optic disc coloboma (ODC). METHODS: This was a population-based, cross-sectional study of 31 children between 2 and 18 years of age diagnosed with ODC. The children were part of a larger cohort of 184 children with congenital optic disc malformations. Clinical ophthalmological examinations, neurological assessments, behavioural and developmental screening were performed. RESULTS: The prevalence of ODC was 8.9/100 000 children. Of the 31 patients, 18 had unilateral ODC (p = 0.21). The best-corrected visual acuity (BCVA) in the ODC eye ranged from blindness to 1.3 (median 0.3). BCVA was 0.82 in eyes with an isolated ODC (range 0.4-1.3) and 0.15 (range 0-0.5) in eyes with concurrent macular involvement (p < 0.0001). Nystagmus was observed more often in patients with bilateral ODC (9/13 versus 3/17, p = 0.004). Two patients had retinal detachment. Behavioural/psychological screening was performed in 21 patients with severe deficits identified in six cases. Intellectual disability was present in seven patients. Neurological dysfunction was diagnosed in 8/22 cases. All of the above children had already systemic diagnoses before the ODC diagnosis was made. CONCLUSIONS: ODC was the second most common optic disc malformation in this cohort after optic nerve hypoplasia. The children had a wide range of ocular comorbidity. An isolated ODC without macular involvement was not associated with profound vision loss. The ability of screening in the regular child care centres to diagnose extraocular comorbidities was very good and referral to a paediatrician appears redundant in cases of normal development.

Executive function in CHARGE syndrome.

This study addressed the presence of executive dysfunction in children with CHARGE syndrome, a genetic disorder with multiple physical anomalies and severe challenging behaviors. Ninety-eight children were included in the study. More than half received clinically significant scores on the Behavior Rating Inventory of Executive Function (BRIEF; Gioia et al., 2000) scales of Shift, Monitor, and the Behavioral Regulation Index, with additional high scores on Inhibit and the Global Executive Composite. Associations were found with the age the child first walked, scores on the Autism Behavior Checklist (ABC; Krug et al., 1993), and being classified as deafblind. Difficulties with making transitions and flexible problem solving, monitoring their work and their effect on others, and acting on impulse, may be related to the behavioral difficulties exhibited by children with CHARGE. Interventions targeting improved self-regulation may help to manage this challenging behavior.

Comprehensive First-Line Magnetic Resonance Imaging in Hypertension: Experience From a Single-Center Tertiary Referral Clinic.

European guidelines recommend that patients with hypertension be assessed for asymptomatic organ damage and secondary causes. The authors propose that a single magnetic resonance imaging (MRI) scan can provide comprehensive first-line imaging of patients assessed via a specialist hypertension clinic. A total of 200 patients (56% male, aged 51±15 years, office BP 168±30/96±16 mm Hg) underwent MRI of the heart, kidneys, renal arteries, adrenals and aorta. Comparisons were made with other imaging modalities where available. A total of 61% had left ventricular hypertrophy (LVH), 14% had reduced ejection fraction, and 15 patients had myocardial infarcts. Echocardiography overdiagnosed LVH in 15% of patients and missed LVH in 14%. Secondary causes were identified in 14.5% of patients: 12 adrenal masses, 10 renal artery stenoses, seven thyroid abnormalities, one aortic coarctation, one enlarged pituitary gland, one polycystic kidney disease, and one renal coloboma syndrome. This comprehensive MRI protocol is an effective method of screening for asymptomatic organ damage and secondary causes of hypertension.

Congenital Microphthalmia, Anophthalmia and Coloboma among Live Births in Denmark.

PURPOSE: This study aims to quantify the occurrence of the congenital eye malformations anophthalmia (AO), microphthalmia (MO) and coloboma among liveborn infants in Denmark, and to estimate the rate of chromosomal abnormalities in this group of patients. METHODS: A cohort of patients born in 1995-2012 with diagnoses of MO/AO or coloboma was identified from the Danish National Patient Registry (DNPR), and their ocular and extra-ocular diagnoses were reviewed. In order to assess the occurrence of chromosomal abnormalities in the cohort, the data were cross-referenced with the Danish Cytogenetic Central Registry (DCCR). RESULTS: We identified 415 patients with MO/AO/coloboma in the DNPR. The total number of live births from 1995-2012 was 1,174,299, and the average birth prevalence of MO/AO/coloboma was 3.6/10,000 live births and of MO/AO was 1.2/10,000 live births. Extra-ocular abnormalities were observed in 32.1% of MO/AO cases and 21.7% of coloboma cases. Chromosome analysis was performed in 36.1% of the cohort, and 14.7% of cases had an abnormal karyotype. In 8.7% of the cohort, a chromosome microarray analysis was performed, and in 44.4% of cases, a possibly pathogenic copy number variation was observed. CONCLUSION: The birth prevalence of MO/AO/coloboma in Denmark has been steady at 3.6/10,000 live births during the last 17 years. The rate of syndromic cases was lower compared to other studies. A relatively high rate of pathogenic chromosomal aberrations was observed, suggesting an important role for cytogenetic analysis in this group of patients.

A clinical study of Aicardi syndrome in Northern Ireland: the spectrum of ophthalmic findings.

PurposeAicardi syndrome is a rare disorder, affecting ~1 in 100 000 live births. Chorioretinal lacunae feature alongside agenesis of the corpus callosum and spasms in flexion to make up a diagnostic triad. Recently ophthalmic findings such as microphthalmia and optic disc anomalies have been recognised in association with Aicardi syndrome. This population study aims to determine the presence of ocular findings and identifies some novel associations in these patients.MethodsA retrospective review of charts for seven patients with Aicardi syndrome was carried out.ResultsThe incidence of Aicardi syndrome in Northern Ireland was found to be 1 in 110 000 live births. Four patients who had microphthalmus also had iris abnormalities; two patients with bilateral microphthalmus had partial aniridia and two patients with unilateral microphthalmus had iris coloboma in the same eye. Optic disc abnormalities were found in 11 eyes of six patients. Two patients were found to have areas of fibrovascular proliferation with a thickened white ridge and avascular zone beyond. Both of these patients developed retinal detachments.ConclusionsOur review of patients with Aicardi syndrome in Northern Ireland has revealed some novel clinical findings, including aniridia in two cases. We also found a higher than previously reported rate of excavated disc anomalies of 50% in our cohort. We found two cases of peripheral retinal dysplasia, which has not been previously reported. This finding was associated with microphthalmus and severe optic disc abnormalities, and we feel this warrants early EUA to enable early treatment and hopefully result in better visual prognosis.

A population-based case-control study of isolated ocular coloboma.

AIMS: To attempt the detection of possible etiological factors in the origin of isolated ocular, mainly iris coloboma. METHODS: The data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-2002, was used. Exposure data and family history were based on (1) prospective medical records, (2) retrospective maternal information, and (3) information obtained by regional nurses at home visit. RESULTS: Of 46 cases, 40 were affected with iris coloboma and 19 had bilateral manifestation. The positive family history indicated a hereditary origin in 4.3% (2/46) of cases. An association was found between the isolated ocular coloboma and hydroxyethylrutoside treatment (adjusted POR with 95% CI: 5.4, 2.2-12.9). Another association was seen between isolated ocular coloboma and hypothyroidism (adjusted OR with 95% CI = 12.6, 3.0-52.7), but it was based only on two cases. CONCLUSIONS: It is necessary to study the preventable environmental factors in the origin of these ocular defects.

National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology.

We report an epidemiological and genetic study attempting complete ascertainment of subjects with microphthalmia, anophthalmia, and coloboma (MAC) born in Scotland during a 16 year period beginning on 1 January 1981. A total of 198 cases were confirmed giving a minimum live birth prevalence of 19 per 100 000. One hundred and twenty-two MAC cases (61.6%) from 115 different families were clinically examined and detailed pregnancy, medical, and family histories obtained. A simple, rational, and apparently robust classification of the eye phenotype was developed based on the presence or absence of a defect in closure of the optic (choroidal) fissure. A total of 85/122 (69.7%) of cases had optic fissure closure defects (OFCD), 12/122 (9.8%) had non-OFCD, and 25/122 (20.5%) had defects that were unclassifiable owing to the severity of the corneal or anterior chamber abnormality. Segregation analysis assuming single and multiple incomplete ascertainment, respectively, returned a sib recurrence risk of 6% and 10% in the whole group and 8.1% and 13.3% in the OFCD subgroup. Significant recurrence risks were found in both unilateral and bilateral disease. In four families, one parent had an OFCD, two of which were new diagnoses in asymptomatic subjects. All recurrences in first degree relatives occurred in the OFCD group with a single first cousin recurrence seen in the non-OFCD group. A total of 84/122 of the MAC cases were screened for mutations in the coding regions of PAX6, CHX10, and SIX3. No pathogenic mutations were identified in the OFCD cases. A single PAX6 homeodomain missense mutation was identified in a subject with partial aniridia that had been initially misclassified as coloboma.

The incidence, embryology, and oculofacial abnormalities associated with eyelid colobomas.

PURPOSE: To describe a cohort of patients with congenital eyelid coloboma, to identify associated ocular and craniofacial abnormalities, and to establish any correlation between the size and location of eyelid colobomas and the presence of such abnormalities. METHODS: An observational case series of 55 patients with eyelid coloboma treated by a single surgeon (JROC) between 1985 and 2005. RESULTS: Eyelid colobomas predominantly affected the upper lids (93%), and were typically unilateral (76%). About a third (29%) were an isolated finding, with the remainder associated with other ocular (62%) and/or craniofacial (53%) abnormalities. Of those with ocular abnormalities; 19 (56%) had conjunctival traction bands, 16 (47%) choristomas, and 8 (24%) an abnormal globe. Of those with craniofacial abnormalities; 13 (45%) had Goldenhar Syndrome, 10 (35%) clefting disorders, and 4 (14%) Fraser Syndrome. Clefting disorders were typically associated with more severe colobomas and a higher incidence of conjunctival traction bands, first arch syndromes with smaller colobomas and more choristomas. Overall large colobomas were significantly associated with the presence of other craniofacial defects compared with small colobomas (P<0.01, χ(2)), but coloboma size did not correspond with the presence of other ocular abnormalities. CONCLUSIONS: Coloboma size, location, and associations in this series are consistent with our current understanding of eyelid embryogenesis. It is likely that those colobomas associated with other craniofacial and ocular abnormalities are those which result from errors earlier in embryogenesis during eyelid specification, growth, and closure, whereas isolated colobomas arise later during eyelid separation, and after codependent structures have developed.

Congenital eye malformations: clinical-epidemiological analysis of 1,124,654 consecutive births in Spain.

We analyzed Spanish Collaborative Study of Congenital Malformations (ECEMC) data on a series of 1,124,654 consecutive births to study congenital eye malformations from an epidemiological standpoint. We studied their frequencies as well as some causal and clinical aspects. Four hundred fourteen infants had eye malformations, for an overall prevalence of 3.68/10,000 newborns. Most frequent were: anophthalmia/microphthalmia (21.34/100,000), congenital cataract (6.31), coloboma (4.89), corneal opacity (3.11), and congenital glaucoma (2.85). In our data, the tendency of eye malformations to be associated with other congenital abnormalities is evident (only 21.01% of cases were isolated). Eye defects are heterogeneous, since we have observed them in clinical patterns with all modes of inheritance or caused by different environmental agents. Chromosomal syndromes represent 60% of total syndromes, followed by syndromes of autosomal-recessive inheritance (15%), environmental syndromes (10%), autosomal-dominant syndromes (5.83%), and other types which have a lower frequency. Regarding defects associated with eye malformations, most frequent are limb anomalies (affecting 59.3% of multiply malformed cases), auricular/facial (47.1%), central nervous system (42.5%), osteomuscular excluding limbs (42.2%), genital defects (30.6%), oral clefts (29.4%), and the rest of the body systems, which are less frequent. Using the method outlined by Prieto and Martínez-Frías [1996: Am J Med Genet 62:61-67], it was demonstrated that the association of coloboma and anophthalmia/microphthalmia was specific, as was the combination of cataract and anophthalmia/microphthalmia, and that of anophthalmia/microphthalmia with holoprosencephaly. From these statistical associations some pathogenetic relationships in human embryos can be inferred, supporting several previously proposed mechanisms.

The familial contribution to non-syndromic ocular coloboma in south India.

AIMS: To identify the proportion of familial cases of isolated ocular colobomatous malformations in a case series from south India. METHODS: Children with ocular coloboma without systemic features were recruited from multiple sources in Andhra Pradesh, India. Their families were traced, pedigrees drawn, and family members examined. RESULTS: 56 probands, 25 females (44.6%) and 31 males (57.4%) with a colobomatous malformation were identified. In 12 cases (21.4%) another family member was affected. The risk to siblings was 3.8%. The parents were consanguineous in 25 cases (44.6%). CONCLUSIONS: 21.4% of cases of isolated ocular coloboma in this highly consanguineous population of south India were familial, with both autosomal dominant and autosomal recessive mechanisms likely in different families.