I Russell‐Eggitt

<b>Background/aim:</b> Paediatric cataract is a major cause of childhood blindness. Several genes associated with congenital and paediatric cataracts have been identified. The aim was to determine the incidence of cataract in a population, the proportion of hereditary cataracts, the mode of inheritance, and the clinical presentation. <b>Methods:</b> The Royal Children9s Hospital and the Royal Victorian Eye and Ear Hospital have a referral base for almost all paediatric patients with cataracts in south eastern Australia. The database contains cases seen over the past 25 years. The medical histories of these patients were reviewed. <b>Results:</b> 421 patients with paediatric cataract were identified, which gives an estimated incidence of 2.2 per 10 000 births. Of the 342 affected individuals with a negative family history, 50% were diagnosed during the first year of life, and 56/342 (16%) were associated with a recognised systemic disease or syndrome. Unilateral cataract was identified in 178/342 (52%) of sporadic cases. 79 children (from 54 nuclear families) had a positive family history. Of these 54 families, 45 were recruited for clinical examination and DNA collection. Ten nuclear families were subsequently found to be related, resulting in four larger pedigrees. Thus, 39 families have been studied. The mode of inheritance was autosomal dominant in 30 families, X linked in four, autosomal recessive in two, and uncertain in three. In total, 178 affected family members were examined; of these 8% presented with unilateral cataracts and 43% were diagnosed within the first year of life. <b>Conclusions:</b> In the paediatric cataract population examined, approximately half of the patients were diagnosed in the first year of life. More than 18% had a positive family history of cataracts. Of patients with hereditary cataracts 8% presented with unilateral involvement. Identification of the genes that cause paediatric and congenital cataract should help clarify the aetiology of some sporadic and unilateral cataracts.

CHARGE association includes patients with at least four features prefixed by the letters of the mnemonic: Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies and/or hearing loss. Many also have facial palsy. We report a series identified by collaboration within one centre of all specialties concerned in the management of the CHARGE association. Ocular abnormalities were found in 44 out of 50 patients with the CHARGE association. Of these, 41 had 'typical' colobomata. The majority had retinochoroidal colobomata with optic nerve involvement, but only 13 patients had an iris defect. Two patients had atypical iris colobomata with normal fundi. Additional features were microphthalmos in 21 patients, optic nerve hypoplasia in four, nystagmus in 12, and a vertical disorder of eye movement in four of the 22 cases with facial palsy. We report an incidence of coloboma in the CHARGE association of 86% (43/50) compared with a previous cumulative reported incidence of 66% (112/170). We believe that there may have been previous underdiagnosis of colobomata in children with multiple congenital abnormalities.

OBJECTIVES: To identify CRB1 mutations in a large cohort of patients with recessive retinal dystrophies and to document the retinal phenotype and visual prognosis. DESIGN: A hospital-based cross-sectional study of children and adults with recessive retinal dystrophies. PARTICIPANTS: Three hundred and six patients with Leber congenital amaurosis (LCA), early-onset childhood retinal dystrophy or juvenile onset retinitis pigmentosa were recruited to the study and gave blood samples for molecular genetic analysis. METHODS: A detailed clinical examination was performed, including: logMAR visual acuity, refraction, Goldmann visual fields, slit-lamp biomicroscopy, fundus photography, autofluorescence imaging and optical coherence tomography. The results of electrophysiology testing were available in all patients. DNA was obtained for molecular genetic analysis. Initial screening for mutations was performed using the LCA chip. Patients who had one or more CRB1 mutations identified on the chip, and other patients whose phenotype suggested a CRB1 genotype, underwent direct sequencing. In addition, consanguineous families segregating recessive RP underwent a whole genome scan using Affymetrix gene chips, and affected family members showing linkage to the RP12 locus underwent sequencing of the CRB1 gene. MAIN OUTCOME MEASURES: Identification of patients with mutations in CRB1 and detailed documentation of the clinical phenotype. RESULTS: Mutations in CRB1, including 17 novel mutations, were identified in 41 patients from 32 families. The authors identified both disease mutations in 34 patients from 26 families, and these patients underwent detailed phenotyping. Common phenotypic features included hypermetropic refractive error, nummular pigmentation at the level of the RPE and increased retinal thickness on optical coherence tomography. Most patients had a clinical and electrophysiological phenotype consistent with a diagnosis of LCA or rod-cone dystrophy, but three patients had electroretinogram evidence of cone-rod degeneration. A minority of patients developed peripheral retinal telangiectasia, which in some cases led to seclusio pupillae and angle-closure glaucoma. CONCLUSION: Mutations in CRB1 are associated with a range of recessively inherited retinal dystrophies, including LCA, childhood- and juvenile-onset rod-cone and cone-rod dystrophies. Although the phenotype is usually severe, in milder cases there is a window of opportunity for therapeutic intervention in early childhood.

Clinical experience of 50 patients with the CHARGE association is reviewed and problems with management of children born with multiple system involvement is highlighted. It was found that the outlook for survival was poor if more than one of the following three features was present: cyanotic cardiac lesions, bilateral posterior choanal atresia, or tracheo-oesophageal fistula. Mortality was largely due not to the structural heart defects or choanal abnormalities, but reflected underlying pharyngeal and laryngeal incoordination, which resulted in aspiration of secretions. Outcome is likely to be improved if collaboration between specialist surgical teams allows necessary procedures to be performed using the minimum number of anaesthetics. Examination of both the short and long term management of these children has stressed the importance of a multidisciplinary approach to their care.