John Pater

Prevalence of CYP1B1 mutations in Australian patients with primary congenital glaucoma

Analysis of CYP1B1 in primary congenital glaucoma (PCG) patients from various ethnic populations indicates that allelic heterogeneity is high, and some mutations are population specific. No study has previously reported the rate or spectrum of CYP1B1 mutations in Australian PCG patients. The aim of this study is to determine the frequency of CYP1B1 mutations in our predominately Caucasian, Australian cohort of PCG cases. Thirty‐seven probands were recruited from South‐Eastern Australia, along with 100 normal control subjects. Genomic DNA was extracted and the coding regions of CYP1B1 analysed by direct sequencing. Sequence analysis identified 10 different CYP1B1 disease‐causing variants in eight probands (21.6%). Five subjects were compound heterozygotes, two subjects heterozygous and one homozygous for CYP1B1 mutations. Three missense mutations are novel (D192Y, G329D, and P400S). None of the novel mutations identified were found in normal controls. One normal control subject was heterozygous for the previously reported CYP1B1 R368H mutation. Six previously described probable polymorphisms were also identified. Mutations in CYP1B1 account for approximately one in five PCG cases from Australia. Our data also supported the high degree of allelic heterogeneity seen in similar studies from other ethnic populations, thereby underscoring the fact that other PCG‐related genes remain to be identified.

Paediatric endoscopic endonasal dacryocystorhinostomy in congenital nasolacrimal duct obstruction

ObjectivesThe objectives of this study were to report a series of paediatric patients who underwent endoscopic endonasal dacryocystorhinostomy (DCR) for primary congenital nasolacrimal duct obstruction (NLDO).MethodsThis is a retrospective, noncomparative review of all consecutive cases in two lacrimal clinics between January 1999 and October 2004. The main outcome measures were patients’ demographics, previous treatments, clinical presentation, operative and postoperative complications, postoperative follow-up and resolution of epiphora.ResultsTwenty-one patients (15 males) with a mean age of 6±3.5 years (range, 2–14 years) underwent 26 endoscopic DCR operations for congenital NLDO. Sixteen cases were unilateral, and five were bilateral. In 13 cases (50.0%), there was a history of epiphora and chronic dacryocystitis with or without a mucocele. Two cases (7.7%) presented with acute dacryocystitis, and 11 (42.3%) had only a history of epiphora. Previous procedures included probing and irrigation in 25 cases (96.2%) and insertion of Crawford tubes in 19 cases 973.1%). During a mean postoperative follow-up period of 18±8 months, the anatomical success rate (free flow of fluorescein sodium and patency of ostium on nasal endoscopy) was 100%, and the clinical success rate (resolution of epiphora) was 92.3%.ConclusionEndoscopic endonasal DCR is an effective treatment modality for congenital NLDO that compares favourably with the reported success rates of external DCR.

Identification of a Novel Oligomerization Disrupting Mutation in CRYΑA Associated with Congenital Cataract in a South Australian Family

Congenital cataract is a heterogeneous disorder causing severe visual impairment in affected children. We screened four South Australian families with autosomal dominant congenital cataract for mutations in 10 crystallin genes known to cause congenital cataract. We identified a novel segregating heterozygous mutation, c.62G>A (p.R21Q), in the CRYΑA gene in one family. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of the high‐molecular‐weight oligomers seen in the lens material of an unaffected individual. We conclude that the p.R21Q mutation, which is located in the highly conserved and structurally significant N‐terminal region of the protein, is responsible for the cataract phenotype observed in the family as this mutation likely reduces the formation of the functional oligomeric alpha‐crystallin.

Endoscopic Drainage of a Superiorly Based Subperiosteal Orbital Abscess

INTRODUCTION Subperiosteal orbital abscess (SPOA) is an uncommon complication of acute sinusitis and is seen most commonly in toddlers and teenagers. Many cases can be successfully treated with intravenous antibiotics,1 but if the patient’s condition does not improve rapidly, or if he or she initially presents with reduced visual acuity, surgical drainage is indicated. In the past, most patients with SPOA have been treated by an external approach via a Lynch-Howarth or transcaruncular incision. Recently, some centers have used transnasal endoscopic approaches to drain the abscess,2 but this technique has been limited to treating those abscesses that are sited medially, directly adjacent to the lamina papyracea. Most centers treating SPOAs located superior to the lamina papyracea do so via an external approach. The purpose of this article is to report our initial experience with treating abscesses that are located above the frontoethmoidal suture line, confined to the superior or superomedial compartments of the orbit (Fig. 1), by using a fully endoscopic transnasal approach. It is important to determine the relationship between the abscess and the anterior ethmoidal artery on computed tomography (CT) scans. A subperiosteal abscess that develops in the superior compartment of the orbit has its origin in most cases from the frontal sinus. Consequently, the abscess is located anterior to the anterior ethmoidal artery, although in some cases it may track posteriorly along the orbital roof. This is important to understand because it determines the transnasal endoscopic route to the abscess. The endoscopic entry into the superior orbital region should be performed anterior to the anterior ethmoidal artery, as described below.

High-throughput genetic screening of 51 pediatric cataract genes identifies causative mutations in inherited pediatric cataract in South Eastern Australia

Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected individuals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency <1% in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA, and MIP; and three previously reported cataract-causing mutations in GJA8, CRYAA, and CRYBB2. The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for >60% of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified.

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

Partial duplication of the CRYBB1-CRYBA4 locus is associated with autosomal dominant congenital cataract

Congenital cataract is a rare but severe paediatric visual impediment, often caused by variants in one of several crystallin genes that produce the bulk of structural proteins in the lens. Here we describe a pedigree with autosomal dominant isolated congenital cataract and linkage to the crystallin gene cluster on chromosome 22. No rare single nucleotide variants or short indels were identified by exome sequencing, yet copy number variant analysis revealed a duplication spanning both CRYBB1 and CRYBA4. While the CRYBA4 duplication was complete, the CRYBB1 duplication was not, with the duplicated CRYBB1 product predicted to create a gain of function allele. This association suggests a new genetic mechanism for the development of isolated congenital cataract.

Case series of cat-scratch-inflicted full-thickness corneal lacerations and a review of the literature.

Background:  To describe the clinical features and management of cat‐scratch‐inflicted corneal lacerations.

A novel genetic syndrome characterized by pediatric cataract, dysmorphism, ectodermal features, and developmental delay in an Indigenous Australian family

A novel syndrome initially presenting with cataract and developmental delay within an Indigenous Australian family is described. We present the extended four generation pedigree and describe in detail the phenotypic appearance of five clearly affected male second cousins in this family. The common features of these children include developmental delay, short stature, cortical cataract, facial dysmorphism, clinodactyly, thin hair and an erythematous skin rash. Initial inspection of the pedigree suggested an inherited disorder with possible X‐linked inheritance. However, a thorough scan of the X chromosome failed to reveal linkage. This family represents a new syndrome of familial cataract, dysmorphic features, short stature and developmental delay with probable autosomal inheritance and variable expressivity.

Congenital glaucoma with anterior segment dysgenesis in individuals with biallelic CPAMD8 variants

Purpose Congenital glaucoma is a significant cause of irreversible blindness. In some instances glaucoma is associated with developmental abnormalities of the ocular anterior segment, which can impair drainage of aqueous humor, leading to an increase in intraocular pressure. Methods Genome sequencing was performed on a parent-proband congenital glaucoma trio, with exome sequencing of 79 additional individuals with suspected primary congenital glaucoma. Results We describe a unique ocular anterior segment dysgenesis associated with congenital glaucoma in four individuals from three unrelated families. In each case, disease was associated with compound heterozygous variants in CPAMD8, a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation of key drainage structures and the development of high intraocular pressure and glaucoma. Conclusions This study reveals a unique genetic cause of childhood glaucoma, and expands the phenotypic spectrum of CPAMD8-associated ocular disease.