[The Wiedemann-Beckwith syndrome and a congenital cataract]

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Wiedemann-Beckwith syndrome is a congenital syndrome with characteristic abnormalities: omphalocele, macroglossia, neonatal gigantism, visceromegaly, hemihypertrophy and a predisposition to embryonic tumors. Ophthalmologic abnormalities have not been described with Wiedemann-Beckwith syndrome. The authors report one case of Wiedemann-Beckwith syndrome associated with bilateral congenital cataract. Family studies indicate linkage of the Wiedemann-Beckwith syndrome locus to the marker 11p15,5. The genetics of cataract is heterogenic. Several mutations responsible for congenital cataract have been described. The association of the Wiedemann-Beckwith syndrome and cataract may contribute to the understanding of the genetics of congenital cataract.

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... Congenital cataract was previously described in a case report. 4 Here we report a rare finding of sectoral iris heterochromia occurring in an infant known to have BWS. ...
... 3 M momtival et al. reported a case of bilateral congenital cataract in a patient with BWS, where it was not claimed to be genetically associated. 4 Iris heterochromia has known to be associated with other genetic syndromes, for example; congenital Horner syndrome, Waardenburg syndrome, Sturge-Weber syndrome, and Fuchs heterochromic iridocyclitis 14,15,16 ; however, it has not been reported among BWS cases. Iris heterochromia can be acquired by eye trauma, chronic anterior uveitis, retained metallic intra-ocular foreign body (siderosis bulbi), ocular tumors and the use of topical prostaglandin analogues. ...
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Purpose To report a case of unilateral sectoral iris heterochromia in an infant with Beckwith-Wiedemann syndrome (BWS). Observations An 8-month-old girl known case of BWS, due to hypomethylation of the DMR2 (KCNQ1OT1) on chromosome 11p15.5, with features of macroglossia, neonatal hypoglycaemia and an unusual finding of partial iris hypopegmentaion in her left eye. Conclusions and Importance: This is the first reported case of iris heterochromia in a BWS patient. Further studies are needed to support the association between eye findings and BWS related genetic defects.
To determine the nature and course of ophthalmologic abnormalities in congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome in a genetically verified group of 9 patients. Observational case series. Nine affected male individuals of 5 pedigrees aged 1.3 to 16.8 years were examined. Four individuals were recruited during an ongoing prospective study of congenital cataracts; 5 individuals could be assigned to the CCFDN group on the basis of our retrospective data. Linkage and haplotype analysis, neurologic examinations, bilateral cataracts, axial length, corneal diameter, pupil diameter and pupillary reactions, intraoperative and postoperative complications, lid changes, aphakic correction problems, refractive results, and visual function. All families originated from the eastern part of Serbia, close to the border with Romania. The 8 tested individuals were homozygous for the conserved ancestral CCFDN haplotype in the telomeric region of chromosome 18q. All patients showed a peripheral, demyelinating neuropathy and varying degrees of ataxia. In the older patients, muscular atrophy in distal muscles and facial dysmorphism was evident. Early-onset bilateral congenital cataracts associated with microcornea, microphthalmos, and micropupil could be found in all patients. All children had floppy eyelid syndrome and pseudoptosis. An increased inflammatory reaction to contact lenses and intraocular lenses could be documented in all. All patients had syndrome-associated nystagmus and congenital esotropia. Distant visual acuity could be classified as severe to moderate impairment, whereas near visual acuity was much better (mild to moderate impairment). Early-onset congenital cataracts associated with microcornea, microphthalmos, and micropupil are essential ocular features of the CCFDN syndrome and are the first recognizable signs during early infancy. Awareness of this syndrome by pediatric ophthalmologists is important, because these typical findings, combined with information on ethnic origin, may lead to very early diagnosis at an age when the nature and severity of nonophthalmologic features are not apparent. Affected individuals may benefit from careful ophthalmologic treatment and follow-up, as well as from early management of the neurologic problems and developmental delay. Affected families will benefit from genetic counseling and predictive testing.
CZP1, a locus for autosomal dominant "zonular pulverulent" cataract, previously had been linked with the Duffy blood-group-antigen locus on chromosome 1q. Here we report genetic refinement of the CZP1 locus and show that the underlying mutation is present in GJA8, the gene for connexin50. To map the CZP1 locus we performed linkage analysis using microsatellite markers on two distantly related branches of the original Ev. pedigree, which now spans eight generations. Significantly positive two-point LOD score (Z) values were obtained for markers D1S2669 (maximum Z [Zmax] = 4.52; maximum recombination frequency [thetamax] = 0) and D1S514 (Zmax = 4.48; thetamax = 0). Multipoint analysis gave Zmax = 5.22 (thetamax = 0) at marker D1S2669. Haplotyping indicated that CZP1 probably lies in the genetic interval D1S2746-(20.6 cM)-D1S2771. Sequence analysis of the entire protein-coding region of the GJA8 gene from the pedigree detected a C-->T transition in codon 88, which introduced a novel MnlI restriction-enzyme site that also cosegregated with the cataract. This missense mutation is predicted to result in the nonconservative substitution of serine for a phylogenetically conserved proline (P88S). These studies provide the first direct evidence that GJA8 plays a vital role in the maintenance of human lens transparency and identify the genetic defect believed to underlie the first inherited disease to be linked to a human autosome.
To detect and characterize mutations in cases of familial and sporadic aniridia in Maritime Canada, and to look for indications of genotype/phenotype correlation within the cohort. Twelve consecutive and unrelated patients (probands) who had total or nearly complete absence of irides, and four affected relatives, were recruited from Maritime Canada. Clinical data were obtained by chart review and electroretinogram testing. Mutations in the PAX6 gene were detected by single-strand conformation polymorphism and characterized by sequence analysis. Eleven different PAX6 mutations, 10 of which are novel, were found. The four patients with congenital cataracts all had mutations in the C-terminal proline-serine-threonine (PST)-rich domain of the PAX6 protein. Electroretinograms of nine of 11 patients displayed depressed scotopic maximum response b-wave amplitudes. The greatest decrease in b-wave amplitudes was seen in patients in whom the paired domain was disrupted by mutation. Some aspects of the phenotype of aniridia appear to correlate with the predicted effect of point mutations on the paired and PST domains of the PAX6 protein.
Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein alpha-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Zmax]=>7.0; maximum recombination frequency [thetamax] =0). Haplotyping indicated that CZP3 probably lies in the genetic interval D13S1236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared approximately 88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A-->G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens.