J. Timothy Stout

Localization of a Gene for Duane Retraction Syndrome to Chromosome 2q31

Duane retraction syndrome (DRS) is a congenital eye-movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, restricted adduction, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. DRS has a prevalence of approximately 0.1% in the general population and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead to amblyopia, a permanent uncorrectable loss of vision. A large family with autosomal dominant DRS was examined and tested for genetic linkage. After exclusion of candidate regions previously associated with DRS, a genomewide search with highly polymorphic microsatellite markers was performed, and significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum LOD score 11.73 at maximum recombination fraction. 0). Haplotype analysis places the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No recombinants were seen with markers between these two loci. The linked region contains the homeobox D gene cluster. Three of the genes within this cluster, known to participate in hindbrain development, were sequenced in affected and control individuals. Coding sequences for these genes were normal or had genetic alterations unlikely to be responsible for the DRS phenotype. Identifying the gene responsible for DRS may lead to an improved understanding of early cranial-nerve development.

Clinical diversity of hereditary Duane’s retraction syndrome

OBJECTIVEnTo define the spectrum of ophthalmic manifestations of Duanes retraction syndrome (DRS) in a large family.nnnDESIGNnCross-sectional study of 110 among 114 living relatives in an extended family.nnnMETHODSnHistory and ophthalmic examination obtained on all participants.nnnMAIN OUTCOME MEASURESnOcular motility, strabismus, visual acuity, binocularity, associated neurologic problems.nnnRESULTSnTwenty-five individuals were affected with DRS. Twenty-four subjects (96%) had bilateral DRS, but there was a broad spectrum of severity. Strabismus occurred in 76% and amblyopia in 48%. Associated findings included fourth cranial nerve palsy, partial third cranial nerve palsy, nystagmus, seizures, and deafness. Fourth cranial nerve palsies and manifest strabismus tended to cluster within single family units.nnnCONCLUSIONSnStrabismus and amblyopia are much more common with bilateral DRS than with unilateral DRS. There is much phenotypic variability among individuals within families with hereditary Duanes syndrome. The responsible gene(s) may affect the development of many cranial nerves. Genetic compounding may play a role in the phenotypic segregation seen within this large family.

Histopathology of the eye in diffuse neonatal hemangiomatosis

PURPOSEnTo report the ocular presentation and histopathology of a patient with diffuse neonatal hemangiomatosis.nnnMETHODSnCase report. A 3.7-kg female was born at term. Multiple hemangiomas were present, and the patient died 39 days after birth.nnnRESULTSnWidespread cutaneous and visceral hemangiomas were present. Ophthalmic examination disclosed bilateral eyelid and conjunctival hemangiomas. The right eye had multiple iris hemangiomas, hyphema, vitreous hemorrhage, and discrete subretinal lesions. Histopathology of the right eye demonstrated hemangiomas involving the iris, ciliary body, and ciliary processes.nnnCONCLUSIONnDiffuse neonatal hemangiomatosis was associated with ophthalmic findings of multiple hemangiomas involving eyelid, conjunctiva, iris, ciliary body, and ciliary processes.

Exclusion of candidate genetic loci for Duane retraction syndrome.

PURPOSEnTo report preliminary linkage analysis of a large Hispanic family showing autosomal dominant inheritance for Duane retraction syndrome.nnnMETHODSnMicrosatellite analysis was used to examine genomic DNA isolated from members of a large family with autosomal dominant Duane retraction syndrome for linkage to candidate loci for Duane retraction syndrome. Chromosomes 4, 8, and 22 were chosen for study because previous reports had documented karyotypic abnormalities in unrelated patients with Duane retraction syndrome.nnnRESULTSnNo lod scores over 0.5 were found for markers on chromosomes 4, 8, or 22. This analysis excludes these candidate sites.nnnCONCLUSIONSnStudies do not support linkage between Duane retraction syndrome in this family and chromosomes 4, 8, and 22. Duane retraction syndrome may result from mutations in a heterogeneous group of genes.

DNA-based diagnosis of the von Hippel–Lindau syndrome ☆

PURPOSEnTo evaluate the etiology of a unilateral hemangioblastoma noted in a male with a family history remarkable only for spine surgery in the probands father.nnnMETHODSnGenomic DNA was isolated from peripheral blood of family members, and the three exons of the von Hippel-Lindau gene were examined for mutations by direct sequencing.nnnRESULTSnA three base pair (bp) deletion in exon 1 of the VHL gene was found in the father and both sons. This in-frame deletion results in the loss of a phenylalanine residue from the von Hippel-Lindau protein product, at amino acid position 76.nnnCONCLUSIONnGenetic screening has confirmed that von Hippel-Lindau syndrome is responsible for the hemangioblastoma in the proband. Magnetic resonance imaging scans performed as a consequence of these results indicated spinal tumors present in the father and tumors present in the cerebellum of the probands sibling. As close, lifelong follow-up is warranted with this disease, this case demonstrates the value of DNA testing in patients with ocular findings consistent with von Hippel-Lindau disease in the absence of a recognized family history.