Partial aniridia, cerebellar ataxia, and mental deficiency (gillespie syndrome) in two brothers
Ehrenfried O. WittigCarlos A. MoreiraN. Freire‐MaiaAngela Maria Vianna‐MorganteJohn M. OpitzJames F. Reynolds
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Abstract We report on two brothers (in a sibship of three) with partial aniridia, cerebellar ataxia, and moderate mental retardation, with normal G‐banded chromosomes. Both present cerebellum hypoplasia; the younger also has congenital pulmonic stenosis. A review of the literature is presented. Cause is unknown, although the possibility of an autosomal recessive gene cannot be ruled out.Keywords:
Aniridia
Cerebellar hypoplasia (non-human)
Cerebellar ataxia
Abstract Aniridia is a congenital complex ocular malformation characterized by complete or partial iris hypoplasia and foveal hypoplasia, resulting in nystagmus and low visual acuity from early infancy. In the majority of cases, aniridia is caused by the loss of function of one functional copy (haploinsufficiency) of the PAX6 protein resulting from mutations in PAX6 gene or chromosomal rearrangement at the 11p13 locus. High‐resolution foveal imaging by spectral‐domain optical coherence tomography (SD‐OCT) has improved over recent years the evaluation of foveal architecture analyze. We have analyzed foveal anomalies on SD‐OCT in a large cohort (89 patients) of aniridia patients. We have shown that the grade of foveal hypoplasia is correlated to visual acuity. We have also shown that foveal hypoplasia is a constant finding in PAX6 aniridia patients, although iris defects could vary from complete aniridia to slight iris defects, even in the same family. Foveal imaging and grading by SD‐OCT could offer a non‐invasive tool to determine the visual potential of aniridia eyes and indicate further investigations or treatments. Additionally, SD‐OCT could contribute in the diagnosis of congenital aniridia by detecting foveal hypoplasia as the first sign of the disease.
Aniridia
PAX6
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• Although defective development of the fovea has long been known to occur in patients with aniridia and albinism, only rarely has isolated foveal hypoplasia unassociated with these conditions been reported. We have identified such foveal hypoplasia in nine patients with varying degrees of congenital nystagmus and poor visual acuity, but no evidence of albinism or aniridia. Isolated foveal hypoplasia may be more common as a cause of congenital sensory nystagmus than has been appreciated in the past.
Aniridia
Fovea centralis
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Congenital aniridia is a kind of eye disease characterized by complete or partial hypoplasia of the iris and is associated with other ocular anomalies including corneal opacity, glaucoma, and foveal hypoplasia. Heterozygous mutation of paired box 6 (PAX6) gene was identified in most cases of aniridia, with iatrogenic mutations accounting for about two-third of the cases and chromosomal rearrangements accounting for the other one-third. We report rare cases of variant aniridia, congenital iris ectropion associated with foveal hypoplasia in both a woman and her son with a mutation of PAX6 gene. To our knowledge, deletion c. 936delC in exon 8 of PAX6 gene has not been reported until now.
Aniridia
PAX6
IRIS (biosensor)
Maldevelopment
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Aniridia
Optic nerve hypoplasia
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Congenital aniridia is caused by a mutation in the PAX6 gene [1] and is characterized by partial or complete absence of iris tissue. Apart from the hypoplasia of iris tissue, other ocular features such as foveal hypoplasia, nystagmus, aniridia-related keratopathy, Peters anomaly, Axenfeld-Rieger anomaly and glaucoma are seen in these eyes [1,2]. Cases have been reported with persistent pupillary membranes [3] and iris strands [4].
Aniridia
IRIS (biosensor)
PAX6
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In a 48-year-old man, marked unilateral cerebellar hypoplasia was diagnosed by CT scans and angiographic examinations, later confirmed on autopsy. Clinical findings in cerebellar hypoplasia/aplasia are discussed here, along with the pathogenesis of cerebellar hypoplasia. In this case, several grand mal seizures and persistent headache were the only neurological symptoms. Repeated neurologic explorations did not reveal any abnormality. The clear demonstration of cerebellar hypoplasia associated with ipsilateral hypoplasia of the vertebral artery favors the concept of a vascular genesis of cerebellar hypoplasia/aplasia.
Cerebellar hypoplasia (non-human)
Aplasia
Abnormality
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Aniridia
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To correlate the degree of foveal hypoplasia in congenital aniridia with visual acuity, iris phenotype, and PAX6 mutations.Retrospective case series.Ninety-five consecutive patients with high-quality spectral-domain optical coherence tomography records and available genotype were included in a single referral center. Iris hypoplasia was classified as complete, presence of iris root or remnants, and mild atypical aniridia. Spectral-domain optical coherence tomography images were assessed to classify foveal hypoplasia as grade 1 to 4 and to determine mean thicknesses for retinal layers. For statistical analysis 1 eye for each patient was used and 1 member of the same family has been included (n = 76 eyes).Most eyes (n= 158/169, 93.5%) showed variable degree of foveal hypoplasia. PAX6-positive patients presented higher degree of foveal hypoplasia than patients negative for PAX6 (P < .0001). PAX6 deletions, PAX6 variants subjected to nonsense-mediated decay and C-terminal extension variants were mostly associated with grade 3 or 4 foveal hypoplasia. Deletions restricted to the 3' flanking regulatory regions of PAX6 were associated with grade 1 or 2 foveal hypoplasia (P < .0001). Best-corrected visual acuity was higher and foveal outer retinal layers were thicker in patients with deletions in the 3' regulatory region of PAX6 (P = .001 and P < .0001). Patients with missense mutations presented with variable degree of foveal hypoplasia. The degree of foveal hypoplasia was most frequently correlated with the severity of iris defects, with 95% of eyes with complete aniridia presenting grade 3 or 4 foveal hypoplasia (P = .005). However, among eyes with mild iris phenotype, 70% (n=9/13) showed severe foveal hypoplasia.All types of PAX6 variants, even those associated with mild iris defects, may be at risk for severe foveal hypoplasia with poor visual prognosis, except for deletions restricted to the 3' regulatory PAX6 regions.
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PAX6
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The purpose of this study is to define the imaging features in a group of fetuses with suspected cerebellar hypoplasia and to evaluate the clinical outcome of these pregnancies. This is a retrospective study on a cohort of fetuses diagnosed with suspected cerebellar hypoplasia, between 2011 and 2018. The records of each patient, including US and MR examinations were reviewed. The results were compared with postnatal clinical evaluation, imaging and genetic and pathology examinations. 48 patients with suspected cerebellar hypoplasia were included in the study. Nine patients were diagnosed with isolated cerebellar hypoplasia; eight delivered with average follow up of 40.5 months (range of 2.5-57 months); two children had normal neurological development, five children had neurodevelopmental delay, and one child was lost to follow up. One patient was lost to follow up. Two other patients had cerebellar hypoplasia with parvovirus infection during pregnancy. One delivered (normal neurodevelopment at age 24 months) and one had a termination of pregnancy (TOP). Three patient had unilateral cerebellar hypoplasia; two delivered (one normal neurological development, one mild developmental delay) and one was lost to follow up. 34 patients had cerebellar hypoplasia with associated malformations; 32 of them had other CNS malformation with and without non-CNS malformations and two patients had only non-CNS malformation. Four patients delivered (one with global developmental delay and genetic syndrome, three were lost to follow up). Twenty-two had TOP and eight patients were lost to follow up. MRI was performed in 28 patients. Cerebellar hypoplasia is a subgroup of congenital cerebellar malformations. The information on long term outcome is limited especially on isolated cases. In our study children with cerebellar hypoplasia had a high prevalence of neurological deficit even in isolated cases.
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We report three sibling pairs with congenital cerebellar hypoplasia. All six children presented in the first years of life with delays in motor and language development. All patients showed cerebellar and/or vermal dysfunction and, on formal psychometric testing, cognitive abilities ranged from normal to moderately retarded. Abnormalities on CT scan ranged from prominent valleculla to an enlarged cisterna magna with hypoplasia of the cerebellar hemispheres and vermis. The pedigrees are consistent with autosomal recessive inheritance.
Cerebellar hypoplasia (non-human)
Autosomal recessive inheritance
Cerebellar vermis
Cerebellar hemisphere
Cisterna magna
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