Gillespie (1965) described brothers and sisters with aniridia, cerebellar ataxia, and mental retardation, which had apparently not been reported previously, although cerebellar ataxia, mental deficiency and congenital cataracts are known in the Marinesco-Sjogren syndrome. The karyotype of each ... Gillespie (1965) described brothers and sisters with aniridia, cerebellar ataxia, and mental retardation, which had apparently not been reported previously, although cerebellar ataxia, mental deficiency and congenital cataracts are known in the Marinesco-Sjogren syndrome. The karyotype of each patient was normal. Sarsfield (1971) reported a further example of the above syndrome complex occurring in a male, the second child of normal parents. Bilateral partial aniridia was noted at birth and developmental milestones were subsequently delayed. Although muscle biopsies and nerve conduction times were normal, there was persistent hypotonia with normal tendon reflexes and sensation, but with gross uncoordination, attention tremor, and scanning speech. There was some improvement in motor performance with age, but mental retardation was evident. All laboratory investigations, including karyotype, were normal. Crawfurd et al. (1979) described an affected brother and sister in a sibship of 3 and an affected son of the sister. Although no consanguinity had been established, Crawfurd et al. (1979) suggested that the affected female's husband was a carrier. The possibility of remote consanguinity was supported by the finding of another family with this very rare syndrome in a nearby town (Sarsfield, 1971). Noteworthy is the observation that the lens and cornea of Gillespie syndrome are clear, whereas congenital cataract and corneal opacities are relatively common among autosomal dominant aniridia patients (106210). Lechtenberg and Ferreti (1981) reported a single case in an 18-month-old girl. This family was apparently nonconsanguineous, as was also the family reported by Wittig et al. (1988); in the last family, 2 brothers in a sibship of 3 had the triad. All 3 sibs had cerebellar hypoplasia; the younger brother also had congenital pulmonic stenosis. Francois et al. (1984) reported a family with 2 affected sisters. Nevin and Lim (1990) described an isolated case. Nelson et al. (1997) described 2 unrelated patients with Gillespie syndrome. The typical presentation is the discovery of fixed dilated pupils in a hypotonic infant. They considered the iris abnormality specific and pathognomonic for Gillespie syndrome. It can be distinguished clinically from other forms of aniridia and a presumptive diagnosis of Gillespie syndrome can be made in the first months of life on the basis of the ocular findings. On slit-lamp examination, the pupil border of the iris typically shows a scalloped 'festooned' edge with tufts of iris strands extending onto the anterior lens surface at regular intervals. Pupillary membrane remnants are frequently present, and the cornea and lens are typically clear. In 1 of the patients, Nelson et al. (1997) found cerebral and cerebellar atrophy with white matter changes on MRI scan, suggesting that patients with Gillespie syndrome may have more extensive CNS involvement than previously described. The parents of this child were first cousins, thus supporting autosomal recessive inheritance. In addition to the family reported by Crawfurd et al. (1979) suggesting autosomal dominant inheritance, Nelson et al. (1997) called attention to the report of the syndrome in mother and daughter by Verhulst et al. (1993). Dollfus et al. (1998) reported an 8-month-old girl with bilateral partial aniridia consisting of a superior coloboma and inferior iris hypoplasia, foveomacular dysplasia, nystagmus, mild craniofacial asymmetry, axial hypotonia, developmental delay, and mild mental retardation; MRI revealed hypoplasia of the inferior cerebellar vermis, frontal cortical atrophy, and a thin corpus callosum. The authors suggested that these findings represented a Gillespie syndrome phenotype. Donald et al. (2006) described 2 unrelated boys with Gillespie syndrome, both born of nonconsanguineous parents. One was an 8-year-old boy with the cognitive function of a 5-year-old, who had bilateral ptosis, aniridia, dysarthric speech, globally decreased tone, and a broad-based, unsteady gait. Slit-lamp examination revealed absence of the sphincter pupillae, with lack of the entire sheet of mesoderm, resulting in the collarette forming the papillary margin. Funduscopy was normal. CT scan in infancy and MRI at age 10 years showed cerebellar atrophy and anterior cerebral atrophy. The other boy was 4 years old and functioning at a 3-year-old level; he had a fine tremor, an ataxic gait, reduced tone that was more marked in the lower limbs, and mildly dysarthric speech. Ophthalmic examination revealed 'findings within the aniridia spectrum,' with a flat-looking iris and absence of structures from the collarette to pupil margin (absence of the sphincter pupillae); the fundi were normal. MRI and CT of the brain at age 2 years were normal. Neither boy had dysmorphic features, nystagmus, or involuntary movements. Ticho et al. (2006) described a 6-year-old Caucasian boy with 'atypical Gillespie syndrome,' who had partial aniridia, balance disorder, hand tremor, and learning disability. His eye findings included mild bilateral ptosis, exotropia, corectopia, decreased visual acuity, patchy temporal absence of the anterior iris leaflet, iris processes crossing the trabecular network, anterior lens capsule opacities, foveal hypoplasia, retinal vascular tortuosity, and retinal hypopigmentation. He had slight facial dysmorphism. He had received therapy for a mild balance disorder, low tone in his upper extremities, and rigidity in the lower extremities, and had been evaluated for mild psychomotor delay, which led to a diagnosis of attention deficit hyperactivity disorder and a central auditory processing delay. Brain MRI revealed no focal abnormalities, including absence of cerebellar findings. Boughamoura et al. (2006) reported a sister and brother, born of consanguineous parents, who had congenital bilateral partial aniridia, cerebellar ataxia, and mental retardation. Brain MRI showed cerebellar atrophy in the girl and mild cortical and subcortical atrophy involving the subtentorial region and hypoplasia of the inferior vermis in the boy. Ophthalmologic examination of the boy revealed bilateral partial aniridia with peripheral tufting, iris strands on the anterior lens, and dysgenesis of the iridocorneal angle. The karyotype was normal in both children. Luquetti et al. (2007) described an 8-year-old Brazilian girl, born of first-cousin parents, who had bilateral aniridia, hypotonia, ataxia, and mild mental retardation. Dysmorphic features included low anterior hairline, synophrys, downslanting palpebral fissures, anteverted nostrils, prognathism, high arched palate, and marked broad distal phalanges with hyperconvex nails in hands and feet. Ophthalmologic examination showed decreased visual acuity, incomplete formation of the iris with small strands in the direction of the lens consistent with a pupillary membrane, and normal fundi with no suggestion of foveal hypoplasia or optic atrophy. Brain MRIs at 6 months and 8 years of age were read as normal; single photon emission computed tomography (SPECT) of the CNS showed signals of cerebellar hypoperfusion. X-rays of the hands and feet revealed enlargement of soft tissues surrounding the distal phalanges but no bone alterations. She had a normal karyotype. Defreyn et al. (2007) reported a 30-month-old girl, born of nonconsanguineous parents, who had bilateral iris hypoplasia, clear cornea and lens, normal intraocular pressure, and diffuse retinal hypopigmentation. She had mild psychomotor delay, axial hypotonia, and difficulties with balance. There were no dysmorphic features. Brain MRI at 18 months of age was normal. Graziano et al. (2007) described a 9.5-year-old girl, born of nonconsanguineous parents, who had aniridia, ataxia, and moderate mental retardation. Dysmorphic features included an asymmetric face with high forehead, ptosis, strabismus, hypertelorism, depressed nasal bridge with anteverted nostrils, high and narrow palate, folded ears with hypoplastic antihelix, arachnodactyly, and cervical, dorsal, and lumbar kyphosis. She had an ataxic gait, intention and action tremor of both upper limbs, axial hypotonia, and lower limb hypertonia. Ophthalmologic examination revealed clear cornea and lens and bilateral symmetric aniridia; the rudimentary iris stump was regular without tufts. Cerebral MRI at 6 months of age showed dilation of the left Sylvian fissure and normal myelinization; magnetic resonance spectroscopy at age 9.5 years was consistent with mild neurodegenerative alteration of the cerebellar area. Karyotyping at 6 years of age was normal. Marien et al. (2008) performed a detailed neurocognitive investigation of a mother and daughter diagnosed with Gillespie syndrome and found that both had marked asymmetry in their IQ profiles, with significantly better results on the verbal than nonverbal testing; they also displayed a pattern of behavioral and cognitive abnormalities that closely resembled the cerebellar cognitive and affective syndrome. Ophthalmic examination revealed 'bilaterally underdeveloped iris' in the mother and 'widely dilated pupils' that were nonreactive in the daughter; funduscopy was normal in both. Brain MRI showed cerebellar hypoplasia, particularly of the vermis, in both patients.
In a 6-year-old Caucasian boy with 'atypical Gillespie syndrome' (see 206700), consisting of partial aniridia, mild balance disorder, hand tremor, and learning disability, Ticho et al. (2006) identified a splice site mutation in the PAX6 gene (607108.0024). ... In a 6-year-old Caucasian boy with 'atypical Gillespie syndrome' (see 206700), consisting of partial aniridia, mild balance disorder, hand tremor, and learning disability, Ticho et al. (2006) identified a splice site mutation in the PAX6 gene (607108.0024). In a 9.5-year-old girl with a phenotype suggestive of Gillespie syndrome, Graziano et al. (2007) identified heterozygosity for a nonsense mutation in the PAX6 gene (607108.0025). The authors stated that due to the small number of patients with a diagnosis of Gillespie syndrome and the absence of a recurrent molecular defect, it was difficult to delineate the clinical criteria for the diagnosis; they suggested that screening of PAX6 in patients with suspected Gillespie syndrome should be performed with up-to-date methodology. - Genetic Heterogeneity Using single-strand conformation polymorphism (SSCP) analysis in affected individuals from 3 families with Gillespie syndrome, 1 of which had previously been reported by Crawfurd et al. (1979), Glaser et al. (1994) found no alteration of PAX6 sequences. In 2 families, the disease traits segregated independently from 11p markers flanking PAX6, suggesting that some forms of Gillespie syndrome are distinct from autosomal dominant aniridia due to mutations in PAX6. In a 30-month-old girl diagnosed with Gillespie syndrome, Defreyn et al. (2007) analyzed the PAX6 and PITX2 (601542) genes using PCR and DHPLC but found no mutations. In a mother and daughter diagnosed with Gillespie syndrome, who had features consistent with cerebellar cognitive affective syndrome rather than global mental retardation, Marien et al. (2008) performed molecular studies, including Southern blot analysis and PCR, that did not demonstrate any rearrangements on chromosome 11 but did not exclude point mutations in the PAX6 gene.