Gillespie Syndrome

A number sign (#) is used with this entry because of evidence that Gillespie syndrome (GLSP) is caused by heterozygous mutation in the ITPR1 gene (147265) on chromosome 3p26. Some patients have been reported with homozygous or compound heterozygous mutation in the ITPR1 gene.

Description

Gillespie syndrome is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (summary by Gerber et al., 2016 and McEntagart et al., 2016).

Clinical Features

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 this triad 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 which 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.

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.

Marien et al. (2008) performed a detailed neurocognitive investigation of a mother and daughter diagnosed with Gillespie syndrome, originally reported by Verhulst et al. (1993), 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.

Gerber et al. (2016) studied 5 unrelated patients with Gillespie syndrome, including a 16-year-old Brazilian girl who was originally described by Luquetti et al. (2007). All presented at birth or within the first few months of life with hypotonia and iris hypoplasia (bilateral partial aniridia). Cerebellar signs included nystagmus, ataxia, slurred speech, and general hypotonia; in addition, 3 patients had mild to moderate intellectual disability, 1 was reported to have normal intelligence, and 1 was too young to evaluate. MRI findings in the first several months of life were unremarkable, but later imaging studies revealed marked cerebellar atrophy.

Clinical Variability

Van Dijk et al. (2017) reported a 6-year-old girl with a phenotype consistent with Gillespie syndrome. She presented with poor head control, hypotonia, and delayed psychomotor development in the first 6 months of life. She had severe truncal titubation with limb ataxia and brisk reflexes. However, there were no ocular abnormalities aside from strabismus. Brain imaging showed nonprogressive, but severe, pontine and cerebellar hypoplasia. The inferior vermis was almost absent and the superior vermis was hypoplastic with superimposed atrophy. At age 4, she could sit and stand with support and eat by herself, but could only speak single words. Exome sequencing identified a de novo heterozygous missense mutation in the ITPR1 gene (I2550N; 147265.0014) affecting the transmembrane domain of the protein, similar to mutations identified in other patients with Gillespie syndrome. Functional studies of the variant and studies of patient cells were not performed. Van Dijk et al. (2017) noted that the phenotype in this child expanded the spectrum of ataxias associated with mutations in the ITPR1 gene.

Inheritance

Families with apparent autosomal recessive inheritance of Gillespie syndrome have been reported (Gillespie, 1965; Wittig et al., 1988; Nelson et al., 1997); however, instances of autosomal dominant transmission have also been reported (Verhulst et al., 1993).

Cytogenetics

In an 8-month-old girl with features consistent with Gillespie syndrome, Dollfus et al. (1998) found a de novo balanced translocation t(X;11)(p22.32;p12). FISH studies showed that the PAX6 gene (607108), mutations in which have been identified in patients with aniridia, is distal to the breakpoints on chromosome 11p; no mutations or microdeletions were detected by SSCP or direct sequencing of PAX6. The authors stated that these findings suggested that PAX6 is not directly involved in their patient's phenotype, but that a positional effect of the translocation on the PAX6 gene could not be excluded. Kim et al. (2012) noted that the translocation in this patient disrupted the PHF21A gene (608325) on chromosome 11 and the ARHGAP6 gene (300118) on the X chromosome. Kim et al. (2012) included this patient in a study demonstrating that translocations disrupting PHF21A result in intellectual disability and craniofacial anomalies, features of Potocki-Shaffer syndrome (601224).

Molecular Genetics

In a 4.5-year-old Tunisian girl with Gillespie syndrome, who was negative for variation in the PAX6 gene (607108), Gerber et al. (2016) performed exome sequencing and identified homozygosity for a nonsense mutation in the ITPR1 gene (Q1558X; 607108.0005) that was present in heterozygosity in her unaffected consanguineous parents. Analysis of ITPR1 in 4 more probands with Gillespie syndrome revealed homozygosity for another nonsense mutation (R728X; 607108.0006) in an 8-year-old Brazilian girl previously reported by Luquetti et al. (2007), and compound heterozygosity for 2 splice site mutations (607108.0007-607108.0008) in a 7.5-year-old French girl. The remaining 2 patients carried de novo heterozygous mutations in ITPR1: the first was an 18-year-old French woman with an in-frame 3-bp deletion (K2569del; 607108.0009), and the second was a 1.5-year-old girl from the French Caribbean island of La Guadeloupe, who had a missense mutation (F2553L; 607108.0010) that was not found in her consanguineous parents. All 5 patients exhibited similar iris anomalies and neonatal ataxia with progressive cerebellar atrophy; however, the 3 patients with biallelic mutations had moderate to severe intellectual disabilities, whereas the 18-year-old heterozygote was reported to have normal intelligence. However, the latter patient was also studied by McEntagart et al., 2016 and designated as having 'mild' intellectual disability. The other heterozygous patient was too young to be evaluated at age 18 months. Ophthalmologic examination of the heterozygous parents from the Tunisian and French families, which included gonioscopy and funduscopy, revealed no abnormalities. Gerber et al. (2016) concluded that their findings demonstrated the long-suspected coexistence of autosomal recessive and autosomal dominant patterns of inheritance in Gillespie syndrome.

Exclusion Studies

Ticho et al. (2006) and Graziano et al. (2007) reported patients with phenotypes suggesting Gillespie syndrome (see 106200) who had mutations in the PAX6 gene (607108). 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.

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.