Temtamy Syndrome

A number sign (#) is used with this entry because Temtamy syndrome (TEMTYS) is caused by homozygous or compound heterozygous mutation in the C12ORF57 gene (615140) on chromosome 12p13.

Description

Temtamy syndrome is a mental retardation/multiple congenital anomaly syndrome characterized by variable craniofacial dysmorphism, ocular coloboma, seizures, and brain abnormalities, including abnormalities of the corpus callosum and thalamus (summary by Akizu et al., 2013).

Clinical Features

Among the 6 children of a first-cousin marriage, Temtamy et al. (1991) observed a boy and 2 girls with a syndrome consisting of craniofacial dysmorphism, absent corpus callosum, and iris coloboma. Two of the 3 sibs had aortic dilatation with aortic regurgitation, and one had moderate mental retardation. The craniofacial anomalies consisted of macrodolichocephaly, arched eyebrows, antimongoloid slant of the eyes, beaked nose, low-set and simple lop ears, long philtrum, short upper lip, and micrognathia. In conjunction with the 'keyhole' coloboma of the iris, retina, and choroid, the lenses were dislocated upward and there was myopia and hypertelorism. Electron microscopy of the gingiva showed widening of the intercellular space, thickness of collagen fibers, and lack of periodicity. The sister, who died at age 22 years from heart failure, had moderate dilatation of the aorta, myocardial impairment, and bulbous thumbs. The affected male and his father had a satellited long arm of the Y chromosome (Yq). Temtamy et al. (1996) provided a full report of these 3 sibs. Photographs and comparisons with autosomal recessive and autosomal dominant disorders with iris coloboma and associated anomalies were provided.

Chan et al. (2000) described a male infant, born of nonconsanguineous parents, with right-sided iris coloboma and agenesis of the corpus callosum. Ophthalmologic examination revealed a very large chorioretinal coloboma involving the macula and optic nerve in the right eye in addition to the iris coloboma, and ultrasound and CT scan of the brain showed an absent corpus callosum. Developmental milestones were mildly delayed. Clinical manifestations shared by this case and the 3 children described by Temtamy et al. (1991) included agenesis of the corpus callosum, ocular coloboma, hypertelorism, frontal bossing, downslanting palpebral fissures, and micrognathia. Regarding their patient's relative macrocephaly, Chan et al. (2000) pointed out that, using the Nellhaus head circumference chart, 2 of the 3 previously reported cases also had relative macrocephaly rather than macrodolichocephaly. Chan et al. (2000) concluded that the primary clinical manifestations of the newly described syndrome include agenesis of the corpus callosum, ocular coloboma, hypertelorism, and relative macrocephaly.

Li et al. (2007) reported a brother and sister, born of consanguineous parents of Middle Eastern origin, with partial and complete agenesis of the corpus callosum, respectively, as well as colpocephaly and Probst bundles, optic coloboma, craniofacial dysmorphism, and skeletal anomalies. Li et al. (2007) noted that the sibs differed from the patients originally described by Temtamy et al. (1991) in that neither had cardiac anomalies, and both had severe mental retardation, intractable seizures, and interhemispheric colloid cyst, suggesting a more severe disruption of brain development. Linkage analysis did not identify a candidate disease locus.

Zahrani et al. (2013) reported a consanguineous Saudi Arabian family in which 4 sibs, ranging in age from 2.5 years to 19 years, had global developmental delay and early-onset refractory seizures. Two of the patients had colobomatous microphthalmia. Three had corpus callosum abnormalities: 1 with hyperplasia of the corpus callosum and 2 with agenesis of the corpus callosum. Another Saudi girl who belonged to the same tribe had profound global developmental delay, seizures, microphthalmia and coloboma involving the iris, choroid, and retina and extending to the optic cup. Her brain MRI was normal.

Akizu et al. (2013) reported 10 patients from 4 consanguineous families with Temtamy syndrome who were ascertained from a large cohort of families with corpus callosum hypoplasia. The families were from Kuwait, eastern Libya, and the United Arab Emirates; the fourth family was of Palestinian origin and had previously been reported by Li et al. (2007). The phenotype included hypotonia and moderate to severe intellectual disability with features of autism. Eight patients had epilepsy, 7 had dysmorphic craniofacial features, 5 had spasticity, and 4 had variable eye abnormalities, including esotropia and optic atrophy. One patient had microphthalmia and coloboma. Eight patients had brain imaging, which showed absent corpus callosum or hypoplasia of the corpus callosum, thalamic hypoplasia, and reduced white matter. Other more variable imaging findings included decreased anterior commissure, enlarged ventricles, and abnormal septum pellucidum.

Salih et al. (2013) reported a consanguineous Saudi Arabian family in which 4 of 6 sibs had features consistent with Temtamy syndrome, including developmental abnormalities of the brain and eyes. All 4 affected children had delayed motor and cognitive development with seizures in early childhood. The 3 older children had progressive, severe cognitive decline with spasticity beginning at age 3 to 5 years; decline was not seen in the youngest child, who was last examined at age 2 years. The 3 older children had progressive visual impairment; the youngest had grossly normal visual function but demonstrated oculodigital signs, which might be an early sign of visual impairment. On ophthalmologic examination, iris and chorioretinal colobomas, posterior staphyloma, microcornea with corneal opacity and dense cataract, and congenital nystagmus was seen in 1 child, and chorioretinal coloboma and posterior staphyloma was seen in another. The eyes of the 2 youngest affected sibs were normal on ophthalmologic examination. Magnetic resonance imaging of the brain was abnormal with agenesis, thickening, or dysgenesis of the corpus callosum seen in 3 of the 4 children.

Platzer et al. (2014) reported 2 sibs, born of unrelated German parents, with global developmental delay, severe intellectual disability, lack of speech acquisition, early-onset intractable seizures, and visual impairment. One child had bilateral chorioretinal coloboma and the other had an atrial septal defect. Additional findings in both children included nonspecific dysmorphic facial features, hypoplasia of the corpus callosum, short stature, and ataxic gait.

Inheritance

The transmission pattern of Temtamy syndrome in the families reported by Zahrani et al. (2013), Akizu et al. (2013), and Salih et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 Saudi Arabian sibs with mental retardation, early-onset seizures, and variable coloboma and corpus callosum abnormalities, Zahrani et al. (2013) identified a homozygous mutation in the C12ORF57 gene (c.1A-G; 615140.0001). The mutation was identified by exome sequencing of 1 of the patients. An unrelated Saudi girl with a similar disorder was compound heterozygous for the 1A-G mutation and another C12ORF57 mutation (L51Q; 615140.0002). In 10 patients from 4 consanguineous families of Arab descent with a phenotype consistent with Temtamy syndrome, including the family reported by Li et al. (2007), Akizu et al. (2013) identified homozygosity for the same 1A-G mutation in C12ORF57. The mutation was found by whole-exome sequencing, confirmed by Sanger sequencing, and coincided with linkage data. All tested parents were heterozygous for the mutation, which was not found in more than 1,400 individuals, including 1,000 of Arab descent, or in public SNP databases. Haplotype analysis was consistent with a founder effect. In vitro cellular expression studies indicated that the mutation decreased protein synthesis, but some protein could be formed, likely resulting in phenotypic variability. These findings suggested a loss-of-function mechanism.

In 4 sibs, born to second-cousin Saudi Arabian parents, with Temtamy syndrome, Salih et al. (2013) found homozygosity for the c.1A-G mutation in the C12ORF57 gene (M1V; 615140.0001). The parents were heterozygous for the mutation, which was not found in 1 unaffected sib or in more than 350 normal individuals. Salih et al. (2013) noted that Najmabadi et al. (2011) had previously identified M1V as a possible causative mutation for nonsyndromic mental retardation in this family (G001).

In 2 sibs, born of unrelated German parents, with Temtamy syndrome, Platzer et al. (2014) identified compound heterozygous mutations in the C12ORF57 gene: the recurrent c.1A-G transition and a novel nonsense mutation (Q62X; 615140.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

History

Talisetti et al. (2003) described a 5-year-old girl who had features resembling Temtamy syndrome, including agenesis of the corpus callosum, ventriculomegaly, frontal bossing, peaked eyebrows, ptosis, malformed and low-set ears, depressed nasal bridge, long philtrum, and iris and chorioretinal colobomas. Features unique to this child included profound mental retardation, bilateral sensorineural hearing loss, patent ductus arteriosus, ventricular septal defect, unilateral renal agenesis, neurogenic bladder, and hydronephrosis. The patient was found to have a de novo balanced translocation t(2;9)(p24;q32); Talisetti et al. (2003) noted that there was phenotypic overlap with monosomy for chromosome 2p. Ramocki et al. (2003) analyzed the breakpoints in the patient reported by Talisetti et al. (2003) using FISH and PCR analysis and identified disruption of 2 zinc finger-encoding transcripts, KIAA1803 (ZNF462; 617371) on chromosome 9 and ASXL2 (612991) on chromosome 2.

In a consanguineous family of Middle Eastern origin with a Temtamy-like syndrome, Li et al. (2007) performed homozygosity mapping for the ASXL2 and ZNF462 genes, as well as for VAX1 (604294), a gene known to cause agenesis of the corpus callosum when its homolog is inactivated in mice; however, at no locus were the 2 affected sibs homozygous, while the 3 healthy sibs were either heterozygous or homozygous for a different allele, thus excluding the possibility that a recessive allele for the syndrome lies at 1 of these 3 loci.