Zttk Syndrome
A number sign (#) is used with this entry because of evidence that ZTTK syndrome (ZTTKS) is caused by heterozygous mutation in the SON gene (182465) on chromosome 21q22.
DescriptionZTTK syndrome is a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability. Affected individuals have characteristic dysmorphic facial features, hypotonia, poor feeding, poor overall growth, and eye or visual abnormalities. Most patients also have musculoskeletal abnormalities, and some have congenital defects of the heart and urogenital system. Brain imaging usually shows developmental abnormalities such as gyral changes, cortical and/or cerebellar atrophy, and thin corpus callosum (summary by Kim et al., 2016).
Clinical FeaturesZhu et al. (2015) reported a 5-year-old girl with developmental delay, seizures, minor dysmorphisms, macrocephaly, brain white matter abnormalities, intestinal atresia, and ventriculoseptal defect.
Takenouchi et al. (2016) described a male patient with postnatal growth retardation with relative macrocephaly, infantile hypotonia, severe intellectual disability, congenital heart disease, long slender extremities with hyperextensible joints, and smooth velvety skin. He showed distinctive facial features with a prominent forehead, curly hair, sparse eyebrows, epicanthal folds, a flat nasal bridge, protruding ears, a short nose, and full cheeks.
Kim et al. (2016) reported 20 unrelated patients, including a patient previously reported by Zhu et al. (2015), with a complex neurodevelopmental disorder associated with mild to severe intellectual disability. Many had neonatal feeding difficulties and hypotonia. Dysmorphic facial features included facial asymmetry, midface retraction, low-set ears, downslanting palpebral fissures, deep-set eyes, horizontal eyebrows, broad and/or depressed nasal bridge, and short philtrum. Fifteen patients had visual problems, such as cortical visual impairment, hypermetropia, optic atrophy, and strabismus. Brain imaging showed significant abnormalities in 89% of patients: these abnormalities varied and included abnormal gyral patterns, ventriculomegaly, arachnoid cysts, hypoplasia of the corpus callosum, cerebellar hypoplasia, and loss of periventricular white matter. About half of patients developed seizures between 1 and 6 years of age. About half had short stature, and many had various musculoskeletal abnormalities, such as hemivertebrae, scoliosis or kyphosis, contractures, joint hypermobility, and small hands and feet. Several patients had variable congenital malformations, including urogenital malformations (6 patients), heart defects (5 patients), gut malformations (3 patients), craniosynostosis (3 patients), and high or cleft palate (2 patients).
Tokita et al. (2016) reported 7 unrelated individuals, ranging in age from 3 to 23 years, with a severe multisystem developmental disorder. Poor feeding, respiratory difficulties, and hypotonia were noted soon after birth. Common dysmorphic facial features included frontal bossing, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, epicanthal folds, smooth philtrum, and thin lips. All patients had developmental delay, and some showed developmental regression; 3 had autism spectrum disorder. Visual problems were also common and included strabismus, exotropia, esotropia, nystagmus, visual loss, and optic atrophy. Variable musculoskeletal features included joint laxity, scoliosis, hemivertebrae, rib abnormalities, and arachnodactyly. Brain imaging of 5 of 6 patients showed various abnormalities, including enlarged ventricles, thin corpus callosum, arachnoid cysts, and periventricular leukomalacia. Three patients had decreased levels of IgA and/or IgG, and 2 had coagulation abnormalities. Five patients had congenital abnormalities of other organ systems, such as cardiac and urogenital.
Molecular GeneticsIn a 5-year-old girl with ZTTK syndrome, Zhu et al. (2015) identified heterozygosity for a de novo frameshift mutation (182465.0001) in the SON gene.
In a 13-year-old boy with ZTTKS, Takenouchi et al. (2016) identified heterozygosity for the same frameshift mutation in the SON gene that had been identified by Zhu et al. (2015).
In 20 unrelated patients with ZTTKS, including the patient reported by Zhu et al. (2015), Kim et al. (2016) identified de novo heterozygous truncating mutations in the SON gene (see, e.g., 182465.0001-182465.0004). The mutations, which were found by whole-exome sequencing, were demonstrated to result in haploinsufficiency. Four patients carried the same frameshift mutation (182465.0001). Examination of cells from 3 of the patients with SON haploinsufficiency showed decreased mRNA expression and abnormal RNA splicing products of multiple genes that play a role in neuronal cell migration, brain development, and metabolism (e.g., FLNA, 300017 and TUBG1, 191135). Similar gene dysregulation was observed in HeLa cells with knockdown of the SON gene. The findings demonstrated that SON is a master RNA splicing regulator with an important role in neurodevelopment.
In 6 unrelated patients with ZTTKS, Tokita et al. (2016) identified de novo heterozygous truncating mutations in the SON gene (see, e.g., 182465.0001; 182465.0005-182465.0007). The patients were ascertained by whole-exome sequencing of over 6,000 patients, primarily children, with neurologic disorders. Two of the patients carried the recurrent frameshift mutation (182465.0001). A seventh patient with 2 de novo missense mutations in cis was subsequently identified. Functional studies of the variants and studies of patient cells were not performed, but the findings suggested that haploinsufficiency for the SON gene is responsible for the phenotype, which may represent a spliceosomal disorder.
Animal ModelKim et al. (2016) found that haploinsufficiency of the son gene in zebrafish embryos resulted in multiple developmental defects, including bent and shortened tails, eye malformations, microcephaly, and deformed body axes with body curvatures. Embryos that survived longer developed even more severe phenotypes including spinal malformations and brain edema.