ZTTK syndrome

Other Names

Zhu-Tokita-Takenouchi-Kim syndrome; Brain malformations-musculoskeletal abnormalities-facial dysmorphism-intellectual disability syndrome

Pathophysiology

ZTTK Syndrome (Zhu-Tokita-Takenouchi-Kim syndrome) is a rare disease caused in humans by a genetic mutation of the SON gene.

Symptoms

Common symptoms include moderate to severe intellectual disability and developmental delay.

Characteristic abnormalities include cerebral cortex malformations, vision difficulties, musculoskeletal abnormalities and congenital defects. Individuals with a mutation in the SON gene may not all display these features. However, SON loss of function (LoF) variants appear to cause a clinically distinguished phenotype.

Signs and Symptoms

The key signs and symptoms associated with ZTTK Syndrome patients include ocular, facial and systemic features.

Ocular Features

Distinctive ocular features of the ZTTK syndrome are deep-set eyes, down-slanting palpebral fissures and horizontal eyebrows.

Facial Features

Individuals with ZTTK syndrome have distinctive minor to moderate facial dysmorphisms. Distinct facial features include facial asymmetry, low-set ears, midface retraction, frontal bossing, a depressed and or broad nasal bridge and a smooth or short philtrum.

Systemic Features

Multi-system abnormalities are common in ZTTK syndrome. The majority of individuals diagnosed with ZTTK syndrome display congenital malformations such as urogenital and malformations, heart defects, and a high or cleft palate.

Congenital defects such as a thinned atrial septum, ventricular septal defects, patent ductus arteriosus, dysplastic kidney and agenesis of the lung and gallbladder have also been noted.

Central Nervous System

Developmental delay is common in ZTTK syndrome patients, and appears to progressively increase the severity of intellectual disability with age.

Physiological

Mutations of the SON gene can affect metabolism and mitochondrial function in newborns with ZTTK syndrome. Metabolic screening confirmed mitochondrial dysfunction and O-glycosylation defects in individuals with ZTTK syndrome. Decreased levels of immunoglobulin A and or immunoglobulin G identified in ZTTK syndrome patients resulted in coagulation abnormalities.

Genetics

ZTTK syndrome is caused by heterozygous mutations in the SON gene. As an autosomal dominant disease, children with parents carrying a SON mutation have a 50% risk of inheriting the mutation. However, the majority of affected individuals have de novo mutations in the SON gene and ZTTK syndrome is not inherited to their children.

Diagnosis

Brain Imaging

Early diagnosis of the ZTTK syndrome can be determined by brain imaging. Magnetic resonance imaging (MRI) of the brain of ZTTK syndrome patients have revealed significant abnormalities.

Abnormal gyration patterns were seen, including polymicrogyria; many unusually small folds in the brain, simplified gyria; reduced number and shallow appearance of gyri, and periventricular nodular heterotopia; failure of neurons to migrate properly during early development of the fetal brain.

Ventriculomegaly can also be observed in MRI where the lateral ventricles become dilated in the foetus and can contribute to developmental delays in ZTTK syndrome individual.

Other pathological features seen on MRI scans of ZTTK syndrome individuals include arachnoid cysts, hypoplasia of the corpus callosum and cerebellar hemispheres and loss of periventricular white matter.

Most individuals with ZTTK syndrome are identified early in childhood due to developmental delays and intellectual disabilities. However, a formal diagnosis of intellectual disability can only be conducted by a performance of an IQ test score of below 70.

Whole Exome Sequencing

Whole exome sequencing (WES) can be used as a non-biased tool in the diagnostic evaluation of individuals with suspected genetic disorders such as the ZTTK syndrome. Using WES, individuals were identified with truncating variants of SON and overlapping clinical features.

ZTTK syndrome has been identified as a neurodevelopmental disorder associated with a de novo mutation in the SON gene using WES. The SON gene is known to be a major cause of severe intellectual disability and consequent developmental disorders. The first de novo truncating variant in SON was recognised in a group of individuals with severe intellectual disabilities. Sanger sequencing or the use of WES of parental samples confirmed the de novo status of the truncating and missense mutations of the SON gene in the sampled ZTTK syndrome individuals. Variants identified included a premature stop variant in exon 3, frame-shift variants in exon 3 and a frameshift variant in exon 4.

Treatment

There is currently no treatment for ZTTK syndrome. However, physical therapy and addressing the specific problems of multi organ disorders may be helpful. The main focus should be on the diagnosis and care of individuals with ZTTK syndrome.

References

Portions of content adapted from Wikipedia's article on ZTTK syndrome which is released under the CC BY-SA 3.0.