Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome) is a rare, severe multisystem neurodevelopmental disorder. It profoundly affects the development of the brain and multiple other organ systems. The syndrome is named after the four researchers—Zhu, Tokita, Takenouchi, and Kim—who were instrumental in its initial description around 2015 and 2016.
The Genetic Origin
The cause of ZTTK syndrome is traced to pathogenic variants in the \(SON\) gene. This gene is located on chromosome 21 at position 21q22.11. The mutations are almost always de novo, meaning they are new changes not inherited from either parent.
The \(SON\) gene produces the \(SON\) protein, which regulates RNA splicing. RNA splicing is a step in gene expression where non-coding sections (introns) are removed from messenger RNA, and the coding sections (exons) are joined together. The \(SON\) protein ensures this editing process is done correctly and efficiently for hundreds of other genes.
The \(SON\) gene mutation typically results in a loss-of-function, leading to haploinsufficiency. This means one functional copy of the gene is not enough to produce the necessary amount of \(SON\) protein for normal development. This shortage causes widespread errors in the RNA splicing of many downstream target genes. Since these target genes are involved in processes like neuronal cell migration and multiorgan development, the resulting missteps lead to the widespread developmental defects seen in ZTTK syndrome.
Primary Clinical Features
ZTTK syndrome involves multiple body systems, presenting a wide range of developmental and physical challenges. Every individual experiences neurological and developmental impairment. This includes global developmental delay and moderate to profound intellectual disability, which is observed in virtually all reported cases.
Many individuals exhibit structural brain anomalies, such as a thin or underdeveloped corpus callosum. Imaging studies frequently reveal abnormal gyration patterns, including simplified gyri or polymicrogyria (unusually small and numerous folds in the brain’s surface). Seizures are common, affecting more than half of individuals, and generalized hypotonia (low muscle tone) is often present from infancy.
Physical and growth characteristics are commonly affected, sometimes beginning before birth with intrauterine growth restriction. Microcephaly (smaller than average head size) is a frequent finding, as is short stature and failure to thrive during infancy. Distinctive facial features can include deep-set eyes, a depressed or broad nasal bridge, a short or smooth philtrum, and facial asymmetry.
The syndrome affects organs outside of the central nervous system, leading to various congenital anomalies. Cardiac defects are frequently reported, including ventricular septal defects (VSDs) and atrial septal defects (ASDs). Musculoskeletal abnormalities like scoliosis, kyphosis, and generalized joint hypermobility are also seen. Congenital defects of the genitourinary system, such as dysplastic kidneys or ureter reflux, have also been documented.
Diagnostic Pathway and Testing
Diagnosis of ZTTK syndrome is established through clinical evaluation and confirmation via molecular genetic testing. A physician may first suspect the condition based on characteristic clinical features, such as severe developmental delay, hypotonia, and multisystem congenital anomalies. Because the symptoms overlap with many other neurodevelopmental disorders, a definitive genetic test is necessary.
The standard method for confirming the diagnosis is through sequencing of the \(SON\) gene. Whole Exome Sequencing (WES) is frequently the initial and most effective testing approach, especially for unexplained global developmental delay with congenital anomalies. WES analyzes all the protein-coding regions of the genome, allowing clinicians to identify a pathogenic variant in the \(SON\) gene.
Genetic testing confirms the presence of a heterozygous pathogenic variant in \(SON\), the unique molecular signature of ZTTK syndrome. Once a mutation is identified, Sanger sequencing can confirm that the pathogenic variant occurred de novo in the affected individual. Genetic counseling is an important part of the diagnostic process to help families understand the test results.
Supportive Care and Therapeutic Approaches
Since ZTTK syndrome is a genetic disorder, there is currently no curative treatment that directly addresses the \(SON\) gene deficiency. Management is entirely supportive and focuses on addressing the wide range of symptoms and complications as they arise. Care requires a comprehensive, multidisciplinary team involving specialists such as neurologists, cardiologists, orthopedists, and endocrinologists.
Physical therapy (PT) and occupational therapy (OT) are initiated early to manage generalized hypotonia and improve motor skills and daily living activities. Speech and language therapy (SLT) is important for communication delays and managing feeding and swallowing issues common in infancy. Nutritional support, which may involve tube feeding, is often necessary for those who struggle to gain weight.
Medical professionals manage co-occurring conditions, including the use of anti-epileptic medications to control seizures. Cardiac and genitourinary anomalies frequently require surgical or medical intervention, with ongoing monitoring by a cardiologist or nephrologist. Adaptive equipment, such as braces, walkers, or wheelchairs, is often incorporated to aid mobility and posture due to musculoskeletal issues.
Educational support is tailored to the individual’s intellectual disability and developmental level, aiming to maximize their potential in a structured environment. Because the severity of symptoms varies widely, the specific combination of therapies and specialist consultations is individualized to the patient’s unique needs.