Clinical characteristics.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental delay and intellectual disability. Behavioral issues and seizures are reported in more than half of affected individuals. Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short and/or smooth philtrum, thin vermilion of the upper lip, bifid uvula, and high palate. Skeletal and ocular abnormalities, short stature, and genitourinary and kidney manifestations are common. Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported.

Diagnosis/testing.

The diagnosis of ZTTK syndrome is established in a proband with characteristic features and a heterozygous pathogenic variant in SON identified by molecular genetic testing.

Management.

Treatment of manifestations: None of the treatments available directly address SON deficiency. Supportive measures include developmental and educational support; standard treatment for seizures and movement disorder; treatment of craniosynostosis per craniofacial team; treatment of musculoskeletal manifestations per orthopedist; treatment of refractive errors and strabismus per ophthalmologist; low vision services as needed; nutritional support for feeding issues; treatment of growth hormone deficiency per endocrinologist; treatment of genitourinary and kidney manifestations per nephrologist and/or urologist; treatment of hematologic disorders per hematologist; surgical and/or medical treatment for cardiac anomalies; treat infections aggressively; in those with immune deficiency irradiated blood products are recommended; standard treatment of recurrent otitis media; management of bowel dysfunction and other gastrointestinal issues per gastroenterologist; hearing aids may be helpful; family and social work support.

Surveillance: Assess developmental progress, educational needs, behavioral issues, neurologic manifestations, musculoskeletal evaluation, growth, nutrition, gastrointestinal and hematologic issues, and for recurrent infections at each visit; ophthalmologic evaluation per ophthalmologist; endocrine evaluation in those with growth hormone deficiency; kidney ultrasound annually or as needed; audiology evaluation annually; assess family and social work needs at each visit.

Genetic counseling.

ZTTK syndrome is an autosomal dominant disorder. Almost all probands reported to date with ZTTK syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo SON pathogenic variant. Each child of an individual with ZTTK syndrome has a 50% chance of inheriting the SON pathogenic variant (data on reproduction in affected individuals are currently lacking, as most reported individuals are not yet of reproductive age). Once the SON pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome should be considered in individuals with the following clinical and imaging findings [Kim et al 2016b, Tokita et al 2016, Dingemans et al 2022] and family history.

Clinical findings

• Mild-to-profound developmental delay with occasional neurodevelopmental regression
• Moderate-to-severe intellectual disability
• Generalized hypotonia of infancy and infantile feeding difficulties
• Skeletal anomalies: scoliosis, kyphosis, thumb agenesis, syndactyly, contractures of large or small joints, and/or generalized joint hypermobility
• Ophthalmologic involvement: strabismus, hypermetropia, cortical vision impairment
• Craniofacial features: facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, depressed nasal bridge, low-set ears, short and smooth philtrum, thin vermilion of the upper lip, bifid uvula, and high-arched palate; craniosynostosis also reported (See Figures 1, 2, and 3.)
• Poor weight gain, short stature, and microcephaly
• Neurobehavioral/psychiatric manifestations: sleep disturbance, autism spectrum disorder, emotional dysregulation, and aggression
• Epilepsy: complex partial and complex febrile seizures
• Movement disorder: dystonia, tremors
• Genitourinary and kidney manifestations: chordee, single kidney, horseshoe kidney, kidney dysplasia, polycystic kidneys, undescended testes, inguinal hernia, and shawl scrotum
• Thrombocytopenia and deep venous thrombosis
• Structural cardiac anomalies: ventricular septal defect, atrial septal defect, and dysplastic aortic valve
• Immunodeficiency: Immunoglobulin (Ig) A deficiency, IgG deficiency, and recurrent infection
• Gastrointestinal manifestations: malrotation of the gut, gastroesophageal reflux disease, diarrhea, constipation, and gallbladder agenesis
• Endocrinologic abnormalities: growth hormone deficiency

Figure 1.

Facial features of individuals with Zhu-Tokita-Takenouchi-Kim syndrome. Affected individuals shown are individuals 2, 4, 5, 6, 8, and 10 (top row, left to right), and individuals 11, 13, 15, 16, 18, and 19 (bottom row, left to right) as reported in Kim (more...)

Figure 2.

Facial features of individuals with Zhu-Tokita-Takenouchi-Kim syndrome. Affected individuals shown are individuals 1 and 5 (top row, left to right), individuals 2 and 6 (middle row, left to right), and individuals 3 and 7 (bottom row, left to right) as (more...)

Figure 3.

Facial features of the individual with Zhu-Tokita-Takenouchi-Kim syndrome reported in Takenouchi et al [2016] Reproduced with permission from Takenouchi et al [2016]

Imaging findings

• Brain MRI findings. Ventriculomegaly, periventricular nodular heterotopia, subependymal gray matter heterotopia, corpus callosum dysplasia, cerebellar dysplasia, white matter hypoplasia or atrophy, abnormal cerebral gyration (polymicrogyria, smooth or underdeveloped cortex), enlarged subarachnoid space
• Radiographic findings. Hemivertebrae, rib fusions, delayed bone age

Family history. Because ZTTK syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of ZTTK syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in SON identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous SON variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability should begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023, Rodan et al 2025]. Other options include use of chromosomal microarray analysis (CMA) or a multigene panel. Note: Single-gene testing (sequence analysis of SON, followed by gene-targeted deletion/duplication analysis) is rarely useful and NOT recommended.

• A brain malformation, intellectual disability, autism spectrum disorder, or epilepsy/seizures multigene panel that includes SON and other genes of interest is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Because some companies are unaware of the developments regarding ZTTK syndrome, some commercial panels for these conditions may not include SON. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to know which gene(s) are likely involved. Exome sequencing is most commonly used, and yields results similar to a multigene panel with the additional advantage that it includes other genes as well (i.e., it would provide data about a recently identified disease-causing gene that has yet to be added to a multigene panel). To date, the majority of SON pathogenic variants reported (e.g., frameshift, nonsense) are in the coding region of the gene and are likely to be identified via exome sequencing. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental delay and intellectual disability with a broad range of abnormalities in multiple organs. The phenotypic delineation is limited, particularly with respect to potential age-related manifestations such as neurodegeneration or clinical regression; the majority of reported individuals are children and adolescents younger than age 20 years and longitudinal data remain sparse. To date, approximately 79 individuals with a pathogenic variant in SON have been documented in the literature [Tang et al 2023]. However, as of May 2025, the estimated number of individuals with a SON pathogenic variant identified was 450-500 worldwide (communication with ZTTK SON-Shine Foundation). The following description of the phenotypic features associated with this condition is based on these reports [Kushary et al 2021, Dingemans et al 2022, Tang et al 2023].

Developmental delay and intellectual disability. Mild-to-profound developmental delay / intellectual disabilities has been reported in all individuals. Hypotonia is common. Reported delays include motor delays in rolling over, sitting up, crawling, and walking. Infants have feeding difficulties. Speech delay is common. Developmental regression has been reported in several individuals. One study reported developmental regression in three of seven individuals [Tokita et al 2016]; an additional study reported developmental regression in two of 15 individuals [Kushary et al 2021].

Brain malformations include ventriculomegaly, periventricular nodular heterotopia, subependymal gray matter heterotopia, corpus callosum dysplasia, cerebellar dysplasia, white matter hypoplasia or atrophy (often reduced volume of periventricular white matter), abnormal cerebral gyration (polymicrogyria, smooth or underdeveloped cortex), and enlarged subarachnoid space.

Neurobehavioral/psychiatric manifestations. Behavioral problems include sleep disturbances and autism spectrum disorder [Dingemans et al 2022].

Seizures are common with age of onset ranging from infancy to six years [Zhu et al 2015, Kim et al 2016b, Tokita et al 2016, Kushary et al 2021]. Complex partial and complex febrile seizures have been reported. Other seizure types described include generalized tonic-clonic seizures and focal seizures, although the seizure spectrum can vary among individuals. Status epilepticus was reported in 16% of individuals [Kushary et al 2021].

Movement disorder. Dystonia and tremor have been reported, although these features have not been fully documented. Cervical dystonia and dystonic posturing of limbs have been reported in one adult with childhood onset; this worsened over time, contributing to functional impairment. The same individual had an intention tremor affecting the limbs [Indelicato et al 2022].

Craniofacial features. Some combination of characteristic facial features have been reported in approximately 95% of individuals including facial asymmetry (30%), prominent forehead, horizontal eyebrows (32%), ptosis, downslanted palpebral fissures (52%), epicanthal folds (20%), deep-set eyes (27%), midface retrusion (34%), depressed or other abnormality of the nasal bridge (56%), low-set ears (53%), posteriorly rotated ears (15%), short and/or smooth philtrum (54%), thin vermilion of the upper lip (13%), bifid uvula, and high-arched palate.

Craniosynostosis has been reported in six individuals (10%) [Kim et al 2016b, Kushary et al 2021, Halliday et al 2022], involving the metopic, sagittal, and coronal sutures.

Skeletal manifestations. Scoliosis and kyphosis have been reported (combined estimated frequency is 6%) [Kim et al 2016b, Tokita et al 2016]. Thumb agenesis, syndactyly, flat feet, small feet, short toes, rib fusion, generalized joint hypermobility, and/or contractures of large and small joints have been reported. Hyperextensibility of the interphalangeal joints of the hand and elbow joints has been described [Kushary et al 2021].

Ophthalmologic involvement. More than half (58%) of the individuals who reported vision abnormalities presented with strabismus [Kushary et al 2021]. Hypermetropia with childhood onset (20%) and cortical visual impairment (11%) have been reported.

Growth deficiency. Intrauterine growth restriction was reported in 12/36 infants (33%) [Dingemans et al 2022]. Microcephaly was reported in 11/40 examined individuals [Dingemans et al 2022]. To date, it is unclear how many infants had congenital microcephaly. Weight below the third centile was reported in 14/25 individuals. Short stature (below the third centile) was reported in 26/48 individuals. It is likely that postnatal growth failure is exacerbated by feeding difficulties. Growth hormone deficiency was reported in 6/43 individuals [Dingemans et al 2022] and also identified in two additional individuals [Yang et al 2019, Yang & Yang 2020]. The final adult height has not been documented, as many affected individuals are currently in infancy or childhood.

Genitourinary/kidney manifestations. Chordee, undescended testes, inguinal hernia, shawl scrotum, and hypoplastic labia major are reported. Kidney abnormalities include single kidney, horseshoe kidney, kidney dysplasia, and polycystic kidneys [Kim et al 2019].

Hematologic findings. Thrombocytopenia and deep vein thrombosis have been reported [Kim et al 2016b, Tokita et al 2016, Pietrobattista et al 2023].

Heart abnormalities. Ventricular septal defect (VSD), atrial septal defect (ASD), and dysplastic aortic valve have been reported [Kim et al 2016b, Tokita et al 2016]. Dingemans et al [2022] examined additional individuals and reported that 15/46 (33%) individuals had a heart defect, especially ASD (6/35, 17%) and VSD (4/46, 9%).

Immunologic manifestations. Immunoglobulin (Ig) deficiency, particularly IgA and IgG deficiency, has been reported in 15/46 assessed individuals [Dingemans et al 2022]. Reported recurrent infections include respiratory tract, urinary tract, and ear.

Gastrointestinal manifestations include malrotation of the gut, gastroesophageal reflux disease, diarrhea, constipation, and gallbladder agenesis; chronic liver cirrhosis with micro- and macronodularity and spongiosis hepatitis have been reported [Pietrobattista et al 2023].

Hearing impairment. Hearing loss was reported in 3/7 individuals in one report [Halliday et al 2022]; hearing impairment was described as conductive in one individual. Age of onset of hearing loss is not known. The ages of these three individuals at their last examination were 17 years, four years, and five years eight months.

Other. Recurrent hemiplegic migraine was reported in one individual [Langford et al 2023].

Prognosis. Based on current data, life span is not limited by this condition, as several adults have been reported, including one individual alive at age 50 years [Dingemans et al 2022]. However, three affected individuals died in childhood (communication with ZTTK SON-Shine Foundation), although the exact causes of death were not documented. Considerable variability in clinical course has been observed, with preliminary reports indicating that some individuals may experience progression or regression of neurologic and behavioral features, whereas others do not. The underlying basis of this variability remains uncertain and may reflect differences in genetic background, environmental or nutritional influences, or other modifying factors rather than allelic heterogeneity alone. This represents a significant knowledge gap and underscores that a molecular diagnosis of ZTTK syndrome does not inherently imply a uniformly severe or lethal prognosis. Longitudinal studies across broader age ranges will be essential to clarify the natural history of the disorder.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Nomenclature

ZTTK syndrome may also be referred to as SON-related neurodevelopmental disorder (based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders) or SON haploinsufficiency syndrome (based on the mechanism of disease causation).

Prevalence

To date, approximately 79 individuals with a pathogenic variant in SON have been documented in the literature. However, as of May 2025, the estimated number of individuals with ZTTK syndrome is 450-500 worldwide (communication with ZTTK SON-Shine Foundation).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ZTTK syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for ZTTK syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK) syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Almost all probands reported to date with ZTTK syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo SON pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the SON pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the SON pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].

Offspring of a proband

• Each child of an individual with ZTTK syndrome has a 50% chance of inheriting the SON pathogenic variant.
• Data on reproduction in affected individuals are currently lacking, as most reported individuals are not yet of reproductive age.

Other family members. Given that almost all probands with ZTTK syndrome reported to date have the disorder as a result of a de novo SON pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the SON pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SON encodes protein SON, which is a nuclear protein with both DNA- and RNA-binding abilities and is ubiquitously expressed in all tissues and cell types. SON is required for correct RNA splicing at splice sites with suboptimal splice junction sequences, called weak splice sites [Ahn et al 2011, Sharma et al 2011, Lu et al 2013, Hickey et al 2014]. SON also binds DNA at transcription initiation sites and represses gene transcription by attenuating histone modifications (H3K4me3) [Kim et al 2016a]. Additionally, SON forms the core of nuclear speckles [Ilik et al 2020], which are critical for supplying multiple transcription and splicing factors to transcription sites. Reduction in SON expression leads to aberrant RNA splicing, predominantly resulting in degradation of the affected RNA or nonproductive protein translation. Many of the misspliced RNAs following SON reduction are functionally associated with microtubule dynamics, centrosome function, cell cycle progression, DNA repair, cell stemness, neuronal migration/brain development, and metabolism [Ahn et al 2011, Sharma et al 2011, Lu et al 2013, Kim et al 2016b]. All affected individuals have a heterozygous SON pathogenic variant, suggesting that SON is indispensable for cell survival.

The most prevalent pathogenic variant, c.5753_5756delTTAG (p.Val1918GlufsTer87), accounts for approximately 20%-25% of reported pathogenic variants. Other pathogenic variants are distributed throughout the gene, with the highest concentration in exon 3 [Kushary et al 2021, Dingemans et al 2022].

Mechanism of disease causation. Loss of function

Author Notes

Dr Eun-Young Erin Ahn is a molecular biologist and a professor of pathology (Molecular and Cellular Pathology) at the University of Alabama at Birmingham. She is a co-founder of the ZTTK SON-Shine Foundation, as well as the co-chair of the Scientific Advisory Board and the Lead Researcher of the foundation. Her research focuses on understanding the molecular mechanisms of SON function and developing therapies for ZTTK syndrome.

Dr Mari Mori is an associate professor at Emory University. She is a biomedical genetics section editor and technical reviewer for Genetics in Medicine and Chair of the Society for Inherited Metabolic Disorders Education Committee. Her ongoing research focuses on the role of tandem repeat expansion in genetic disorders.

Dr Mathieu Lemaire is a staff nephrologist at the Hospital for Sick Children, a translational scientist in the Cell Biology program at the SickKids Research Institute, and an associate professor of Pediatrics in the Faculty of Medicine at the University of Toronto, Canada. He is also the Director of the KRESCENT program (Kidney Research Scientist Core Education and National Training) dedicated to developing future Canadian kidney researchers. His clinical interest and ongoing research are focused on rare genetic diseases that affect the kidneys of children.

Dr Grace Raines is a clinical genetics resident at the University of Alabama at Birmingham School of Medicine. She is also a Captain in the United States Army. Her professional interests include rare diseases and advocacy.

Dr Brandon Stone is a clinical geneticist at Nationwide Children's Hospital and an assistant professor of pediatrics at The Ohio State University. He is a member of the Clinical Advisory Board of the ZTTK SON-Shine Foundation.

All the authors are interested in hearing from clinicians treating families affected by ZTTK syndrome in whom no causative variant has been identified through molecular genetic testing.

Contact Dr Ahn to inquire about review of SON variants of uncertain significance.

Acknowledgments

We are grateful to the ZTTK SON-Shine Foundation for their unwavering support in patient advocacy, raising awareness, and advancing research on ZTTK syndrome. We thank Ada Lio, Kerry Tirrell, and all the board members of the ZTTK SON-Shine Foundation for reviewing this report.

Revision History

• 25 September 2025 (sw) Review posted live
• 6 January 2025 (eyea) Original submission

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