Last updated:
4/16/2024
Years published: 2024
NORD gratefully acknowledges Josephine Gao, MS, Stanford Medicine Children’s Health and Walla Al-Hertani, MD, MSc, FRCPC, FCCMG, FACMG, Harvey Levy Chair and Director of the Metabolism Program, Lysosomal Disorders (BoLD) Program and the Glycogen Storage Diseases Program, Division of Genetics and Genomics, Associate Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, for the preparation of this report.
Summary
ZTTK syndrome is a rare, variable disorder of neurodevelopment that can impact multiple body systems. Characteristics include short stature, developmental delay, intellectual disability, behavioral differences, vision and hearing issues, recurrent infections, feeding and digestive issues and seizures. Individuals may be born with characteristic facial features as well as differences of the brain, heart, urogenital system and gastrointestinal system. Skeletal, nail, hair and teeth differences have been reported as well.
ZTTK syndrome is an autosomal dominant genetic condition caused by a change (pathogenic variant) in a gene called SON. Most people with ZTTK syndrome have a new (de novo) variant in the SON gene that was not inherited from either biologic parent.
Introduction
ZTTK syndrome was named after the scientists and doctors who first described it in two different patients in 2015 and 2016. While there is no specific treatment, early diagnosis and supportive therapies and management can improve quality of life.
ZTTK syndrome is highly variable, meaning the symptoms and severity can be different for every person. Major features can include abnormalities in growth, development and various organs in the body. Reported signs and symptoms include:
Other findings may include:
ZTTK syndrome is caused by changes (pathogenic variants) in a gene called SON. Pathogenic variants alter the function of the gene and its resulting protein. The SON protein is important for regulating other genes that play important roles in development and metabolism. Abnormalities in multiple body systems have been reported more commonly in individuals with gene variants that cause inactivation (loss of function) of the SON protein.
ZTTK syndrome is an autosomal dominant disorder. Dominant genetic disorders occur when only a single copy of a pathogenic gene variant is necessary to cause the disease. The pathogenic variant can be inherited from either parent or can occur for the first time in the affected individual. The risk of passing the pathogenic variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Most people with ZTTK syndrome have a new (de novo) variant in the SON gene that was not inherited from either biologic parent.
As of 2024, over 60 individuals have been reported in the medical literature with ZTTK syndrome.
A diagnosis of ZTTK syndrome may be considered based upon a thorough clinical evaluation, a detailed patient and family history and the identification of characteristic findings. Molecular genetic testing for SON gene variants is available to confirm the diagnosis.
Management is supportive and based on symptoms. A specialist care team may include genetics/genetic counseling, neurology, psychiatry, cardiology, nephrology, ophthalmology, audiology, immunology, orthopedics and gastroenterology. Affected individuals should have imaging to screen for kidney and heart abnormalities. Imaging of the brain may include MRI to identify structural brain differences and EEG if seizures are suspected. Growth, feeding and development should be monitored. Supportive therapies such as speech, occupational and physical therapies may be helpful, and school aged children may benefit from accommodations such as an individualized education plan (IEP).
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
A Rare Connect Community is available for this condition: https://www.rareconnect.org/en/community/zttk-syndrome
Dingemans AJM, Truijen KMG, Kim JH, et al. Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON. Eur J Hum Genet. 2022;30(3):271-281. doi:10.1038/s41431-021-00960-4
Eid M, Bhatia S. Novel de novo heterozygous variants in the SON gene causing ZTTK syndrome: a case report of two patients and review of neurological findings. Child Neurol Open. 2022;9:2329048X221119658. doi:10.1177/2329048X221119658
Pavone P, Saia F, Pappalardo X, Barbagallo M, Prato A, Rizzo R. Novel malformations: Chiari type 1 and hydrocephalus in Zhu‐Tokita‐Takenouchi‐Kim syndrome and novel SON variants. Clin Case Rep. 2022;10(12):e6529. doi:10.1002/ccr3.6529
Kushary ST, Revah-Politi A, Barua S, et al. ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature. Am J Med Genet A. 2021;185(12):3740-3753. doi:10.1002/ajmg.a.62445
Quintana Castanedo L, Sánchez Orta A, Maseda Pedrero R, et al. Skin and nails abnormalities in a patient with ZTTK syndrome and a de novo mutation in SON. Pediatr Dermatol. 2020;37(3):517-519. doi:10.1111/pde.14113
Slezak R, Smigiel R, Rydzanicz M, et al. Phenotypic expansion in Zhu‐Tokita‐Takenouchi‐Kim syndrome caused by de novo variants in the SON gene. Mol Genet Genomic Med. 2020;8(10):e1432. doi:10.1002/mgg3.1432
Yang Y, Xu L, Yu Z, Huang H, Yang L. Clinical and genetic analysis of ZTTK syndrome caused by SON heterozygous mutation c.394C>T. Mol Genet Genomic Med. 2019;7(11):e953. doi:10.1002/mgg3.953
Kim JH, Shinde DN, Reijnders MRF, et al. De novo mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome. The American Journal of Human Genetics. 2016;99(3):711-719. doi:10.1016/j.ajhg.2016.06.029
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