NORD gratefully acknowledges Bregje van Bon, MD, PhD and the SETBP1 Society, for assistance in the preparation of this report.
SETBP1 disorder is an extremely rare genetic neurodevelopmental disorder in which there is a variation (mutation) in the SETBP1 gene. Variations in the SETBP1 gene can potentially cause a variety of signs and symptoms; how the disorder affects one child can be very different from how it affects another. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common symptoms include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), delays or difficulty in being able to speak (speech delays), and distinctive facial features. In most instances, variations in the SETBP1 gene occur spontaneously and there is no family history of the disorder (de novo variations). Treatment is based on the specific symptoms present in each individual.
Schinzel Giedion syndrome (SGS) is an extremely rare genetic disorder that is caused by a new (de novo), gain-of-function variation in the SETBP1 gene that is not inherited from the parents. Although SGS and SETBP1 disorder are associated with the same gene, they are completely different disorders. Individuals with SGS develop characteristic facial features, skeletal abnormalities, and obstruction of the tube that carries urine from the kidney to the bladder (ureter). This obstruction may lead to enlarged and damaged kidneys (hydronephrosis). Additional symptoms include excessive hair-growth (hypertrichosis), a flat midface (midface retraction), seizures, clubfeet, broad ribs, profound intellectual disability and short arms and legs. SGS is a severe progressive syndrome and most affected individuals do not survive infancy. (For more information on this disorder, choose “Schinzel Gideon” as your search term in the Rare Disease Database.)
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
The majority of children with SETBP1 disorder have intellectual disability that can range from mild to moderate to severe. The degree of intellectual disability may be hard to determine at first, because other symptoms may make evaluation difficult. Most children experience delays in reaching developmental milestones like sitting up or crawling. Speech delays are also common, and can be significant. Most children have better receptive language skills, which means that they can understand more information spoken to them than they are able to speak themselves (expressive language skills). The degree of speech difficulty can vary. Some children may have problems moving the muscles needed to speak and forming the mouth movements needed to speak (apraxia of speech) while others may not speak at all (nonverbal).
Additional symptoms include diminished muscle tone (hypotonia) so that infants may appear ‘floppy,’ and, less often, seizures. Other children may have increased muscle tone (hypertonia) so that muscles are stiff and hard to move. Some individuals may have difficulty planning and processing motor tasks (dyspraxia). Motor tasks are those that require the movement and coordination of the muscles. Affected individuals may experience fine and gross motor delays. Fine motor skills are those that require small movements involving the hands and wrists. Gross motor skills are those that require whole body movements and involve large muscles.
Some individuals with SETBP1 disorder have behavioral issues including attention deficit hyperactivity disorder (ADHD) and autism-like traits such as repetitive behaviors, fixation on objects, anxiety and poor social skills. Repetitive behaviors can include stereotypic hand movements, which include hand clapping, hand flapping, flicking hands, hand washing, fingers crossing, and frequent hand-to-mouth movements. Some children may show aggression or self-injury including head banging or persistent scratching.
Affected individuals may have distinctive facial features including a long, pointed chin, which contributes to the face appearing longer than normal, mild drooping of the upper eyelid (mild ptosis), a prominent forehead, sparse eyebrows, a thin upper lip, and abnormal fullness of the area around the eyes (periorbital fullness). Misalignment of the eyes (strabismus) has also been reported. The skull may appear shorter (brachycephaly) or longer (dolichocephaly) than usual.
SETBP1 disorder is caused by a variation in the SET binding protein 1 (SETBP1) gene, or in a small loss (microdeletion) of genetic material on chromosome 18 that contains the SETBP1 gene, but no other genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The SETBP1 gene contains instructions to produce (encode) the SET binding protein 1. This protein is found in cells throughout the body including the brain and binds to another protein called SET. The exact function of this protein is not fully understood, but the SET binding protein 1 may be extremely important in the development of and/or function of brain cells. Affected individuals have a loss-of-function variation in the SETBP1 gene that leads to low levels of SET binding protein 1. A different type of variation, called a gain-of-function variation, can lead to overproduction of this protein. This leads to a different, more severe disorder called Schinzel Giedion syndrome (see the Related Disorders section below).
In cases where a variation in SETBP1 is disease is causing the disorder, it almost always occurs as a new (sporadic or de novo) variation, which means that in nearly all instances the gene change has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, affected individuals can pass on the altered gene in an autosomal dominant pattern.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
SETBP1 disorder affects males and females in equal numbers. More than 45 people from many different countries are known to have the disorder. The exact number of affected individuals is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. SETBP1 disorder is likely under-recognized and underdiagnosed.
A diagnosis of SETBP1 disorder is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Children with mild or moderate intellectual disability and speech development problems, but no other anomalies may be suspected of having SETBP1 disorder. A diagnosis is confirmed through molecular genetic testing.
Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variations in the SETBP1 gene, but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having a SETBP1 disorder and the sample will undergo whole exome sequencing (WES). WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the SETBP1 gene that are known to cause disease, or variations in other genes known to cause symptoms similar to this disorder.
Affected individuals may undergo additional tests before molecular genetic testing to rule other conditions, or after molecular genetic testing to assess the extent of the disease. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain.
Neurologic examination is important for individuals with the symptoms of SETBP1 disorder. Neurologic examination helps identify the specific features affecting a person. Laboratory tests, neurophysiologic testing, and neuroimaging; routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions); and analysis of cerebrospinal fluid (obtained by “spinal tap”) may be conducted to help exclude alternate and co-existing diagnoses.
The treatment of SETBP1 disorder is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating disorders of the brain and central nervous system in children (pediatric neurologists) and adults (neurologists), speech therapists, physical therapists, occupational therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with SETBP1 disorder.
Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical, and speech therapies be instituted. Speech therapy is required and can include one-on-one sessions with a speech therapist, combined sessions where children learn language and social skills as a group, and the use of augmentative and alternative communication (AAC). AAC includes the use of communication devices, both high tech and low tech ones, that can help children express thoughts, wants, needs and ideas.
A full behavioral assessment may be necessary and can help to identify triggers of aggressive or self-injurious actions. Behavioral issues including ADHD, repetitive behaviors, depression, anxiety, aggression and self-injury can be treated with standard medications for these conditions.
Periodic reassessments and adjustment of services should be provided with all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. The organizations listed in the Resources section provide support and information on SETBP1 disorder or specific symptoms.
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Eising E, Carrion-Castillo A, Vino A, et al. A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Mol Psychiatry. 2018;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29463886
Kornilov SA, Rakhlin N, Koposov R, et al. Genome-wide association and exome sequencing study of language disorder in an isolated population. Pediatrics. 2016;137:[Epub 2016 Mar 25]. https://www.ncbi.nlm.nih.gov/pubmed/27016271
Hamdan FF, Srour M, Capo-Chichi JM, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014;10:e1004772. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214635/
Coe BP, Witherspoon K, Rosenfeld JA, et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014;46:1063-1071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177294/
Marseglia G, Scordo MR, Pescucci C, et al. 372 kb microdeletion in 18q12.3 causing SETBP1 haploinsufficiency associated with mild mental retardation and expressive speech impairment. Eur J Med Genet. 2012;55:216-221. https://www.ncbi.nlm.nih.gov/pubmed/22333924
Filges I, Shimojima K, Okamoto N, et al. Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel-Giedion syndrome. J Med Genet. 2011;48:117-122. https://www.ncbi.nlm.nih.gov/pubmed/21037274
Medical Management of Neurodevelopmental Concerns in SETBP1 Disorder. Srivastava S., Simos VIP Connect. Available at: https://www.youtube.com/watch?v=LEfCoNTLi18; 2018.
Genetics Home Reference. SETBP1 gene. January 2012. Available at: https://ghr.nlm.nih.gov/gene/SETBP1 Accessed November 30, 2018.
Unique. 18q Deletions from 18q11.2 to 18q21.2. Available at: https://www.rarechromo.org/media/information/Chromosome%2018/18q%20deletions%20from%20%2018q11.2%20to%2018q21.2%20FTNW.pdf Accessed December 3, 2018.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:616078; Last Update:10/30/2014. Available at: https://omim.org/entry/616078?search=setbp1&highlight=setbp1 Accessed December 3, 2018.
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