NORD gratefully acknowledges Juan F. Sotos, MD, Endocrinology, Nationwide Children's Hospital, and The Ohio State University, College of Medicine, Columbus, Ohio, USA, for assistance in the preparation of this report.
Sotos syndrome is a genetic disorder, described in 1964, characterized by excessive growth before and after birth, a large, elongated (dolichocephalic) head, distinctive facial configuration, and a non-progressive neurological disorder with intellectual disability. Advanced bone age is present in approximately 75 to 85% of patients.
The main clinical finding is prenatal and postnatal overgrowth. The growth velocity is particularly excessive in the first 3 to 4 years of life and subsequently proceeds at the normal rate, but in the high percentiles. The mean height is usually 2 to 3 years ahead of peers during childhood. The weight is usually appropriate for the height and the bone age is advanced mean by 2 to 4 years over chronological age, during childhood. Adult height usually exceeds the average of normal men or women. Some individuals may reach excessive adult heights; males of 193 cm to 203 cm (6 ft. 4 in. to 6 ft. 8 in.) and females up to 188 cm (6 ft. 2 in.) are known.
The craniofacial configuration is most characteristic, with a prominent forehead and receding forehead hairline in 96% of patients, dolichocephalic head, widely spaced eyes (hypertelorism), down slanting of the eye lids and folds (palpebral features), high narrow palate, pointed chin, a long narrow face and a head shape that is similar to an inverted pear. The typical facial features are most apparent in childhood. As the child matures, the chin becomes more prominent and square in shape. In adults, the craniofacial characteristics are less distinctive but the chin is prominent and the dolichocephalic and receding hairline (frontal bossing) remain.
Central nervous system manifestations are frequent. Delay in the attainment of milestones of development, walking and talking and in particular speech, is almost always present and clumsiness is frequent (60 to 80%), as is low muscle tone (hypotonia) and lax joints. Intellectual disability is present in 80 to 85% of the patients, with an average IQ of 72 and a range from 40 to borderline mild intellectual disability. Fifteen to 20% may have normal intelligence. Seizures may occur in 30% of those affected. Some brain abnormalities (enlarged ventricles) may occur.
Individuals with Sotos syndrome can also experience behavioral problems at all ages that can make it difficult for them to develop relationships with others.
Newborns often have jaundice, difficulty feeding and low muscle tone (hypotonia). Heart defects are present in about 8 to 35% of children with Sotos syndrome but are usually not severe. Abnormalities in the genital and/or urinary systems occur in about 20% of affected individuals. Other findings associated with Sotos syndrome include conductive hearing loss that may be associated with an increased frequency of upper respiratory infections, eye abnormalities such as crossed eyes (strabismus), and skeletal problems. A curved spine (scoliosis) is present in about 40% of those affected but is usually not severe enough to require bracing or surgery. Premature eruption of teeth occurs in 60 to 80%. Approximately 2.2 to 3.9% of patients develop tumors including sacrococcygeal teratoma, neuroblastoma, presacral ganglioma and acute lymphoblastic leukemia.
Affected infants and children usually experience a delay in achieving certain developmental milestones (e.g., sitting, crawling, walking, etc.). They may not begin to walk until approximately 15 to 17 months of age. Affected children may also experience difficulty performing certain tasks requiring coordination (such as riding a bicycle or playing sports), fine motor skills (e.g., the ability to grasp small objects), and may demonstrate unusual clumsiness. Children with this disorder typically experience delays in attaining language skills. In many cases, affected children may not begin to speak until approximately two to three years of age.
Sotos syndrome is caused by mutations (abnormalities) in the NSD1 (nuclear receptor-binding SET domain protein 1) gene. Mutations in this gene have been identified in approximately 90% of affected patients (Sotos syndrome 1). A few years ago, mutations in the NFIX gene (nuclear factor I, X type) were identified in 5 patients with Sotos syndrome (Sotos syndrome 2). In 2015, a loss-of-function mutation in the APC2 (adenomatous polyposis coli 2) gene was reported in 2 siblings with some neural features of Sotos syndrome including intellectual disability, abnormal brain structure, and typical facial features, but no other features such as bone or heart abnormalities (Sotos syndrome 3). The parents were blood relatives (consanguineous). The APC2 gene is specifically expressed in the nervous system, and is a crucial downstream gene of NSD1. In other words, mutations in the NSD1 gene affects the APC2 gene and results in the neural abnormalities.
Sotos syndrome is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal variant of a gene is necessary to cause a particular disease. The abnormal variant 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 abnormal variant gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Most people with Sotos syndrome have the NSD1 mutation as the result of a new mutation that was not inherited from a parent. When the parents are unaffected, the risk of having another child with the syndrome is very low (<1%). The symptoms of Sotos syndrome can vary from person to person, even when they have the same NSD1 gene mutation.
Sotos syndrome 3 is an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits an abnormal variant of a gene from each parent. If an individual receives one normal gene and one abnormal variant gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal variant gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Sotos syndrome affects males and females in equal numbers, occurs in all ethnic groups and has been detected throughout the world. This condition occurs in about one in 14,000 live births.
There is no biochemical marker for the disease. The diagnosis is based on clinical grounds. The most characteristic manifestations are the craniofacial configuration, excessive growth, and developmental delay. The diagnosis of a patient with the typical craniofacial configuration and excessive growth can be made at the first site. The craniofacial configuration is the most distinctive, and only rarely (~ 1%), is not present. Ten percent of the children and adolescents may be below +2 SD in height and 10 or 15% of the patients may not have developmental delay. Advanced bone age may be present in 76 to 86% of the patients and is helpful but not specific. Brain abnormalities are present in 60 to 80% of patients, such as communicating hydrocephalous, and others, but are not diagnostic and are non-specific.
The diagnosis can be confirmed by DNA studies by FISH (fluorescence in situ hybridization) analysis to detect microdeletions or MLPA (multiplex ligation-dependent probe amplification), a simple and reliable method to detect chromosome 5q35 microdeletions and partial NSD1 gene deletions, which account for approximately 10-15% of the cases in western populations. DNA analysis by genome sequencing can determine the specific NSD1 gene mutations.
In patients without NSD1 gene mutations, genetic testing for mutations in NFIX and APC2 genes should be obtained.
The treatment of Sotos syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric endocrinologists, geneticists, neurologists, surgeons, speech pathologists, specialists who diagnose and treat skeletal disorders (orthopedists), physicians who diagnose and treat eye disorders (ophthalmologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
When a child is diagnosed with Sotos syndrome, a heart examination and kidney ultrasound should be performed and if abnormalities are identified, an appropriate specialist should be consulted. Children with Sotos syndrome should have a thorough examination every one to two years that includes a back exam for scoliosis, eye exam, blood pressure measurement, and a speech and language evaluation. Appropriate specialists should be consulted as needed.
Clinical evaluation should be conducted early in development and on a continuing basis to help confirm the presence and extent of developmental delay, psychomotor delay, and/or intellectual disability. Such evaluation and early intervention may help ensure that appropriate steps are taken to help affected individuals reach their highest potential. Special services that may be beneficial to affected children may include infant stimulation, special education, special social support, physical therapy, occupational therapy, speech therapy, and adaptive physical education.
A small percentage (2.2 to 3.9%) of individuals with Sotos syndrome may be more prone to developing certain benign tumors and malignancies than the general population. Owing to the low risk for these problems, that the age of onset or detection is from infancy to adulthood and the location variable (~1/3 intra-abdominal, 2/3 extra-abdominal), there is no recommended routine screening.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.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: [email protected]
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:
Sotos Syndrome Resources (Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., growth disorders, mental retardation, etc.].
Visser R. NSD1 and Sotos Syndrome, Chapter 113. In Eds.: Epstein CJ, Erickson RP, Wynshaw-Boris A. Inborn errors of development: the molecular basis of clinical disorders of morphogenesis. New York, NY: Oxford University Press: 2008:1032-1037.
Sotos JF. Sotos Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins: 2003:255-6.
Lane C, Milne E, Freeth M. Cognition and Behaviour in Sotos Syndrome: A Systematic Review. PLoS One. 2016 Feb 12;11(2):e0149189. doi:10.1371/journal.pone.0149189. eCollection 2016. Review. PubMed PMID: 26872390.
Almuriekhi M, Shintani T, Fahiminiya S, Fujikawa A, Kuboyama K, Takeuchi Y, Nawaz Z, Nadaf J, Kamel H, Kitam AK, Samiha Z, Mahmoud L, Ben-Omran T, Majewski J, Noda M. Loss-of-Function Mutation in APC2 Causes Sotos Syndrome Features. Cell Rep. 2015 Mar 3. [Epub ahead of print] PubMed PMID: 25753423.
Novara F, Stanzial F, Rossi E, Benedicenti F, Inzana F, Di Gregorio E, Brusco A, Graakjaer J, Fagerberg C, Belligni E, Silengo M, Zuffardi O, Ciccone R. Defining the phenotype associated with microduplication reciprocal to Sotos syndrome microdeletion. Am J Med Genet A. 2014 Aug;164A(8):2084-90.
Sotos JF. Sotos syndrome 1 and 2. Pediatric Endocrine Reviews (PER). 2014 Sept;12(1):374-388.
Visser R, Kant SG, Wit JM, Breuning MH. Overgrowth syndromes: from classical to new. Pediatr Endocrinol Rev. 2009;6(3):375-94.
Sotos JF, Argente J. Overgrowth Disorders Associated with Tall Stature. Advances in Pediatrics. 2008;55:213-254.
Tatton-Brown K, Douglas J, Coleman K, et al. Childhood Overgrowth Collaboration: Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet. 2005;77(2):193-204.
Tatton-Brown K, Rahman N. Clinical features of NSD1-positive Sotos syndrome. Clin Dysmophol. 2004;13:199-204.
Kurotaki N, Imaizumi K, Harada N, et al.: Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet. 2002;30(4):365-366.
Sotos JF, Dodge PR, Muirhead D, et al. Cerebral gigantism in childhood: a syndrome of excessively rapid growth and acromegalic features and a nonprogressive neural disorder. N Engl J Med. 1964;271:109-116.
For additional recent articles: PubMed.gov. US National Library of Medicine, National Institutes of Health, https://www.ncbi.nlm.nih.gov/pubmed/. Search: Sotos syndrome.
Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. SOTOS SYNDROME 1; SOTOS1. MIM Number: 117550. Date last edited: 10/09/2017. Available at http://omim.org/entry/117550 Accessed April 18, 2018.
Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. SOTOS SYNDROME 2; SOTOS2. MIM Number: 614753. Date last edited: 02/07/2017. Available at http://omim.org/entry/614753 Accessed April 18, 2018.
Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. SOTOS SYNDROME 3; SOTOS3. MIM Number: 617169. Date last edited: 10/21/2016. Available at http://omim.org/entry/617169 Accessed April 18, 2018.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100