Last updated:
5/19/2025
Years published: 1986, 1990, 1995, 1997, 1998, 2005, 2009, 2012, 2015, 2018, 2025
NORD gratefully acknowledges Reagan Long, Madeleine Menkhaus and Ella Gaul, Editorial Interns from the University of Notre Dame, G. Bradley Schaefer, MD, FAAP, FACMG, Professor of Genetics and Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Northwest and Juan F. Sotos, MD (deceased) for assistance in the preparation of this report.
Sotos syndrome, also known as cerebral gigantism, is a rare genetic condition characterized by rapid physical growth during early childhood.1 Newborns with Sotos syndrome tend to be larger, taller and heavier than other children. The head is large (macrocephalic), long and narrow (dolichocephalic), the forehead is prominent and broad, and hair is often thin surrounding the forehead and ears.1,2 People affected with Sotos syndrome have characteristic facial features generally noticed at birth but become more noticeable between the ages of 1-6 years.3,4 Other features may include developmental delay and intellectual disability. 5,6
Diagnosis is based on clinical features including distinct craniofacial features, excessive growth, advanced bone age and developmental delay as well as genetic testing.7
There is no cure yet. Treatment is directed toward specific symptoms that are apparent in each individual.6
Introduction
Sotos syndrome was first recognized in 1964 by Juan Sotos, MD, who described a child with rapid growth and a large head.1 The major criteria for diagnosis were established in 1994.8 In 2002, Japanese researchers identified a change (variant) in the NDS1 gene in people with Sotos syndrome. The symptoms of Sotos syndrome can vary from person to person, even when they have the same NSD1 gene variant.14
The following features are present in ≥ 90% of individuals with Sotos syndrome:1,3,6,10
Characteristic facial appearance
The craniofacial features most characteristic are a prominent forehead and receding forehead hairline in 96% of individuals with Sotos syndrome.5,11
○ long, narrow face (dolichocephalic head)
○ widely spaced eyes (hypertelorism)
○ down slanting eyelids and folds (palpebral features)
○ high narrow palate
○ pointed chin
The typical facial features are noticed at birth but become most apparent in childhood and as the child matures, the chin becomes more prominent and squarer in shape.3,12 In adults, the craniofacial characteristics are less distinctive, but the chin is prominent, and the dolichocephalic and receding hairline (frontal bossing) remain.13
Developmental delay
Affected infants and children usually have 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.1,10 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 have unusual clumsiness.6 Most children have low muscle tone (supranuclear hypotonia) which is a major contributor to motor delays. Children with this disorder typically have delays in obtaining language skills. Many affected children do not begin to speak until approximately two to three years of age.11
Intellectual disability
Intellectual disability is present in 80 to 85% of the people affected with Sotos syndrome, with an average IQ of 72 and a range from 40 to borderline mild intellectual disability. About 15 to 20% may have normal intelligence.10 Intelligence quotient (IQ) is a standardized measure used to assess cognition and intelligence.
Overgrowth/advanced bone age
The main clinical finding is prenatal and postnatal overgrowth. The rate of growth is particularly excessive in the first 3 to 4 years of life and then proceeds at the normal rate but in the high percentiles. The mean height is usually 2 to 3 years ahead of peers during childhood.9 Weight is usually appropriate for the height and the bone age is advanced by 2 to 4 years over chronological age during childhood.6 Adult height is usually taller than average for males and females. Final adult height typically reaches 5-6” above the predicted adult height in males and 3-4” in females.8 Some individuals may reach excessive adult heights; males from 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.10
Other signs and symptoms in people with Sotos syndrome include:
Behavioral findings: Individuals with Sotos syndrome can have behavioral problems at all ages that can make it difficult for them to develop relationships with others.15 These behavioral problems include an increased risk for autism spectrum disorder (ASD).15
Sleep disorders: Along with behavioral problems, many children have sleep disorders. 16
Cardiac anomalies: Heart defects are present in about 8 to 35% of children with Sotos syndrome but are usually not severe.10 The most commonly reported are a hole in the wall of the heart between chambers (septal defects) and a lack of enclosure of the blood vessel that connects the aorta and pulmonary arteries after birth (patent ductus arteriosus).17
Cranial anomalies: Some brain abnormalities (enlarged ventricles) may occur.7,10 Characteristic MRI changes include increased size of extra-axial fluid spaces, increased size of ventricles with increased size of posterior aspects of lateral ventricles (like that of colpocephaly, when an area of the brain, called the occipital horn, is larger than expected), midline defects such as persistence of the cavum septum pellucidum, a normal space between the two leaflets of the septum pellucidum, a thin membrane in the brain, and thinning of the middle 1/3 of the corpus callosum, the brain structure that divides both of the cerebral hemispheres.18
Joint hyperlaxity: Low muscle tone (hypotonia) and lax joints are almost always present, and clumsiness is frequent (60 to 80%).4
Neonatal complications: Newborns often have jaundice, difficulty feeding and low muscle tone (hypotonia).
Renal anomalies: Abnormalities in the genital and/or urinary systems occur in about 20% of the affected people.4
Scoliosis: A curved spine is present in about 40% of those affected but is usually not severe enough to require bracing or surgery.6
Seizures: Seizures may occur in 30% of those affected.10
Additional symptoms19
The following features are seen in ≥2% and <15% of individuals with Sotos syndrome: 4
Eye problems
Ear and hearing problems
Digestive and abdominal conditions
Bone, muscle, and joint conditions
Skin and nail conditions
Growth and development conditions
Reproductive and urinary conditions
Other conditions
Approximately 2.2 to 3.9% of people with Sotos syndrome develop tumors, including sacrococcygeal teratoma, neuroblastoma, presacral ganglioma and acute lymphoblastic leukemia.5,6
Sotos syndrome is not a life-threatening disorder and individuals with the disorder may have a normal life expectancy.19
Sotos syndrome can be caused by changes (variants) or deletions (losses) of the NSD1 gene, 2,6 or by variants in the NFIX gene14 or the APC2 gene.14
Sotos syndrome 1 is caused by variants in the NSD1 gene or by deletions involving this gene. Variants in this gene have been identified in approximately 90% of people with Sotos syndrome 1.2,6 The NSD1 gene is found on the long arm (q) of chromosome 5 in the q35 region, and, therefore, Sotos syndrome can also be caused by a deletion of the NSD1 gene, which is missing when a person has a 5q35 deletion.
Sotos syndrome 2 is caused by variants in the NFIX gene. Variants in this gene have been identified in five individuals.14
Sotos syndrome 3 is caused by a loss-of-function variant in the APC2 gene. This was reported in two 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.14 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, variants in the NSD1 gene affect the APC2 gene and result in neural abnormalities.14
Inheritance
Sotos syndrome 1 and 2
Sotos syndrome 1 and 2 are autosomal dominant genetic conditions. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. Most people with Sotos syndrome have a de novo NSD1 gene variant. When the parents are unaffected, the risk of having another child with the syndrome is very low (<1%).4 The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Sotos syndrome 3
Sotos syndrome 3 is an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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.9 In patients of Japanese descent, people are more often affected by a gene deletion rather than disease-causing gene variant.
Doctors may first suspect Sotos syndrome before birth if unusual features show up during a prenatal ultrasound, such as grooves or indentations in the baby’s developing brain.21
After birth, the most recognizable signs and symptoms include:
The facial features are the most consistent feature and almost all children with Sotos syndrome have them.1,4About 10% of children may be shorter than expected, and around 10–15% might not have any developmental delays.⁶
Other signs doctors may look for include:
Genetic testing can confirm the diagnosis of Sotos syndrome.
In people without NSD1 gene variants, genetic testing for variants in NFIX and APC2 genes should be done.14
Treatment
The treatment of Sotos syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of several specialists who should work together as a team in a coordinated way. The team may include 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. The team may need to systematically and comprehensively plan an affected child’s treatment.5,6
Management
To establish the extent of the disease and needs in a person diagnosed with Sotos syndrome, the following evaluations are recommended:
A small percentage (2.2 to 3.9%) of people with Sotos syndrome may be more prone to developing certain benign tumors and malignancies than the general population, but because the risk of developing tumors or malignancies is low, routine screening is not recommended.5,6
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For information about clinical trials conducted in Europe, contact:
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
View reportMedlinePlus has information about this condition that may include a description, frequency, causes, inheritance, and links to more information. The information is written for the public, including patients, caregivers and families. MedlinePlus is a service of the National Library of Medicine (NLM), which is part of the National Institutes of Health (NIH).
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