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 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 the cases, dolichocephalic (elongated) large 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 large elongated head (dolicocephaly) 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 an abnormality (mutation) in the NSD1 gene located in chromosome 5q35.2-q35.3. An abnormality in this gene has been identified in approximately 80-90% of affected individuals (Sotos syndrome 1). Recently abnormalities (mutations) in the NFIX gene (Nuclear Facotre I, X type) on chromosome 19p13.3 were identified in 5 patients with Sotos syndrome (Sotos syndrome 2).
Sotos syndrome is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. 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. The genetic studies in affected patients have confirmed that the main characteristics of the syndrome are the large elongated head (dolicocephaly), the distinctive facial configuration, excessive growth and a non-progressive neurological disorder with intellectual disability.
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 the cases, 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 5q35 microdeletions and partial NSD1 deletions, which account for approximately 10-15% of the cases in western populations. DNA analysis by sequencing would determine NSD1 mutations.
In patients without NSD1 abnormalities, genetic testing for NFIX should be obtained.
Prenatal diagnosis for Sotos syndrome is available by DNA analysis obtained from fetal cells by amniocentesis or chorionic villus sampling, that could be obtained if one of the parents is affected.
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 retardation, 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, routine screening is not necessary.
Genetic counseling is beneficial for affected individuals and their families.
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