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Sotos Syndrome

Sotos Syndrome


What is Sotos Syndrome?

Sotos syndrome is an uncommon genetic condition characterized by a physical overgrowth in childhood, a distinctive facial appearance and learning disabilities. Sotos syndrome is caused by a fault in the NSD1 gene. It is inherited as an autosomal dominant trait.

Mutations in the NSD1 gene are the primary cause of Sotos syndrome, accounting for up to 90 percent of cases.

The syndrome was first described in 1964 by Juan F Sotos in the New England Journal of Medicine.

Facts and Statistics on Sotos Syndrome

Sotos syndrome affects both males and females equally.

This condition occurs in about 1: 14,000 live births throughout the world.

In general, the head circumference and height of children with Sotos syndrome is greater than 2 standard deviations above the mean.

Sotos syndrome is not life-threatening and children with Sotos syndrome have a normal life expectancy.

What is the Genetics Behind Sotos syndrome?

  • In 2002 a group of Japanese scientists linked Sotos syndrome to mutations in a gene called NSD1 [Nuclear SET domain 1] located in chromosome 5q35.2-q35.3. The NSD1 gene controls the protein activity involved in normal growth and development. 90% of patients diagnosed with Sotos had NSD1 mutations (Sotos syndrome 1).
Mutations in NSD1 Gene are Linked to Sotos Syndrome
  • Recently, abnormalities in the NFIX gene (Nuclear Factor I, X type) on chromosome 19p13.3 were identified in patients with Sotos syndrome (Sotos syndrome 2).
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  • Sotos syndrome is inherited in an autosomal dominant manner. 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 in the affected individual. The risk of a child inheriting the syndrome is 50% if parents have Sotos syndrome. When the parents are unaffected, the risk of having a child with the syndrome is <1%.
  • Prenatal testing is possible for pregnancies at risk if the NSD1 gene variant has been identified in an affected family member. Also, the symptoms of Sotos syndrome can vary from person to person, even though they have the same NSD1 gene mutation.
  • Studies also indicate that people of Japanese heritage are mostly affected whereas only about 10% of patients had different ancestry.

What are the Risk Factors of Sotos Syndrome?

Parents diagnosed with Sotos have a high risk of transferring the gene mutation to the offspring. Studies also indicate that people suffering from Sotos syndrome also have high risk of developing cancer, though the exact reason is still not understood.

What are the Symptoms of Sotos Syndrome?

Characteristic facial appearance - is diagnostic of Sotos syndrome. It is evident at birth and becomes most prominent at around 3 years. This include:

  • Prominent forehead with receding hairline
  • Hypertelorism
  • Cross eyes (strabismus)
  • Reddish hue over cheeks
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  • Large sized skull with the head longer than its width (dolichocephaly)
  • High arched palate
  • Downward slanting eyelid fissures
  • Narrow jaw with a long chin

Learning disability- ranges from mild to severe.

  • Children have difficulties with speech and language along with intellectual impairment
  • Developmental milestones and motor skills are also delayed
  • Intellectual disability is present in 80 to 85% of the patients, with an average IQ of 72
  • Affected children may also experience difficulty in riding a bicycle or playing sports, ability to grasp small objects, and may demonstrate unusual clumsiness

Prenatal and postnatal overgrowth - the average birth length and head circumference are between 95-98 percentiles. Before 10 years there is rapid linear growth and children are considerably taller than their peers. Data suggests there is predominantly an increase in limb length with large hands and feet.

Behavioral problems- such as phobias, aggression, autism, attention deficit disorders can make it difficult to develop relationships with others.

Bone age is advanced in 75% of prepubertal children. Premature eruption of teeth occurs in 60 to 80%.

Congenital cardiac anomalies exist in 20% of patients. These include patent ductus arteriosus, septal defects and aortic dilatation.

Genital and/or urinary systems abnormalities occur in about 20% of affected individuals. Vesicoureteral reflux is the most common and may result in renal impairment in adults.

Increased frequency of upper respiratory infections and otitis media.

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Scoliosis is present in about 40% of patients but is usually not severe enough to require bracing or surgery. Scoliosis may be diagnosed at any age from infancy to adulthood.

Seizures occur in about 25% of individuals. Non-febrile seizures, tonic, clonic, myoclonic, and partial complex seizures have been reported.

Cranial abnormalities- such as ventricular dilatation, hydrocephalus, cerebral atrophy.

Hypotonia, rheumatic symptoms like joint hyperlaxity and flat feet (pes planus) are reported in at least 20% of individuals with Sotos syndrome.

Maternal preeclampsia occurs in about 15% of pregnancies.

Neonatal conditions like jaundice, hypotonia and inability to feed properly.

Approximately 2 - 4% of patients are at an increased risk to develop tumors including neuroblastoma, presacral ganglioma and acute lymphoblastic leukemia. However routine screening is not recommended.

Symptoms & Signs of Sotos Syndrome

How do you Diagnose Sotos Syndrome?

Medical history - to check whether any other family member has been affected

Clinical diagnosis - The diagnostic criteria include higher than normal birth weight/length, large head, and neonatal hypotonia, the characteristic facial features, large hands and feet, poor co-ordination, clumsiness and developmental delay with respect to learning and behavioral impairments.

DNA studies by FISH (fluorescence in situ hybridization) analysis to detect microdeletions and partial NSD1 deletions, which account for approximately 10-15% of the cases. In patients without NSD1 abnormalities, genetic testing for NFIX should be done.

Prenatal diagnosis by DNA analysis obtained from fetal cells by amniocentesis or chorionic villus sampling.

Screening protocol for mutation detection in NSD1 using a highly efficient denaturing high-performance liquid chromatography (DHPLC).

How do you Treat Sotos Syndrome?

Treatment is aimed at symptomatic management as there is no specific treatment for Sotos syndrome. The treatment of Sotos syndrome is directed toward the specific symptoms that are apparent in each individual. Coordinated efforts of pediatricians, geneticists, neurologists, surgeons, orthopedists, ophthalmologists, physical therapists and other health care professionals may be needed to systematically and comprehensively plan an affected child’s treatment.

If scoliosis is present then non-surgical procedures are usually advised to tone and strengthen the back muscles.

Particular attention to growth parameters to help confirm the presence and extent of developmental delay, psychomotor retardation, and intellectual disability.

Echocardiogram to rule out congenital heart defects.

Renal ultrasound to detect kidney and bladder problems.

Regular follow up every 1-3 years in children depending upon the complexity of their problems. A clinical geneticist should see all young adults with Sotos syndrome to discuss the inheritance of the condition.

If raised intracranial pressure is suspected, investigation and management in consultation with neurosurgeon is advised.

If MRI shows ventricular dilatation, shunting is usually not necessary as the hydrocephalus associated with Sotos syndrome is typically non-obstructive and not associated with raised intracranial pressure.

Occupational and physical therapy to tone the muscles.

Behavioral therapy and positive reinforcements to control aggressiveness and improve social contacts.

Regular dental and eye examination to monitor changes.

Ongoing surveillance is key to prevent future complications.

Symptomatic Management to treat Sotos Syndrome

How do you Prevent Sotos Syndrome?

Sotos syndrome is genetic; hence one cannot prevent it. However with preventive healthcare one can detect and rectify problems early thus preventing later complications.

If eye anomalies such as strabismus and cataract occur then an ophthalmologist should be consulted at the earliest.

In case of scoliosis, hypotonia, and joint laxity an orthopedic referral is necessary.

Regular surveillance for urinary tract infections, uretral reflux and cardiac anomalies is required.

MRI of the head is done to rule out hydrocephalus and corpus callosum defects especially in children with seizures.

Abdominal ultrasound up to 6 years of age may be done to rule out Wilm’s tumor, a common cancer in children that starts in the kidneys.

Latest Publications and Research on Sotos Syndrome

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