What is Sotos syndrome?

Sotos syndrome is a disease caused by mutations – or genetic changes – in the NSD1 gene. It is characterized by a distinctive shape of the face, developmental delays, and macrosomia.

How is Sotos syndrome diagnosed?

Suspected Diagnosis

Sotos syndrome is suspected with presentation of the following:

  • Distinctive shape of the face (readily evident at the age of 1-6 years):

    • Broad, prominent forehead with a long, narrow head shape (dolichocephaly)
    • Sparse hair around the temples
    • Drooping palpebral fissures
    • Reddened cheeks
    • Long, narrow face
    • Long chin
  • Developmental delay:

    • Early developmental delay and learning disability
    • Mild to severe intellectual retardation
  • Macrosomia:

    • Length and/or head circumference ≥ 97th percentile

Genetic Diagnostics

The diagnosis of “Sotos syndrome” is confirmed by detection of a mutation – or genetic change – in the NSD1 gene.

What is the risk of cancer?

The risk of cancer is slightly increased at around 3%. Malignant diseases that have been described to date are tumors of the ovaries, neuroblastomas, and gangliomas (nerve tissue tumors), acute lymphatic leukemia (ALL), acute myeloid leukemia (AML), and cancer of the liver, stomach, testicles, and lungs.

Besides a slightly increased risk of cancer, a large number of symptoms can manifest as part of Sotos syndrome. They are classified as cardinal symptoms, major symptoms, and associated symptoms.

Cardinal Symptoms

They are present in ≥ 90% of persons with Sotos syndrome.

  • Distinctive shape of the face
    While already present at birth, it is most prominent between 1 and 6 years of age. Characteristic features are a long, narrow head shape, a broad and prominent forehead, sparse hair around the temples, drooping palpebral fissures, and reddened cheeks. A small jaw and long chin appear later on during childhood as well. The symptoms are usually less pronounced during adulthood.

  • Developmental delays
    There are usually developmental delays with regards to motor, speech, and cognitive functions. Motor milestones are often achieved behind schedule, something that is sometimes caused by body size, weak muscles, and a lack of coordination. The cognitive impairment may only be slightly evident, or it may be so pronounced that it is not possible for the affected persons to live on their own.

  • Macrosomia
    Macrosomia already develops before birth and is mainly the result of increased growth of arms and legs. Children with Sotos syndrome are usually born at full term and exhibit a body length and head circumference ≥ 97th percentile, with weight generally within the average range. Affected patients grow steadily during childhood and adolescence, which is why macrosomia at ≥ 97th percentile persists. Not until adulthood is it possible for the height to normalize. The head circumference usually remains at the ≥ 97th percentile even in adulthood.

Major Symptoms

The following are present in 15-89% of persons with Sotos syndrome.

  • Behavioral problems
    Autism spectrum disorders, phobias, aggression, difficulties in group settings, naivety, a lack of awareness of social behaviors

  • Advanced bone age
    In 75-80% of prepubertal patients

  • Anomalies of the heart
    In 20% of patients in the form of mild to severe defects

  • Anomalies in the MRI/CT of the head
    In the majority of patients in the form of enlarged spinal fluid chambers, centrally located changes, a reduction in brain matter, and structural changes in the cerebellum

  • Hyperelastic joints, flat feet
    In 20% of patients

  • Preeclampsia
    In 15% of pregnancies

  • Complications in newborns
    Jaundice (65%), weak muscles (75%), and feeding difficulties (70%): these usually normalize spontaneously , rarely requiring intervention

  • Anomalies of the kidneys
    In 15% of patients, mainly in the form of urine reflux from the bladder via the ureters into the renal pelvis

  • Scoliosis (curvature of the spine)
    In 30% of patients, rarely requiring surgery

  • Cramping seizures
    In 25% of patients, cramping seizures without a fever during the course of their lives

Associated Symptoms

The following symptoms can occur in 2-15% of patients:

  • Eyes: corneal curvature, cataracts, far or nearsightedness, squinting, eye twitching

  • Ears: chronic middle ear infection (otitis media), conductive deafness

  • Skeleton: one-sided macrosomia, stiff joints, closed cranial sutures, funnel chest, spinal abnormalities, fusion of the 2nd and 3rd toes, clubfoot

  • Abdomen: constipation, acid reflux into the esophagus, hernia, umbilical hernia

  • Skin, nails, teeth: blood blisters (hemangiomas), skin with excess or too little pigment, underdeveloped nails, missing teeth

  • Genitals: intra-abdominal testicles, hydrocele, a displaced aperture of the urethra, a constricted foreskin

  • Metabolism: calcium level in the blood too high, glucose level in the blood too low in newborns

What causes Sotos syndrome?

Sotos syndrome is caused by mutations – or genetic changes – in the NSD1 gene. This gene encodes for the NSD1 protein, which is necessary for reading and amplifying DNA – the genetic material – in our body,

Now if the NSD1 gene is altered, the NSD1 protein will not be produced properly and will no longer be able to perform its normal function. This can result in the defective development of various structures in our body.

Sotos syndrome occurs in approximately one out of 14,000 live births and can be passed on by parents to their children. In these cases, it is inherited as an autosomal dominant disease. However, around 95% of cases involve a spontaneous or new mutation, called a de novo mutation.

Is there a treatment?

In light of the large number of potential manifestations, treatment should always be symptom-orientated and involve different specialist disciplines working together.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

There are no standard surveillance recommendations to date. Patients with Sotos syndrome should undergo regular medical examinations (e.g. once a year), which should include the following:

  • Detailed medical history

  • Auscultation of (listening to) the heart

  • Blood pressure measurement

  • Clinical examination of the spinal column

  • Urine test

If any anomalies are found, other examinations should be conducted as needed and the patient transferred to specialists.

Patients should be informed about their slightly increased risk of cancer. Specific cancer surveillance is not recommended.

Self-Care and Support

What should I pay special attention to?

You should see a doctor as soon as changes in the spinal column or joints occur. Moreover, restrictions or changes affecting sight and hearing should be noted and reported to a doctor as well. You should likewise go to a doctor right away if new anomalies or complaints develop.

Support Groups and Additional Information

Unfortunately, we are as yet unaware of any existing support groups for patients with Sotos syndrome. We will add new information as it becomes available.