Sotos syndrome (OMIM #117550) is a genetic disease caused by mutations in the NSD1 gene. It features characteristic facies, developmental delays, and macrosomia.

Key Data

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Synonyms Cerebral gigantism
Chromosome 5q35 deletions syndrome
Gene NSD1
Gene product NSD1 (nuclear receptor-binding SET domain protein 1)
Function Histone methyltransferase acting as a transcription factor
Heredity Autosomal dominant, 95% de novo mutations
Prevalence 1:14.000 live births
Genotype-phenotype correlation 5q35 microdeletions exhibit less pronounced macrosomia but greater developmental delays than intragenic mutations.
Penetrance 100%
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Suspected Diagnosis

Sotos syndrome is suspected when patients present with the following findings:

Characteristic Facies (Readily Evident at the Age of 1-6 Years):

  • Broad, prominent forehead, with a dolichocephalic head shape

  • Sparse hair in the frontotemporal region

  • Drooping palpebral fissures

  • Reddened cheeks

  • Long, narrow face (especially with bitemporal narrowing)

  • Long chin

Developmental Delay:

  • Early developmental delay and learning disability

  • Mild to severe intellectual retardation


  • Length and/or head circumference ≥ 97th percentile

Genetic Diagnostics

The diagnosis of “Sotos syndrome” is confirmed by detecting a heterozygous germline mutation in the NSD1 gene through sequence analysis or deletion/duplication analysis. It may be helpful to use panel examinations consisting of multiple genes.

Differential Diagnoses

Clinical Presentation

The symptoms involving Sotos syndrome are classified as cardinal symptoms, major symptoms, and associated symptoms.

Cardinal Symptoms

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

  • Characteristic facies
    While already present at birth, they are most prominent between 1 and 6 years of age. Characteristic features are a dolichocephalic head shape, a broad and prominent forehead, sparse hair in the frontotemporal region, 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
    These usually encompass the motor, speech, and cognitive areas. Motor milestones are often achieved later than expected, this is sometimes due to issues related to height, hypotonic muscles, and a lack of coordination. The cognitive impairment may only be mild, or may be so pronounced that it is not possible for the affected persons to live independently.

  • Macrosomia
    Macrosomia already develops prenatally and is mainly the result of increased growth of the extremities. Children with Sotos syndrome are usually born fully developed and exhibit a height and head circumference ≥ 97th percentile, with a body weight generally within the average range. Growth progresses linearly during childhood and adolescence, and therefore there continues to be macrosomia ≥ 97th percentile. Height anomalies do not normalize until adult age is reached The head circumference usually remains ≥ 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

  • Cardiac abnormalities
    In 20% of patients in the form of PDA, ASD, VSD, non-compaction cardiomyopathy or aortic dilatation

  • Abnormalities in cranial MRI/CT
    In the majority of patients in the form of expanded ventricles, midline shifts, cerebral atrophy, and small cerebellar vermis

  • Hypermobility of the joints, pes planus
    In 20% of patients

  • Maternal preeclampsia
    In 15% of pregnancies

  • Neonatal complications
    Icterus (65%), hypotension (75%), and feeding difficulties (70%): there is usually spontaneous normalization, and interventions are rarely required

  • Renal abnormalities
    In 15% of patients, predominantly in the form of vesicoureteral reflux

  • Scoliosis
    In 30% of patients, rarely requiring surgery

  • Cramping seizures
    In 25% of patients, afebrile cramping seizures during the course of their lives. They can be tonic-clonic, myoclonic, or partial-complex or be absent altogether.

Associated Symptoms


Affecting approximately 3% of patients in the form of ovarian fibromatosis, sacrococcygeal teratomas, neuroblastomas, presacral gangliomas, acute lymphatic leukemia (ALL), acute myeloid leukemia (AML), hepatoblastomas, and gastric, testicular, and small cell bronchial carcinomas


In 2-15% of patients

  • Eyes: astigmatism, cataract, hyperopia, myopia, strabismus, nystagmus

  • Ears: cholesteatoma, conductive hearing loss

  • Skeleton: hemihypertrophy, contractures, craniosynostosis, pectus excavatum, vertebral body abnormalities, 2/3 toe syndactyly, clubfoot

  • GIT, abdomen: constipation, gastroesophageal reflux, inguinal hernia, umbilical hernia

  • Skin, nails, teeth: hemangiomas, hyperpigmented or hypopigmented skin, hypoplastic nails, hypodontia

  • Genitals: cryptorchidism, hydrocele, hypospadias, phimosis

  • Endocrinology: hypercalcemia, neonatal hypoglycemia

Therapeutic Considerations

In light of the large number of potential manifestations, treatment should always be symptom-oriented and interdisciplinary, with the involvement of the corresponding specialist disciplines.

Surveillance Recommendations

Surveillance Recommendations

There are no standard surveillance recommendations to date. Patients with Sotos syndrome should undergo regular medical examinations, which should include the following:

  • Detailed medical history

  • Cardiac auscultation

  • Blood pressure measurement

  • Clinical examination of the spinal column

  • Urine stick tests

If any anomalies are detected, other examinations should be conducted as needed and the patient referred to the corresponding specialists.

Patients should be made aware of their moderately increased risk of cancer. Specific cancer surveillance is not recommended.

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with Sotos syndrome that we can recommend to you for more information.

Support Groups

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