Sotos Syndrome – Definition
Sotos syndrome (OMIM #117550) is a genetic disease caused by mutations in the NSD1 gene. It features characteristic facies, developmental delays, and macrosomia.
Synonyms:
Cerebral gigantism
Chromosome 5q35 deletion syndrome
Gene:
NSD1
Gene product:
NSD1 (Nuclear receptor-binding SET domain protein 1)
Function:
Histone methyltransferase acting as a transcription factor
Pattern of inheritance:
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%
Sotos Syndrome – Diagnosis
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
Macrosomia
- 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
- Weaver syndrome
- Beckwith-Wiedemann syndrome
- Simpson-Golabi-Behmel syndrome type 1
- Bannayan-Riley-Ruvalcaba syndrome
- Benign familial macrocephaly
- Fragile X syndrome
- Gorlin syndrome (nevoid basal cell carcinoma syndrome)
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 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 also appear later in childhood. 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, sometimes due to issues related to height, hypotonic muscles, and a lack of coordination. The cognitive impairment may only be mild or 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 bodyweight generally within the average range. Growth progresses linearly during childhood and adolescence, so macrosomia ≥ 97th percentile continues. 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
Tumors
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
Others:
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
Special Features of Treatment
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.
Diagnosis of Sotos Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Sotos Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
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 should be referred to the corresponding specialists.
- Patients should be made aware of their moderately increased risk of cancer. Specific cancer surveillance is not recommended.
Sotos Syndrome – Further Information
Further Information
Unfortunately, we are currently not aware of any support groups for patients with Sotos syndrome. New information will be added as soon as it becomes available.
