Sotos syndrome

Sotos syndrome is inherited in an autosomal dominant pattern with a high rate of de novo variants. It is characterised by pre- and postnatal overgrowth, a variable learning disability and a distinctive facial appearance.

Growth

• pre- and postnatal overgrowth (height and/or head circumference two standard deviations above the mean), with peak growth velocity occurring in early childhood; and
• advanced bone age.

Neurodevelopmental

• intellectual disability (mild to severe);
• neonatal hypotonia; and
• hyperlaxity.

Distinctive facial appearance (most evident in early childhood)

• prominent jaw;
• long, narrow face with pointed chin; and
• down-slanting palpebral fissures.

Other features

• cardiac and renal anomalies;
• seizures;
• scoliosis;
• strabismus and/or astigmatism;
• neonatal jaundice and poor feeding; and
• tumours, including sacrococcygeal teratoma, neuroblastoma, presacral ganglioglioma and acute lymphoblastic leukaemia – though these occur rarely and routine screening is not currently recommended.

Sotos syndrome is caused by genetic variants (missense, splicing, nonsense and frameshift) and large deletions in the NSD1 gene (located at chromosome 5q35). The NSD1 gene provides instructions for making a protein (histone methyltransferase) involved in the modification of chromatin, which determines gene expression essential for normal growth and development.

There are no formal clinical diagnostic criteria for Sotos syndrome. However 90% of affected individuals will have all three cardinal features of the condition (facial appearance, learning disability and overgrowth).

Many individuals will be diagnosed through broad-based testing as Sotos syndrome is rare, can present in different ways and there is significant clinical overlap with other genetic conditions. The NSD1 gene is analysed as part of several genomic tests. This includes R27 Paediatric disorders, R29 Intellectual disability, R59 Early onset or syndromic epilepsy and R359 Childhood solid tumours.

For more information about testing, see Presentation: Child with a suspected overgrowth-intellectual disability syndrome and Presentation: Child with macrocephaly.

Sotos syndrome is an autosomal dominant condition caused by a pathogenic variant in one copy of the NSD1 gene. Most cases (95%) occur de novo (for the first time) in the child. Where blood tests do not identify the pathogenic variant in either parent, the chance of recurrence is low (under 1%). The chance remains slightly above that of the background population due to the small possibility of germline mosaicism.

Around 5% of cases have an affected parent, in which case the chance of recurrence in future pregnancies is 50%. Families should be offered counselling by the local clinical genetics service in advance of future conception as reproductive options are available.

Management of children with Sotos syndrome should be delivered via a multidisciplinary team. Suggested approaches have been published by several authors.

Guidelines may include echocardiogram and ultrasound scan, ophthalmology and audiology assessments and developmental support. Routine cancer screening is not currently recommended. Please see recommended management guidance resources in the list below.

For clinicians

• GeneReviews: Sotos syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Orphanet: Sotos syndrome
• OMIM: 117550 Sotos syndrome; Sotos
• U.S. National Library of Medicine: ClinicalTrials.gov database

For patients

• Child Growth Foundation: Sotos syndrome
• National Institute of Neurological Disorders and Stroke: Sotos syndrome
• Sotos Syndrome Support Association