Clinical Guidance

Through the evaluation of 234 individuals with Sotos syndrome with an NSD1 abnormality, it has been shown that individuals with a 5q35 microdeletion have less overgrowth and more severe learning disability than individuals with an NSD1 intragenic pathogenic variant overall . Genotype-phenotype correlations for intragenic pathogenic variants and 5q35 microdeletions are not evident for other clinical features associated with Sotos syndrome (i.e., cardiac abnormalities, renal anomalies, seizures, scoliosis), nor were correlations observed between the type of intragenic pathogenic variant (missense vs truncating) and phenotype or between position of pathogenic variant (5' vs 3' UTR) and phenotype . Recent studies have replicated these findings .

Source: GeneReviews — "Sotos Syndrome"

Penetrance

To date, no unaffected parent or sib with an NSD1 pathogenic variant or deletion encompassing NSD1 has been reported [, , , ]. Thus, Sotos syndrome appears to be a fully penetrant condition. Of note, expressivity is highly variable. Individuals with the same genetic alteration, even within the same family, can be affected differently .

Source: GeneReviews — "Sotos Syndrome"

Diagnostic Criteria

No consensus clinical diagnostic criteria Sotos syndrome have been published.

Suggestive Findings

Sotos syndrome should be suspected/considered in probands with the following features. Characteristic facial appearance (most easily recognizable between ages 1 and 6 years):

• Broad, prominent forehead with a dolichocephalic head shape

• Sparse frontotemporal hair

• Downslanting palpebral fissures

• Malar flushing

• Long narrow face (particularly bitemporal narrowing)

• Tall chin

Note: Facial shape is retained into adulthood. However, with time the chin becomes broader (squarer in shape).

Learning disability

• Early developmental delay

• Mild-to-severe intellectual impairment

Overgrowth

Source: GeneReviews — "Sotos Syndrome"

Differential Diagnosis

Overgrowth conditions that may be confused with Sotos syndrome are summarized in . Table 3. Overgrowth Conditions to Consider in the Differential Diagnosis of Sotos Syndrome

Management Guidelines

No clinical practice guidelines for Sotos syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Sotos syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended .

Table 4.

Sotos Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Assess serial growth measurements (stature, weight, OFC). |

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

Neurobehavioral/

Psychiatric

| Neuropsychiatric eval | For persons age 12 mos: screening for concerns incl sleep disturbances, ADHD, anxiety, /or findings suggestive of ASD

Cardiovascular

| Cardiac eval | • To incl baseline echocardiogram

• Blood pressure measurement

Genitourinary

| Nephrology eval | • To include baseline renal US

• In adults in whom diagnosis has just been established, renal US to evaluate for renal damage from quiescent chronic VUR

• Assessment for cryptorchidism, hydrocele, hypospadias

Neurologic

| Neurologic eval | • To incl brain MRI if progressive macrocephaly or unexplained neurologic features are present

• Consider EEG if seizures are a concern.

Musculoskeletal

| Orthopedics/ physi...

Source: GeneReviews — "Sotos Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Sotos Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended .

Table 6.

Sotos Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

Feeding

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

| At each visit

Gastrointestinal

| Monitor for constipation.

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations such as seizures, changes in tone, movement disorders.

Development

| Monitor developmental progress educational needs.

Neurobehavioral/Psychiatric

| Assessment for anxiety, ADHD, ASD, aggression, self-injury

Musculoskeletal

| Physical medicine OT/PT assessment of mobility self-help skills

Ophthalmologic involvement

| • Monitor those w/eye abnormalities as clinically indicated.

• Assess for changes in visual acuity.

| Per treating ophthalmologist(s)

Cardiovascular

| Monitor those w/cardiovascular abnormalities as clinically indicated. | Need for timing of follow-up studies determined by cardiologist

Audiologic

| Assess for signs symptoms of hearing difficulties. | At each visit

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

Source: GeneReviews — "Sotos Syndrome"