Clinical Guidance

No genotype-phenotype correlations are evident among individuals reported with EZH2-related overgrowth, as findings along the entire phenotypic spectrum have been observed in individuals with heterozygous truncating or missense pathogenic variants in EZH2, within or outside the conserved SET domain .

Source: GeneReviews — "EZH2-Related Overgrowth"

Penetrance

Data are currently insufficient to determine the penetrance of EZH2 germline pathogenic variants. However, given the subtlety of the phenotype in some individuals with a pathogenic EZH2 variant, the penetrance for some EZH2 pathogenic variants may be reduced .

Source: GeneReviews — "EZH2-Related Overgrowth"

Diagnostic Criteria

Suggestive Findings

EZH2-related overgrowth should be suspected in an individual with the following clinical and imaging findings .

Clinical findings

• Tall stature (height or length ≥2 standard deviations [SD] above the mean)

• Macrocephaly (head circumference ≥2 SD above the mean)

• Intellectual disability

• Characteristic facial appearance (See .)

• In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple

• In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum

Source: GeneReviews — "EZH2-Related Overgrowth"

Differential Diagnosis

Significant overlap in findings is observed between EZH2-related overgrowth, Sotos syndrome (associated with pathogenic variants in NSD1), Cohen-Gibson syndrome (associated with pathogenic variants in EED), and Imagawa-Matsumoto syndrome (associated with pathogenic variants in SUZ12). Additional disorders of interest in the differential diagnosis of EZH2-related overgrowth are summarized in . Table 4. Disorders to Consider in the Differential Diagnosis of EZH2-Related Overgrowth

Management Guidelines

No clinical practice guidelines for EZH2-related overgrowth 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 EZH2-related overgrowth, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

EZH2-Related Overgrowth: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Measurement of height, weight, head circumference |

Neurologic

| Neurologic eval | • Consider brain MRI scan if progressive macrocephaly or unexplained neurologic features are present.

• Consider EEG if seizures are suspected.

Musculoskeletal tone abnormalities

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

• Scoliosis, camptodactyly, /or ligamentous laxity

• Mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

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

Malignancy

| Assessment for...

Source: GeneReviews — "EZH2-Related Overgrowth"

Clinical Guidance

Histone-lysine N-methyltransferase EZH2 (EZH2), encoded by EZH2, is an enzymatic catalytic subunit of the polycomb repressive complex 2 (PRC2) . These proteins contribute to cell cycle regulation, apoptosis, and DNA damage repair and have therefore been identified as targets for cancer therapies . The efficacy and side effect profile of EZH2 inhibitors and PRC2 inhibitors may be altered in individuals with EZH2-related overgrowth (see EED-Related Overgrowth).

Source: GeneReviews — "EZH2-Related Overgrowth"

Therapies Under Investigation

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

Source: GeneReviews — "EZH2-Related Overgrowth"

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 7.

EZH2-Related Overgrowth: Recommended Surveillance

System/Concern | Evaluation | Frequency 1

Feeding

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

| At each visit

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

• Monitoring by pediatrician for resolution/improvement of camptodactyly /or hypotonia

• If scoliosis is present, monitor per orthopedist.

| Regular follow up w/frequency dependent on severity

Malignancy

| Neuroblastoma surveillance: current recommendations incl clinical vigilance thorough investigation of possible tumor-related symptoms.2 | Neuroblastoma surveillance has been inconsistent internationally, w/no data supporting modality of surveillance, screening interval, or duration. US guidelines recommend imaging urine biochemistry surveillance in affected persons with inactivating EZH2 pathogenic variants up to age 10 yrs.3

Family/Community

| Assess family need for social work support, care coordination, or follow-up genetic counseling if new...

Source: GeneReviews — "EZH2-Related Overgrowth"