Clinical characteristics.

EZH2-related overgrowth is a variable overgrowth syndrome characterized by tall stature, macrocephaly, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant, but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency, though a few have been reported.

Diagnosis/testing.

The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing.

Management.

Treatment of manifestations: For individuals with developmental delay and/or learning disability, referral for learning/behavior/speech assessment and support may be indicated. Occasionally, toe camptodactyly may require surgical release. Physiotherapy may be of benefit to those experiencing joint pain secondary to ligamentous laxity or joint contractures. Standard treatment with appropriate specialist referral(s) is indicated for epilepsy, scoliosis, and other clinical issues.

Surveillance: Regular medical follow up of young children with EZH2-related overgrowth to monitor developmental progress, camptodactyly (for resolution/improvement), and/or hypotonia; medical follow up of older children/teenagers who do not have medical complications may be less frequent. If scoliosis is present, monitoring per the recommendations of an orthopedist. Although current data do not support specific tumor surveillance programs, clinicians should have a low threshold for investigating any possible tumor-related symptoms.

Pregnancy management: Families and their health care providers should be made aware that an affected baby may be large so that appropriate delivery plans can be made.

Genetic counseling.

EZH2-related overgrowth is inherited in an autosomal dominant manner. Some individuals diagnosed with EZH2-related overgrowth have an affected parent; some individuals diagnosed with EZH2-related overgrowth have the disorder as the result of a de novo EZH2 pathogenic variant. The proportion of individuals with EZH2-related overgrowth caused by a de novo pathogenic variant is unknown. Each child of an individual with EZH2-related overgrowth has a 50% chance of inheriting the pathogenic variant; the phenotype in individuals who inherit a familial EZH2 pathogenic variant cannot be predicted. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

EZH2-related overgrowth should be suspected in an individual with the following clinical and imaging findings [Tatton-Brown et al 2013, Imagawa et al 2023].

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 Figure 1.)
  • 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
  The characteristic facial appearance (which is most distinctive at a younger age) evolves over time; therefore, review of younger childhood photographs may help the clinician reach a clinical diagnosis.
• Poor coordination
• Soft, doughy skin
• Excessive loose skin
• Camptodactyly of the fingers and/or toes (See Note.)
• Umbilical hernia (that is occasionally significant enough to require surgical reduction)
• Abnormal tone (central hypotonia and/or peripheral hypertonia) (See Note.)
• Hoarse, low-pitched cry (sometimes described as a quiet cry)

Figure 1.

Retrognathia present in younger children with EZH2-related overgrowth usually resolves with age. In individuals of all ages the palpebral fissures are frequently almond shaped and the eyes are widely spaced.

Note: A detailed medical history may be necessary to determine if these findings were present in the newborn period / infancy, given that they can resolve or improve throughout childhood.

Imaging findings

• Skeletal imaging. Advanced bone age on plain radiographs or skeletal surveys
• Neuroimaging. The true prevalence of brain MRI abnormalities in EZH2-related overgrowth is currently uncertain, as baseline brain MRI scans are not routinely performed. However, the following brain MRI abnormalities have been reported, although it is currently unclear whether they are associated with EZH2-related disorders or incidental: ventriculomegaly, periventricular leukomalacia, cerebellar infarct, cerebellar hypoplasia, and neuronal migration defects (polymicrogyria) [Gibson et al 2012, Al-Salem et al 2013, Tatton-Brown et al 2013, Cohen et al 2016, Griffiths et al 2019].

Establishing the Diagnosis

The diagnosis of EZH2-related overgrowth is established in a proband by identification of a heterozygous germline EZH2 pathogenic (or likely pathogenic) variant on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous EZH2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of EZH2-related overgrowth has not been considered are more likely to be diagnosed using comprehensive genomic testing (see Option 2). Further, epigenetic signature analysis or a methylation array is an option.

Clinical Description

Primary phenotypic features associated with EZH2-related overgrowth include tall stature, macrocephaly, and intellectual disability, which are observed in association with a characteristic facial appearance (round face, flattened occiput, hypertelorism, almond-shaped palpebral fissures, retrognathia, large, fleshy ears, and a "stuck on" appearance to the chin) [Tatton-Brown et al 2013, Imagawa et al 2023].

The phenotypic spectrum associated with germline EZH2 pathogenic variants is broad, with classic EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous germline EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome [Tatton-Brown et al 2011, Gibson et al 2012]. Thus, the full extent of the phenotypic spectrum of heterozygous EZH2 pathogenic variants is not yet known.

To date, at least 68 individuals have been identified with a pathogenic variant in EZH2 [Tatton-Brown et al 2011, Gibson et al 2012, Al-Salem et al 2013, Tatton-Brown et al 2013, Cohen et al 2016, Usemann et al 2016, Lui et al 2018, Griffiths et al 2019, Turkkahraman et al 2021, Imagawa et al 2023, Oh et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Growth. From data available on 23 newborns, the mean birth length was 2.2 standard deviations (SD) above the mean, with a range of 0.5 SD below the mean to 4.9 SD above the mean. The mean birth weight of 45 newborns was 1.7 SD above the mean, with a range of 1.6 SD below the mean to 4.6 SD above the mean [Tatton-Brown et al 2013].

Tall stature is a near-consistent finding: height in 59 of 65 individuals was at least two SD above the mean (ages 1-70 years). Of note, three of four individuals with a height less than two SD above the mean had been tall as young children. The mean postnatal height was 3.5 SD above the mean.

Of 59 individuals for whom information is available, 27 had a head circumference less than two SD above the mean and 32 had macrocephaly (>2 SD above the mean), with a head circumference reaching up to 5.5 SD above the mean. Head circumferences at birth were at least two SD above the mean in 5 of 6 infants for whom data is available [Gibson et al 2012, Cohen et al 2016]. These data suggest that macrocephaly in EZH2-related overgrowth is likely to be present from birth but longitudinal follow up is required.

Neurologic. Ventriculomegaly, reported in seven individuals, was generally associated with normal cerebrospinal fluid pressure and did not require shunting [Gibson et al 2012, Tatton-Brown et al 2013, Griffiths et al 2019]. Other reported brain MRI findings include neuronal migration defects (including polymicrogyria in several individuals), periventricular leukomalacia (two individuals), and cerebellar abnormalities (two individuals).

Intellectual disability in those with a brain MRI abnormality was:

• Mild in seven individuals (ventriculomegaly [5 individuals], periventricular leukomalacia [1 individual], and cerebellar hypoplasia [1 individual]);
• Moderate in three individuals (periventricular leukomalacia with ventriculomegaly [1 individual] and isolated ventriculomegaly [2 individuals]);
• Severe in two individuals with polymicrogyria and pachygyria [Tatton-Brown et al 2013, Griffiths et al 2019]; in contrast, the individual with polymicrogyria reported by Al-Salem et al [2013] had normal developmental milestones and body asymmetry (left side smaller than the right) with brisk reflexes and increased tone on the left. The degree of intellectual disability of the individual with polymicrogyria reported by Cohen et al [2016] is unknown.
  Note: The degree of intellectual disability was not reported for one individual with ventriculomegaly.

Several reported individuals with EZH2-related overgrowth had seizures. Four individuals had afebrile seizures [Gibson et al 2012, Usemann et al 2016, Griffiths et al 2019]. Seizure types include tonic-clonic (age of onset 13 years) [1 individual] and brief absence (age of onset 15 years) [Gibson et al 2012]. Two individuals had seizures associated with a febrile illness [Tatton-Brown et al 2013, Cohen et al 2016].

Abnormal tone. In general, abnormal tone (hypotonia, hypertonia, or mixed central hypotonia and peripheral hypertonia), if present, resolves during childhood.

• Hypotonia (predominantly central) was reported in 22 of 47 individuals.
• Hypertonia (predominantly peripheral manifesting as stiffness in the limbs with brisk reflexes) was reported in 14 of 51 individuals.
  Note: Three of the individuals presenting with peripheral hypertonia were also reported to have central hypotonia [Tatton-Brown et al 2013].

Cognitive features. Information on cognitive function is available for 61 individuals. Eight had normal intellect; 52 individuals had variable intellectual disability (ID), including the following:

• Mild ID (30/61). Children attend mainstream school but need some extra help – e.g., a statement of educational needs – and are expected to live independently as adults and likely to have their own family.
• Moderate ID (13/61). Children develop speech and need a high level of support in mainstream education but are likely to require special educational needs. While unlikely to live independently as adults, they may live in sheltered accommodation or with additional support.
• Severe ID (3/61). Individuals require special education during school and are likely to require considerable support during adulthood.
• Unclassified ID (6/61). Insufficient information was provided regarding degree of ID.

Behavioral issues including autistic features, phobias, and anxiety have been anecdotally reported [Tatton-Brown et al 2013].

Skeletal features

• Advanced bone age. Of 33 individuals evaluated, all had advanced bone age.
• Scoliosis was reported in 13 individuals and pectus abnormalities (excavatum or carinatum) in four individuals. Scoliosis ranged from severe (early-childhood onset requiring surgical intervention) to mild (requiring monitoring but no therapeutic intervention).
• Camptodactyly. Some affected individuals had camptodactyly of the fingers, some had camptodactyly of the toes, and some had camptodactyly of fingers and toes. On occasion, the toe camptodactyly required surgical correction.
• Adult boutonniere deformity. Several adults developed hyperextension of the distal interphalangeal joints and flexion of the proximal interphalangeal joints of the hands analogous to a mild boutonniere deformity (see Figure 2).
• Talipes equinovarus. Eight individuals had talipes equinovarus ranging from fixed and bilateral (requiring surgery) in two individuals to mild (unilateral that resolved with physiotherapy) in three.

Figure 2.

Mild hyperextension of the distal interphalangeal joints and flexion of the proximal interphalangeal joints in a woman age 22 years with a heterozygous EZH2 pathogenic variant

Connective tissue features

• Ligamentous laxity. While ligamentous laxity with associated joint hypermobility and pes planus is common, it is not usually reported unless complicated by joint pain. Individuals with EZH2-related overgrowth are frequently reported to have poor coordination that may be (at least partially) attributable to lax ligaments.
• Skin that was soft and doughy to the touch has been reported in 23 of 43 affected children.
• Umbilical hernia has been seen in 28 of 57 children and was sufficiently large to require surgery in eight neonates.

Poor feeding has been reported in 10 of 28 neonates, including one who required nasogastric tube feeding for two weeks. Although poor feeding may be attributable to neonatal hypotonia, this was only reported in three of the infants with poor feeding.

Hoarse, low-pitched cry was reported in 16 of 35 affected infants.

Tumors have been reported in seven of 68 affected individuals [Tatton-Brown et al 2013, Usemann et al 2016, Cohen et al 2016, Oh et al 2023]. A summary of reported tumor types is provided in Table 3.

Additional clinical features reported in a small number of individuals (and therefore possibly not associated with the EZH2 pathogenic variant) are included for completeness:

• Café au lait macules (2 individuals), hemangioma (4 individuals), pigmented nevi (3 individuals)
• Large hands and feet (1 individual)
• Hypermetropia (hyperopia; 3 individuals), strabismus (3 individuals), myopia (1 individual)
• Hydrocele (2 individuals), cryptorchidism (1 individual), hypospadias (1 individual)
• Cleft palate (3 individuals)
• Hearing loss (conductive and sensorineural; 3 individuals)
• Cardiac anomalies (4 individuals), including mitral valve prolapse (1 individual), ventricular septal defect (2 individuals), and patent ductus arteriosus (1 individual)
• Gastroesophageal reflux (1 individual), hiatal hernia (1 individual)
• Neonatal hypoglycemia (2 individuals)
• Neonatal hypocalcemia (2 individual)

Genotype-Phenotype Correlations

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 (see Molecular Genetics).

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 [Tatton-Brown et al 2013].

Nomenclature

Weaver syndrome is named after David Weaver, who reported two boys with accelerated osseous maturation, unusual facies, and camptodactyly [Weaver et al 1974].

Prevalence

As individuals with a mild phenotype may escape clinical diagnosis, it is currently difficult to estimate the prevalence of EZH2-related overgrowth.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EZH2-related overgrowth, the evaluations summarized Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for EZH2-related overgrowth. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6). If additional clinical issues are detected through the history and/or examination, the appropriate specialist referral(s) should be made.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Histone-lysine N-methyltransferase EZH2 (EZH2), encoded by EZH2, is an enzymatic catalytic subunit of the polycomb repressive complex 2 (PRC2) [Duan et al 2020]. These proteins contribute to cell cycle regulation, apoptosis, and DNA damage repair and have therefore been identified as targets for cancer therapies [Duan et al 2020]. 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).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, pregnancies in which the mother and/or fetus has a heterozygous EZH2 pathogenic variant are uncomplicated. Families and their health care providers should be made aware that an affected baby may be large so that appropriate delivery plans can be made; in addition, information about the EZH2-related overgrowth phenotype should be provided.

See MotherToBaby for further information on medication use during pregnancy.

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.

Mode of Inheritance

EZH2-related overgrowth is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with EZH2-related overgrowth have an affected parent.
• Some individuals diagnosed with EZH2-related overgrowth have the disorder as the result of a de novo EZH2 pathogenic variant. The proportion of individuals with EZH2-related overgrowth caused by a de novo pathogenic variant is unknown.
• Of 68 individuals with EZH2 pathogenic variants, 34 individuals represented simplex cases (i.e., the only family member known to be affected) and had a de novo pathogenic variant,18 individuals had a familial pathogenic variant, and 16 individuals could not be confirmed to have a de novo or a familial pathogenic variant as parental testing was not performed or clinical information was not available from a parent [Gibson et al 2012, Al-Salem et al 2013, Tatton-Brown et al 2013, Cohen et al 2016, Usemann et al 2016, Lui et al 2018, Griffiths et al 2019, Turkkahraman et al 2021].
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
  * A parent with somatic and germline mosaicism for an EZH2 pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with EZH2-related overgrowth may appear to be negative because of failure to recognize the disorder in a parent with a milder phenotype. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the EZH2 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The phenotype in individuals who inherit a familial EZH2 pathogenic variant cannot be predicted.
• If the EZH2 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the EZH2 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband is unclear because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with EZH2-related overgrowth has a 50% chance of inheriting the EZH2 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an EZH2 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the EZH2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues can be helpful.

Molecular Pathogenesis

Histone-lysine N-methyltransferase EZH2 (EZH2) is a histone methyltransferase with a critical SET (su(var)3-9, enhancer of zeste, trithorax) domain, a pre-SET CXC domain, and two additional SANT (Sw13, Ada2, N-cor TFIIIB) domains [Wu et al 2013]. In combination with polycomb protein SUZ12 (SUZ12) and polycomb protein EED (EED), which form the polycomb repressor complex 2 (PCR2), EZH2 acts to repress transcription through the methylation of lysine residue 27 of histone 3, a function catalyzed by the SET domain [Cao et al 2002]. The protein alterations and the mechanism by which pathogenic EZH2 missense and truncating variants cause overgrowth are currently unknown. It is, however, noteworthy that pathogenic missense variants are the primary mutational mechanism; the few pathogenic truncating variants identified to date target the final exon and thus are likely to escape nonsense-mediated RNA decay. Current evidence suggests that EZH2-related overgrowth may be caused by impaired histone methyltransferase function [Cohen et al 2016, Lui et al 2018].

Mechanism of disease causation. Functional studies suggest that EZH2 pathogenic variants cause either partial or complete loss of protein function, resulting in impaired histone methyltransferase activity [Cohen et al 2016, Imagawa et al 2017, Lee et al 2018, Lui et al 2018]. However, alternative mechanisms of disease causation are theoretically possible [Cyrus et al 2019].

Epigenetic mutational signature analysis has shown that EZH2 gain-of-function variants may cause transcriptional changes that result in growth restriction, in contrast to EZH2-related overgrowth due to loss-of-function variants [Choufani et al 2020].

Further functional studies are needed to determine the precise mechanism of disease causation in EZH2-related overgrowth and other PRC2-related syndromes including Cohen-Gibson syndrome (see EED-Related Overgrowth) and Imagawa-Matsumoto syndrome.

EZH2-specific laboratory technical considerations. Based on a small number of cases, current data (in which the distribution of EZH2 variants in cases vs controls, conservation of the SET domain residues, and critical function of the SET domain in mediating histone methyltransferase activity were analyzed) suggest that SET domain missense variants are likely pathogenic.

Author History

Sharon Ocansey, MBBS, BSc, MSc (2024-present)
Nazneen Rahman, BM BCh, PhD; Institute of Cancer Research (2013-2024)
Katrina Tatton-Brown, BM BCh, MD (2013-present)

Revision History

• 21 March 2024 (gm) Comprehensive update posted live
• 2 August 2018 (bp) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 18 July 2013 (me) Review posted live
• 23 January 2013 (ktb) Original submission

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