Clinical characteristics.

EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous 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. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known.

Weaver syndrome is characterized by tall stature, 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.

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. Treatment of scoliosis is routine. The appropriate specialist referral(s) should be made for other clinical issues.

Surveillance: Regular medical follow up of young children with EZH2-related Weaver syndrome 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 as 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 findings that may be tumor (particularly neuroblastoma) related.

Pregnancy management: Families and their health care providers should be 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; however, many germline pathogenic EZH2 variants arise de novo. Each child of an individual with an EZH2 pathogenic variant has a 50% chance of inheriting the pathogenic variant; the severity of the phenotype in an individual inheriting the EZH2 pathogenic variant cannot be predicted. If the pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

EZH2-related overgrowth should be suspected in an individual with combinations of the following clinical and imaging findings [Tatton-Brown et al 2013]:

Clinical findings

• Tall stature (height ≥+2 SD)
• Macrocephaly (head circumference ≥+2 SD)
• Intellectual disability
• Characteristic facial appearance
  • In children younger than age three years: retrognathia, large and fleshy ears, and a "stuck on" appearance to the chin associated with a horizontal skin crease and sometimes a central dimple
  • In affected individuals of all ages, additional features including (Figure 1):
    • Broad forehead
    • Widely spaced eyes
    • Almond-shaped palpebral fissures
  Note: 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 and doughy 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 Weaver syndrome 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/improve throughout childhood.

Imaging findings. Advanced bone age on plain radiographs

Brain MRI. In many individuals a brain MRI has not been undertaken and thus imaging data are not available. One or more abnormalities identified in ten individuals included: isolated ventriculomegaly ( in 5); ventriculomegaly and periventricular leukomalacia (1); periventricular leukomalacia (1); cerebellar infarct (1); and cerebellar hypoplasia and neuronal migration defects (polymicrogyria) with and without pachygyria (2) [Al-Salem et al 2013, Tatton-Brown et al 2013].

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: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of single-gene testing, multigene panel testing, and comprehensive genomic testing (exome sequencing, exome array, genome sequencing):

• Single-gene testing. Single-gene testing requires that the clinician recognize the Weaver syndrome / EZH2-related overgrowth phenotype and request EZH2 molecular genetic testing. However, given that the phenotype is broad and the facial gestalt subtle, this can be challenging even for the experienced dysmorphologist.
  Sequence analysis of EZH2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. If sequence analysis does not identify a pathogenic variant, targeted deletion/duplication analysis to detect intragenic deletions or duplications can be considered. Note: Whole- or partial-gene deletions have been reported in several individuals with increased growth possibly due to Weaver syndrome [Imagawa et al 2017, Suri & Dixit 2017].
• Multigene panel testing. More frequently, an individual with EZH2-related overgrowth is diagnosed following testing with a multigene panel for conditions characterized by increased growth (height and/or head circumference) in association with intellectual disability (see Differential Diagnosis). EZH2 is frequently included in such multigene panels. Such a panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.
  Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing. Comprehensive genomic testing allows the sequencing of many genes, often with unrelated phenotypes, in a single experiment. This has particular clinical utility when the clinician does not recognize a particular phenotype and/or genes involved. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The phenotypic spectrum associated with germline EZH2 pathogenic variants is broad, with classic 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 extent of the phenotypic spectrum of heterozygous EZH2 pathogenic variants is not yet known. While data are still limited, clinical associations reported to date in 54 individuals with Weaver syndrome are summarized below [Tatton-Brown et al 2011, Gibson et al 2012, Al-Salem et al 2013, Tatton-Brown et al 2013, Usemann et al 2016, Suri & Dixit 2017, Lui et al 2018]. The denominators reflect the numbers of individuals for whom data are available.

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

Tall stature is a near-consistent finding: height in 47/52 individuals was at least two standard deviations above the mean (ages 1-70 years). Of note, three of the four individuals with a height less than +2 SD had been tall as young children. The mean postnatal height was +3.5 SD.

Of 45 individuals on whom information was available, 24 had a head circumference less than +2 SD and 21 had macrocephaly with a head circumference ranging up to +5.5 SD.

Cognitive features. Information on cognitive function was available for 50 individuals. Eight had normal intellect; 42 individuals had variable intellectual disability (ID) including the following:

• Mild ID (24/50). Children attend mainstream school and need some extra help – e.g., a statement of educational needs – but would be expected to live independently as adults and would be likely to have their own family.
• Moderate ID (14/50). Children develop speech and need a high level of support in mainstream education but more likely will attend a school for individuals with special educational needs. While unlikely to live independently as adults, they may live in sheltered accommodation or with some additional support.
• Severe ID (2/50). Individuals require special education during schooling and are likely to require considerable support in adulthood.
• Unclassified ID (2/50). Information provided is insufficient to make a determination.

Behavioral issues including autistic spectrum disorder, phobias, and anxiety have been anecdotally reported.

Neurologic. Ventriculomegaly, reported in six individuals, was generally associated with normal CSF pressure and did not require shunting [Tatton-Brown et al 2013]. Other brain MRI findings included neuronal migration defects (pachy/polymicrogyria; in 2 individuals), periventricular leukomalacia (2 individuals), and cerebellar abnormalities (2 individuals).

Intellectual disability in those with a brain MRI abnormality was:

• Mild in six (ventriculomegaly [4], periventricular leukomalacia [1], and cerebellar hypoplasia [1]);
• Moderate in three (periventricular leukomalacia with ventriculomegaly [1] and isolated ventriculomegaly [2]);
• Severe in an individual with polymicrogyria and pachygyria; 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.
• Note: The degree of intellectual disability was not reported for one individual with ventriculomegaly.

Four individuals had afebrile seizures.

Skeletal features

• Advanced bone age. Of 29 individuals evaluated, all had advanced bone age.
• Scoliosis was reported in nine individuals and pectus abnormalities (excavatum or carinatum) in three. 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 (Figure 2).
• Talipes equinovarus. Six 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

• 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 was seen in 19/37 affected children.
• Umbilical hernia, seen in 21/44 children, was sufficiently large to require surgery in the neonatal period in eight.

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

• Hypotonia (predominantly central) was reported in 22/45 individuals.
• Hypertonia (predominantly peripheral manifesting as stiffness in the limbs with brisk reflexes) was reported in 13/41.
  Note: Five of the individuals presenting with peripheral hypertonia were also reported to have central hypotonia.

Poor feeding was reported in 10/28 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 10/27 affected infants.

Tumors have been reported in four of 54 affected individuals [Tatton-Brown et al 2013, Usemann et al 2016].

• One boy with a c.2233G>A pathogenic variant developed a pre-T cell non-Hodgkins lymphoma at age 13 years. At age 25 years he remains well with no relapses or additional tumors.
• One boy with a c.2044G>A pathogenic variant was diagnosed at age 13 months with acute lymphoblastic leukemia and neuroblastoma, both of which responded to therapy; he is well at age seven years.
• One girl with a c.458A>G pathogenic variant was diagnosed with a neuroblastoma at age four years.
• One girl with a c.395C>T pathogenic variant was diagnosed with acute myeloid leukemia and secondary hemophagocytic lymphohistiocytosis at age 16 years.

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 (in 2 individuals), hemangioma (in 4)
• Hypermetropia (hyperopia) (3), myopia (1), strabismus (3)
• Cryptorchidism (1), hydrocele (2), hypospadias (1)
• Cleft palate (3)
• Hearing loss (3) – conductive and sensorineural
• Cardiac anomalies (4) including mitral valve prolapse (1), ventricular septal defect (2), and patent ductus arteriosus (1)
• Gastroesophageal reflux (1), hiatal hernia (1)
• Neonatal hypoglycemia (2)
• Neonatal hypocalcemia (1)

Genotype-Phenotype Correlations

Because findings along the entire phenotypic spectrum have been observed in individuals with heterozygous truncating pathogenic variants or heterozygous missense pathogenic variants, within or outside the conserved SET domain (see Molecular Genetics, Normal gene product), no genotype-phenotype correlations are evident among the small number of individuals reported with EZH2-related overgrowth.

Penetrance

Data are currently insufficient to determine penetrance of EZH2 germline pathogenic variants. However, given the subtlety of the phenotype in some persons 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].

Although pathogenic variants in NSD1 (the cause of Sotos syndrome) were once reported to cause Weaver syndrome [Douglas et al 2003], this association has been refuted [Tatton-Brown et al 2005].

Prevalence

Because EZH2 pathogenic variants have only recently been shown to cause Weaver syndrome, and individuals with a mild phenotype may escape clinical diagnosis, it is currently difficult to estimate the prevalence of Weaver syndrome.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a heterozygous EZH2 pathogenic variant, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

If additional clinical issues are detected through the history and/or examination, the appropriate specialist referral(s) should be made.

Surveillance

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 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.

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 EZH2-related overgrowth caused by a de novo pathogenic variant is unknown. In the series of 48 individuals identified with an EZH2 pathogenic variant [Tatton-Brown et al 2013]:
  • 23 were simplex cases with a de novo pathogenic variant.
  • 14 were familial cases.
  • 11 could not be confirmed as having a de novo or a familial pathogenic variant as parental testing was not performed or clinical information was not available from a parent.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo germline EZH2 pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported it remains a possibility).
• Evaluation of parents may determine that one has a heterozygous germline EZH2 pathogenic variant but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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

• If testing reveals that a parent of the proband has the EZH2 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. The phenotype of an individual inheriting the EZH2 pathogenic variant cannot be predicted.
• If the EZH2 pathogenic variant 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 (or germline mosaicism) in a parent.

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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 testing for a pregnancy at increased risk 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.

Cancer and Benign Tumors

Somatic activating and inactivating mono- and biallelic EZH2 pathogenic variants have been identified in various hematopoietic malignancies. Of particular note, a recurrent activating pathogenic variant targeting the Tyr646 residue has been identified in lymphomas, particularly large B-cell lymphomas and follicular lymphomas; inactivating pathogenic variants throughout the gene are identified in myelodysplastic and myeloproliferative neoplasms with a poor prognosis [Morin et al 2010, Sneeringer et al 2010, Chase & Cross 2011].

Despite the association between somatic inactivating EZH2 pathogenic variants and older-onset, chronic myeloproliferative/dysplastic syndromes, these malignancies do not appear to occur at increased frequencies in individuals with EZH2-related overgrowth. Possible explanations for this finding:

• Myeloproliferative/dysplastic syndromes usually occur at ages older than the age of most individuals currently identified with a germline (constitutional) EZH2 pathogenic variant.
• The mechanisms by which EZH2 somatic pathogenic variants cause malignancy and EZH2 germline pathogenic variants cause overgrowth differ.
• Relatively few individuals with EZH2 germline pathogenic variants have been identified to date.

Revision History

• 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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