Clinical characteristics.

EED-related overgrowth is characterized by fetal or early childhood overgrowth (tall stature, macrocephaly, large hands and feet, and advanced bone age) and intellectual disability that ranges from mild to severe.

Diagnosis/testing.

The diagnosis of EED-related overgrowth is established in a proband with suggestive findings and a heterozygous germline EED pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental delay / intellectual disability requires early referral for developmental support and educational interventions tailored to the child's needs. Seizures, cervical spine instability, palatal abnormalities, kyphoscoliosis, congenital heart defects, cryptorchidism, and ophthalmologic findings are treated per standard practice.

Surveillance: Routine assessment of the following: development; spine for scoliosis or deformities; joint range of motion for joint contractures; and eyes for refractive errors, myopia, and strabismus.

Agents/circumstances to avoid: Activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks) because of the possible increased risk for cervical spine instability.

Genetic counseling.

EED-related overgrowth is an autosomal dominant disorder. Most probands whose parents have undergone molecular genetic testing have the disorder as the result of a de novo EED pathogenic variant. Transmission of an EED pathogenic variant from an affected mother to affected children has been reported in two families. Each child of an individual with EED-related overgrowth has a 50% chance of inheriting the EED pathogenic variant. Once a family member has a confirmed molecular diagnosis of EED-related overgrowth, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

EED-related overgrowth should be suspected in individuals with the following clinical and radiographic findings.

Clinical findings

• Overgrowth manifesting as:
  • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean)
    Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth.
  • Macrocephaly (z score ≥2 for age)
  • Large hands and feet (length z score ≥2 for age)
• Intellectual disability, developmental delay
  • Delay of gross motor skills
  • Delay of fine motor skills
  • Delay of speech acquisition
  • Delay of social development
  • Intellectual disability (by clinical assessment and/or formal testing)

Skeletal radiographic findings

• Advanced bone age (bone age z score ≥2 for chronologic age)
• Abnormalities of the cervical spine are uncommon but significant when present.
• Metaphyses may be widened, flared, and/or abnormally lucent.
• Skeletal surveys have variously revealed flattened glenoid fossae, humeral heads, femoral heads, and flattened acetabulum. Other findings include small iliac wings and coxa valga or congenital dislocation of the hips, as well as asymmetric limb lengths (1 individual) and flaring of the distal clavicles and distal ribs (1 individual).
• Osteopenia has been documented on skeletal survey; however, to date no increased risk of fractures has been documented.

Supportive findings include characteristic craniofacial features that are more evident in infancy and childhood and tend to become less evident with age (see Figure 1): a round face; prominent (tall, wide, or broad) forehead; hypertelorism; low, wide, and/or depressed nasal bridge; large ears (with or without posterior helical pits and earlobe creases), which may appear low set; prominent and/or long philtrum; horizontal chin crease; and retrognathia. Facial hypotonia may contribute to an open-mouthed appearance. Published photographs showing the characteristic craniofacial features of EED-related overgrowth are accessible (with registration or institutional access) in Cohen et al [2015] (full text; see Figure 1), Cohen & Gibson [2016] (full text; see Figure 2), Cooney et al [2017] (full text; see Figure 1), Imagawa et al [2017] (full text; see Figure 2), Smigiel et al [2018] (full text; see Figure 1), Griffiths et al [2019] (full text; see Figure 1), and Goel et al [2024] (full text; see Figure 1).

Figure 1.

Photographs of a male with EED-related overgrowth at age one day (A), 3.5 weeks (B), three months (C), six months (D), one year (E), two years (F), seven years (G), 11 years (H), 12 years (I), and 33 years (J, K, L, M, N, O, P) Note round face with prominent (more...)

Establishing the Diagnosis

The diagnosis of EED-related overgrowth is established in a proband with suggestive findings and a heterozygous germline pathogenic (or likely pathogenic) variant in EED identified by 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 variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous EED variant of uncertain significance does not establish or rule out the diagnosis.

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

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of disorders of overgrowth with intellectual disability (OGID) can be indistinguishable, children with the distinctive findings described in Suggestive Findings who have not undergone previous genetic testing are likely to be diagnosed using a multigene panel or genomic testing (see Scenario 1), whereas children with OGID who have previously undergone genetic testing that did not include sequence analysis of EED may be diagnosed using single-gene testing (see Scenario 2).

Clinical Description

EED-related overgrowth is characterized by fetal or early childhood overgrowth (tall stature, macrocephaly, large hands and feet, and advanced osseous maturation), psychomotor delay, and intellectual disability that ranges from mild to severe. Characteristic craniofacial features are more evident in infancy and childhood and tend to become less evident with age (see Figure 1 for photographs of one individual from age one day to 33 years). Other common features include scoliosis, hernias, cryptorchidism in males, and cardiovascular, genitourinary, and ophthalmologic manifestations. To date, EED-related overgrowth has been reported in 19 individuals [Cohen et al 2015, Cohen & Gibson 2016, Cooney et al 2017, Imagawa et al 2017, Tatton-Brown et al 2017, Smigiel et al 2018, Griffiths et al 2019, Spellicy et al 2019, Kang & Kim 2021, Hetzelt et al 2022, Goel et al 2024].

Prenatal overgrowth. Gestational age at delivery has ranged from 36 to 42 weeks.

Birth weight ranges from appropriate to large for gestational age, with weights ranging from 3,550 g (male, 38 weeks' gestation [Smigiel et al 2018]) to 5,160 g (male, 40 weeks' gestation [Spellicy et al 2019]) with z scores from 0 to 4.2. To date, birth weights below the mean for gestational age have not been reported.

Birth length typically ranges from 52 cm (z score = 0.5) to 57 cm (z score = 3.0).

Birth head circumference ranges from 35 cm (z score = 0) to 37.2 cm (z score = 2.0).

Postnatal overgrowth. During childhood and adolescence, increased height, weight, and head circumference manifest as increased z scores in height (0.84 to 5.1), weight (1.0 to 3.8), and head circumference (0.6 to 4.0). Z scores for body mass index vary from approximately 1.4 to 1.8; thus, based on data available to date, obesity does not appear to be a major feature of EED-related overgrowth. Large body weight is typically accompanied by tall stature.

Growth parameter z scores in adults using World Health Organization curves vary from 1.85 to 3.1 in height and 1.46 to 3.9 in head circumference. The two adults reported by Griffiths et al [2019] had body mass indices of 32.6 kg/m² and 38.2 kg/m² (in the obese range) in their mid-20s. Registry-based longitudinal growth curves are not yet available.

Psychomotor delay. Delay of gross motor, fine motor, and speech milestones is common.

Intellectual disability, present in all individuals reported to date, may be mild [Cohen et al 2015], moderate [Cooney et al 2017], or severe [Tatton-Brown et al 2017]. Difficulties with coordination and balance may persist into adulthood.

Two affected individuals had relatively sociable, friendly personalities; a third was somewhat hyperactive and lacking inhibition, with occasional aggression toward peers at school. In one individual who had had more detailed testing, specific weaknesses were noted in problem solving and memory, whereas visual memory was a relative strength.

Craniofacial features. The voice may be hypernasal, low, or hoarse.

Characteristic craniofacial features that are more evident in infancy and childhood and tend to become less evident with age (see Figure 1 for photographs of one individual from age one day to 33 years) include a round face; prominent (tall, wide, or broad) forehead; hypertelorism; low, wide, and/or depressed nasal bridge; large ears (with or without posterior helical pits and earlobe creases), which may appear low set; prominent and/or long philtrum; horizontal chin crease; and retrognathia. Facial hypotonia may contribute to an open-mouthed appearance. Published photographs showing the characteristic craniofacial features of EED-related overgrowth are accessible (with registration or institutional access) in Cohen et al [2015] (full text; see Figure 1), Cohen & Gibson [2016] (full text; see Figure 2), Cooney et al [2017] (full text; see Figure 1), Imagawa et al [2017] (full text; see Figure 2), Smigiel et al [2018] (full text; see Figure 1), Griffiths et al [2019] (full text; see Figure 1), and Goel et al [2024] (full text; see Figure 1).

Bilateral cleft palate has been reported in one individual, and bifid uvula has been reported in another.

Musculoskeletal findings. Large hands and feet are notable in childhood and into adulthood. Fingers may be long and slender. Broad thumbs were seen in two individuals. Camptodactyly, joint contractures, flat feet (pes planovalgus), and/or clubfoot may be seen.

Scoliosis and/or kyphoscoliosis of the thoracic spine have been reported frequently.

Hypermobility of the small joints of the hands, recurrent patellar subluxation, and dislocation have also been described; with reported skin fragility (poor wound healing, fragile nails), these suggest more generalized laxity of connective tissue.

Stenosis of the cervical spine has been reported in three individuals, one of whom required laminectomy and arthrodesis; another had associated myelopathy at the level of the third cervical vertebra. Laminectomy and fusion have also been required in a fourth individual, in the context of atlantoaxial instability with C1-C2 instability. Lumbar spinal stenosis or spondylolisthesis has also been reported in two individuals.

Osteopenia, reported in two individuals, was a secondary finding on bone age radiographs or skeletal survey.

Neurologic findings. Low muscle tone with delayed gross motor milestones is common. Gait may appear clumsy; coordination is often poor.

Epilepsy has been reported in six individuals; one of them had seizures associated with hyperinsulinemic hypoglycemia (see Endocrine in this section).

Cerebral imaging has shown nonspecific enlargement of the ventricles, white matter volume loss, an arachnoid cyst, a cyst of the septum pellucidum that required surgical decompression, and a pituitary microadenoma in one individual each. Thinning or shortening of the corpus callosum has been described in two individuals. Cerebral imaging has also been normal in several individuals.

Skin and nail findings have included the following:

• Multiple pigmented nevi (3 individuals)
• Soft, doughy skin with increased elasticity (1 individual)
• Small nails (2 individuals)
• Fragile fingernails and toenails (1 individual)
• Poor wound healing with hyperpigmentation and keloid overgrowth of a surgical scar (1 individual)

Hernias. Inguinal and femoral hernias may be seen. Umbilical hernias may be large enough to require surgical management.

Cardiovascular manifestations. Structural cardiac anomalies (patent ductus arteriosus, septal defects, and mild or moderate mitral valve prolapse) have been reported.

Genitourinary manifestations. Bilateral cryptorchidism has been reported in males and may require surgical correction.

One female had nephromegaly and a duplicated collecting system.

Ophthalmologic findings. Ocular findings have included hypertelorism; narrow and/or short palpebral fissures with a downward slant to the lateral aspect of the upper eyelid have also been reported. Eversion of the lateral lower eyelid has also been suggested, based on panel review of published photographs.

The following were reported in one individual each:

• Ptosis requiring surgical correction
• Early-onset cataracts (age 30 years)
• Chororetinal degeneration

Hearing loss

• Bilateral hypoacusis of 50 dB (frequencies not specified) (1 individual)
• Mild-to-moderate conductive hearing loss (1 individual)

Endocrine manifestations

• Neonatal hyperinsulinemic hypoglycemia; treated by glucose infusion and resolved at 21 days (1 individual)
• Childhood-onset hyperinsulinemic hypoglycemia; treated with octreotide (1 individual).
• Calcification of one of the adrenal glands with hypocortisolism (1 individual)

Respiratory issues. Neonatal respiratory distress may be seen. One individual had significant tracheomalacia requiring surgical intervention, as well as frequent respiratory infections. One individual was readmitted to hospital in the first weeks of life for pneumonia.

Feeding/gastrointestinal findings include:

• Gastrostomy tube feeds in infancy, later requiring partial bowel resection for obstruction (the latter possibly associated with anticholinergic medications) (1 individual)
• Chronic constipation (1 individual)
• Intestinal malrotation and Hirschsprung disease (1 individual)

Cancer predisposition. No instances of benign or malignant tumors in childhood among individuals with germline EED pathogenic variants have been reported to date. One adult was reported with an anal squamous cell carcinoma at age 61 years [Goel et al 2024]. The risk for certain cancers, such as hematologic cancers and malignant peripheral nerve sheath tumors, could theoretically be increased (see Genetically Related Disorders, Cancer and Benign Tumors).

Genotype-Phenotype Correlations

With only 19 probands reported to date, data are insufficient to consider genotype-phenotype correlations.

Penetrance

Because most germline EED coding variants associated with overgrowth are de novo, penetrance is expected to be high. Estimates of penetrance for inherited EED coding variants are not yet available.

Prevalence

To date, 19 individuals have been reported with EED-related overgrowth [Cohen et al 2015, Cohen & Gibson 2016, Cooney et al 2017, Imagawa et al 2017, Tatton-Brown et al 2017, Smigiel et al 2018, Griffiths et al 2019, Spellicy et al 2019, Kang & Kim 2021, Hetzelt et al 2022, Goel et al 2024].

Cancer and Benign Tumors

Though to date malignant peripheral nerve sheath tumors (MPNSTs) have not been reported in individuals with EED-related overgrowth caused by germline EED pathogenic variants, the presence of somatic variants in EED in individuals with MPNSTs [Lee et al 2014] suggests that persons with EED-related overgrowth may also be at increased risk for these tumors.

Wassef & Margueron [2017] reviewed the role of polycomb repressive complex 2 (PRC2) alterations in MPNSTs and other cancers that included somatic variants in EED.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EED-related overgrowth, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is symptomatic; no therapy specific to the disorder is available. 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 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Although malignant peripheral nerve sheath tumors (MPNSTs) have not been reported to date in individuals with EED-related overgrowth caused by germline EED pathogenic variants, the observation of somatic EED pathogenic variants in malignant MPNSTs [Lee et al 2014] suggests that lesions with features suspicious for MPNSTs should be followed with clinical examination and/or imaging as per guidelines for such lesions in individuals with neurofibromatosis type 1.

Agents/Circumstances to Avoid

In one individual, neurologic compromise resulting from neck motion during gymnastics required surgical intervention. Caution is advised for activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks).

Side effects of pharmacologic agents that inhibit the activity of polycomb repressive complex 2 (PRC2) (which includes the polycomb protein EED, encoded by EED) may be increased (e.g., tazemetostat). In addition, the efficacy of such agents in individuals with EED-related overgrowth may differ from that in other individuals.

Evaluation of Relatives at Risk

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

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

EED-related overgrowth is an autosomal dominant disorder.

Risk to Family Members

Parents of a proband

• Most probands reported to date with EED-related overgrowth whose parents have undergone molecular genetic testing have the disorder as a result of a de novo EED pathogenic variant.
• Some individuals diagnosed with EED-related overgrowth have an affected parent. Two families with multiple affected individuals have been reported; in each of these, an affected mother gave birth to more than one affected child [Kang & Kim 2021, Goel et al 2024].
• If a parent of an individual with an identified EED pathogenic variant does not have any clinical features of EED-related overgrowth, that parent is unlikely to have a pathogenic variant in EED. However, molecular genetic testing of both parents for the EED pathogenic variant identified in the proband is generally advisable.
• 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 gonadal (or somatic and gonadal) 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 (gonadal) cells only.
    * 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment.

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 affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the EED 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 possibility of parental gonadal mosaicism [Rahbari et al 2016].

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the EED 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 parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once a family member has a confirmed molecular diagnosis of EED-related overgrowth, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

EED encodes polycomb protein EED, a highly conserved, ubiquitously expressed protein that is a core member of the polycomb repressive complex 2 (PRC2). Other PRC2 members include EZH2, SUZ12, RBBP7, and RBBP4; their complex with EED is thought to be necessary for the lysine methyltransferase activity of PRC2.

There are seven WD40 domains, though whether these domains have redundant or distinct functions is not yet known. The C-terminal domain of EED binds specifically to trimethylated H3K27 (i.e., H3K27me3) histone tails, and this function is thought to be necessary for the propagation of H3K27me3 marks to daughter cells that initially lack sufficient H3K27 marks after mitosis. In so doing, EED is believed to provide the epigenetic reader function of the PRC2 complex’s epigenetic reader-writer function.

In general, PRC2 is a key chromatin modifier involved in the maintenance of transcriptional silencing. PRC2-mediated trimethylation of H3K27 is thought to correlate with transcriptional repression of local DNA. Correct propagation of H3K27me3 marks is in turn thought necessary in order for repressive domains to persist in the newly synthesized chromatin [Margueron et al 2009].

In an ex vivo assay, a lymphoblastoid cell line derived from a Japanese individual with EED pathogenic variant p.Arg236Thr showed reduced levels of H3K27 trimethylation by Western blotting, consistent with reduced methyltransferase activity of the mutated PRC2 complex toward this substrate [Imagawa et al 2017]. These data suggest that EED-related overgrowth is caused by partial loss of function of EED protein.

Mechanism of disease causation. Loss of function

Author Notes

Dr William T Gibson's clinical and laboratory research focuses on Cohen-Gibson syndrome, Weaver syndrome, and similar rare disorders, including rare genetic versions of common, complex diseases.

Dr Gibson (ac.rhccb@nosbigtw) is actively involved in clinical research regarding individuals with EED-related overgrowth. He would be happy to communicate with persons who have any questions regarding diagnosis of EED-related overgrowth or other considerations.

Dr Gibson is also interested in hearing from clinicians treating families affected by childhood overgrowth and intellectual disability disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Gibson to inquire about review of EED, EZH2, and SETD1B variants of uncertain significance.

Acknowledgments

We gratefully acknowledge the patients and their families who have generously participated in the research described and referenced here. We also gratefully acknowledge the contributions of Professor Steven JM Jones and Dr Yaoqing Shen for helpful discussions of EED variation recorded in online databases of human cancers.

Dr Gibson gratefully acknowledges both research salary support and laboratory support provided by the British Columbia Children's Hospital Foundation through the BC Children's Hospital Research Institute's IGAP Intramural Salary Award program, as well as various Childhood Diseases Theme and Diabetes Theme funding programs. Dr Gibson is also grateful for the operating funds provided competitively through various programs run by the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI), Genome Canada, and Genome British Columbia.

Dr Cohen would like to thank the generous gifts to Children's Mercy Research Institute and the Genomic Answers for Kids program at Children's Mercy Kansas City.

Revision History

• 8 May 2025 (sw) Comprehensive updated posted live
• 11 April 2019 (bp) Review posted live
• 8 April 2018 (wtg) Original submission

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