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. To date, EED-related overgrowth has been reported in eight individuals.

Diagnosis/testing.

The diagnosis of EED-related overgrowth is established in a proband with suggestive findings and a heterozygous germline EED pathogenic variant 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 inherited in an autosomal dominant manner. To date all probands whose parents have undergone molecular genetic testing have the disorder as a result of a de novo EED pathogenic variant. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the EED pathogenic variant found 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. Once a family member has a confirmed molecular diagnosis of EED-related overgrowth, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

EED-related overgrowth should be suspected in individuals with the following major findings.

Clinical findings

Overgrowth manifesting as:

• Tall stature (Z-score ≥2 for age, equivalent to SD ≥2)
  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 radiographs

• Advanced bone age (bone age ≥2 chronologic age)
• 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 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: 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 (see Figure 1). 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), and Griffiths et al [2019] (full text; see Figure 1).

Figure 1.

Photographs of an affected male 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 forehead, (more...)

Establishing the Diagnosis

The diagnosis of EED-related overgrowth is established in a proband with suggestive findings and a heterozygous germline EED pathogenic (or likely pathogenic) variant identified by 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 gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, 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 (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 (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) and intellectual disability that ranges from mild to severe. See Figure 1 for photographs of one individual from age one day to 33 years.

To date, EED-related overgrowth has been reported in eight 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].

Prenatal growth. 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 4,800 g (female, 36 weeks' gestation [Cooney et al 2017]) 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 34 cm (Z-score -0.78) to 37.2 cm (Z-score +2.0).

Postnatal growth. During childhood and adolescence, increased height, weight, and head circumference manifest as increased Z-scores in height (+2.8 to +5.1), weight (+1.4 to +3.8), and head circumference (+2.0 to +2.6). 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.

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 development. 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. The voice may be hypernasal, low, or hoarse.

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

Skeletal. Large hands and feet are notable in childhood and into adulthood. Fingers may be long and slender. Broad thumbs and small nails were seen in two individuals.

Camptodactyly, joint contractures, flat feet (pes planovalgus), and/or clubfoot may be seen.

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

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

Stenosis of the cervical spine has been reported in two individuals, one of whom required laminectomy and arthrodesis; the other had associated myelopathy at the level of the third cervical vertebra.

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

Skeletal findings reported in one individual each:

• Atlantoaxial instability requiring surgical intervention after neurologic compromise
• Above-knee amputation as a result of vascular circulatory failure following patellar surgery

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

Epilepsy has been reported in one individual; a second had seizures associated with hyperinsulinemic hypoglycemia (see Endocrine in this section).

Cerebral imaging has shown nonspecific enlargement of the ventricles in one individual and moderate-to-severe thinning of the corpus callosum and loss of white matter (disproportionately affecting the frontal lobe) in another; both had moderate intellectual disability. Cerebral imaging has also been normal in several individuals.

Skin findings have included the following:

• Multiple pigmented nevi (2 individuals)
• Soft, doughy skin with increased elasticity (1 individual)
• 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. Structural cardiac anomalies (patent ductus arteriosus, septal defects, and mild or moderate mitral valve prolapse) have been reported.

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

One female had nephromegaly and a duplicated collecting system.

Ophthalmologic. Ocular findings have included hypertelorism, telecanthus, hyperopia, myopia, exotropia, astigmatism, and strabismus. Narrow and/or short palpebral fissures with a downslant 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)

Hearing loss

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

Respiratory. Neonatal respiratory distress may be seen. One individual had significant tracheomalacia requiring surgical intervention, as well as frequent respiratory infections.

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)

Endocrine

• Neonatal hyperinsulinemic hypoglycemia was treated by glucose infusion and resolved at 21 days (1 individual).
• Childhood-onset hyperinsulinemic hypoglycemia was treated with octreotide (1 individual).

Cancer predisposition. No instances of benign or malignant tumors in individuals with germline EED pathogenic variants have been reported to date. The risk for certain cancers, such as hematologic cancers and malignant peripheral nerve sheath tumors, could theoretically be increased (see Molecular Genetics).

Genotype-Phenotype Correlations

With only eight 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 eight individuals have been reported with EED-related overgrowth.

Ancestry has included Turkish [Cohen et al 2015], European American [Cohen & Gibson 2016], Hispanic American [Cooney et al 2017], Japanese [Imagawa et al 2017], and Polish [Smigiel et al 2018]. Three individuals were identified in a UK international consortium [Tatton-Brown et al 2017, Griffiths et al 2019].

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 3 (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. The appropriate interventions are summarized in Table 4.

Surveillance

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] (see Molecular Genetics, Cancer and Benign Tumors) 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 the PRC2 complex (which includes the protein EED) may be increased; also the efficacy 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 inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• All 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.
• 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.
• 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. 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 the EED pathogenic variant found 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].

Offspring of a proband. To date, individuals with EED-related overgrowth are not known to reproduce.

Other family members. Given that all probands with EED-related overgrowth (in whom parental samples have been analyzed) have the disorder as a result of a de novo EED pathogenic variant, the risk to other family members is presumed to be low.

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 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 may be helpful.

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 PCR2 alterations in MPNSTs and other cancers that included somatic variants in EED.

Author Notes

Dr 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.

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.

Revision History

• 11 April 2019 (bp) Review posted live
• 8 April 2018 (wtg) Original submission

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