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 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 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
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).