Clinical characteristics.

EBF3 neurodevelopmental disorder (EBF3-NDD) is associated with developmental delay (DD) / intellectual disability (ID), speech delay, gait or truncal ataxia, hypotonia, behavioral problems, and facial dysmorphism. Variability between individuals with EBF3-NDD is significant. Although all affected children have DD noted in early infancy, intellect generally ranges from mild to severe ID, with two individuals functioning in the low normal range. Less common issues can include genitourinary abnormalities and gastrointestinal and/or musculoskeletal involvement. To date, 42 symptomatic individuals from 39 families have been reported.

Diagnosis/testing.

The diagnosis of EBF3-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in EBF3 identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental delay / intellectual disability, speech delay, hypotonia and ataxia, behavioral issues, genitourinary abnormalities, gastrointestinal involvement, and musculoskeletal involvement are managed as per standard care.

Surveillance: Follow up of manifestations at each clinic visit.

Genetic counseling.

EBF3-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If a parent is known to have the EBF3 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the EBF3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Once the EBF3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

EBF3 neurodevelopmental disorder (EBF3-NDD) should be considered in individuals with the following clinical and brain MRI findings and family history.

Clinical findings include developmental delay (DD) or intellectual disability (ID) AND any of the following features presenting in infancy or childhood:

• Microcephaly
• Generalized hypotonia
• Feeding difficulties
• Genitourinary abnormalities such as micropenis, cryptorchidism, vesicoureteral reflux, renal anomalies
• Strabismus
• Speech delay, mainly expressive speech delay, dysarthria
• Ataxia
• High pain threshold or decreased pain sensitivity
• Behavioral anomalies including stereotypic movements (e.g., rotating movements, chewing on clothes, head retropulsion), perseverative social behavior, short attention span
• Facial dysmorphism. See Chao et al [2017] (full text; see Figure 1), Harms et al [2017] (full text; see Figure 1), Lopes et al [2017] (full text; see Figure 1), Sleven et al [2017] (full text; see Supplementary figure S3), Tanaka et al [2017] (full text; see Figure 2).

Brain MRI findings. The following MRI findings were observed in a smaller number of affected individuals:

• Cerebellar vermis hypoplasia (5 individuals) [Chao et al 2017, Harms et al 2017, Sleven et al 2017, Tanaka et al 2017]
• Cerebellar atrophy or hypoplasia (1 individual) [Ignatius et al 2020]
• Small inferior posterior cerebellar lobes and hypoplasia of the posterior vermis with mild prominence of the ventricles and sulci (1) [Chao et al 2017]
• Abnormal configuration of cerebellar folia arranged in radial shape (1) [D'Arrigo et al 2020]

Family history. Because EBF3-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of EBF3 neurodevelopmental disorder (EBF3-NDD) is established in a proband with suggestive findings and a heterozygous pathogenic variant in EBF3 identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous EBF3 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Clinical Description

EBF3 neurodevelopmental disorder (EBF3-NDD) is associated with developmental delay, intellectual disability, speech delay, gait or truncal ataxia, hypotonia, behavioral problems, and facial dysmorphism. Less common issues can include genitourinary abnormalities, gastrointestinal involvement, and/or musculoskeletal involvement.

To date, 42 symptomatic individuals from 39 families have been reported [Iossifov et al 2014, Blackburn et al 2017, Chao et al 2017, Eldomery et al 2017, Harms et al 2017, Sleven et al 2017, Tanaka et al 2017, Monies et al 2019, Beecroft et al 2020, D'Arrigo et al 2020, Harkness et al 2020, Hildebrand et al 2020, Husson et al 2020, Ignatius et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports (when information is available on these features).

Developmental delay (DD) and intellectual disability (ID). All affected individuals have developmental delay noted in early infancy. The severity of intellectual disability is highly variable (mild to severe). IQ is in low normal range for two individuals [Author, unpublished data]. Marked delay in speech (mostly in expressive speech) is common, though the severity of speech delay is also highly variable. Some individuals have articulation defects and dysarthria.

Other neurodevelopmental features. Hypotonia is generalized and present from early infancy. Gait ataxia or truncal ataxia is commonly observed. Frequent falls may be noted. Most affected individuals did not have seizures. Two individuals had febrile seizures [Harms et al 2017]. A single febrile seizure was reported in an additional individual [Sleven et al 2017].

Behavioral abnormalities. Short attention span and features of ADHD were seen in six individuals. Five individuals had decreased pain sensitivity or high tolerance to pain. Stereotypic behaviors were observed in two individuals. Affected individuals may have autistic features or pervasive behavioral abnormalities.

Genitourinary abnormalities include the following:

• Vesicoureteric reflux (4 individuals)
• Undescended testes (3)
• Bicornuate uterus (1 of 24 females)
• Neurogenic/atonic bladder (2 individuals)
• Renal dysplasia (1)
• Recurrent urinary tract infections

Gastrointestinal

• Gastroesophageal reflux disease (3 individuals)
• Dysphagia (3)
• Constipation (3)
• Cyclical vomiting with failure to thrive (1)

Musculoskeletal

• Syndactyly of second and third toe (2)
• Pectus excavatum (2)
• Bilateral talipes (2)
• Severe scoliosis in a mother and son that required corrective surgery (2)
• Scoliosis and severe hip and knee contractures (1)

Growth

• Short stature (3)
• Microcephaly (3)

Prognosis. It is unknown whether life span in EBF3-NDD is abnormal. One individual is alive at age 31 years, demonstrating that survival into adulthood is possible [Beecroft et al 2020].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

To date 42 individuals from 39 families with this disorder have been described (additionally, 2 mothers who are mosaic are asymptomatic). As it is a recently identified condition, exact prevalence is not known.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EBF3-NDD, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Ataxia and intellectual disability could result in frequent falls in childhood; supervision of patient activity at home is recommended to limit the risk.

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

EBF3 neurodevelopmental disorder (EBF3-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with EBF3-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo EBF3 pathogenic variant.
• Some individuals with EBF3-NDD have the disorder as the result of a pathogenic variant inherited from an affected parent [Beecroft et al 2020] or from an unaffected parent with somatic/germline mosaicism [Harms et al 2017, Sleven et al 2017, Ignatius et al 2020].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • 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 only in the germ cells.)
    Maternal somatic/germline mosaicism has been reported [Harms et al 2017, Ignatius et al 2020]. In one family two affected sibs had a heterozygous pathogenic variant in EBF3 but the pathogenic variant was not identified in parental leukocyte DNA [Sleven et al 2017]
    * A parent with somatic and germline mosaicism for an EBF3 pathogenic variant may be mildly/minimally affected.

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

• If a parent is known to have the EBF3 pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
• If the EBF3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Harms et al 2017, Sleven et al 2017].

Offspring of a proband. Each child of an individual with EBF3-NDD has a 50% chance of inheriting the EBF3 pathogenic variant.

Other family members. Given that most probands with EBF3-NDD reported to date have the disorder as a result of a de novo EBF3 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 young adults who are affected and parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the EBF3 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 may be helpful.

Molecular Pathogenesis

EBF3 encodes early B cell factor 3 (EBF3), one of four members of the EBF transcription factor family, involved in neuronal differentiation and maturation [Dubois & Vincent 2001, Pozzoli et al 2001].

Mechanism of disease causation. Missense variants affect the DNA binding domain of EBF3. Additional EBF3 pathogenic variants include nonsense, splice, frameshift, and in-frame duplication. Both dominant negative and loss-of-function mechanisms are discussed [Chao et al 2017, Harms et al 2017, Sleven et al 2017].

Acknowledgments

The authors acknowledge the Indian Council of Medical Research for supporting this work (63/01/2019-Genomics/BMS titled IMCR Virtual Centre for Molecular Medicine with focus on Rare Genetic Disorders).

Revision History

• 6 May 2021 (bp) Review posted live
• 1 February 2021 (kmg) Original submission

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