TET3-Related Beck-Fahrner Syndrome

Clinical characteristics: TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is a condition within the spectrum of mendelian disorders of the epigenetic machinery (MDEMs) or chromatinopathies. Clinical features typically include intellectual disability / developmental delay ranging from mild to severe affecting both motor and language skills. Most affected individuals are verbal and ambulatory, with most walking by age 15-36 months. Hypotonia in infancy and childhood can exacerbate motor and expressive speech delay and, in some cases, cause feeding difficulties that require nasogastric or gastrostomy tube feeding. Some affected individuals display movement disorders. About one third of affected individuals have epilepsy. Other neurobehavioral features can include autism, anxiety, and attention-deficit/hyperactivity disorder. Strabismus and refractive errors are found in about half of affected individuals. Both conductive and sensorineural hearing loss have been observed. Approximately half of individuals exhibit typical growth and half exhibit growth abnormalities, with overgrowth being more common than undergrowth and macrocephaly being the most common manifestation of altered growth. While many affected individuals have dysmorphic features, these are typically nonspecific. Congenital heart defects, brain malformations, and genitourinary anomalies are less common findings.

Diagnosis/testing: The diagnosis of TET3-BEFAHRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in TET3 identified by molecular genetic testing. DNA methylation profiling can help confirm variant pathogenicity.

Management: Treatment of manifestations: Standardized treatment with anti-seizure medication (ASM) by an experienced neurologist; feeding therapy; gastrostomy tube placement may be required for persistent feeding issues; pressure-equalizing tubes for conductive hearing loss; hearing aids for sensorineural hearing loss; standard treatment for constipation, musculoskeletal issues, refractive error, strabismus, nystagmus, behavioral issues, developmental delay / intellectual disability, congenital heart defects, and genitourinary anomalies.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status and safety of oral intake; assessment for new manifestations, such as seizures and changes in tone; monitoring of developmental progress and educational needs; behavioral assessment; assessment for signs and symptoms of constipation; assessment of mobility and self-help skills; clinical evaluation for kyphosis and/or scoliosis. At least annually: complete ophthalmology evaluation and audiology evaluation.

Pregnancy management: Exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling: TET3-BEFAHRS is an autosomal dominant disorder. Most probands have a de novo pathogenic variant, though inherited variants have been reported. Rarely, affected individuals can have biallelic pathogenic variants inherited in trans from heterozygous parents who have milder features of TET3-BEFAHRS. This is now thought to represent autosomal dominant inheritance with variable expressivity as opposed to autosomal recessive inheritance. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If one parent of the proband has a TET3 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and being affected is 50%. If both parents of a proband have a TET3 pathogenic variant, sibs have a 75% chance of inheriting one or two pathogenic variants and being affected and a 25% chance of inheriting neither pathogenic variant and not being affected. Once the TET3 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.