• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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Beck-Fahrner Syndrome

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Last updated: 7/10/2024
Years published: 2024


Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for assistance in the preparation of this report.


Disease Overview

Beck-Fahrner syndrome (BEFAHRS) is a very rare genetic condition characterized by intellectual disability and global developmental delay associated with other features.1,2

The other additional signs and symptoms may include low muscle tone (hypotonia), feeding difficulties, movement disorders, seizures, neurobehavioral problems, vision problems, hearing loss, facial differences and growth differences including an increased head size (macrocephaly) or decreased head size (microcephaly). Less common symptoms include heart problems that are present at birth (congenital heart defects), brain malformations and genital and urinary differences.1

Beck-Fahrner syndrome is caused by changes (disease-causing variants) in the TET3 gene.1,2 BEFAHRS follows autosomal dominant inheritance in most patients.1,2

The diagnosis is suspected based on signs and symptoms and confirmed with a genetic test. There is no cure for Beck-Fahrner syndrome. However, a diagnosis allows for appropriate monitoring and treatment of associated symptoms.1

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Synonyms

  • BEFAHRS
  • TET3-BEFAHRS
  • TET3 deficiency
  • TET3-related Beck-Fahrner syndrome
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Signs & Symptoms

The BEFAHRS abbreviation can be used for the most common features: Behavioral differences, Epilepsy, common Facial features, Autistic features, Hypotonia, Retardation of psychomotor development and Size differences.1

The onset, progression and severity of symptoms can differ from person to person. Not everyone with this syndrome will have all the symptoms described below. The signs and symptoms that have been reported include:1,2

  • Developmental delay / intellectual disability (the most common finding), ranging from mild to severe (most affected people can speak and most can walk by age 15-36 months)
    • Intellectual disability can be mild
      • Some affected people only have learning difficulties
    • Developmental delay is often global, meaning that two or more areas are affected, including gross motor, such as walking, fine motor, such as writing and/or speech
  • Other neurodevelopmental features
    • Low muscle tone (hypotonia) that can worsen mobility and speech problems
    • Feeding difficulties, which in some people have required nasogastric or gastrostomy tube feeding
    • Usual muscle tightness (spasticity)
    • Movement disorders, including motor tics, uncontrolled and quick muscle twitches (myoclonic jerks), difficulty controlling the speed, distance and range of movements (dysmetria), abnormal posture and movement disorder that causes the muscles to contract involuntarily (dystonia)
  • Epilepsy (in about one third of patients) with different types of seizures
  • Behavioral and psychiatric problems (in many patients) such as:
    • Autistic features
    • Anxiety
    • Attention-deficit/hyperactivity disorder (ADHD)
    • Depression
    • Aggressive behavior
  • Cranial and facial features (in about 21-23% of patients)
    • Cranial problems
      • Large head size (macrocephaly) in some patients
      • Small head size (microcephaly) in a few patients
      • Flat back of the head (brachycephaly)
    • Facial features
      • Long face
      • Expressionless face with sunken cheeks, droopy eyelids (bilateral ptosis) and inability to elevate the corners of the mouth due to muscle weakness (myopathic face)
      • Broad forehead
      • Flat vertical groove between the nose and upper lip (smooth philtrum)
      • Ears that stick out more than usual
      • Skin of the upper eyelid that covers the inner corner of the eye (epicanthal folds)
      • Downward slanting eyes
      • Thick eyebrows
      • Short nose
      • Open mouth
      • High-arched palate
    • Vision problems (in about 50% of patients)
      • Misalignment of the eyes (strabismus) (most common)
      • Farsightedness (hyperopia)
      • Nearsightedness (myopia)
      • Abnormal eye movements (nystagmus)
      • Droopy eyelids (ptosis)
    • Hearing loss
    • Musculoskeletal features including the following:
      • Joints with large range of motion (joint hypermobility or laxity)
      • Hip socket that doesn’t fully cover the ball portion of the upper thighbone (hip dysplasia in infancy)
      • Abnormal curvature of the spine (scoliosis)
    • Growth abnormalities
      • Overgrowth (in some patients)
      • Poor growth (in some patients)
    • Brain abnormalities, such as:
      • Large brain ventricles (ventricles are cavities in the brain that make and store cerebrospinal fluid)
      • Absence of the brain structure that connect the left and right cerebral hemispheres (corpus callosum)
      • Small cerebellum (the cerebellum controls complex motions like walking and standing)
    • Other associated features
      • Stomach and intestinal problems
      • Heart and vascular anomalies
      • Genital and urinary anomalies.
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Causes

Beck-Fahrner syndrome is caused by changes (disease-causing variants) in the TET3 gene. The TET3 gene provides instructions to make the TET3 protein. The TET3 protein is very important for the brain to develop and mature normally and for the function of cells in the brain (neuronal function). In Beck-Fahrner syndrome, a disease-causing variant in the TET3 gene may make a TET3 protein that does not work correctly or can result in not enough of the protein to be made, ultimately disrupting normal development and causing health problems.1

Beck-Fahrner syndrome is a Mendelian disorder of the epigenetic machinery (MDEM), also known as chromatinopathy. All the MDEM disorders are caused by disease-causing variants in genes that provide the instructions for proteins involved in gene regulation through epigenetics.2-5

DNA (deoxyribonucleic acid) is the molecule that carries the body’s genetic information. Chromatin consists of the mixture of DNA and histone proteins. The histone proteins pack the DNA into a highly compact form that can fit in the cell nucleus. Epigenetics refers to chemical markers added to chromatin (DNA or histones) that turn genes on or off without changing the DNA sequence.3,6-7

The MDEM genes are involved in adding, removing, or interpreting these chemical marks on DNA that affect how genes work. Beck-Fahrner syndrome involves problems with the genes that remove (erase) these marks (it is considered a disorder of the “DNA methylation eraser system”). Erasing these marks can lead to the various symptoms of the disease, but understanding exactly how these changes affect the different tissues in the body, such as the brain, is still unknown.1,3

Inheritance

Inheritance is autosomal dominant with variable expressivity.1 Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) altered gene in the affected person. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition.

A parent with an autosomal dominant condition has a 50% chance of having a child with the condition. This is true for each pregnancy and for both males and females. Children who do not inherit the gene variant will not develop or pass on the disease. If someone is diagnosed with an autosomal dominant disease, their parents should also be tested for the gene variant.

There are a few reports of affected children who have two disease-causing variants of the TET3 gene, one inherited from each parent, who both have milder features of the syndrome. In these families, inheritance may be autosomal recessive, but this is not confirmed yet, and it is thought that in most families, inheritance is autosomal dominant .1,8,9   An autosomal recessive disorder means two copies of disease-causing variants must be present for the disease to develop.

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Affected populations

Beck-Fahrner syndrome (BEFAHRS) was recently described, and it is very rare. As of 2023, there were 28 individuals from 16 families who were reported in published medical reports with disease-causing variants in TET3.2 It is thought that there are more people affected with Beck-Fahrner syndrome who remain undiagnosed or are misdiagnosed with other disorders.

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Diagnosis

Beck-Fahrner syndrome may be suspected when a young child has mild-to-severe developmental delay or intellectual disability AND any of the following features:1

  • Generalized hypotonia of infancy
  • Infant feeding difficulties
  • Movement disorders
  • Seizures
  • Psychiatric/behavioral problems
  • Growth problems
  • Eye problems
  • Muscular and skeletal problems
  • Cranial or facial features described in the syndrome.

The diagnosis is established with the identification of a disease-causing variant in the TET3 gene by genetic testing.1

Once the disease-causing variant in the TET3 gene has been identified in an affected family member, prenatal and preimplantation genetic testing (PGT) are possible. PGT is an early form of prenatal genetic diagnosis where embryos can be tested for disease-causing gene variants, and only embryos without disease-causing variants are used for implantation.2

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Standard Therapies

Treatment

There is currently no cure or specific guidelines for the treatment of Beck-Fahrner syndrome (BEFAHRS). Treatment is directed at improving the symptoms that the affected person has and to increase their quality of life.1

Supportive care to improve quality of life, maximize function and reduce complications is recommended.1 The best management ideally involves several specialists who work together as a team. The team may include pediatricians, neurologists, psychiatrics, orthopedists, ophthalmologists, gastroenterologists and others. One of the team’s doctors should coordinate all healthcare needs.

After the diagnosis, the recommended evaluations include:1

  • Assessment of growth problems
  • Neurologic evaluation, including brain images and electroencephalogram (EEG) to measure the brain activity
  • Orthopedics/physical medicine and rehabilitation with physical therapy and occupational therapy evaluation to assess motor delays and mobility and to determine specific needs
  • Developmental evaluation including cognitive and speech evaluation, behavioral and psychiatric evaluation
  • Other evaluations as needed, such as gastrointestinal evaluation for feeding difficulties and/or ophthalmologic evaluation for vision problems and/or evaluation of hearing problems
  • Genetic counseling for the family

All the symptoms are treated the same way as in the general population.  For example, seizures are treated with anti-seizure medication as needed. Treatment for movement disorders may include physical medicine and rehabilitation and treatment for feeding difficulties may require the placement of a feeding tube.1

Early intervention is recommended for children with intellectual disability and developmental delay.

It is important for parents and caregivers to learn about common seizure presentations. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Physical therapy is recommended to maximize mobility and reduce the risk for later-onset orthopedic complications such as scoliosis and hip dislocation. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing and writing.1

A psychologist and a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD) when necessary. Serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.1

It is not known if people with BEFAHRS have a decreased life expectancy, but the condition is not progressive, meaning it does not get worse over time.1,2

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Fahrner JA. TET3-Related Beck-Fahrner Syndrome. 2023 May 18. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK591837/ Accessed July 9, 2024.

2. Levy MA, Beck DB, Metcalfe K, et al. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood [published correction appears in NPJ Genom Med. 2021 Nov 24;6(1):100. doi: 10.1038/s41525-021-00269-7]. NPJ Genom Med. 2021;6(1):92. Published 2021 Nov 8. doi:10.1038/s41525-021-00256-y https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576018/

3. Fahrner JA, Bjornsson HT. Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states. Annu Rev Genomics Hum Genet. 2014;15:269-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406255

4. What is epigenetics? MedlinePlus. June 11, 2021. https://medlineplus.gov/genetics/understanding/howgeneswork/epigenome/ Accessed July 9, 2024.

5. Di Fede E, Grazioli P, Lettieri A, et al. Epigenetic disorders: Lessons from the animals-animal models in chromatinopathies. Front Cell Dev Biol. 2022 Sep 26;10:979512. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9548571/

6. Chromatin. National Human Genome Research Institute. May 4, 2024. https://www.genome.gov/genetics-glossary/Chromatin Accessed July 9, 2024.

7. Methylation. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/methylation Accessed July 9, 2024.

8. Beck-Fahrner syndrome (BEFAHRS). Online Mendelian Inheritance in Man (OMIM). April 12, 2024. https://omim.org/entry/618798 Accessed July 9, 2024.

9. Beck DB, Petracovici A, He C, et al. Delineation of a human Mendelian disorder of the DNA demethylation machinery: TET3 deficiency. Am J Hum Genet. 2020;106(2):234-245. doi:10.1016/j.ajhg.2019.12.007 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010978/

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