Beck–Fahrner syndrome, also known as BEFAHRS and TET3 deficiency, is a rare genetic disorder caused by mutations of the TET3 gene. It can occur de novo or can be inherited in an autosomal dominant manner. Mutations in the TET3 gene disrupts DNA demethylation (an epigenetic mechanism) during early embryogenesis and neural development. Most common clinical presentation includes global developmental delay, psychomotor retardation, neurodevelopmental disorders, hypotonia, epilepsy and dysmorphic features. It is diagnosed using molecular and genetic testing in setting of typical symptoms. Management is supportive and intended to improve quality of life.
Signs and symptoms
Beck–Fahrner syndrome is also known as "BEFAHRS", which is a mnemonic for its most common features: behavioral differences, epilepsy, facial features, autistic features, hypotonia, retardation of psychomotor development, and size differences.
Global developmental delay is the most common symptom with psychomotor retardation, speech delay, disrupted fine and gross motor skills. Intellectual disability and learning disability are often present, sometimes concurrently. Over two-thirds of affected individuals have autism spectrum disorder or social communication disorder. Attention deficit hyperactivity disorder, obsessive–compulsive tendencies, anxiety, depression and psychosis have also been noted.
Neurodevelopmental anomalies, motor and movement disorders such as hypotonia (most common), dystonia, spasticity, tic disorder, myoclonus, dysmetria and abnormal posturing have been observed with varying intensity and frequency. Epilepsy affects over one-third individuals with Beck–Fahrner syndrome; generalized tonic-clonic seizures, complex partial seizures, absence seizures, epileptic spasms and electrical status epilepticus during slow-wave sleep have been seen. Neuroimaging yields non-specific findings in some cases, such as ventriculomegaly, periventricular leukomalacia, cerebellar hypoplasia and agenesis of the corpus callosum.
Craniofacial abnormalities include myopathic facies, long face syndrome sometimes with wide forehead, brachycephaly, protruding ear, epicanthic folds, downslanted palpebral fissures, short nose with long philtrum, asymmetrical jaw, open-mouth appearance, high-arched palate, cleft lip and cleft palate. Musculoskeletal abnormalities such as kyphosis, scoliosis, joint hypermobility, hip dysplasia, pes planus and inguinal hernia have been reported. Individuals that exhibited overgrowth sometimes had macrocephaly and tall stature; one such case also had concurrent nephromegaly and cardiomegaly. Undergrowth, when present, is associated with microcephaly and short stature.
Strabismus is the most commonly seen ophthalmologic abnormality. Ophthalmoplegia, nystagmus, ptosis, myopia, hyperopia, microphthalmia and lacrimal duct stenosis can also occur. Otologic involvement can result in sensorineural hearing loss, conductive hearing loss and microtia. Congenital heart defects such as tetralogy of Fallot, pulmonic stenosis, aortic insufficiency and ventricular septal defect have been reported. Infants with Beck–Fahrner syndrome can experience feeding difficulties and constipation. One case of associated pyloric stenosis has been seen. Hypospadias and cryptorchidism have been observed.
Genetics
TET3 gene encodes for Tet methylcytosine dioxygenase 3 (TET3) which—similar to other TET enzymes—helps in mediating active DNA demethylation. TET3 catalyzes oxidative reaction of converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is an intermediate step in DNA demethylation and hypothesized to be essential for neural development. TET3 is expressed in embryonic stem cells, where it helps in sustaining neural stem cells and terminal differentiation of neurons.
Beck–Fahrner syndrome is caused by homozygous, heterozygus or compound heterozygous mutations in the TET3 gene on chromosome 2 (2p13.1). Nonsense, missense or frameshift mutations of the TET3 gene results in disruption of DNA demethylation during early embryogenesis and development of the nervous system. It can occur de novo (genetic mutations occurring for the first time) or it can be inherited in an autosomal dominant manner with variable expressivity and hypomorphic alleles. Some individuals affected with Beck–Fahrner syndrome have biallelic variants, which may indicate a possibility for autosomal recessive inheritance as well. However, their family histories and DNA methylation profiling have been consistent with an autosomal dominant mode of inheritance.