WHAT IS CTNNB1 SYNDROME?
CTNNB1 Syndrome is a severe neurodevelopmental disorder caused by disruption of chromosome 3p22.1 of the CTNNB1 gene (Verhoeven et al. 2020). It is a recently discovered condition associated with developmental delay, intellectual disability and speech delay. The first cases of CTNNB1 syndrome were reported in 2012, so there are probably many more undiagnosed cases living with this disease. Recent studies report that the CTNNB1 gene is the most common cause of misdiagnosed cerebral palsy cases (Jin et al. 2020; Moreno-De-Luca et al. 2021).
CTNNB1 Syndrome affects 1 out of 50.000 children worldwide (Chung for ACCT, 2019). It is inherited in an autosomal dominant pattern, meaning only one copy of a gene variant is needed in order to express an observable phenotype. CTNNB1 syndrome occurs when one of the two copies of the CTNNB1 gene has lost its normal function. It usually occurs de novo, meaning that it was not inherited from parents.
CTNNB1 is important in the development and maturation of the brain and de novo mutations cause learning and memory problems. This is why CTNNB1 syndrome is primarily associated with developmental delay/intellectual disability.
De novo loss-of-function mutations in CTNNB1 gene are causative for Neurodevelopmental Disorder with Spastic Displegia and Visual Defects (NEDSDV) and Familial Exudative Vitreoretinopathy (FEVR). FEVR is a dominant disorder characterized by the incomplete development of the retinal vasculature. NEDSDV is a neurodevelopmental disorder characterized by global developmental delay, impaired intelectual development with absent or very limited speech, craniofacial anomalies features with microencephaly, axial hypotonia, and spasticity (Verhoever et al. 2020; Kuechler et al. 2015).
WHAT ARE THE SYMPTOMS?
Axial Hypotonia and Peripheral Spasticity
Most babies are born with low muscle tone, which often leads to motor delays and feeding problems. Some babies also develop spasticity in their arms and legs. This may lead to scoliosis, foot deformities and heel cord tightness.
Microencephalic or small head size
The majority of children have microencephaly or a small head size. Usually microencephaly is diagnosed at birth or even during pregnancy. It can also be developed later in the first year of life.
Eyes and eyesight
Most patients have eye and eyesight problems, which are quite varied and can include strabismus, longsightedness, nearsightedness, or more serious conditions, such as retinal atrophy or FEVR.
The majority of patients have normal brain MRI scans. A minority showed changes including dilated ventricles [fluid-filled parts] of the brain, underdevelopment of the corpus callosum [the band of nerve fibres between the two sides of the brain] and brainstem, abnormal wrinkles and folds on the surface of the brain, and/or delayed myelination (www.rarechromo.org). EEG is in most cases normal (no epilepsy).
A recent study published in JAMA Cardiology showed an increased frequency of CTNNB1 LoF variant in congenital heart disease (Morton et al. 2020).
GROWTH AND DEVELOPMENT
Babies are usually a normal length at birth and most have a normal birth weight. Half of the babies have a small head circumference at birth. Head growth often lags behind and eventually most children have a below average head circumference. Height and weight are mostly normal (www.rarechromo.org).
Sitting and walking
Most children show significant delay in reaching motor milestones. Based on a systematic review from Kharbanda et al. (2017) children sit unsupported at 17 months, and if walking – they start on average at 30 months. Only 40% of children can walk without support. They often walk on tiptoes and can have a broad-based or unsteady [ataxic] walking. Most people need the support of a walker frame, or are not able to walk (www.rarechromo.org).
Some children are able to use full sentences, some only simple sentences, some speak only a few words, and there are others who are not able to speak. Patients using full sentences were usually only mildly delayed; if speaking simple sentences, first words were spoken on avarege at 4 years; if speaking single words, first words occured at 14 years. Understanding is usually much better than speaking.
Most children have some form of autistic features. Although the majority of children generally have a friendly disposition, about half have behaviour problems, which can include sleep problems, ADHD [attention deficit and hyperactivity], and aggression to others or themselves (www.rarechromo.org)