Clinical Characteristics

ZFHX-associatedsyndrome is a rare cause of developmental delay and intellectual disability (ID). The first description of this gene being associated with problems in humans was in 2011. Since then, only a few cases have been recognized affecting males and females. People with ZFHX4-associated syndrome have a characteristic (and sometimes subtle) facial appearance, and variable degrees of developmental delay, learning difficulties and behavioral difficulties. Other features seen in some affected individuals include low muscle tone (hypotonia), visual problems, cleft lip or palate and skeletal abnormalities.

The medical problems a person with ZFHX4-associatedsyndrome will have, can be very variable and difficult to predict. However, there are some common problems that could be observed in affected individuals.

Growth parameters
People with ZFHX4­-associated syndrome have difficulties with development and learning. The degree of how severely a child is affected is variable but most children have mild-moderate learning disabilities. There are some children who have no learning or development difficulties. Some children may have speech delay and/or motor development delay.

Neurological features
In about one out of three of the people with ZFHX4-associated syndrome some abnormalities are seen on a brain MRI scan. These can be diverse but include underdevelopment of the corpus callosum (the band of nerve fibers between the two sides of the brain), enlarged ventricles (the ventricles are the fluid-filled parts of the brain), and disorders affecting normal ridges in the brain’s outer layer (abnormal gyration).

Neuropsychological features
People with ZFHX4-associated syndrome may have behavioral difficulties such as repetitive behavior, sleep disturbance, overfriendliness, anxiety and autism/autistic traits. Imbalance and seizures are also described in some individuals. Low muscle tone (hypotonia) is often present. This can result in a delay in reaching certain developmental milestones such as rolling, sitting, crawling and walking. It may also contribute to the feeding difficulties seen in some children.

Visual and hearing impairments
Eyes may be involved with astigmatism (the front of the eye is not perfectly rounded, causing blurry vision). Some children have poor vision so this should be tested. Mostly this is seen to be due to a refractive error (i.e. long or short sighted) which is easily correctable with glasses. Strabismus, where the eyes do not look in the same direction, is frequent. Other common visual problems include nystagmus (uncontrolled eye movement), sclerocornea (an anomaly of the eye in which the cornea blends with sclera resulting in corneal opacity), a small cornea or microcornea, a clouding of the lens in the eye (cataracts), and Peters anomaly (an eye problem that occurs in an area at the front part of the eye known as the anterior segment that can lead to an opaque cornea causing blurred vision). Some individuals develop “lazy eye” (amblyopia). There have been a couple of children identified as having ‘cortical visual impairment’ which means the brain has difficulty processing images or individuals have unusually small eyeballs (microphthalmia).

Hearing problems have been noted in a minority of people. If you have any doubt about your child’s hearing ability, this should be tested.

Cardiovascular defects
A small proportion of people with a ZFHX4 change have heart problems, most commonly septal defects (holes between the chambers of the heart) or a condition characterized by obstruction of blood flow from the right ventricle to the pulmonary artery (pulmonary stenosis). In young children heart screening is therefore recommended.

Immune system defects
Frequent infections have been found in some children with ZFHX4 syndrome, though no confirmed abnormalities of the immune system have been reported. At the moment, there is no clinical evidence to support taking extra precautions to prevent infections.

As we identify more children and adults affected by ZFHX4-associated syndrome, we hope to better understand the syndrome and its affects.