Pitt-Hopkins syndrome (PTHS) is a rare genetic condition that primarily affects brain development and the nervous system. It is characterised by significant developmental delay, intellectual disability, limited speech, distinctive facial features and, in many people, episodes of abnormal breathing. Other features can include epilepsy, constipation, sleep difficulties, vision problems and characteristics associated with autism spectrum disorder.
What causes Pitt-Hopkins syndrome?
Pitt-Hopkins syndrome is caused by a change in a gene called TCF4, located on chromosome 18. The TCF4 gene provides instructions for making a protein called transcription factor 4. This protein helps regulate the activity of other genes, including genes that are important for the development and function of the nervous system. When one working copy of TCF4 is not sufficient, normal brain development and neurological function can be affected.
Most people with Pitt-Hopkins syndrome have a new (de novo) genetic change that has occurred for the first time in them. This means their parents generally do not have the genetic change and the condition has not been inherited from either parent. Rarely, however, a TCF4 change can be inherited, including from a parent who has mosaicism for the variant.
What are the features of Pitt-Hopkins syndrome?
Children with Pitt-Hopkins syndrome usually have developmental delays from early childhood. Motor milestones such as sitting and walking may be delayed, and muscle tone may be reduced. Speech and language development is particularly affected. Many individuals do not develop functional spoken language, although their ability to understand language can be considerably stronger than their ability to communicate verbally. Alternative and augmentative communication can therefore be extremely important.
Distinctive facial features are also common, although these may become more recognisable as a child gets older. Other features can include frequent smiling or laughter, hand-flapping or other repetitive movements, anxiety and autistic characteristics.
One of the more distinctive features of Pitt-Hopkins syndrome is abnormal breathing. Some individuals experience episodes of rapid breathing (hyperventilation), sometimes followed by breath-holding or periods of reduced breathing. These episodes can be triggered by excitement or anxiety. Not everyone with Pitt-Hopkins syndrome develops breathing abnormalities, however, so their absence does not exclude the diagnosis.
Epilepsy, constipation, feeding difficulties, sleep problems, short stature, severe myopia and strabismus can also occur. The range and severity of features varies between individuals.
How is Pitt-Hopkins syndrome diagnosed?
A diagnosis is confirmed through genetic testing. Testing may identify a pathogenic variant within the TCF4 gene, or a deletion involving TCF4 on chromosome 18. Gene sequencing, deletion/duplication analysis and chromosomal microarray may therefore all have a role depending on the clinical circumstances.
Because Pitt-Hopkins syndrome can overlap with other neurodevelopmental conditions, genetic testing can provide an important explanation for a child’s developmental differences and help guide appropriate medical and developmental care.
What does the future look like?
There is currently no cure for Pitt-Hopkins syndrome, but supportive therapies can make an important difference. Management may involve speech and communication therapy, physiotherapy, occupational therapy, developmental support, neurological care for epilepsy, and management of gastrointestinal, respiratory, vision and sleep difficulties. Regular review helps ensure that care changes as the person’s needs change.
For families, receiving a genetic diagnosis can provide answers to longstanding questions and help them access appropriate support. Genetic counselling can also explain what the diagnosis means for other family members and discuss reproductive options, including prenatal and preimplantation genetic testing where appropriate.
At Rosalind Genetics, we provide genetic counselling to help families understand genetic diagnoses and make informed decisions about testing and ongoing care.
