Pitt-Hopkins Syndrome is a poorly understood and rare genetic disorder. It is usually inherited at random as a new genetic mutation and leads to a series of neurological symptoms. Some experts refer to this syndrome as a severe autism spectrum disorder. 

Pitt-Hopkins Syndrome can first be seen in newborns and infants. Its hallmark symptoms include distinct facial features, moderate to severe intellectual disability, delay in achieving child development milestones and more. Read below for more details on the genetic causes, symptoms, treatments and future research of this disorder. 

Introduction

Pitt-Hopkins Syndrome, or PTHS, is a rare genetic condition characterised by developmental delay, intellectual disability, distinctive facial features and breathing abnormalities. Pitt-Hopkins Syndrome is sometimes associated with autism spectrum disorder, due to the overlapping symptoms of neurodevelopmental delay, social and intellectual disability and an increased tendency to epilepsy.¹

It is impossible to know the exact number of individuals with Pitt-Hopkins Syndrome due to the symptom overlap with other disorders, and the fact that it can only be accurately diagnosed with genetic testing. In literature, it is estimated that the incidence of Pitt-Hopkins syndrome ranges anywhere from 1 in 34,000 to 1 in 300,000. The known total number of people with this disorder worldwide is only in the hundreds.^2,3,4

Pitt-Hopkins Syndrome can be inherited from a parent who has this disorder, but it usually arises as a random new mutation.⁵

Causes and genetics

Pitt-Hopkins syndrome is caused by a genetic mutation that occurs when a fetus develops. It involves the deletion or other mutation of a gene called the TCF4 gene on human chromosome 18. The TCF4 gene is responsible for making a transcription factor, a protein which is responsible for regulating the making of other proteins. This specific transcription factor (transcription factor 4) is required for normal development and is associated with the development of the central nervous system (the brain and spinal cord) as well as its maintenance in maturity.⁶ Besides this, the TCF4 gene is also associated with the eyes, gut and muscles.³

This genetic mutation usually occurs de novo, which means that it happens at random without being inherited from the parents. However, this disorder is regarded as being autosomal dominant. This means that if one parent carries the gene, it will be passed on to the offspring. The reason why this disorder is not treated as an inherited disorder is that, typically in cases of severe intellectual disability, as seen with Pitt-Hopkins syndrome, individuals do not procreate.⁷

The TCF4 gene is considered a big gene, and Pitt-Hopkins syndrome can be a result of a mutation at many different sites of this gene. This means that this disorder exists on a spectrum with many different severities, which further complicates its diagnosis and research.⁶

Key symptoms and characteristics

Physical 

The first signs of Pitt-Hopkins syndrome are observable in newborns and infants. Those who suffer from it have distinct facial features, such as:^3,8,9,10

• Wide mouth and upper jaw (palate)
• Wide Cupid’s bow
• Protruding philtrum
• Abnormally small head (microcephaly)
• Deep-set eyes
• Squared forehead
• Wide or beaked nose bridge
• Decreased muscle tone (hypotonia)
• Clubbed fingers and toes
• Widely spaced teeth

Developmental 

Pitt-Hopkins syndrome is a neurological disorder, meaning that it affects the brain. This leads to a range of delays in developmental milestones, including:¹⁰

• Impairment or absence of language development
• Delays in walking
• Delays in muscle coordination and ataxia
• Impairments in social development 
• Cognitive impairment or moderate to severe intellectual disability
• Sensory processing differences

Behavioural

Individuals with Pitt-Hopkins syndrome have been described to have a specific behaviour and temperament. Some of these are specific to Pitt-Hopkins syndrome, and some have an overlap with associated disorders, such as autism spectrum disorder or Angelman syndrome. Behaviours seen in Pitt-Hopkins syndrome include:¹⁰

• Easy-going demeanor
• Smiling appearance
• Repetitive behaviours
• Restricted interests
• Difficulties with social interaction and communication
• Self-stimulatory behaviour (stimming)
• Anxiety 
• Episodes of aggression

Respiratory issues

In addition to developmental and behavioural symptoms, a hallmark symptom of Pitt-Hopkins syndrome is issues with the respiratory system. This presents itself as periods of hyperventilation followed by breath holding. These problems with breath control have a negative impact on the quality of life of those suffering from Pitt-Hopkins syndrome. Furthermore, they contribute to the leading cause of death in those with this disorder, which is aspiration pneumonia.¹¹ Aspiration pneumonia occurs when something (such as food or water) enters the lungs. 

Other health concerns

Other common health concerns associated with Pitt-Hopkins syndrome include:^3,8,12

• Epilepsy, which usually presents itself under the age of 10
• Constipation or other gastrointestinal problems
• Excessive drooling 
• Severe short-sightedness
• Astigmatism

Diagnosis

The diagnosis of Pitt-Hopkins syndrome can prove to be a challenge. This is because many of the symptoms are present in other diseases and syndromes. For example, a patient with Angelman syndrome may also experience seizures and similar facial features to a patient with Pitt-Hopkins syndrome. The most accurate form of diagnosis for Pitt-Hopkins syndrome is genetic testing. 

When to seek a diagnosis

Pitt-Hopkins syndrome is not considered clinically dangerous. This means that the thing which affects the life expectancy of the patient is not the genetic mutation itself, but the complications associated with the symptoms it causes. Having a diagnosis early on can aid parents and caretakers in dealing with serious symptoms, increasing the knowledge of what to look out for to ensure the highest standard of living for the affected individual.  

Because Pitt-Hopkins syndrome presents itself very early on in childhood, there are a few signs of this syndrome in newborns and infants. Firstly, the appearance of the baby, as outlined above. Secondly, developmental delays are a tell-tale sign of an underlying condition. Furthermore, a medical professional/ hospital should always be contacted in the first instance of a seizure. 

Treatment and management

Currently, there is no cure for Pitt-Hopkins syndrome. Treatment is limited and focuses on managing the symptoms responsible for a decreased quality of life. There is some evidence that medications for epilepsy (such as carbamazepine, lamotrigine and clobazam) can help decrease the number of seizures in some individuals with Pitt-Hopkins syndrome.³ Constipation can also be treated with widely available treatments, such as laxatives. However, there are no current therapies on the market for breathing abnormalities, excessive drooling or autism spectrum disorder traits experienced by those suffering from Pitt-Hopkins syndrome.^3,13

The rarity of the Pitt-Hopkins syndrome means that no sure conclusions can be made about treatments, as they are usually observed and managed on a case-by-case basis. 

Research and future directions

Pitt-Hopkins is considered an orphan disease. This means that it is a rare disorder which is often neglected in clinical trials and new research due to its rarity.¹⁴ Currently, there are two different approaches to treating Pitt-Hopkins syndrome more broadly. One active clinical trial is aiming to treat this syndrome with stem cells. The other focuses on restoring neural connections in the brain. Current and accurate clinical trial information can be obtained on clinicaltrials.gov. 

Treatments for Pitt-Hopkins syndrome are still far from being made a reality, as the rarity of the disease limits the number of participants, hence delaying research. 

Support for guardians

Having a loved one suffering from a disorder as rare as Pitt-Hopkins syndrome may feel isolating. It is important to have a sense of community when dealing with a lifelong disability, and knowing that someone relates to you can bring comfort and motivation. Joining Pitt-Hopkins syndrome support groups, such as Pitt-Hopkins UK or Pitt-Hopkins Research Foundation, can help make sense of a new diagnosis or be there for general support. 

Summary

Pitt-Hopkins syndrome is a rare neurodevelopmental disorder. It is caused by a genetic mutation of the TCF4 gene on human chromosome 18. This gene is responsible for the production of a protein called transcription factor 4, which is important in development, specifically of the central nervous system. TCF4 is a big gene, and mutations (such as deletions) can occur at many different points, giving rise to a spectrum of varying symptoms. These include moderate to severe intellectual disability, developmental delays, distinct facial features, breathing problems and seizures. Due to social and behavioural symptoms, Pitt-Hopkins is sometimes considered a severe autism spectrum disorder. Diagnosis is difficult and most accurately based on genetic testing. 

Treatments for Pitt-Hopkins syndrome are limited to managing symptoms to improve quality of life. For example, treating epilepsy and constipation with widely available treatments. Novel research is limited because of how rare this disorder is. Hence, families and caretakers of those with Pitt-Hopkins may find it helpful and comforting to join support groups.