Signs and symptoms – how Pitt-Hopkins syndrome is diagnosed

Pitt-Hopkins syndrome is caused when a specific gene is not working properly either because it is missing or has what’s known as a spelling mistake in it (meaning a mutation or variant). This gene is called TCF4 and is on chromosome 18. 

However, it is possible that someone who has a change in the TCF4 gene may not have Pitt-Hopkins syndrome but some other condition. That’s why it is important to be able to make a diagnosis not just from genetic testing but from obvious signs and symptoms. This is called a clinical diagnosis.

Someone with Pitt-Hopkins syndrome typically has:

* learning disabilities 

* delays in their development, such as being slow learning to walk

* lack of speech

* distinctive facial features

* possible changes in their breathing, including periods of breathing very fast (hyperventilation), or times when they stop breathing before restarting (apnoea)

* possible seizures (epilepsy)

* digestive problems, particularly constipation.

Doctors and parents have agreed which of these signs are most important and have created a points system that will allow a doctor to make a diagnosis. 

This is based on the number of signs or symptoms someone has and the resulting overall score. This system helps distinguish a child or adult with Pitt-Hopkins from an individual with two other syndromes that can both resemble Pitt-Hopkins syndrome ,Rett Syndrome and Angelman Syndrome.

The most important signs a doctor will look for (known as cardinal signs) are:

Unusual facial features: 

– a narrow forehead

– the outer part of the eyebrows are thin compared to the inner part

– a wide and prominent nose 

– the wings of the nostrils (alae) flare outwards a bit

– full cheeks

– large mouth, with a ‘cupid’s bow’ in the upper lip, and a full lower lip

– rims of the ears that are thick and slightly folded.

These facial features together are given 4 points.

Moderate to severe learning difficulties (with no or only limited speech). This is given 2 points.

Unusual breathing patterns: rapid breathing (hyperventilation or hyperbreathing) and pauses in breathing (apnoea). This is given 2 points.


Less important signs (known as supportive signs) are:

– short sight (myopia)

– constipation

– unusual hands: slender fingers, and abnormal creases in the palm

– unstable gait when walking.

1 point for each of the above.

How points lead to a diagnosis

With a score of 9 or more, a doctor will diagnose a child or adult with PTHS. You should then be offered genetic testing to look for a fault in the TCF4 gene, which causes Pitt-Hopkins syndrome.

If the score is between 6 and 8 and the unusual facial features are present, it is possible for a doctor to diagnose PTHS and you should be offered genetic testing.

If the score is below 6 it is unlikely the child or adult has PTHS, and you won’t need further testing for the syndrome.

Some doctors who have a lot of experience of PTHS will be able to make a confident clinical diagnosis without going through the checklist. Nonetheless this scoring system provides a clear way to diagnose PTHS.

We also need a scoring system to show how severely a person with the syndrome is affected. No such system exists and needs to be developed.


1/ The clinical diagnosis of PTHS is based on a combination of signs and symptoms. The diagnosis is made by a score of 9 or higher. With a score between 6 and 8 including the facial features there is a possibility of PTHS and genetic (DNA) studies should be carried out to confirm.

2/ There is currently no set of criteria that indicates how severely someone is affected by PTHS. Health care professionals together with families need to develop a scoring system to measure this.

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