2. Characteristics of people with Pitt-Hopkins syndrome
2.1 Exact description (definition)
At the moment, we know that mutations in a single gene (TCF4) cause Pitt-Hopkins syndrome. So you could say that it is possible to decide someone has this syndrome (diagnosis) simply by checking for changes in this particular gene. So it would not be necessary anymore to have a list of differences that you can see (clinical criteria) to diagnose Pitt-Hopkins syndrome. But there are still people that have the typical Pitt-Hopkins characteristics, but who do not have this particular change in their DNA.
On the other hand, there are also people who have a change in TCF4, who don't at all look and behave like people with Pitt-Hopkins syndrome. This is very important, since these days checking all of the DNA of a patient is the first thing we do when someone has problems with thinking. It might be that based on the DNA, a doctor would say such a person has Pitt-Hopkins, but they clearly need other help than people with this syndrome. Therefore, we decided that we still need a list of reliable clinical criteria.
Two sets of clinical diagnostic criteria have been published.(2,3)
Both sets are based on the presence, and sometimes the absence, of a number of signs and symptoms, and can be useful. However, when the two sets of criteria were used to check whether a large number of individuals who had already been diagnosed with Pitt-Hopkins syndrome (4) also turned out to get the diagnosis based on these lists of signs and symptoms, it was clear that these criteria were not sufficiently precise. So, we need a better list.
FIGURE 1 (A) Faces of eight people with Pitt-Hopkins syndrome who also have the typical DNA changes. Ages are 15, 20 months, 8, 10, 15, 16,18, and 31 years, respectively.
To decide how important it is for someone to have a sign or symptom in order to be correctly diagnosed with Pitt-Hopkins (this is called sensitivity of a test), we collected information about 100 people with this syndrome, who also have been shown to have the DNA differences that are connected with Pitt-Hopkins syndrome(Table 1; illustrated in Figure 1 1). We used the characteristics of these individuals as they had been described in their files. That way, we made sure that weren't suggesting a person had a characteristic just because we were doing the study. We considered any sign that was described in at least three out of four individuals (75%) as sufficiently characteristic of Pitt-Hopkins to be used to check the sensitivity of the list. In addition, we included the breathing problems in the list; whether people with Pitt-Hopkins syndrome have these problems, depends a lot on how old they are.
Then we had to decide how important it is for someone to have a a sign or symptom in order to be correctly diagnosed as NOT having Pitt-Hopkins (this is called specificity of a test). The two syndromes that are most similar to Pitt-Hopkins syndrome are Angelman syndrome and Rett syndrome. So the most important goal for us was that the list of diagnostic criteria would be able to settle whether an individual does not have Pitt-Hopkins, but rather one of these other syndromes. We collected the same information as in individuals with Pitt-Hopkins in 50 individuals with either Angelman or Rett syndrome. Only people who had been proven to have the DNA differences typical for these two syndromes we included Table 1). It turned out that they way someone's face looks is the most important sign that can be used to decide whether someone has Angelman syndrome or Rett syndrome rather than Pitt-Hopkins syndrome.
TABLE 1 Most important differences in a group of 100 individuals with Pitt-Hopkins syndrome (this group was labeled PTHS1), another group of 50 individuals with Pitt-Hopkins syndrome (this group was labeled PTHS2), 50 individuals with Angelman syndrome (AS) and 50 individuals with Rett syndrome
| PTHS1 | PTHS2 | AS | Rett | |
|---|---|---|---|---|
| Signs | % | % | % | % |
| Narrow forehead | 83 | 88 | 18 | 0 |
| Thin eyebrows on the sides of the face | 75 | 68 | 14 | 16 |
| Wide nasal bridge (part of the nose between the eyes) /ridge (long bony part of the nose) /tip of the nose | 91 | 92 | 18 | 30 |
| Flared nasal alae (wide nostrils) | 72 | 94 | 8 | 22 |
| Full cheeks/prominent midface (mouth, cheeks and nose bigger than usual) | 81 | 92 | 20 | 32 |
| Wide mouth, full lips,cupid bow upper lip (curve in the middle of the upper lip) | 92 | 100 | 80 | 16 |
| Thickened or overfolded helix (helix=rim of the ear) | 59 | 77 | 6 | 4 |
| Development | ||||
| Severe intellectual disability (significant limitations in reasoning, learning, problem solving ) | 98 | 96 | 98 | 80 |
| Very limited or absent speech (speaks in short sentences, single words, or not at all) | 89 | 92 | 94 | 42 |
| Gait ataxia (unsteady, staggering walking) | 64 | 79 | 96 | 10 |
| Infantile axial hypotonia (baby's have a limp rump) | 73 | 74 | 74 | 0 |
| Delayed gross motor development (children learn to crawl and walk later than usual) | 92 | 100 | 100 | 30 |
| Autonomic dysregulation (problems in controlling functions such as breathing and intestines) | ||||
| Any breathing anomalies (breathing problems) | 47 | 73 | 10 | 40 |
| Intermittent hyperventilation (sometimes breathing very fast, but not all the time) | 40 | 69 | 6 | 34 |
| Apnea (breathing stops) | 38 | 51 | 4 | 14 |
| Constipation (trouble with pooping) | 75 | 92 | 20 | 14 |
| Visual anomalies (problems seeing) | ||||
| Myopia (problems seeing things far away) | 52 | 58 | 4 | 2 |
| Strabismus (eyes not aiming at the same point in space) | 44 | 58 | 28 | 18 |
| Astigmatism (distorted or blurred vision at all distances) | 28 | 38 | 18 | 6 |
| Neurological /behavioral features | ||||
| Microcephaly (small brain in a small skull) | 18 | 23 | 78 | 84 |
| Seizures (seizures are sudden, uncontrolled electrical disturbances in the brain. They can cause changes in behavior, movements or feelings) | 40 | 32 | 74 | 48 |
| Wide ventricles (all brains contain a number of open areas, called ventricles, filled with liquid that protects the brain. Here, these can be wider than usual) | 39 | 17 | 15 | 2 |
| Small corpus callosum (small part of the brain connecting the left and right half of the brain) | 43 | 31 | 7 | 2 |
| Inappropriate laughter (laughing at strange times) | 20 | 27 | 90 | 4 |
| Regression (when children can do less than they could when they were younger) | 1 | 10 | 0 | 82 |
| Hand features (characteristics of the hands) | 76 | 76 | 23 | 6 |
| Slender fingers | 50 | 46 | 15 | 6 |
| Single transverse palmar crease (only one crease across the palm of the hand) | 49 | 50 | 10 | 0 |
| Hand washing movements | 6 | 10 | 6 | 88 |
| Other stereotypic (repetitive, purposeless) hand movements | 66 | 48 | 42 | 0 |
We decided on the list of clinical diagnostic criteria for Pitt-Hopkins by first proposing a group of characteristics called 'cardinal features'. These are the signs and symptoms which we feel are characteristic for Pitt Hopkins syndrome, and which are highly specific - which means that if a person has these characteristics, it is unlikely that he or she actually has some other syndrome, such as Angelman or Rett (Table 2; Figure 2). Second, we decided on a group of characteristics called 'supportive features'. If someone has one of these signs or symptoms, that should mean he or she is suspected of having Pitt-Hopkins, but it still could be another syndrome, so these characteristics are less specific.
FIGURE 1 (B) Important facial signs in Pitt-Hopkins syndrome, used to decide whether someone has Pitt Hopkins based on how they look
After making these lists of criteria, we talked about them. This way, we agreed together about the clinical diagnostic criteria, based on whether a person has certain cardinal and supportive features: if an individual scores 9 or more of the characteristics on the lists, he or she can be clinically diagnosed with Pitt-Hopkins syndrome(R1). This score can only be reached if a person has at least two of the three cardinal features. A score of 6 to 8 in combination with the facial characteristics suggests a person may have Pitt-Hopkins ('possibly Pitt-Hopkins') but needs a DNA-check to see if he or she has the typical differences seen in people with Pitt-Hopkins syndrome.
We wanted to know how sensitive our list of criteria is. Can you correctly pick out whether someone has Pitt-Hopkins based on these criteria? So we checked off the list for the 100 individuals we had originally used to define the diagnostic criteria. We also checked off the list for a second set of 50 individuals who had not been used to make the list, but who had been shown to have the DNA differences seen in people with Pitt-Hopkins syndrome. We also used the list to score 50 individuals with Angelman syndrome and 50 with Rett syndrome (Table S1, Supporting Information).
After we made these lists, we compared all the scores. All individuals with Pitt-Hopkins in both groups scored 6 or higher, which means nobody would have been missed as having this syndrome based on our list of "clinical criteria". So the list was completely sensitive. Besides, none of the individuals with Angelman and Rett syndromes incorrectly got the clinical diagnosis of Pitt-Hopkins based on our list. Based on their scores, three of the people with Angelman syndrome were considered to possibly have Pitt-Hopkins. None of the individuals with Rett syndrome fulfilled the criteria for possible Pitt-Hopkins syndrome. Together, this means that specificity (the ability of a test to show someone does not have a disease or syndrome) was very high, but not complete.
Another nine individuals with Angelman syndrome reached a total score of 6 to 8 but did not have the facial characteristics of Pitt-Hopkins, which suggests the facial shape differences form the most specific way to decide someone has this syndrome. We have also found in our work in hospitals that we have seen a few patients where we had a lot of trouble deciding whether they had Angelman syndrome or Pitt Hopkins syndrome, based on clinical signs and symptoms. This was especially true while the individuals were young. Despite these good results, we need a study that checks new patients (a 'prospective study') based on our list to decide how good it really is at deciding whether someone does or does not have Pitt-Hopkins syndrome (Box 1).
TABLE 2 Clinical diagnostic criteria for PTHS
Cardinal (most important)
- Face (at least three of seven)
- Narrow forehead
- Thin lateral eyebrows (eyebrows are thin at the sides of the face)
- Wide nasal bridge/ridge/tip (wide part of the nose between the eyes) /ridge (long bony part of the nose) /tip of the nose)
- Flared nasal alae (wide nostrils)
- Full cheeks/ prominent midface (mouth, cheeks and nose bigger than usual)
- Wide mouth/full lips/cupid bow upper lip (curve in the middle of the upper lip)
- Thickened/overfolded helix (rim of the ear)
4 points
- Severe intellectual disability (lots of trouble thinking) and can hardly speak or not at all (less than 5 words)
2 points
- Problems with breathing (sometimes breathing too quickly and superficially (hyperventilation) and/or having breathing stops (apnea))
2 points
Supportive (increases likelihood in combination with most important characteristics)
- Myopia (problems seeing things far away)
- Constipation (problems with pooping)
- Hand (slender fingers and/or abnormal crease in the palm of the hand)
- Unstable gait (unstable walking)
each 1 point
Clinical diagnosis of Pitt-Hopkins syndrome (A person definitely has Pitt Hopkins based on how they look and behave).
Score ≥ 9. Molecular confirmation indicated.
Possible clinical diagnosis of Pitt-Hopkins syndrome (A person may have Pitt Hopkins based on how they look and behave).
Presence of facial characteristics + additional criteria, either cardinal or supportive, totaling a score of 6-8. A person who gets this score, should have a DNA test for changes of the TCF4 gene.
Insufficient clues for the presence of Pitt-Hopkins syndrome.
Score < 6. No further studies specifically for PTHS indicated. In this case, it is necessary to look for other causes of problems.
2.2 Severity scores
It is important for families to know as early as possible how much - how severely - having Pitt-Hopkins syndrome will affect their child and his or her family. This is not the same for each person with Pitt-Hopkins. Before now, nobody has described such a 'severity score'.
According to us, families should be asked which differences of the body, mind and behavior have the greatest impact on the lives of individuals with Pitt-Hopkins and their families. These make up the criteria for the severity score. We feel it would be best to organize such a list by linking each difference as much as possible to the change in the DNA that caused it.(R2).
Recommendations
- R1
- The clinical diagnosis of PTHS is based on a combination of signs and symptoms (Table 2): the clinical diagnosis can be confirmed if a score of 9 or higher is reached, and a score of 6 to 8 including the presence of the facial characteristics indicates a suspicion for PTHS and needs further confirmation by molecular testing. A++
- R2
- A set of criteria to indicate the severity of PTHS should be developed in collaboration with families. A++
Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement. Clin Genet. 2019; 1–17. https://doi.org/10.1111/cge.13506
, published on 24 Jan 2019