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.

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.

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).

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).

Here, we write about the characteristics of the DNA that cause Pitt-Hopkins syndrome. Everybody has two copies of the gene that forms the 'recipe' for TCF4 (transcription factor 4) on the long arm (called the q-arm) of chromosome 18. These changes can be that one of the two copies doesn't make a functional TCF4 (this is called a 'heterozygous loss-of-function variant)' or that one of the two copies has disappeared altogether, so there is only one functional copy (this is called hemizygosity), which is not enough for normal functioning (this is called haploinsufficiency). 

At the moment, scientists have described more than 140 different TCF4 changes that cause problems, including chromosomal translocations (bits of the DNA that have been cut out and pasted in another place on a chromosome), large deletions (large bits that have been cut out completely), intragenic deletions (small bits that block the gene from working), and truncating (part of the end of the gene can't be read through this change, which probably blocks the gene from working) or missense variants (this means that a little bit of the gene is changed, resulting in an incorrect bit in the protein that is made based on the gene). Also, scientists have pointed out common single nucleotide variants (these are incorrect bits in the gene that DON'T lead to incorrect bits in the protein) in TCF4 which may lead to a higher chance of getting schizophrenia (a serious mental disease),⁶ Fuchs corneal dystrophy (a disease of the outer part of the eyeball),⁷ and primary sclerosing cholangitis (a disease of the liver).⁸ TCF4 should not be confused with TCF7-like 2 (TCF7L2), which codes for a protein also named TCF4 (T cell factor 4).

3.1 What TCF4 does

TCF4, like other similar transcription factors, is used in many different processes and places in the body.⁹ We know that TCF4 is involved the development of B- and T-cells (two important cell-types which help defend your body against sicknesses),^10,11 in epithelial mesenchymal transition (the process through which cells from skinlike parts of your body can get loose and travel through your body to make new parts grow before you are born, or to make wounds heal) ¹² and in neurodevelopment (the development of your nerves and brain).¹³ It has a specific part (called the bHLH domain) which can stick to DNA and which can form combinations with another identical TCF4 protein (homodimer) and with other proteins (heterodimer).^9,10,11 ASCL1 is another  transcription factor involved in the development of a specific part of the nerves (noradrenergic neuronal development). Changes in TCF4 that cause Pitt Hopkins syndrome have been shown to make interaction with ASCL1 hard or impossible. The interaction problems between TCF4 and ASCL1 may explain at least some of the Pitt Hopkins symptoms, such as breathing too fast (hyperbreathing)^14,15 (Figure 2A).

FIGURE 2 Functions of TCF4.
(A)
Within the basic region of its bHLH domain, TCF4 binds to E-box motifs in promoter regions of transcriptional target genes. It forms homodimer and heterodimer, for example, with other bHLH domain proteins such as ASCL1 which is involved in regulation of the noradrenergic system via the ASCL1-PHOX2B-RET pathway. Mutations in this pathway are associated with breathing phenotypes and Hirschsprung disease.
(B)
The long arm of chromosome 18 (UCSC genome browser) with location of TCF4 in 18q21.2. Deletions within the region represented by the dark blue bar are associated with a typical PTHS phenotype. Larger deletions including TCF4 and expanding into the regions represented by the middle blue bars are associated with a less typical phenotype but with severe ID and other clinical aspects of PTHS.
(C)
Schematic drawing of TCF4 with non-coding (light gray), coding (dark gray), and bHLH domain encoding (black) exons. Above the scheme, different aberrations associated with a PTHS or PTHS-like phenotype are depicted, below the scheme are aberrations associated with mild intellectual disability. Sequence variants or deletions affecting exons represented by the dark blue bar cause typical PTHS, those in exons represented by the middle blue bar are associated with a more variable PTHS-like phenotype with severe intellectual disability, and variants located in regions represented by the light blue bar are associated with mild and/or non-specific intellectual disability. *, truncating variants; orange circles, missense variants; #, frameshifting variants with protein elongation; magenta circle: in-frame inclusion of an amino acid; black circles with lines: translocations; red lines, deletions; blue line, duplication

3.2 Chromosome changes that include TCF4

Sometimes, a long stretch of a chromosome is gone. This is called a 'deletion'. When the bit is at the end of a chromosome, this is called a 'terminal' deletion. And when the missing bit is somewhere in the middle of the chromosome, this is called an 'interstitial' deletion. These bits can be of different lengths, and the effect of such a deletion depends on the genes that were encoded in the missing bit. In people with Pitt-Hopkins syndrome, scientists have found deletions of certain lengths (ranging between 1.2 and 12 million base pairs) that include a the part of the long arm of chromosome 18 (18q) that coded for TCF4. These people look and behave exactly like people who only have mistakes within the part of the DNA that codes for TCF4.^2,3,14,16-22 As long as the missing bits are within the mentioned range, it doesn't make any difference how large the bit is that has been lost, or how many other genes were coded by that bit: the effect is still that people look and behave and develop like people with Pitt-Hopkins syndrome.^18,23 Therefore, people with such deletions should also be diagnosed as having Pitt-Hopkins. (Figure 2B). 

Sometimes the missing bits from the long arm of chromosome 18 are larger (up to 25 million base pairs) or the missing bit comes from the end of the chromosome (terminal deletion). Scientists have reported about individuals with such changes in the dna, who don't exactly look and behave like people with Pitt-Hopkins, but only share some characteristics of Pitt-Hopkins syndrome.^22,23 These large deletions should be considered 'contiguous gene syndromes', which means 'syndromes caused by changes in genes lying next to each other on a chromosome. Not just the missing bit encoding for TCF4, but also other genes might contribute to the way people look and behave. When describing an individual with these DNA changes, it is better to say they have “18q deletion syndrome”, adding the exact breakpoints on the long arm of chromosome
18 (Figure 2B). 

In other cases, people only have such large deletions of this part of chromosome 18 in some of the cells in their body. When a person has a change in a part of their cells, but not in all, this is called a 'mosaic', just like when a mosaic of tiles is made that has parts of one color of tile and parts of another color. When such a mosaic-like change in the long end of chromosome 18 causes a set of symptoms, this should also be called a "18q deletion syndrome" ,^18,21,24. Another possibility is that deletions happen at both ends of a chromomsome, after which the remaining ends stick together and form a ring ('ring chromosome').²⁵ Again, if this happens with a large part of the long arm of chromosome 18q, the result should be called a 18q deletion syndrome.

Scientists have described individuals with other changes in the long arm of chromosome 18q, such as 'balanced translocations'. This is when a part of a chromosome has broken off and gotten attached to another chromosome, which in turn has a bit broken off that has attached to the first chromosome. These people don't actually miss any dna, it's just in another location. Sometimes the break happens in such a way that the part coding for TCF4 can't function normally.^2,26–29 The way individuals look and behave varies, and the diagnosis of PTHS should only be accepted if the the clinical criteria are fulfilled).

3.3 TCF4 variants

First some basic facts about DNA. In DNA, there are four different kinds of nucleotides, which are adenine (A), guanine(G), thymine (T) and cytosine (C). Every three nucleotides together make up one 'codon' that codes for a specific amino-acid. There are 64 different codons, 61 encode amino acids and three are stop-codons that tell the cell where to stop translating. There are 20 different types of amino-acids, comparable to 20 different kinds of ingredients in a recipe. So, multiple codons can code for the same amino-acid. For example, there are four codons (GTT, GTC, GTA, GTG) that all code for the amino-acid valine.

Different kinds of DNA variants, also called mutations, have been described. If a change of nucleotide results in a codon which still codes for the same aminoacid, this is called a 'silent mutation'. When the change in a protein is such that it can't function properly, resulting in problems for the individual, these are called 'pathogenic'(causing disease). These are the most important possible variants:

Splice site
In the DNA, some parts of the nucleotides form codons that determine which amino-acids are used to make the protein, as described above. These parts are called exons. Exons can be short or long, but always are a multiple of 3 (because three nucleotides together code for one aminoacid). Other parts - before, after and in between the codons - are still made up of nucleotides, but these don't code for amino-acids; these bits are called 'introns'. The exons are numbered: the first is exon 1, then comes an intron, then the next exon (2), and so on. Mistakes in DNA can happen both in the intron and extron parts of DNA, and both can cause problems in the way proteins are put together. When the translation is made from DNA into protein, the introns get cut out or 'spliced out'. In case of a splice site mutation, a number of nucleotides in the specific site at which splicing takes place are inserted, deleted or changed, causing changes in the final protein which can cause problems in the functioning of the protein. 

Nonsense
A nonsense mutation is a change in the DNA that results in a stop codon where there should not yet be one. When this happens, the protein that is encoded by the DNA will be too short, incomplete and usually nonfunctional.

Frameshift
If a number of nucleotides is added or deleted that is not divisible by three, then this can change the 'reading frame' (the grouping of the codons), resulting in a completely different translation from what it was meant to be. The earlier in the sequence the deletion or insertion occurs, the more altered the protein. This is called a 'frameshift' variant. 

Missense
A 'missense' variant mutation is when a single nucleotide change results in a codon that codes for a different amino acid. Not every change results in a missense variant, because each aminoacid is encoded by several different codons. 

Deletions
A 'deletion' is a mistake in the DNA in which a part of a chromosome or a sequence of DNA is left out. Any number of nucleotides can be deleted, from just one to an entire piece of a chromosome. 

DNA mutations in Pitt-Hopkins
So what's up in the DNA of people with Pitt-Hopkins syndrome? Nearly all of the changes ('mutations') found in people with Pitt-Hopkins are unique. That means that nearly every person with Pitt-Hopkins whose DNA has been checked has a different variant. Most of the reported variants in people with Pitt-Hopkins syndrome are found between exons 7 and 19 on the long arm of the 18th chromosome. This part of the DNA codes for the protein 'Transcription Factor 4' (TCF4). These are the mutations that have been found:  

Most of the mutations found in people with Pitt-Hopkins are splice site, nonsense or frameshift variants.
In about 20% of individuals with Pitt-Hopkins, pathogenic missense variants are identified. Deletions within the gene ('intragenic') involving one or several exons of TCF4, that probably cause a shift in the reading frame, have been found in about 12% of published cases.^3,19,31–33 

The DNA mutations in people with Pitt-Hopkins are usually found in the 'bHLH domain', or basic helix-loop-helix domain, encoded by exon 18. The bHLH domain is a part of the protein which determines its shape. It is characterized by two curves (similar in shape to a spiral staircase) connected by a loop: that's where the name comes from. One TCF-4-protein usually works together with another TCF4 protein. It is the bHLH-domain that makes it possible for the two proteins to connect (which scientists call 'dimerizing'). So, if this part of the TCF-4-protein is non-functional, then TCF-4 can't do what it is supposed to do in many different parts of the body. 

3.4 TCF4 variants and non-PTHS phenotype

'Phenotype' is a word used by scientists to describe the combination of characteristics or traits of a person: the way they look, the way they develop, the way they move and behave. The 'clinical diagnostic criteria' (see section 2) describe parts of a person's phenotype. The word 'genotype' is used to talk about a person's DNA. As written above, most people who have the characteristics of Pitt Hopkins syndrome have a change in the DNA concerning the gene for the protein called 'Transcription Factor 4'. But not all the changes that have been found in the part of the DNA coding for transcription factor 4 lead to Pitt Hopkins syndrome. 

In some cases, the only problem that seems associated with such changes is mild problems with thinking (mild intellectual disability), in other cases, the intellectual disability is worse and these people also have a few of the Pitt Hopkins characteristics. ^{22,26,29,33-37} However, if a person does not look and act as described in the 'clinical diagnostic criteria' (see section 2), they should not get the diagnosis Pitt Hopkins just because they have a mutation in the DNA coding for TCF4 (R3).

We don't completely understand why some TCF4 variants lead to milder differences in behavior and thinking ability. Changes in particular parts of the gene (exons 9 to 19, to be precise) almost always lead to Pitt Hopkins, but people with changes in exons 1 to 4 have mild intellectual disability and people with changes in exons 7 to 8 have worse thinking problems and also sometimes some of the characteristics of Pitt Hopkins - but not enough to actually be diagnosed with Pitt Hopkins syndrome33 (Figure 2B).   

The best explanation that we have so far, is that when the part of the recipe for TCF4 that is described in exon 9 to 19 is wrong, then the TCF-4 protein that is made based on this faulty code never works. But when the changes in the recipe for TCF-4 are in another location (for instance exon 1 to 4 or exon 7 to 8), some of the TCF-4 proteins that get made based on these DNA mutations work after all. This can explain why people with such DNA changes experience fewer problems. ³³ 

3.5 Overlapping phenotypes

Sometimes, people look and behave a lot like people with Pitt Hopkins syndrome, but don't quite qualify for a Pitt Hopkins diagnosis. When their DNA is checked, no changes in the part coding for Transcription Factor 4 is found. Some of these have Pitt-Hopkins-like syndromes I and II. A number of people were suspected to have Pitt Hopkins, but when no mutation in TCF-4 was found, the scientists checked their characteristics again and decided they did not actually have all the clinical diagnostic criteria necessary for the Pitt Hopkins diagnosis.^40,41 

When it looks like someone has Pitt Hopkins syndrome, but no change in the DNA coding for TCF-4 is found, other syndromes should be considered. For instance, they may have Angelman syndrome, Kleefstra syndrome or Mowat-Wilson syndrome, or a number of other syndromes. Because the way these people look, act and develop overlaps with Pitt Hopkins, scientists talk about 'overlapping phenotypes'. 

3.6 Pattern of inheritance

When people have a child who is diagnosed with Pitt Hopkins, they often want to know how high the chance is that they will have another child with this syndrome if they get pregnant again. They want to know about the 'pattern of inheritance'.

In fact, children with mutations in TCF4 that lead to typical Pitt Hopkins Syndrome usually don't get this error in their DNA from their parents. The mutation is then called 'de novo', which is Latin for 'anew'. Because of this, the chance that a brother or sister of a child with Pitt Hopkins will also have this syndrome is low. 

There are only a few cases know in which the mistake in the DNA was inherited from either the father or the mother. Based on the reported cases and the clinical experience of the doctors who helped write this text, the chance that a child with Pitt Hopkins syndrome will have a brother or sister who also has Pitt Hopkins is at maximum 2 % (R4). As far as we know, no persons with typical Pitt Hopkins have ever had children themselves. 

As described in section 3.4, some people are known to have TCF4 variants without fulfilling the diagnostic criteria of Pitt Hopkins. Sisters and brothers of some of these people run a 50% chance of inheriting the same mistake in TCF4.^29,36 

3.7 DNA testing

The first DNA test that is done when a child is thought to have an intellectual disability checks for the absence or duplication of chromosomal material. Chromosomal imbalance will show up on a test called 'chromosomal microarray analysis'. “Microarray” refers to a microchip-based testing platform that allows automated analysis of many pieces of DNA at once. Computer analysis is used to compare a patient's genetic material to that of a reference sample. .⁴⁴ 

Because the DNA-changes that result in Pitt Hopkins syndrome are often caused by chromosomal imbalances, we think that this is the right test to start with for people suspected of having PTHS. If it looks like someone has either Pitt Hopkins or Angelman syndrome, we recommend doing another test as well, called 'methylation analysis', specifically of the part of the DNA where methylation-mistakes can cause Angelman syndrome. 

DNA Methylation
'DNA Methylation' is a process by which gene transcription is suppressed. When a part of the DNA is methylated, this means that it can't be copied to make proteins from. It is important that the right parts of the DNA are methylated at the right points in time, otherwise problems can occur, such as in Angelman syndrome.

In some hospitals and laboratories, Next generation sequencing (NGS) can be done. Using NGS an entire human genome can be sequenced within a single day. Genome is the word for all the DNA of one individual, the whole cookbook so to speak. If NGS testing is available, this should be the next step in DNA testing for Pitt Hopkins syndrome, as there are several syndromes that resemble Pitt Hopkins syndrome that can be checked for with this single test.

If Next generation sequence is not available, if the clinical suspicion of PTHS is very strong, a number of tests can be done that only check the part of the DNA coding for Transcription Factor 4. (Figure 3). Sometimes, these tests don't show up changes in TCF-4, because they look at the wrong chromosome. This can happen in case a part of a chromosome broke off and attached itself to another chromosome. To check for this, the chromosomes should be made visible with a technique called 'classic karyotyping'.

FIGURE 3 Molecular diagnostic pathways for Pitt-Hopkins syndrome (PTHS). Two pathways are depicted, one for an individual clinically suspected to have PTHS and one for individuals without this suspicion. As high throughput analyses are not available worldwide, evaluation using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) is also depicted. The clinical diagnostic criteria are those provided in Table 2

When mutations in TCF4 are found, these should be reported along with a person's clinical characteristics according to the criteria described by the American College of Medical Genetics (ACMG)  (R5). 

If individuals look, act, and develop in ways typical of Pitt Hopkins syndrome, and changes are found in their DNA that probably lead to problems in the functioning of Transcription Factor 4, it is safe to assume these DNA changes caused Pitt Hopkins syndrome. In these cases, parents don't need to be tested to diagnose their child, but we recommend testing them anyway to make sure that the change was 'de novo', meaning that they have almost no chance of having another child with Pitt Hopkins. 

When changes in the DNA are found in areas other than the ones that typically lead to malfunctioning TCF-4, the diagnosis is not as straight-forward, because we know some individuals have such changes without actually looking, acting, and developing as would be typical in case of Pitt Hopkins. The clinical criteria should be checked carefully and it is also useful to check information about variants that have been previously been reported. It is possible to do more testing to check for the effect of the variants on the production of the protein TCF-4. 

One other thing to consider is mosaicism. Mosaicism means the presence of two different sets of DNA (two different cookbooks) in one individual. Normally, all our cells contain the same cookbook, the same DNA. But sometimes, part of our cells contain a variation of the information in the rest of the cells. This situation has also been reported for some people with Pitt Hopkins syndrome. ²⁴. It is especially something to consider in people whose skin is a different color in some places (this is called a pigmentation anomaly).

3.8 Recommendations

R3 TCF4 variants can cause PTHS but can also cause other intellectual disability associated phenotypes which should not be labeled PTHS.
A+++

R4 Empirically, after the birth of an individual with molecularly confirmed PTHS, a recurrence risk of 2% should be given.
A++

R5 Interpretation of variants in TCF4 require consideration of the phenotype of the tested individual, pattern of inheritance of the phenotype and the variant, earlier experience with the variant, and nature and localization of the variant, using ACMG criteria.
A+++

4 PRENATAL DNA DIAGNOSIS

AS mentioned in section 3, most people with Pitt Hopkins syndrome do not have a brother or sister with Pitt Hopkins. The chance that parents who have had a child with Pitt Hopkins have another child that also has it (the 'recurrence risk') is low, around 2% . It is unlikely that a baby before it is born will be diagnosed with Pitt Hopkins during a prenatal ultrasound, as Pitt Hopkins doesn't cause abnormalities that are visible on such an ultrasound. 

Even though Pitt Hokpins is usually caused by a de novo DNA mutation, it is still possible that the mutation comes from a cell with the faulty DNA that has split into more eggs or sperm cells (this is called a 'germ line mutation'). For this reason, families with a previous affected child should be offered the possibility of 'prenatal diagnostic testing', which means that DNA of the baby in the womb is tested (R6). Such testing is reliable if the genetic change in the first child with Pitt Hopkins (the 'index patient' in genetic terms) is known. Testing can be performed through either chorionic villous sampling, amniocentesis, or pre-implantation genetic testing after in vitro fertilization.

It is possible to find out whether an unborn child has a matuation in the DNA coding for Transcription Factor 4 even if parents have not already had a child with Pitt Hopkins. This can be done with non-invasive prenatal testing (NIPT). However, we feel that this would not be useful at present, because we do not yet know enough about which changes in DNA lead to which effects in the child (R7). If such testing is offered anyway, pre-test advice should include discussions about reliability and informative value of the results, as well as questions about what is good to know and what not, and what would be good to do and what not based on the results of such tests.

Zollino M, Zweier C, Van Balkom I, Sweetser DA et al.

Source:

Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement. Clin Genet. 2019; 1–17. https://doi.org/10.1111/cge.13506

Page history

Last modified by Gerritjan Koekkoek on 2022/03/07 13:13

Created by Gerritjan Koekkoek on 2020/03/05 11:55