Pitt Hopkins Syndrome (PTHS) is caused by the deletion or mutation of the TCF4 gene on chromosome 18q21.2.

Pitt-Hopkins syndrome: Causes and patterns of inheritance

Author: Raoul CM Hennekam MD PhD, Professor of Paediatrics and Translational Genetics, University of Amsterdam, The Netherlands, Summer 2010

Our entire body is composed of very many cells. Each cell has its own function. Groups of cells form together the various parts and organs of our body. Each cell has an outside (cell membrane), an inner mass (cytoplasma) and a core (nucleus).

In every single cell there are many different proteins to perform all functions of the cell. All proteins are formed from the DNA that is present in the nucleus. So the DNA can be seen as the ‘cookbook’ for the proteins of the cell.

The DNA is present in the nucleus in nice small packages, to facilitate the reading of the DNA. Each package is called chromosome. All DNA together is divided into 23 different chromosomes, of which you have each time two (a pair). So in total in the human cells there are 46 chromosomes.

From every pair of chromosomes you have inherited one from your father and one from your mother. So everyone has inherited 23 chromosomes from father and 23 from mother, each time one of each pair. This combination is established at the moment of the fertilization.

We have given the chromosomes a number, mainly based on the size of the chromosomes. Chromosome 1 is the largest chromosome, chromosome 2 is a bit smaller, etc, until chromosome 22 which is the smallest one. The last number is not named 23 but either X or Y; the reason for this is that they determine whether a person is a male or a female. Someone with two X chromosomes is a female, someone with one X and one Y chromosome is a male. You can’t have just two Y chromosomes: that is not viable, as there is too much important information present in the DNA of the X chromosome.

Each chromosome consists of many genes. A gene is the information that codes for a protein, and is fixed at a specific spot on the chromosome. Examples of a gene are the gene we have for the protein insulin, or the genes you have for your blood type or genes that determine what colour eyes you have.

There are many variations possible in the DNA. This ensures that no two people are alike. Such changes do not give rise to disorders. Other changes in the DNA are not tolerated well by the body and cause problems. Such a change is called mutation. Such a change manifests itself as a birth defect such as a congenital heart anomaly or a syndrome, and sometimes they manifest as diseases later in life like Alzheimer dementia.

In children with Pitt-Hopkins syndrome a change in the TCF4 gene on chromosome 18 can be present. TCF4 is an important gene because it codes for the protein TCF4. We know that this protein is very important for the development of the brain. We do not know yet all functions of TCF4.

The changes in the TCF4 gene involved in Pitt-Hopkins syndrome patients are found throughout the gene. To date, we can find no link between the exact change (mutation) in the TCF4 gene and the characteristics of the children with Pitt-Hopkins.

Not in all children and adults with Pitt-Hopkins syndrome, a change in TCF4 can be found. It seems likely that in some of them there is still such a change present, but we are unable to detect it with the current technology. It seems also likely that in other children there is second, other gene is involved. The diagnosis of Pitt-Hopkins syndrome remains a clinical diagnosis: if the features in a child are sufficiently similar to those present in Pitt-Hopkins, the diagnosis can be made, even without a change in TCF4. The only difference is that one can state that the diagnosis is confirmed when a change in TCF4 is found. But there are also genuine Pitt-Hopkins patients without a TCF4 mutation.

If a couple have a child with Pitt-Hopkins syndrome, it may be important to know the chance that a next child might also have the syndrome. If in a child a TCF4 change is found, we always check the parents as well, and the change has never been found in one of the parents. So it seems likely that the change started in the child and is not present in one of the parents. This makes the chance for recurrence very low.

To date there is worldwide only two families in which two children with the syndrome were born. This could be explained by assuming that one parent has a change in TCF4 present in some of the cells in his/her body but not in all; because the abnormality is not present everywhere the parent does not show any sign of this. This is called a mosaicism. If the change is present in some of the cells that form either sperm cells or egg cells, the parent can pass the change on more than once to children. This risk is very small (less than 1%) but it still explains the recurrence in those very rare families. So we always inform families that the chance is very low but not 0%.

Parents may wish to check in a subsequent pregnancy whether the next child has the same TCF4 change or not. One uses chorionic villus sampling for this. The reliability of these studies is 100%. The change in TCF4 in the previous child with Pitt-Hopkins should be known for this as otherwise the lab would not know where to look. In families with a previous child with Pitt-Hopkins but without a detectable change in TCF4 a study in early pregnancy is not possible.

If a child who has Pitt-Hopkins syndrome, grows into an adult and has a developmental level that allows him/her to have children, there is a probability of 50% (1 out of 2, fifty-fifty) that he/she will pass on the changed code (mutation) for TCF4, and that the child will have Pitt-Hopkins. Also in such circumstances a reliable prenatal diagnosis by chorionic villus sampling is possible, as long as the change in TCF4 in the child with Pitt-Hopkins will be known.

Brothers and sisters have no increased risk for getting a child with Pitt-Hopkins. They do not have a chance of having a mosaicism: a parents can have this, but a parent with a mosaicism would pass the change in the gene on to all cells of a child, and, this, a child would have the change in all body cells and not again in a mosaic form. So we can be sure that a brother or sister who is healthy did not inherit the changed gene, and the chances of their future children to get Pitt-Hopkins syndrome are not increased.

In 2009 a German group described the two families with each two children in the family with Pitt-Hopkins. At first these were characterized as having Pitt-Hopkins but after a while they realized they were in fact only resembling Pitt-Hopkins syndrome. In these families they found that each affected child had two changes in one of two genes (CNTNAP2 and NRXN1). In these families the gene was inherited in an autosomal recessive way: both parents were carrier of the mistake (but completely healthy), and in each of these families the chances were one in four (25%) that the families would have a second child with the disorder. Such families are extremely rare however, and the manifestations are somewhat different from Pitt-Hopkins, so it is in general not needed for the families to take this into account. It is something the local clinical geneticist should consider however.


  • De Pontual L, et al. Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Hum Mutat 2009;30:669-76.
  • Giurgea I, et al. TCF4 deletions in Pitt-Hopkins Syndrome. Hum Mutat 2008;29: E242-51.
  • Kalscheuer VM, et al. Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome. Am J Med Genet 2008;146A:2053-9.
  • Kim SK, et al. CpG methylation in exon 1 of transcription factor 4 increases with age in normal gastric mucosa and is associated with gene silencing in intestinal-type gastric cancers. Carcinogenesis 2008;29:1623-31.
  • Ouvrier R. Hyperventilation and the Pitt-Hopkins syndrome. Dev Med Child Neurol 2008;50:481.
  • Zweier C, et al. Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patient. J Med Genet 2008;45:738-44.
  • Zweier C, et al. CNTNAP2 and NRXN1 are mutated in autosomal recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 2009;85:655-66.