Interview with Professor Gerard Pals, biochemist (MSc) and geneticist (PhD) at the VU university hospital in Amsterdam, The Netherlands

Who are you and what is your relationship to OI?

I am a biochemist (MSc) and geneticist (PhD). In 1989 I started a diagnostic laboratory for DNA and protein testing of inherited diseases, including OI, at the VU university hospital in Amsterdam, The Netherlands. This is now part of the Amsterdam University Medical Centers (AUMC). We do not only perform genetic testing of OI, but we are also involved in research. Our laboratory has grown from two people in 1989 to more than 200 now.

I am still affiliated with the AUMC, where I play an advisory role in OI research. I am also working 6 months per year in Indonesia, as a professor of human genetics at several universities and setting up a laboratory for genetic testing of inherited diseases at Prodia Widyahusada Tbk in Jakarta, Indonesia.

My experience with OI is in diagnostic testing and research over the past 32 years. Our team has been involved in diagnostic testing of around 1600 patients and we have discovered several new genes involved in recessive and X-linked OI. We are currently working on developing medication for OI that targets the primary problem of the collagen synthesis. We are also developing new gene therapy technology for OI.

Our center has been accredited as an expert center for inherited bone disorders by the Netherlands Federation of University hospitals (NFU) and the ERNs. As director of a genetic testing laboratory, which is a national reference center for many inherited diseases including OI, it has been my responsibility to ensure differential diagnosis in cases of suspected child abuse. If such cases were handled in court, it was also my task to act as expert witness. Because of my expertise in the field of brittle bones, I am still often asked to give advice and act as expert witness in cases of suspected non-accidental injury. Requests come from many countries.

What should the OI-organizations do when they are contacted by parents who have been accused?

The basic problem with suspected child abuse is the fact that the threshold for reporting has been made very low, without any attention for differential diagnosis. In many countries this leads to a situation where Child Protection Services (CPS) or similar organizations with different names, immediately take a child away from the parents after a referral of suspected non-accidental injury (NAI). Subsequently, the CPS doctors start looking for evidence of abuse, often without looking for alternative explanations for the reported injuries. Of course, I realize that child abuse is very serious and should be prevented wherever possible. However, the effect of removing a child from innocent, loving parents is extremely damaging to the child and to the family. In my extensive experience the CPS doctors often do not realize this. I have also noticed that, when I ask medical students or young doctors about NAI, there is no attention at all in the medical curriculum for differential diagnosis in cases of suspected NAI.

It is usually thought that OI is extremely rare and highly unlikely to be found in cases of suspected child abuse. The doctors who are involved do not realize that children with OI, whose parents do not have OI, have an almost 100% chance of unexplained fractures in their first year of life. As a consequence, they have an almost 100% chance of being taken away from their parents due to suspected child abuse. Because of this, the frequency of OI in a setting of suspected child abuse is estimated to be 1 in 15, a thousand time higher than in the general population! (See Pals and Stolk, Am J Roentgenol. 2021 Oct; 217(4):1019).

I do realize that also a child with OI can be abused. That is a very sad situation, but extremely rare. In such cases, I suggest additional evidence of abuse is required. The OIFE and other OI organizations should not get involved with individual cases. However, they should create more awareness of the problem. Individual families that approach the organizations can be referred to organizations such as ADIKIA in France or The Innocence project worldwide, or to people like myself.

                                Dr. Pals works six months of the year in Indonesia

What steps should be taken when an OI-family has been accused of child abuse?

The first step should be to try and prevent separation from the parents. This separation is very damaging to the child, even if there has indeed been NAI. Supervision by social services, as is the common situation in The Netherlands, is in most cases sufficient to prevent further possible abuse and prevents unnecessary damage to the child.

The next step should be to convince the CPS doctors of the necessity of differential diagnosis. It is often very difficult to break through their tunnel vision, but it is necessary. The parents are usually not believed in such cases, so they should get support from an unbiased doctor, if possible. If there is a good relationship with the family doctor, he or she may be able to help.

Genetic testing is the next step, but this in most countries very tricky, because of the ignorance regarding genetics and statistics among doctors. In my experience, the CPS often orders a test of the dominant genes (COL1A1, COL1A2) only. There is an assumption that these are the most common cause of OI and they conclude from a negative test result that OI can be excluded. They do not realize that, if the parents do not have OI, a recessive gene is a much more likely cause of OI.

Our laboratory performs a panel test of 41 genes, related to OI and other causes of brittle bones, in cases of suspected child abuse. But even this comprehensive test cannot exclude OI. Not all mutations can be detected, even with the most advanced techniques, and not all OI-causing genes are known. Moreover, I have not found a single laboratory in any of the countries in which I am active, that offers a comprehensive test for OI. Also, very recent findings show that at least ten additional genes can cause a transient form of brittle bones during the first year of life.

What kind of genes are causing OI?

I have concluded that 30% of OI cases are associated with non-collagen genes. This is probably a low estimate, because most of the non-collagen OI genes have only been discovered in the past ten years and have not yet been tested in all OI patients. Moreover, I have been involved in more than 1600 cases of diagnostic testing for OI and we still have not found causative gene variants in 10% of clinically proven OI cases. It is also argued that the recessive OI genes only cause very severe cases of OI, which can be easily diagnosed without genetic testing. Our recent findings have shown that this is certainly not true. We often find OI type I in families with recessive OI. This misconception is probably caused by the fact that we as researchers started looking for new OI genes in the most severely affected families.

In cases where there are children with OI from parents with no OI, the cause can either be a new mutation in one of the COL1 genes (COL1A1 or COL1A2), or two compound heterozygous or homozygous mutant alleles in one of the recessive genes. In my lab, the most common new mutation we found in COL1A1 is a deletion of the entire gene. This kind of mutation cannot be detected by most laboratories, because only the intact gene allele on the other chromosome is sequenced. For this purpose we developed the MLPA technology.

Can you explain this further?

Most of the variation in genes is caused by change of a single nucleotide or building block of the DNA. However, sometimes larger changes are found. This happens when during copying of the chromosomes a part of the DNA sequence is skipped. Normally we have two copies of each collagen gene, one on the chromosome that we inherit from the mother and one from the father. Sometimes the mutation is so large that one complete copy of the COL1A1 gene is missing. This is called a large deletion. The resulting lower production of collagen 1α1 protein leads to OI type I. This is the most common new mutation that we see in children with OI whose parents do not have OI. This type of mutation cannot be detected by regular DNA sequence analysis, because this only will show the sequence of the normal gene that is present on the other chromosome.

To solve this problem, we have developed a technology, called Multiplex Ligation Mediated Probe amplification (MLPA) which is nowadays the gold standard in detection of large deletions and duplications (see MLPA.com). Our publication in Nucleic Acids Research (NAR 2002; 30:e57) has been cited thousands of times. With the latest DNA sequencing technology, Next Generation Sequencing (NGS), if used properly, it is possible to detect large deletions and duplications. However, most DNA testing laboratories do not perform this analysis.

What can we as OIFE or OI-organizations do to create awareness and/or improve the situation?

You can create awareness of the fact that, in a situation of suspected child abuse, OI is not rare at all! This is an important step. This can be done with publications in journals that have a broad audience among doctors and health professionals. Also websites are a good place for this kind of information.

The fact that some types and combinations of fractures are considered to be “highly specific for NAI” is extremely damaging for OI families. These types and combinations of fractures, such as “multiple fractures in different stages of healing” are actually highly specific for OI.

The extremely one-sided emphasis, in the curriculum of medical professions, on prevention of abuse is also an important issue. The OIFE could draw attention to this problem and ask for more emphasis on taking differential diagnosis much more seriously.

The situation of families in cases of suspected child abuse is actually a humanitarian and legal issue. These families lose their children without any form of process and the parents are forced to prove their innocence to stay out of prison and have a tiny chance of getting their child back. This is preposterous. What happened to “innocent until proven guilty”?

Regarding this human rights issue, a complaint has been deposited at the European Court of Human Rights on behalf of 150 French families, against the French Health Authorities and the French Government. I hope we win this case, as it will get a lot of media attention. In Florida we have gone even further, by filing federal charges against the CPS, regarding abduction, child trafficking and abuse (all with convincing evidence). This is getting national media attention in the USA.