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What is a syndrome, really?

Ola Skjeldal's latest blog entry

[Posted on 18 January, 2019 by Ola Skjeldal]

In 1988 Greta and Peter Beighton published a book which they called “The man behind the syndrome”. The book focused on a number of individuals who had all described and eventually lent their names to new syndromes.

Greta and Peter Beighton presented only a small part of all the syndromes which are described in the literature. Today at least 12 000 different syndromes are known. A substantial number of them are named after the physicians or other persons that first discovered and characterised them. Others are named after the patient who initially presented with the symptoms. Syndromes can also be named descriptively by symptoms or underlying cause. Usually the persons who described the syndromes did not have any idea of what caused the syndrome or what was the pathophysiology behind the condition. Thus, in most cases, a syndrome is a set of medical signs and symptoms that are correlated with each other. The syndrome concept is descriptive and is based on empirically acquired knowledge about the correlation of symptoms and signs.

Over time we have found the causes and/or pathophysiology of more and more syndromes. This is especially true when talking about genetic conditions where the syndrome name and the genetic name sometimes are used interchangeably. Trisomy 21/Down syndrome is one such example. 22q11 deletion syndrome/DiGeorge syndrome is another example. However, the genetic names have not taken over. It is still called Down syndrome and Di George syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder which is characterised by a set of neurological symptoms and signs. It was first described by the Austrian paediatrician Andreas Rett in 1966 which gave clinical criteria for the syndrome.

In 1999 it was found that mutations in MECP2 most probably was the genetic defect in RTT. Today it is known that 95% of the RTT cases is caused by a de novo mutation in the Methyl-CpG Binding Protein 2 gene (MECP2). As MECP2 is responsible for many of the key elements in the neurodevelopmental process, this discovery has proven to be able to explain many of the clinical features. However, the definition of RTT, together with most other described syndromes, is still based on diagnostic standards or criteria consisting of the presence or absence of symptoms and signs.

In the last two-three years it has been found that a number of other genes are implicated in the presentation of RTT. This applies to those cases of RTT where there is no MECP2 mutation. A huge number of genes have been suggested to be responsible for both classical and variant forms of RTT. These “new” genes seem to have different tasks, but still the mutations result in a similar clinical phenotype, namely RTT or Rett-like conditions. Examples of these genes are IQSEC2, TCF4, WDR45 and SCN1A. Such “alternative genes” have also been found in many other syndromes and diseases, for instance Marfan syndrome.

Because of the discovery of this spectrum of genes, it has recently been suggested to characterise and name the syndromes on the basis of the underlying genetic defect. Those who suggest such a classification argue that it will be easier to conduct research on therapeutic interventions which address the basic genetic defect. However, far from all research is genetic research. A significant part of our clinical research is about describing and characterising symptoms and clinical findings, including related to behaviour. Another major area of our research concerns habilitation, where testing of treatment is essential. In order to do that it is absolutely crucial that we get the opportunity to study patients with the same clinical criteria as part of one homogeneous group; however, such classification will certainly only become more and more challenging in the future.

Whichever names we end up choosing for syndromes and diseases, it is essential that we get a system that is appropriate for researchers within all fields and also for families and patients involved.

This is a blog. The purpose of the blog is to provide information and raise awareness concerning important issues. All views and opinions expressed are those of the writer and not necessarily shared by the GNC.