Is dwarfism hereditary

Too small

There are several factors that determine how tall a person will become. Genes play a key role in this: older parents usually also have older children. Basic human genetic research has taken on this exciting topic in recent years and for the first time has been able to name genetic predispositions on the sex chromosomes that are changed or missing in short people. Gudrun Rappold from the Institute for Human Genetics at Heidelberg University describes the state of scientific knowledge and opens up perspectives for new therapies for short stature children.

Too big, too small, too fat, too thin?

Too big, too small, too fat, too thin - the cartoon drawn in 1852 by George Cruikshank in a pointed pen shows four extremes of the human physique. Deviations from the norm - and from one as obvious as that of body structure - have always been viewed with curious interest. For centuries people with extremely short or dwarf stature were admired attractions in the circus, at exhibitions and at fairs. According to the Guinness Book of Records, the smallest woman in the world, Pauline Musters, lived from 1876 to 1895 and measured just 55 centimeters. The Indian Gul Mohammed, born in 1957, can claim to be the smallest man in the world at 57 centimeters. In earlier times, as human "norm variants", people of short stature were also welcome members of court life and were active there as wise advisors or entertainers. In myths, fairy tales and legends, dwarfs, gnomes and other small mythical creatures have always stimulated the imagination of contemporaries.

The sex chromosomes X and Y are particularly important for body length growth. Chromosome irregularities can cause various forms of short stature.

But what is "short stature"? Clinically, the situation is clearly defined: The three smallest of a population of 100 people are described as short. The division is made in percentiles, which can be read off with the help of growth curves. In clinical jargon, a child growing below the third percentile means that 97 percent of their same-sex peers are taller. A child of German parents who was classified as short according to the German growth tables would, for example, still grow within the normal range in Japan, where Japanese growth curves are used as a basis. This example shows: In order to differentiate short stature from normal stature - and thus disease from health - not only clinical but also sociological parameters must be used. It is not without reason that the World Health Organization (WHO) defines health not only as the "absence of disease", but also includes socially induced distress: "health is a state of complete physical, mental and social well-being and not merely the absence of disease and infirmity "is the wording of the WHO definition. From a medical point of view, short stature is seen as a disease and not as a mere variant of normal growth. This conclusion is supported by numerous pathological changes in the skeleton and other organs that can be associated with short stature.

From a genetic point of view, human height is a classic "polygenic characteristic". The influence of genes is obvious, as the target size of the children is usually directly dependent on the height of the parents. However, having a large hereditary component does not mean that the environment does not also play a significant role in body size. Human height has remained relatively constant over the millennia. This is proven by skeletal studies from the Early and Late Stone Age to modern times. However, over the past 150 years, people have steadily grown. Better nutritional conditions and the elimination of many infectious diseases that could adversely affect the development of the population have certainly contributed significantly to this increase in size.

People with a clinically defined reduced height can be short for very different reasons. A more or less protein-rich diet is particularly important in early childhood. It is probably due to the vaccination programs that have been systematically carried out in the Netherlands since World War II that the Dutch are the greatest Europeans today. Hormone deficiency or psychosocial conditions can also affect body size. The most important role, however, is played by genes. Basic research has turned to this exciting topic in recent years. For the first time, short stature could be traced back to changes (mutations) of certain genes. All genetic diseases - called hypoplasias, dysplasias and dysostoses in technical terms - are based on mutations of different genes.

The Heidelberg "court dwarf" Perkeo - a mutation analysis today would probably result in the diagnosis "pseudoachondroplasia".
If the French painter Henri de Toulouse-Lautrec were still alive today, the (probable) clinical diagnosis of "pycnosystosis" was followed by a molecular genetic mutation analysis to confirm the genetic defect. With Giovanni Clementi - better known as Heidelberger Hofzwerg Perkeo - the probable clinical diagnosis of "pseudoachondroplasia" would be confirmed today by a mutation analysis of the genetic make-up for the so-called fibroblast growth factor receptor (FGFR3).

It has long been assumed that the sex chromosomes (XX in women, XY in men) are particularly important for body length growth. The first evidence of this was provided by comparing the height of patients whose sex chromosomes showed changes that were recognizable with the aid of the microscope. A precise cytogenetic and molecular analysis then made it possible to predict certain regions of the chromosomes, the loss of which was always associated with short stature. For example, a gene could be predicted on the long arm of the Y chromosome, which has a significant influence on the height of the man and only occurs in men. Using special molecular biological methods such as deletion mapping, cloning and sequencing, my working group has now been able to narrow the chromosome region in which this growth gene can be found to a size of 700 kilobases on the genetic molecule DNA. We are currently using various methods of molecular biology and bioinformatics to isolate the genes of this delimited region and to prove a causal connection to a very specific growth gene.

Another common sex chromosome irregularity is "Turner Syndrome", medically defined as the absence of a sex chromosome in women. Worldwide there is one woman for every 2500 women who has only one X chromosome instead of two X chromosomes. The disease is therefore also called "monosomy X". It manifests itself in various clinical problems that are likely to arise from the loss of several genes located on the X chromosome. Key symptoms are short stature and sterility; other features such as lymphedema, various skeletal, kidney and heart malformations in varying degrees of severity can, but need not, occur. This variability is explained by the fact that most - if not all living women with Turner syndrome - have cells with only one sex chromosome (so-called 45, X karyotype) and cells with the normal chromosome set (46, XX karyotype). Fetuses growing in the womb, whose cells only have a 45, X karyotype, die in 99 percent of cases: the complete loss of an X chromosome obviously cannot be compensated for.

The chromosomes of a short woman (picture above): the green chromosomes that "light up" are the two X chromosomes. With the help of gene probes it can be determined that a certain genetic makeup, the so-called SHOX gene, is missing on one of the x chromosomes. It is needed early in development. If only half of the normally produced gene product is produced by the cells, the body height is reduced by around 20 centimeters. The picture shows a karyogram - the orderly representation of the individual chromosomes of a normal woman.

In the case of short stature in Turner syndrome, deletion mapping and position cloning showed us the way to find and isolate the underlying gene. The gene that causes the short stature in Turner syndrome is called SHOX ("short stature homeobox containing gene on the X chromosome"). It is a genetic trait that is required early on in the development of a living being. If only half of the normally formed gene product is produced by the cells due to a genetic defect, the body size is reduced by about 13 to 20 centimeters. The greatest activity of the SHOX gene is found in the resulting cartilage and bone structures.

Body length growth is a biological process that begins inside the uterus and continues into early adulthood. It is bound to certain anatomical structures at the ends of the bones, the so-called growth plates. Cells in this area divide and specialize within a hierarchical structure.

The figure above shows the resulting limbs of an approximately 50-day-old human embryo (red = growing upper arm; green = forearm; yellow = entire arm and hand plate). The SHOX2 gene is responsible for the upper arm, SHOX for the forearm and SOX9 for the entire arm. Molecular biological studies have shown that the loss of the SHOX gene can be associated with four different clinical pictures of short stature (see graphic below).

Since SHOX is located in a chromosome region that is identical on the X and Y chromosomes, defects or the complete absence of this gene can lead to short stature, even in women and men with normal 46, XX and 46, XY chromosome sets. By means of mutation analysis on more than 2000 small children, for whom the cause of their small growth was previously unknown, we have now been able to show that around two percent of all idiopathic small children carry a defective SHOX gene in their cells. In addition, SHOX mutations can lead to another short stature disease, Leri-Weill syndrome. If both SHOX copies are defective, this leads to extremely short stature.

The activity of the SHOX and SHOX2 genes in various short stature forms is shown. If SHOX is defective, the forearms and lower legs are only shortened and so-called mesomal short stature occurs. If SHOX2 does not work properly, a "rhizomelic" stature is the result, in which the upper arms and thighs can be shortened.

Genetically engineered (recombinant) growth hormone has been used successfully for many years to treat the short stature of women with Turner syndrome. Since this is the same SHOX gene defect in patients with Leri-Weill syndrome and the two percent idiopathic short stature, it was obvious to examine whether this form of therapy is also helpful in the other two patient groups.

A clinical study is currently underway in patients who have been found to have SHOX mutations. My working group is the reference center to carry out the necessary chromosome analyzes as well as the molecular SHOX diagnostics. We are also the center of data collection. Since treatment with recombinant growth hormone is not a causal therapy in the strict sense, we are currently concentrating on researching the natural target genes of the SHOX protein with the help of cell culture and animal models. We hope that this will help to develop new and rational therapies that can successfully treat short stature in children.

Prof. Dr. Gudrun Rappold,
Institute for Human Genetics,
Im Neuenheimer Feld 328, 69112 Heidelberg,
Telephone (06221) 565059, Fax (06221) 565332,
e-mail: [email protected]