Genetic Studies of HME

The information in this section is based on a talk given at the first meeting of the HME Support Group on 13 September 1997 by Mr Hamish Simpson, Consultant Orthopaedic Surgeon. These pages were edited by Dr D G Small, BM, BCh, MRCP(UK) and were checked by the Speaker. They have been reviewed from time to time by Mr D E Porter, Senior Lecturer & Hon. Consultant in Orthopaedic Surgery, University of Edinburgh, Edinburgh, UK, most recently January 2008

Recent Discoveries

Genetic information in humans is carried on 23 pairs of chromosomes which are present in every cell. Recent studies have identified four chromosomes which may be affected in HME. These are:

Chromosome		Name of Gene
1		EXTL
8		EXT1
11		EXT2
19		EXT3

Changes in EXT1 and EXT2 seem to be the most common in HME. The X and Y sex chromosomes are not involved, confirming the clinical observation that boys and girls of an affected family have a similar chance of developing the condition.

Why are only some bones affected?

If you inherit an EXT gene from one of your parents, it is present in every cell of your body, including all the cells of every growth-plate. Why is it that you only develop lumps on some of your bones?

Chromosomes are present in pairs, one member of each pair coming from each of your parents. If one of your parents has HME due to a faulty EXT1 gene on chromosome 8 and you are affected, you will have inherited the faulty EXT1 gene but you will have also inherited a normal EXT1 from your other parent. Although this faulty EXT gene is present in every cell of your body, it only seems to affect the growth-plate cartilage. But why don't all your millions of growth-plate cells produce lumps?

The current theory is that a lump only develops when both the EXT genes in a growth-plate cell stop working. In most cells, the normal EXT gene ensures that bone growth is normal. It's only when the normal EXT stops working that the cell develops into a lump. (This has been confirmed by examining the chromosomes from a lump. Both EXT genes were faulty.)

So when an otherwise unaffected person develops an exostosis it means that both EXT genes in a growth-plate cell have gone wrong. This doesn't happen very often, so people who haven't got HME either have no lumps at all, or at most one. In contrast, in HME, a lump appears whenever one gene stops working (since the other one is already faulty). This seems to be quite common.
But why some people with HME get lots of lumps and others only a few remains a mystery.

Why are Genetic Studies important?

There are a number of reasons why genetic studies are important in HME:

• Better diagnosis:
• Affected families can be screened for EXT1 and EXT2. This is useful for testing children who may only be mildly affected.
• Variability:
• The changes in EXT1 and EXT2 that can lead to the development of HME seem to be quite varied. Analysis of these changes may make it clearer why some affected people develop lots of lumps and others only one or two.
• Prevention:
• This is quite a long way off but a greater understanding of what causes the lumps might lead to a way preventing them from developing.

All in all, the outlook today for people with HME is much more hopeful than it was only a few years ago.