The Genetics of Chronic Recurrent Multifocal Osteomyelitis (CRMO)

Project summary: Is there a genetic cause for chronic recurrent multifocal osteomyelitis?

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare disease of childhood. The child’s bones become inflamed inappropriately; this is called auto-inflammation. This causes pain, swelling and difficulty using the affected parts of the body. Poor growth or fractures in the affected bone can lead to unequal limb length or abnormal curvature of the spine (scoliosis) which are serious long-term problems. CRMO affects one or many bones and symptoms usually recur over many years. The cause of CRMO is not known but there may be a genetic basis because it sometimes affects more than one member of a family.

This study will look at an Irish CRMO population using state-of-the-art technology to study patients’ genes. The specific genetic test we propose to do is called whole exome sequencing and looks at all the parts of the gene that make proteins. This may lead to the identification of differences in one or more genes that could cause CRMO. This information may allow us to personalise treatment to suit individual patients and control the disease more effectively. This will improve the quality of life of patients with CRMO with less disturbance to schooling, physical activities and social interactions.

The full title of the project is: Whole exome mapping of genetic variants linked with the development of chronic recurrent multifocal osteomyelitis

Project details: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory disease of childhood which affects one child per million. Auto-inflammatory diseases lead to recurrent episodes of inflammation in specific parts of the body with no obvious trigger. In CRMO, this inflammation occurs in bone leading to localised pain, swelling and difficulty using the affected parts of the body. Poor growth or fractures in the affected bone leads to unequal limb length or abnormal curvature of the spine (scoliosis) which are serious long-term problems. CRMO affects one or many bones and symptoms usually recur over many years. The diagnosis is based on the patient’s symptoms and scans of the affected bones although a biopsy sample of the bone is often needed to exclude other causes of bone pain such as infection or cancer.

The cause of CRMO is not known but it is likely that there is a genetic basis because it sometimes affects more than one member of a family. In addition, about 50% of patients with CRMO have a first or second degree relative with another chronic inflammatory condition such as psoriasis, arthritis or inflammatory bowel disease. Studies have looked at a small number of genes which are known to cause other auto-inflammatory diseases but have failed to find a gene which causes CRMO. Since 2006, 43 patients have been diagnosed with CRMO at the National Centre for Paediatric Rheumatology (NCPR) in Dublin. This indicates that the disease affects around 1 in 100,000 rather than 1 in a million. This may mean that there is a stronger genetic cause in the Irish population.

This study will look at a large Irish CRMO population using state-of-the-art technology to study patients’ genes. Genes are made of parts called introns and exons. Exons are the part of the gene that make proteins. Proteins tell a cell what type of cell it is and how it should behave. All the exons together are called the exome. The specific genetic test we propose to do is called whole exome sequencing and looks at the whole exome. Scientists compare the sequence of a patient’s exome with that of a normal exome. The location of differences in the sequence are marked. If the difference affects genes that control bone growth, inflammation and the immune system it will be studied further because it may cause CRMO.

The outcome will be the identification of differences or variants in one or more genes that could cause CRMO. This information may allow us to personalise treatment to suit individual patients and control the disease more effectively. This will improve the quality of life of patients with CRMO with less disturbance to schooling, physical activities and social interactions. It will also reduce healthcare costs associated with hospital admissions. The information will lead to further studies which will look at the function of the cells that the genes control. 

This work will be completed by Dr Daire O'Leary and is supervised by Prof Gerry Wilson, Dr Orla Kileen & Prof Michael McDermott. 

This project is funded by the National Children's Research Centre