MDP syndrome
MDP syndrome, also known as mandibular dysplasia with deafness and progeroid features, is an extremely rare metabolic disorder that prevents fatty tissue from being stored underneath the skin. It is only known to affect a very small number of people worldwide. Research has suggested that it may be caused by an abnormality of the POLD1 gene on chromosome 19, which causes an enzyme crucial to DNA replication to be defective.
Presentation
- mandibular hypoplasia,
- deafness,
- tightening of the skin,
- lipodystrophy,
- low testosterone levels in males,
- contractures of the long tendons of the toes resulting in claw toes and joint stiffness.
Genetics
Initially all people that have been identified with this syndrome have an identical genetic change, an inframe single codon deletion in POLD1 resulting in a loss of serine at position 605. The POLD1 gene is expressed in all cells and the particular change seen in most patients results in loss of DNA polymerase activity but only mildly impairs the proof reading exonuclease activity. In 2014 a second genetic change was reported in an Italian patient, a novel heterozygous mutation in exon 13.Most cases identified to date have been caused by a spontaneous genetic change.
Diagnosis
The diagnosis of MDP syndrome is suggested by the clinical features. It can be confirmed by finding a mutation in the POLD1 gene, a service offered by the molecular genetics team at the Royal Devon and Exeter NHS Foundation Trust / Exeter University who originally discovered the genetic cause.Management
General appearance
Appearance at birth and during the early years is normal but features become more prominent during later childhood prior to puberty. The main issues appear to be lipodystrophy and slow growth of cartilage and ligaments. The slow growth of cartilage and ligaments results in a small nose, small mandible, small ears and tightening of ligaments in the limbs. A small larynx can mean the voice is likely to remain high pitched.Lipodystrophy
A major feature is lipodystrophy. The characteristic changes in facial appearance occur from the loss of fat from the cheeks, and around the eyes. Dry eyes and the failure to close eyes during sleep can be a feature due to the loss of fat around the eyes. Limbs appear very thin due to lack of fat storage and also reduced muscle mass. There is a large amount of fat within the abdominal cavity which, can be particularly marked in the liver and surrounds the other organs. A major result of the lipodystrophy in some people is severe insulin resistance so insulin does not work very well leading to diabetes and high triglyceride levels in the blood. The effect of insulin resistance can be variable and may relate to progression of the lipodystrophy or may reflect variation between individuals.The skin has a lack of fat and fibrosis. These in turn result in the tight skin on the face and limbs. One direct feature of the lipodystrophy is that the skin is fragile and there is not the protection normally provided by fat under the skin.
Management of lipodystrophy
As fat cannot be stored under the skin it is important to have a healthy diet without excess fat. Often due to failure to thrive or lack of subcutaneous fat there may have been encouragement to add supplements or fat to the diet however this will not result in any increase in fat under the skin and can easily result in it going into tissues such as the liver or kidney where it is not desired. In people with moderate / severe lipodystrophy a low fat diet would be recommended but in those where the lipodystrophy has not progressed a healthy relatively low fat diet may be sufficient. The fat and muscle reduction is not the result of dietary insufficiency and cannot be treated with dietary measures. Apart from diet the other thing that is important is exercise which should be encouraged and will make insulin work more effectively.In those who have not developed diabetes it is recommended fasting insulin, triglycerides, glucose and HbA1c should be measured annually to monitor insulin resistance and blood glucose.
In those with diabetes it is suggested using metformin in doses of at least 2g/day as it decreases insulin resistance and improves insulin sensitivity, following appropriate clinical consultation.
The thin skin means if there is trauma there should be rapid attention to any wounds to avoid infection and help primary healing as there can be problems with skin ulcers.