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 (less than 10 cases have been diagnosed as of December 2014). Recent 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.

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.

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 (R507C).

Most cases identified to date have been caused by a spontaneous genetic change (so the parents of the individual are unaffected).

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 (see below) and slow growth of cartilage and ligaments. The slow growth of cartilage and ligaments results in a small nose, small mandible (jaw), small ears and tightening of ligaments in the limbs. A small larynx (due to the reduced growth of cartilage) can mean the voice is likely to remain high pitched (even in boys after puberty).

A major feature is lipodystrophy (a reduction in fat under the skin). 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 (rather than any excessive prominence of the eyeballs). 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 (but not always) 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.

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Wikipedia