PXE is always a genetic disease. That is, it is always caused by a combination, or combinations of altered genes, ie genes that are not normal - also called "mutant" (changed) genes. That is why PXE is always referred to as a genetic disease. Unfortunately, the fact that it is classed as a genetic disease does not mean that we can identify the pattern of inheritance in every single family in which it occurs.

Every human being has to sets of genes, one set of which is inherited from the mother, in the ovum or egg and one set which is inherited from the father, in the sperm. Every human being therefore has two copies of every gene except those that determine gender (sex). There is no form of PXE that is X-linked or sex linked.

Recessive Inheritance

PXE is recessive. In this situation, each parent is a carrier for one mutant copy of a different PXE gene, which, when coupled with a normal copy is undetectable. That is, it causes no recognisable diseases or trait. So, when two carriers have children there are four possible outcomes to any pregnancy:

1. The child gets one normal copy from the male side and one normal copy from the female side. Thus, this is entirely genetically normal and appears normal.
2. The child gets the normal copy from the male side and the PXE copy from the female side and is therefore a carrier same as the parent but has no detectable trait.
3. The child gets the PXE copy from the male side and the normal copy from the female side and is therefore a carrier same as the parent but has no detectable trait.
4. The child gets the PXE copy from the male side AND the PXE copy from the female side, The child thus has two PXE copies and NO NORMAL COPY. This child is therefore affected.

There is no way of proving that the parents are carriers until they have another affected child, in which case, the only reasonable interpretation is that both parents are carriers. The risk to any subsequent pregnancy is one chance out of four to be affected and three chances out of four that the child will not have the trait and will appear normal. (But remember, two of those three normal-appearing children will be carriers, and one of the three will be genetically normal-normal).

Isolated Case

Then there is the isolated case where the affected individual is the only KNOWN individual in the family and there is no known risk factor for a special situation, such as a close genetic relationship between the parents, eg as cousins, which would increase the probability that each parent, descended from the common ancestor, has exactly the same copy of the recessive gene for this trait.

How do we interpret the isolated case? There are a number of considerations, which in this short space cannot be detailed but, in general, there are some operant rules that must be thought about and considered:

1. Has each parent of the affected been examined for minor features of the disease that might have gone unnoticed? This variability is a real and frequent mistake/oversight in dealing with isolated cases. Besides, in cases of later onset of the disease, some parents may be unavailable for examination by distance or by death!
2. Is the stated father of the affected really the biological father of the affected individual? The prevalence of non-paternity is nearly 10% of all live births, and rising!
3. Could there be a genetic relationship between the parents, such as first or second cousins, that would favour the recessive inheritance pattern of inheritance?