Lay Summary: Acquired pseudoxanthoma elasticum after liver transplant

JULY 13, 2012
By Rachel Koren, Research Intern,
and Christine Vocke, Director of Education and Information, PXE International

This article first appeared in the July 2012 PXE eNewsletter

Bercovitch L, Martin L, Chassaing N, Hefferon TW, Bessis D, Vanakker O, Terry SF. Acquired pseudoxanthoma elasticum presenting after liver transplantation. J Am Acad Dermatol 2011 May;64(5):873-8. Epub 2011 Mar 12. PMID: 21397982 Free PMC Article


Pseudoxanthoma elasticum (PXE) is almost always an inherited recessive genetic disorder that is present from birth. Recessive inheritance means that mutations in both genes associated with PXE (the ABCC6 gene) must be present to cause the disease. One mutation is not enough to cause PXE. Two parents who each have one mutation in the ABCC6 gene will not themselves have PXE, but will be carriers of the mutated gene. If his or her child inherits one copy of the mutated gene from each parent, that child will develop PXE. For a more detailed description of how PXE is inherited, please see PXE and Inheritance.

While this is normally how pseudoxanthoma elasticum develops, this article discusses three cases of young women who developed PXE without having inherited two copies of the mutation from their parents. When PXE develops in this way, it is called acquired PXE and it is extremely rare. However, acquired cases are of particular interest to scientists because they might be able to provide additional insight into the processes that directly cause the symptoms of the disease.

Recently a team of researchers examined three cases involving young women who acquired PXE even though they previously had no detectable signs or symptoms of the disease. Using skin biopsies, eye exams and sequencing of the ABCC6 gene, the researchers examined the young women and their families to make sure that they had not inherited PXE in the usual way. It was determined that all three patients were not at risk for the genetic development of PXE – neither they nor their families had any mutations in the ABCC6 gene.

After determining that each patient did in fact have signs and symptoms of PXE, they tried to determine how it had come about. Researchers discovered that each of the three women had received a liver transplant due to varying childhood health problems. Further, each patient reported PXE symptoms only after they had received the transplant. While there was not enough evidence to say for certain, the researchers hypothesize that these cases of acquired PXE were directly related to the liver transplants.

Case #1

The first case of acquired PXE was a 27 year old woman who had been born with a disease that prevented her liver from functioning correctly. She received a full liver transplant from a deceased donor when she was 11 years old. Her body struggled with the new transplant and 13 years later she also had a kidney transplant.

She continued to struggle with both transplants for about a year, and eventually her kidney and liver function stabilized. However, in that year of difficulty, the patient noticed yellowish bumps appearing on her neck, a very common symptom of PXE. Her eyes did not initially show any disease symptoms, but eventually she developed small angioid streaks, breaks in the membrane covering the back of the eye, that are very characteristic of PXE. Her skin symptoms also progressed, resulting in loose and sagging areas of skin and more bumps on her arms, underarms, groin and the backs of her knees.

When it was determined that she did not inherit PXE in the normal way, researchers wanted to test her donated liver and kidneys for mutations in the ABCC6 gene. Because they were not her own organs, her transplanted liver and kidney contained different DNA than her own. The ABCC6 gene is most active in the liver and kidneys, which led the scientists to believe that mutations in the DNA of her donated organs might be the source of her symptoms. They were unfortunately not able to obtain samples of liver that could be tested for the ABCC6 gene. They were able to test the DNA in her kidneys, but they did not find any mutations in the ABCC6 gene that were indicative of PXE.

Case #2

The second patient had a long childhood battle with poor liver function that resulted in a full liver transplant from a deceased donor when she was 21. A few months after the surgery, she developed yellowish bumps on the side of her neck and then in the folds of skin under her arms. A dermatologist recognized them as symptoms of PXE, but unlike the woman in the first case, she did not have any symptoms in her eyes and still had not developed them at the time this study was conducted, eight years later.

Other body systems that sometimes show symptoms of pseudoxanthoma elasticum, such as the heart and vascular systems, also showed no signs of the disease. None of her family members showed any signs of PXE and her own blood tests came back negative for any mutations in the ABCC6 gene. Scientists again wished to test her donated liver for mutations in the ABCC6 gene, but unfortunately no samples were available.

Case #3

The third young woman developed acute liver failure at a very young age and received a full liver transplant from a deceased donor when she was six years old. When she was 12 years old, she developed skin symptoms characteristic of PXE on the back and sides of her neck.

The liver transplant however was not entirely successful, and 11 years later when she was 17, the first transplant was removed and she received a partial liver transplant from a living relative, her mother. Her skin symptoms continued to worsen for two years after the second transplant, but then stopped and did not progress further. Her eyes and other commonly affected body systems were also found to be completely normal six years after her second transplant.

No mutations associated with PXE were found in this patient or any of her family members. Further, the patient and her mother were found to have identical DNA in every place along the ABCC6 gene where PXE mutations are known to occur. Scientists attempted to test samples of the patient’s first liver transplant to see if DNA samples would contain mutations indicative of PXE. However, due to imperfections in the testing method itself, they were unable to test it for any mutations that could cause PXE.


In inherited PXE, angioid streaks and vision impairment very rarely surface in the first 20 years of life, but case 1 developed eye symptoms very soon after her liver transplant. She was also the only case of the three to develop symptoms of PXE in the eyes. It is equally uncommon in inherited PXE to see skin manifestations before three or four years of age. However, case 2 presented skin symptoms only one year after surgery. On the other hand, case 3 did not have skin symptoms until six years after the transplant. All three of these acquired cases of PXE seemed to have a less predictable period of onset than cases of inherited PXE, and the symptoms also appeared to be less severe overall. Long-term studies have not been conducted to determine this with certainty.

While researchers were unable to test the donated liver for PXE mutations in any of the three cases, they still hypothesize that it was mutations in the donor livers that caused the onset of PXE symptoms in these women. Pseudoxanthoma elasticum is commonly thought to be a metabolic disorder, a disease that disrupts the chemical reactions that occur in the body, mostly in the liver, that help create or break down molecules and transport them throughout the body. Scientists hypothesize that those with PXE do not properly move a substance produced in their liver out into the bloodstream. This substance would counteract the mineralization of the elastic fibers in the body that causes the symptoms of the disease.

Acquired PXE is extremely uncommon, but these three cases are unlike any that have been previously observed. Prior case studies have all been women that were older and presented with issues of heart health before the onset of their symptoms. In addition, all three of these patients took different kinds of medications to suppress their immune systems after the transplant surgeries, so their PXE symptoms may not be attributed to any specific medication. Chronic kidney and liver diseases are also not known to cause PXE, and a liver transplant in an individual without PXE has never been known to cause the mineralization of elastic fibers in the body that would result in these PXE-like symptoms. Further, research has shown that other metabolic diseases may be acquired through liver transplantation if the donor liver is affected.

Experiments with PXE knockout (KO) mice have provided further evidence for the theory that PXE is indeed a metabolic disorder. A PXE KO mouse is one that scientists have bred specifically so that it does not possess a functioning ABCC6 gene. The gene has either been deleted altogether, or mutated in some way so that it can’t function properly. And just like humans with the same problem, the mouse develops PXE symptoms as it grows.

When PXE KO mice are surgically conjoined to normal mice with two functioning copies of the ABCC6 gene, so that they share blood circulation, researchers found that the symptoms of pseudoxanthoma elasticum in the PXE KO mice stopped progressing. If PXE symptoms are caused by lack of a substance that the PXE KO mouse inherently cannot produce or cannot move into circulation in the bloodstream, then it is thought that the shared blood flow from the normal mouse halts the progression of symptoms by introducing this substance into the PXE knockout mouse’s bloodstream. In another experiment with PXE KO mice, when liver cells from a normal mouse were grafted on the liver of a knockout mouse, up to 90% reduction in skin symptoms on the mouse’s muzzle were observed. Looking back to the third case study of acquired PXE, the PXE knockout mice point to the possibility that removal of the first transplant and the introduction of a new liver with a fully functioning ABCC6 gene might have halted the progression of her symptoms.


Unfortunately, when the study of these three cases of acquired PXE was conducted, it was well after the transplants had occurred, and there was much information that could not be obtained to complete the story. All three of the original liver donors were deceased, and there were no other tissue samples available from the deceased donors to test for mutations of the ABCC6 gene. In case 2 there were no liver samples to test, and in cases 1 and 3, the samples were not suitable for accurate testing.

In the end, the researchers were not able to provide conclusive evidence that mutation of the ABCC6 gene in the donor livers caused these three individuals to acquire pseudoxanthoma elasticum. However, the experiments performed with the PXE knockout mice do provide evidence that it is a valid theory. Further study with the mice as well as additional case studies of acquired PXE might allow researchers to eventually test the idea more conclusively.