Case Study Highlights Challenges of Diagnosing CEP Before Birth

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by Steve Bryson, PhD |

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before birth | Porphyria News | congenital erythropoietic porphyria | illustration of one person highlighted in red amid a large crowd of bodies

Unusual cases of congenital erythropoietic porphyria (CEP) occurring before birth may lead to miscarriage, as highlighted in a recent study describing the cases of two siblings.

The amniotic fluid — the liquid that surrounds the developing fetus in the womb — in both pregnancies was not dark as expected for prenatal CEP, which made the diagnosis difficult, the researchers noted.

The case study, “An Atypical Case of Congenital Erythropoietic Porphyria,” was published in the journal Genes.

CEP, also known as Günther disease, is the rarest form of porphyria caused by mutations in either the UROS or GATA1 genes, which are essential for heme production, the molecule that helps transport oxygen in living cells.

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Due to faults in these genes, heme metabolites, or porphyrins, build up to toxic levels in bone marrow, urine, and feces, as well as in red blood cells, leading to their destruction (hemolysis).

CEP occurs most often either at birth or in early infancy. To date, eight cases of CEP occurring before birth (antenatal presentation) have been reported in the literature.

Fetuses with CEP typically have fluid buildup in different parts of the body (hydrops fetalis), shorter upper leg bones (femurs), abnormal-looking bowels on ultrasounds, and signs of internal organ damage. Facial deformities and impaired bile flow are also seen. Further, the amniotic fluid surrounding them in the womb typically has a dark-reddish-brown color due to the buildup of porphyrins.

In this case study, researchers at Normandie University in France described the case of two siblings with rare prenatal CEP that was difficult to diagnose.

“This case is of educational interest, and prompt to consider CEP diagnosis even in the absence of dark amniotic fluid,” the team wrote.

A 39-year-old woman was pregnant with twins, and during the second trimester, an ultrasound indicated one male fetus had abnormal-looking bowels and shorter femurs. At 22 weeks of pregnancy, the woman had a miscarriage. The second fetus was healthy.

After examining the male fetus, physicians noted he had short long bones in both legs and arms, along with fluid buildup in different parts of the body and an enlarged spleen. Microscopic analysis revealed malformed red blood cells.

One year later, the woman had a spontaneous miscarriage during a second pregnancy. Then, one year after that, an ultrasound on a fourth fetus showed malformations of the lymphatic system, fluid buildup in the abdomen, short femurs, and a heart defect. At 19 weeks, the healthcare team terminated the pregnancy for medical reasons.

A subsequent examination confirmed fluid buildup, enlarged spleen, short long bones, abnormal bowels, blood vessel defects, smaller-than-normal kidneys, malformed lungs, heart problems, and facial deformities, including a short forehead, large nose, widely spaced eyes, undersized jaw, and low-set ears.

At a microscopic level, there was evidence of iron overload, small blood clots, abnormal red blood cells, kidney cell death, heart muscle defects, and increased immature red blood cells in the placenta.

Yet no dark brown tissue deposits were found in any of the fetuses. Both parents had normal hemoglobin, the protein that binds heme and carries oxygen throughout the body.

Blood sample analysis of the fourth fetus suggested a disease of the lysosomes, the compartments within cells that break down and recycle protein and other molecules. However, further biochemical assessments did not confirm this diagnosis and also ruled out other diseases.

At this point, inherited metabolic diseases were considered, and as a result, tissues from both fetuses were sent for genetic analysis. These tests revealed a mutation in both copies of the UROS gene. According to the literature, this mutation was considered disease-causing with a low frequency in the general population and accounted for 30% of gene variants that cause disease. Further analysis confirmed that both parents carried a single copy of the faulty UROS gene.

“The ultrasound and [bodily] features such as dark brown tissue deposits are not always sufficient in congenital erythropoietic porphyria with antenatal onset and may lead to a diagnostic wavering,” the researchers wrote. “It is therefore important to regularly update the panel gene list and add all the new documented [causes of disease] that can lead to a hydrops fetalis.

“This also highlights the paradigm shift in [inherited metabolic disease] investigations using integrative methods,” they wrote.