Rare mutation causing hereditary iron disorder leads to PCT: Report

Iron overload helped drive development of porphyria cutanea tarda in man, 21

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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A rare mutation in the HFE gene, called H63D, was found to be the cause of hereditary hemochromatosis, a condition marked by iron overload, that ultimately led to porphyria cutanea tarda (PCT) in a 21-year-old man in the U.S., a case report shows.

This case demonstrates the occurrence of “PCT in the setting of previously undiagnosed HH [hereditary hemochromatosis] caused by [two copies of the] H63D mutation in the HFE gene, which has rarely been reported,” researchers wrote.

The case study, “A rare case of porphyria cutanea tarda in a patient with a homozygous HFE H63D mutation in the setting of hereditary hemochromatosis,” was published in JAAD Case Reports.

Porphyria is caused by disruptions in the production of heme, an essential molecule for the transport of oxygen throughout the body, leading to the toxic accumulation of heme precursors and intermediate molecules called porphyrins in the body.

PCT, the most common form of porphyria, is caused by reduced activity of the uroporphyrinogen decarboxylase (UROD) enzyme in the liver. It is characterized by sunlight sensitivity that may cause blisters in exposed skin areas. Although the disease can be inherited, it is most often triggered by environmental factors.

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Hereditary hemochromatosis is known risk factor for PCT

Hereditary hemochromatosis, a disorder marked by iron accumulation, particularly in the liver, is a known risk factor for PCT. It may be caused by certain mutations in both copies of the HFE gene, which provides the instructions to produce a protein of the same name that regulates iron absorption.

Two mutations in the HFE gene, C282Y and H63D, “are essential factors in the development of PCT,” the researchers wrote, but the H63D mutation seems to be less frequent than C282Y in PCT patients.

Such mutations prevent the HFE protein from interacting with other proteins, leading to an accumulation of iron over time.

“It is theorized that iron may inhibit [block] UROD through direct suppression or indirectly as an essential cofactor in generating the UROD inhibitor uroporphomethene,” the researchers wrote.

They described the rare case of a 21-year-old man in the U.S. with signs of PCT which was found to be driven by previously undiagnosed hereditary hemochromatosis caused by the H63D mutation.

“Though the association between PCT and HH is well known, the association with the HFE H63D mutation, to our knowledge, has only been reported once in the medical literature,” the researchers wrote.

In the new report, the patient had experienced three months of recurrent skin blisters on his hands and fingers that were not associated with any other symptom. He reported no chronic conditions and no current use of medications.

Upon examination, the man was found to have noninflammatory vesicles characterized by excessive scar tissue on the back of his hands, and crusting in the fingers.

A skin biopsy showed structural abnormalities consistent with PCT, as was the detection of high levels of porphyrins in the urine.

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Patient underwent genetic testing for hereditary hemochromatosis

Considering the patient’s age and the absence of other predisposing factors, including no viral infections affecting the liver, he underwent genetic testing for hereditary hemochromatosis.

The young man was found to have the H63D mutation in both copies of the HFE gene, confirming hereditary hemochromatosis as the cause of his PCT.

Blood tests revealed higher-than-normal levels of ferritin, a blood protein that stores iron in cells, and slightly higher levels of two liver enzymes that are used as markers of liver damage.

The patient was advised to avoid exposure to sunlight, as well as alcohol and medications that could cause liver damage. He was also prescribed fluocinonide, a topical corticosteroid for skin lesions, but no significant improvements were observed.

Phlebotomies, a procedure that removes blood from the body and commonly used to treat people with elevated blood iron levels, were then performed every two weeks, until the patient showed close-to-normal levels of ferritin and hemoglobin. Hemoglobin is the protein in red blood cells that contains iron and transports oxygen throughout the body.

This treatment resulted in the patient’s complete remission of skin symptoms of the disease.

“In this case, iron overload in the setting of HH played a vital role in the development of PCT in an otherwise healthy individual,” the researchers wrote, adding “the benefit of removing [blood] iron through phlebotomy supports the critical role of iron overload in this disease.”