Rare Mutation in UROS Gene Linked to CEP Cases in Nepal

Three women in Nepal were diagnosed with the rarest type of porphyria, called congenital erythropoietic porphyria or CEP, as described in a recent case report.

Genetic analyses revealed the presence of a rare mutation in the UROS gene, one of the two genes underlying CEP, in two of these women. According to the researchers, these are the first reported cases of CEP in the Southeast Asian country.

The case report, “Congenital erythropoietic porphyria: A case series of a rare uroporphyrinogen III synthase gene mutation in Nepalese patients,” was published in the journal JAAD Case Reports.

CEP is a rare inherited disorder caused by defects in the uroporphyrinogen III synthase (UROS) enzyme, which is required for the production of heme — a molecule essential for transporting oxygen in red blood cells.

The disease is characterized by severe skin sensitivity to sunlight and chronic hemolytic anemia, or red blood cell destruction, due to the toxic buildup of heme precursors, called porphyrins.

In this study, researchers reported the cases of three Nepalese women who were diagnosed with CEP.

The first was a 37 year old who was initially diagnosed with CEP at age 17. This woman had a history of spontaneous blistering following sunlight exposure since she was born. The scarring of the lesions caused deformities in her hands, ears, and nose, which were noticeable by the time she was 18.

In early childhood, she had a red discharge in her diaper, as well as redness and matting of both eyes, according to her mother. The deformities also affected her eyelids, preventing their full closure. She had seven siblings, three of whom also were affected. Two died shortly after birth, and a third, her older sister, died at age 24. Neither parent showed any clinical signs of the disease.

A clinical examination revealed that the patient had thickened skin, skin tone alterations, and scarring of sun-exposed areas, among other symptoms. The skin tone alterations included both hypopigmentation, resulting in lighter skin areas, and hyperpigmentation, with darker skin areas.

Her eyes also were affected with severe ectropion — a condition in which the eyelid turns outward — and abnormally positioned eyelashes that grew back toward the eye. She also had changes in the sclera, the white part of the eye.

Additionally, this patient’s spleen was enlarged and a blood analysis showed several abnormalities. These included pancytopenia or low blood cell counts, and signs of inflammation.

The second described case was the first patient’s older sister, who died at age 24. She also developed skin blisters in her face and extremities following sunlight exposure. This was seen shortly after birth.

Like her sister, she had deformities that affected both hands and feet, ears, and nose. Her eyesight also was affected, particularly in her right eye, from which she reported poor vision since early childhood.

Skin alterations also were noted, including excessive hair growth over the face and arms. This woman had mild anemia and also an enlarged spleen. Genetic and blood analyses were not performed since they were both unavailable at the time. The patient had died from a secondary infection — one of the most common causes of death among CEP patients — at 24.

The third case involved a 35-year-old woman whose parents did not have any disease symptoms. At the time of treatment, she had deformities that affected both hands, and had experienced blisters since birth following sunlight exposure. Those blisters had led to changes in her skin tone, and to scarring that affected her face, arms, and legs.

She had a history of recurrent inflammation of the cornea (the transparent front part of the eye) and conjunctiva (the tissue lining the inside of the eyelids). Those conditions had resulted in the surgical removal of her left eye.

Additional symptoms included excessive hair growth on the face, having a small sized-mouth, and having mutilations to both hands. A blood analysis was normal, except for the porphyrin profile.

In the case of the first and third patient, genetic analysis revealed the presence of a rare mutation in the UROS gene. The women were advised to wear strict protections against light and to take vitamin D supplements. Additional counseling was given regarding the need for long-term follow-ups, wound care, and lifestyle modifications.

“The management of CEP is challenging,” the researchers wrote.

“Prevention of primary manifestations with strict photoprotection along with vitamin D supplementation and frequent monitoring of hematologic indices remains the only applicable management strategy in the context of third world countries like Nepal, where gene therapy and newer drugs are not available,” they wrote.

Despite the challenges in such countries, the team called for increased efforts to diagnose porphyria.

“Early diagnosis and management by a multidisciplinary team of physicians, hematologists, dermatologists, and wound care specialists is recommended. Genetic counseling and prenatal diagnosis are valuable for risk reduction,” they concluded.