Identical 12-year-old twin sisters with the same genetic mutation have ended up with very different lives, with the muscles of one being transformed into bone while the other is developing normally.
The sisters, named Cayetana and Celia, live in Portosín in northwest Spain, and as identical twins share the exact same DNA. This includes the rare genetic mutation that causes the condition progressive osseous heteroplasia (POH).
However, only Cayetana suffers from the effects of the condition, while Celia has next to no symptoms, newspaper El Pais reports.
POH is a genetic condition that causes skin, muscle and fat tissue to slowly transform into bone, or ossify. This can cause ulcers to appear across the body at the sites of bone formation, and be incredibly painful, eventually turning joints and limbs to bone. The only treatment available is surgery to remove newly forming bone plaques.
"Caye has told me that she doesn't know what it's like to live a day without pain," the girls' mother, Loló Suárez, told El Pais.
Cayetana requested a few years ago that both her legs, which had nearly entirely turned to bone, be amputated, and now uses a wheelchair.
POH was only discovered in 1994, by Fred Kaplan of the University of Pennsylvania. He was studying 125 patients with fibrodysplasia ossificans progressiva (FOP), a similar but different condition that causes bone to form where it shouldn't, often known as "stone man disease."
POH is caused by a mutation in the GNAS gene, which controls bone formation in the body. Only around 50 people in the world have been recorded to have POH, according to the National Organization for Rare Disorders.
Doctors have spent years studying the sisters to investigate why only Cayetana suffers from the symptoms of the condition, while Celia does not, despite also having the same GNAS gene mutation.
"It seemed like a perfect experiment: two identical people, one sick and the other healthy, but it's not being so obvious," pediatrician Federico Martinón Torres, who co-leads the group investigating the sisters, told El Pais.
The exact reason for the difference in their symptoms has not yet been found but researchers have a number of theories.
As neither of the girls' parents have the mutation, it must have arisen after the fertilization of the egg that divided to create their two embryos. The researchers suggest that Cayetana received an epigenetic imprint that caused the gene to have been turned on or off at different locations in her body, in what is known as mosaicism.
Epigenetic imprints are changes in the expression of genes, i.e. whether a gene is switched on or off.
"This is all speculative. Unfortunately, we lack evidence. We could be completely wrong," geneticist Antonio Salas, co-director of the research group and professor at the Faculty of Medicine of the University of Santiago de Compostela, told El Pais.
However, research into the girls' epigenetic markers has revealed no difference between the twins as yet.
The next step is to look for differences in other tissues, such as Cayetana's calcified skin, muscles, and bones.
Other doctors have weighed in on the issue, including Kaplan himself.
"I think that the two twins share the same mutation, but the most affected sister probably had a second mutation very early in the development of the embryo, in the GNAS gene itself or in another that interacts with it," he told El Pais.
David Liu from Harvard University, an expert on rare genetic diseases, suggested that the difference between the twins would be hard to discover but may be identified eventually.
"Those modulatory factors can be very difficult to find. It is unlikely that doctors have been able to identify and rule out all possible genetic and epigenetic variations between the twins," he told El Pais.
Because of PHO's rarity, life expectancy is unclear, but for individuals with the similar disease, FOP, the median lifespan is 56 years.
"We are realistic regarding whether anything can be achieved that arrives in time for Cayetana, but we will thank our lucky stars if all…this effort that we have made can help any other child," Suárez said. "I would also be the happiest mother in the world, even if it did not come in time for my daughter."
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Jess Thomson is a Newsweek Science Reporter based in London UK. Her focus is reporting on science, technology and healthcare. ... Read more
