Infantile hypercalcemia type 1 is a rare genetic disorder that affects the regulation of calcium levels in the body. These individuals may exhibit symptoms such as vomiting, constipation, dehydration, and developmental delays in severe cases.
Scientists at the University of East Anglia have discovered a long-standing medical mystery that can cause kidney damage in children and be fatal in infants. Those who suffer the condition are unable to properly utilize vitamin D. This leads to kidney damage and the formation of kidney stones.
In the 1930s and 1940s, infant fatalities increased as a result of fortifying foods such as milk, bread, cereal, and margarine with Vitamin D in an effort to eliminate rickets in children. In the 1930s and 1940s, infant fatalities increased as a result of fortifying foods such as milk, bread, cereal, and margarine with Vitamin D in an effort to eradicate rickets in children.
Recent research demonstrated that infantile hypercalcemia type 1 is caused by a gene mutation. However, about 10% of patients who experience symptoms do not have the genetic mutation.
"We wanted to see why this 10 percent seemed to be suffering with the condition, but without the gene mutation that was discovered to be the cause," said lead researcher Dr. Darrell Green of UEA's Norwich Medical School.
When rickets affected more than 80 percent of children in industrialized Europe and North America, the puzzle began in the early 1900s. It leads to bone pain, poor growth, and soft, weak, deformed bones.
Vitamin D fortifications were fortified in foods, which virtually eradicated the disease by the 1930s. However, severe vitamin D intoxication in children resulted in fortification prohibitions in many European countries by the 1950s.
"Vitamine D was traditionally used in dairy products, but it was eventually banned in many countries, except for in breakfast cereals and margarine," according to Dr. Green. In 2011, scientists discovered that some people develop a mutation in the CYP24A1 gene, which causes them to develop kidney stones and kidney damage, which may be fatal in infants.
After years of recurrent kidney stones and other difficulties, many people today do not realize they have a CYP24A1 mutation. This disorder is now called infantile hypercalcemia type 1, or HCINF1, and they continue to have lifelong difficulties without a proper diagnosis.
The UEA team worked with colleagues from the Norfolk and Norwich University Hospital, where they treated 47 patients.
To study blood samples from those '10 percent' of puzzled patients, they utilized next-generation genetic sequencing and computational modeling.
Nicole Ball, a Ph.D. student in my lab, performed a more extensive genetic examination of six patient blood samples, and we discovered that the physical shape of the CYP24A1 gene in these apparent HCINF1 patients is unusual.
"This demonstrates that gene shape is critical in gene regulation - and that this is the reason why certain individuals lived with HCINF1, but without a definitive diagnosis," said the author.
“We know that genes must have the correct sequence to produce the correct protein on a larger scale relevant to genetics and health, but in an additional layer of complexity, we now know that genes must also have the correct physical shape,” said Dr. Green.
Prof Bill Fraser, from both Norwich Medical School and Norfolk and Norwich University Hospital, co-led the research and treats HCINF1 patients in metabolic bone clinics.
"Genetic causes of vitamin D toxicity may be left undiagnosed for long periods, well into adulthood, sometimes coming to light during pregnancy when fortification of mothers with vitamin D occurs," said the author. We also see patients with undiagnosed causes of recurrent renal stones who have had this condition for many years. Treatment includes avoidance of vitamin D supplementation in people with particular genetic abnormalities."
"Some anti-fungal medications have a beneficial side effect, such as a decrease in active vitamin D levels, which can help patients live a longer life, which we are now prescribing in some patients," he said.
The researchers are now looking into the implications of gene shapes for other conditions, such as cancer.
Shelley O'Connor, a 34-year-old Norwich, was diagnosed with infantile hypercalcemia type 1 eleven years ago when she was pregnant with her first child at the age of 23.
At just 23 weeks, she began taking pregnancy supplements, which included vitamin D. She began to feel a pain such that midwives assumed she was going into an early labor.
"It was very frightening," she said. "The midwives thought I was going into labor. I was really worried for the baby, but the doctors discovered that it was actually a kidney stone caused by taking vitamin D as a pregnancy supplement."
Shelley has since had two children.
"I was diagnosed with HCINF1 and it explained a lot because I had problems with abdominal pain and UTIs in my childhood," she said.
Shelley now has to take pain medication and undergoes an operation every six months to clear calcium deposits that cause kidney stones.
"It was wonderful to be invited to participate in the study, and I hope that the findings will help others like myself," she added.
Nicole Ball, Susan Duncan, Yueying Zhang, Isabelle Piec, Jonathan C. Y. Tang, Inez Schoenmakers, Berenice Lopez, Allison Chipchase, Arun Kumar, Leslie Perry, Heather Maxwell, Yiliang Ding, William D. Fraser, and Darrell Green, 10 January 2023, Journal of Bone and Mineral Research. DOI: 10.1002/jbmr.4769.
UEA collaborated with the John Innes Centre, the Norfolk and Norwich University Hospital, Croydon University Hospital, and the Royal Children's Hospital in Glasgow.
