After 80 Years, Medical Mystery Behind Infant Deaths Is Finally Solved

New research has revealed the science behind an eight-decade-long medical mystery involving a number of infant deaths from kidney damage in the 1930s and ‘40s. The study is published in the Journal of Bone and Mineral Research.

Repercussions of vitamin D fortification

During the early 20^th century in North America and Europe, large numbers of children were affected by rickets, a disease caused by a lack of vitamin D. Rickets softens and weakens the bones, causing pain and bone deformities. It is estimated to have affected around 80% of children in industrialized areas.

After the link between rickets and vitamin D deficiency from a lack of sunlight was discovered, foods such as milk, bread and cereal began to be fortified with the essential vitamin. This initiative had nearly eliminated the disease by the 1930s.

However, fortification bans were put in place during the 1950s in response to a spate of infant deaths caused by vitamin D intoxication – a dangerous buildup of calcium in the blood that can lead to kidney stones and damage to kidney tissue.

Modern research has revealed that these cases of vitamin D intoxication were caused by a genetic mutation leading to a condition known as infantile hypercalcemia type 1 (HCINF1). However, around 10% of patients who experience symptoms of the condition do not carry the mutation.

“This really puzzled us,” said Dr. Darrell Green, co-senior author of the study and lecturer at the University of East Anglia. “So we wanted to find out exactly why this 10% appeared to have the condition, but without the gene mutation that was found to cause it.”

Shaping the investigation

A previous study showed that a mutation in a gene called CYP24A1 is responsible for the condition. However, there is no obvious sign of CYP24A1 mutation in around 10% of suspected HCINF1 patients. Unfortunately, these patients’ symptoms continue to persist and generally go without a formal diagnosis.

In their study, Green and colleagues used computational models and next-generation sequencing to study a group of 47 patients from this population of suspected cases. In-depth genetic analysis of six of these blood samples revealed that CYP24A1 genes were abnormally shaped in the suspected HCINF1 cases.

“This tells us that gene shape is important in gene regulation – and that this is the reason why some people lived with HCINF1 but without a definitive diagnosis,” Green explained. “On a wider scale relevant to genetics and health, we know that genes must have the correct sequence to produce the correct protein, but in an added layer of complexity, we now know that genes also have to have a correct physical shape.”

Implications for other conditions

Professor Bill Fraser, also a co-senior author of the study, treats patients with HCINF1 in metabolic bone clinics. He added: “Genetic causes of vitamin D toxicity can be left undiagnosed for long periods, well into adulthood, sometimes coming to light during pregnancy when fortification of mothers with vitamin D happens. We also see patients with undiagnosed causes of recurrent renal stones who have had this condition for many years.”

The authors currently plan to expand on this research by exploring the implications of gene shapes in other conditions such as cancer.

Reference: Ball N, Duncan S, Zhang Y, et al. 3′ Untranslated region structural elements in CYP24A1 are associated with infantile hypercalcemia type 1. JBMR. 2023. doi: 10.1002/jbmr.4769.

This article is a rework of a press release issued by the University of East Anglia. Material has been edited for length and content.