New Mutations Linked to Fetal Bone Fractures During Pregnancy

Scientists have identified a set of new genetic mutations as the likely cause of bone fractures during the embryonic development of a baby born to a woman with hypermobile Ehlers-Danlos syndrome (hEDS).

One of the mutations was found in the CCDC134 gene, which had been previously linked with bone fragility.

These findings support the addition of CCDC134 to panels screening for genes associated with bone fragility. They also might help design new approaches to treat the issue in babies with these mutations and brittle bones associated with other disorders.

“We will be able to develop new approaches not only for treating bone fragility in infants with this genetic disorder, but also for treating bone brittleness associated with osteoporosis, which is associated with enormous cost both in terms of quality of life and medical expenses,” Michael F. Holick, PhD, MD, professor at the Boston University School of Medicine and the study’s lead author, said in a press release.

The case report, “Fetal Fractures in an Infant with Maternal Ehlers-Danlos Syndrome, CCDC134 Pathogenic Mutation and a Negative Genetic Test for Osteogenesis Imperfecta,” was published in the journal Children.

EDS and osteogenesis imperfecta are two genetic disorders reported to underlie intrauterine bone fractures. Other non-genetic conditions include child abuse (non-accidental trauma) and predisposing maternal metabolic and vascular disorders.

While EDS is characterized by hypermobility in the joints, meaning the joints readily stretch farther than normal, osteogenesis imperfecta is marked by bone fragility and osteopenia (lower than normal bone mineral density).

Osteogenesis imperfecta is a common cause of inherited bone fragility, with the majority of the cases (90% minimum) being caused by mutations in the COL1A1 or COL1A2 genes.

In previous research, however, a number of patients with clinical symptoms of osteogenesis imperfecta lacked mutations known to cause the disorder, indicating other conditions that may result in bone fragility.

In this study, a group of researchers at the Boston University School of Medicine described the case of a baby boy with 23 intrauterine fractures.

The mother, 34, had been previously diagnosed with hEDS, the most common form of the disorder. She and her family had participated in the Genetics of Ehlers-Danlos Syndrome clinical study (NCT03093493), which is recruiting at Boston Medical Center.

At 32 weeks and one day of gestation, ultrasound revealed a delay in fetal growth, a reduced thoracic size, short limbs, and multiple fractures, all suggesting osteogenesis imperfecta.

After the patient gave birth via an uncomplicated C-section at 40 weeks gestation, a follow-up examination confirmed the fractures previously seen in the ultrasound. These included multiple fractures in the ribs, humerus (a long bone located in the upper arm), and the femur or thigh bone.

The newborn was transferred to Boston Children’s Hospital for bisphosphonate therapy (to treat bone loss), further management, and genetic testing.

DNA analysis at six months did not reveal the infant had any disease-causing mutation of osteogenesis imperfecta, EDS, or other genetic disorders resulting in intrauterine or infantile skeletal fragility.

However, he was positive for potential disease-causing variants in genes previously linked with frail bones. These included variants in both copies of the genes CCDC134, COL15A1, and ZFPM1, and variants in a single copy of the genes MYH3, BCHE, and AUTS2.

Overall, “based on these findings, it can be concluded that the multiple intrauterine fractures in this infant may be caused by the combination of these genetic variants,” the researchers wrote.

One particular gene, CCDC134, had been previously linked with bone fragility. 

“We are recommending that the additional gene we identified as being the likely cause for this infant’s fractures, be included in the genetic panel for bone fragility and that careful consideration be given for other causes of infantile fractures other than OI [osteogenesis imperfecta] and non-accidental trauma,” Holick said.

The team wrote: “These findings should also give pause to the diagnosis of nonaccidental trauma in infants or children with fractures characteristic of OI but with negative OI testing.”

Holick added that if the infant “were brought into the hospital with an upper respiratory tract infection at eight weeks of age, an x-ray of his chest would have revealed healing fractures of his arms and multiple healing fractures of his ribs. A skeletal survey would have revealed the healing fractures in both his legs. He would have been tested and found not to have OI, and therefore the diagnosis for the fractures would have been that they were caused by non-accidental trauma.”

“The child would have been immediately removed from the care of his parents and the parents would have been accused of felony child abuse,” he said. “It is hoped that this case report will now give reconsideration for diagnosing child abuse solely based on x-ray findings of a fracture or fractures with a negative genetic test for OI.”