by Tim Bonfield

Drs. Vivian Hwa and Andrew Dauber.

Drs. Vivian Hwa and Andrew Dauber have identified gene variants in DNA damage repair, cell cycle dynamics, growth plate signaling and other aspects of development. Their findings suggest that severe growth disorders require a wider menu of treatments than most medical centers provide.

Andrew Dauber, MD, uses an old joke to illustrate the old ways of thinking about how to treat growth disorders.

A woman heading home from a restaurant encounters a man under the glow of a streetlight, searching for his lost keys. The woman asks the man, “Is this where you think you dropped the keys?” The man says, “No. I think I dropped them back there.” So the woman asks, “Why are you searching for them here?” The man replies, “This is where the light is.”

For a long time, the core approach to correcting severe growth disorders has been to give daily injections of growth hormone, a therapy that sometimes goes on for several years. The therapy can be quite effective when a hormone deficiency is the actual cause of short stature.

However, experience has shown that many children with growth disorders have no hormonal abnormalities. In fact, a 2013 paper in the Journal of Pediatrics, authored by Philippe Backeljauw, MD, and colleagues, reports that standard hormonal metabolic workups provided no answers for at least 80 percent of the patients referred to Cincinnati Children’s to determine the cause of their short stature.

Now, thanks to an explosion of genetic and genomic analysis technology, scientists are learning just how complex the seemingly straightforward outcome of short stature can be.

“As endocrinologists, we have tended to focus heavily on hormonal factors. But if you take a step back, there are many, many biological processes involved in growth,” Dauber says. “Disruptions can start as early in the developmental process as DNA replication or in the centrosomes that regulate cell division. There can be defects that affect DNA damage repair, the growth plates of bones, or the extracellular matrix. And yes, there can be defects in growth hormone and the growth hormone receptor.”

Hundreds, if not thousands, of genes may be involved, and variants anywhere along the line can affect growth.

A NEW CLINIC TAKES SHAPE

The new Center for Growth Disorders at Cincinnati Children’s was formed in August 2014 to bring together an expanded team of experts in endocrinology and genetics.

Dauber, a clinician with expertise in genomic analysis, had been based at Boston Children’s Hospital. He had published research in the field in collaboration with Vivian Hwa, PhD, a microbiologist-turned-endocrinologist who worked on growth hormone-IGF-I axis defects at the Oregon Health & Science University. Both relocated to Cincinnati to work with a growing team that also includes Backeljauw and geneticist Nancy Doan Leslie, MD.

Patients with severe short stature from more than a dozen nations have been referred to the center for deeper evaluation. Data from exome sequencing, hormonal evaluations and other tests are fueling several research advances.

“We have already identified gene variants in DNA damage repair, in proteoglycans and extracellular matrix, in growth plate signaling genes, in the IGF-1 axis, in cell cycle dynamics, and more,” Hwa says.

This explosion of data is redefining our understanding of growth disorders, including the very names of the syndromes.

“I’m a strong believer in the idea that we need to stop calling things by old syndromic names based on physical characteristics,” Dauber says. “We need to think about these conditions in terms of classes and subclasses based on molecular-genetic definitions.”

BETTER DEFINITIONS, BETTER TREATMENTS

It likely will take years to accomplish on a national or global scale, but efforts have already begun to provide therapies that more precisely address the actual causes of short stature.

For example, if a child has a certain gene defect that affects the function of their growth plates, they might benefit from receiving aromatase inhibitors; drugs that are known to prevent growth plates from closing. Growth hormone may not be necessary, or may serve only as a secondary treatment.

One immediate research goal will be to re-evaluate existing hormone-based therapies to document their effectiveness against emerging genetic subclasses of severe short stature. Improved outcomes could flow simply from adjusting dose levels among different groups.

Another level of research will be to find existing, approved drugs that may affect the molecular profiles of particular patient groups; drugs that may never have been thought to be useful in treating short stature.

Longer-term, scientists also will strive to develop new medications that specifically target molecular pathways revealed by rapidly expanding genomic research technology.

Eventually, Hwa and Dauber say treating short stature could become a matter of using gene testing to detect biomarkers that could be used to guide young children as soon as possible to the best available therapy for their conditions, thus giving them more time to grow.

In some cases, there may not be a way to help a child reach normal stature. Even so, knowing more about their condition could allow early interventions to manage co-morbidities that can have their own impacts upon quality of life.