Tag Archive for: Dwarfism

Andrew Dauber, MD, MMSc, at work

Breaking barriers in growth disorder treatment for families

Andrew Dauber, MD, MMSc, at work

Children with hypochondroplasia were previously left with no options for effective long-term treatment, but Andrew Dauber, MD, MMSc, and his team continue to see promising results for treating children with hypochondroplasia using vosoritide.

Paving new roads for families at dead ends

For many children with short stature and other rare genetic growth disorders, there have been no next steps after usual treatment options prove ineffective. Researchers at Children’s National Hospital are digging deeper to find the root genetic causes of short stature disorders and creating novel, nuanced treatment options that have the opportunity to change how the field approaches these cases. From the creation of the growth specialty clinic to creating a study for one patient, the endocrinology team at Children’s National is focused on treating children with the uniqueness that their growth disorders require.

Hypochondroplasia

Many short stature disorders are caused by genetic variations that slow the growth of cells in the growth plate.

Children with hypochondroplasia were previously left with no options for effective long-term treatment, but Andrew Dauber, MD, MMSc, chief of Endocrinology at Children’s National, and his team continue to see promising results for treating children with hypochondroplasia using vosoritide. This drug had previously been approved for treatment of children with achondroplasia, the most common form of dwarfism. Treatment of hypochondroplasia has shown similar and, often, even better results. Study participants have managed the treatment well and have overall been very satisfied with the results.

Children’s National is the only site in the world offering this treatment to patients. The study includes over 50 children from two distinct subsets of patients — those with hypochondroplasia and those with other genetic short stature disorders such as RASopathy conditions, most common of which is Noonan syndrome, and children with mutations in the aggrecan and NPR2 genes. The study has found a significant increase in growth rates for children with hypochondroplasia who underwent treatment with vosoritide for one year.

“These are the first patients in the world to ever receive this medication for their conditions,” said Dr. Dauber. “The results are very promising and may change the way we practice medicine. Patients have come from all over the world to participate in the study.”

The preliminary data is even more promising for children in the study with other genetic conditions, which include defects that are more directly related to C-natriuretic peptide (CNP), which vosoritide targets directly. This is the first medication that directly targets the pathway in chondrocytes (cells in the growth plate that make the bones grow longer) affected by these specific mutations. Those patients are still undergoing their first full year of treatment and results of that section of the study are expected to be released next fall.

“We’re really starting to see this therapeutic landscape open up and develop for patients with this rare condition, for which right now there is no approved therapy, so really exciting times in this space,” says Dr. Dauber.

ACAN study

Dr. Dauber was a part of a study that was the first-of-its-kind to provide genetic testing for children with short stature and their families, finding ACAN gene mutations in multiple family members, and providing hormone therapy to the children impacted. The ability to diagnose this type of gene mutation allows families to be proactive with treatments — both as their child is growing and how other family members can reduce the risk of further complications down the road.

“We’re at the tip of the iceberg with research that explores this gene mutation,” says Dr. Dauber.

Study of one

This type of unique and cutting-edge research isn’t new to the endocrinology team at Children’s National, who is focused on creating unique interventions to find answers for patients and families. When a patient with short stature was found to have a unique mutation in his growth hormone receptor, Dr. Dauber and his team created a single patient trial with a precision medicine approach to overcome the patient’s growth hormone resistance. This isn’t the first time Dr. Dauber led a single patient study. Even when study populations are small, unlocking genetic answers and treatment options for even one patient is at the core of work being done at Children’s National. Dr. Dauber emphasized the importance of these findings for the medical community, particularly for those dedicated to pediatric endocrinology. He noted that understanding the nuanced responses among different children is crucial for optimizing future treatments.

What’s next

Even with improved height and growth outcomes, there is still more to uncover. In addition to the world’s first clinical trial using vosoritide in children for hypochondroplasia, Children’s National researchers are studying the quality of life for children with the disorder and how it may be affected by treatment, aiming to provide this full scope of care for children with these rare conditions. Dr. Dauber and his team continue to study connections between genetic biomarkers and response rates to clinical therapies, with hopes of discovering how these targeted approaches to treatment can be most effective. The work done by the team at Children’s National has shown results to warrant phase three of the trial.

“This ongoing commitment to innovative research underscores the relentless pursuit of targeted therapies, bridging gaps and bringing hope to families and patients worldwide,” says Dr. Dauber.

DNA

International collaboration discovers new cause for dwarfism

DNA

An international collaboration resulted in the identification of a new cause of dwarfism: mutations in a gene known as DNMT3A.

Beyond diabetes, short stature is the most common reason for children in the U.S. to visit an endocrinologist. For the vast majority of children with short stature, the cause remains unknown – even though many of these conditions stem from an as-yet unidentified genetic cause, says Andrew Dauber, M.D., M.M.Sc., division chief of Endocrinology at Children’s National Health System.

“Parents are concerned about why their child isn’t growing and if there are other complications or health problems they’ll need to watch out for,” he says. “Without a diagnosis, it’s very hard to answer those questions.”

Dauber’s research focuses on using cutting-edge genetic techniques to unravel the minute differences in DNA that limit growth. This research recently led him and his colleagues to identify a new cause of dwarfism: mutations in a gene known as DNMT3A. The discovery, which the team published in the January 2019 Nature Genetics, didn’t happen in isolation – it required a rich collaboration of labs spread across the world in Scotland, Spain, France and New Zealand, in addition to Dauber’s lab in the U.S.

The journey that brought Dauber into this group effort got its start with a young patient in Spain. The boy, then four years old, was at less than 0.1 percentile on the growth curve for height with a very small head circumference and severe developmental delays. This condition, known as microcephalic dwarfism, is incredibly rare and could stem from one of several different genetic causes. But his doctors didn’t know the reason for this child’s specific syndrome.

To better understand this condition, Dauber used a technique known as whole exome sequencing, a method that sequences all the protein-coding regions in an individual’s entire genome. He found a mutation in DNMT3A – a change known as a de novo missense mutation, meaning that the mutation happened in a single letter of the boy’s genetic code in a way that hadn’t been inherited from his parents. But although this mutation was clear, its meaning wasn’t. The only clue that Dauber had as to DNMT3A’s function was that he’d read about overgrowth syndromes in which the function of this gene is lost, leading to large individuals with large heads, the exact opposite of this patient’s condition.

To gather more information, Dauber reached out to Andrew Jackson, Ph.D., a researcher who studies human genes for growth at the University of Edinburgh in Scotland. Coincidentally, Jackson had already started studying this gene after two patients with a shared mutation in a neighboring letter in the genetic code – who also had short stature and other related problems – were referred to him.

Dauber and his colleagues sent the results from their genetic analysis back across the Atlantic to Jackson’s Edinburgh lab, and the doctors from Spain sent more information to Jackson’s lab, including the patient’s clinical information, blood samples and skin biopsy samples. Then the whole team of collaborators from around the globe set to work to discover the processes influencing short stature in each of these three patients.

Their results showed that these mutations appear to cause a gain of function in DNMT3A. This gene codes for a type of enzyme known as a methyltransferase, which places methyl groups on other genes and on the protein spools called histones that DNA wraps around. Each of these functions changes how cells read the instructions encoded in DNA. While the mutations that cause the overgrowth syndromes appear to allow stem cells to keep dividing long past when they should taper off and differentiate into different cell types – both normal processes in development – the gain of function that appears to be happening in these three patients prompts the opposite situation: Stem cells that should be dividing for a long time during development stop dividing and differentiate earlier, leading to smaller individuals with far fewer cells overall.

The researchers confirmed their findings by inserting one of the gain-of-function human DNMT3A mutations into a mouse, leading to short animals with small heads.

Eventually, says Dauber, these findings could help lead to new treatments for this and other types of dwarfism that act on these genetic pathways and steer them toward normal growth. These and other scientific discoveries hinge on the type of international collaboration that he and his colleagues engaged in here, he adds – particularly for the types of rare genetic syndromes that affect the patients that he and his colleagues study. With only a handful of individuals carrying mutations in certain genes, it’s increasingly necessary to combine the power of many labs to better understand the effects of these differences and how doctors might eventually intervene.

“The expertise for all aspects of any single research project is rarely centered in one institution, one city, or even one country,” Dauber says. “Often, you really need to reach out to people with different areas of expertise around the world to make these types of new discoveries that can have pivotal impacts on human health.”