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Breaking barriers in growth disorder treatment for families

January 14, 2025

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.

Two new papers advance aggrecan deficiency research

March 2, 2022

Aggrecan (ACAN) is a large protein found in joint cartilage and growth plates.

Andrew Dauber, M.D., M.M.Sc., division chief of Endocrinology at Children’s National Hospital, and colleagues recently published two papers that describe the phenotypic spectrum of aggrecan deficiency and look at treating the condition with human growth hormone.

Aggrecan (ACAN) is a large protein found in joint cartilage and growth plates. It allows joints to move smoothly and without pain. Aggrecan deficiency — due to heterozygous mutations in the ACAN gene — causes dominantly inherited short stature and, in many patients, early-onset osteoarthritis and degenerative disc disease.

Clinical phenotype of patients with aggrecan deficiency

In 2017, Dr. Dauber led an international consortium of researchers that published a manuscript describing the phenotypic spectrum of 103 individuals – 70 adults and 33 children, including 57 females and 46 males – from 20 families with ACAN mutations. In the study, Dr. Dauber and his colleagues established that short stature and accelerated bone age is common among people with ACAN mutations.

In a new study published in the American Journal of Medical Genetics Part A, Dr. Dauber and colleagues further characterize the phenotypic spectrum of aggrecan deficiency, with an emphasis on musculoskeletal health.

Twenty-two individuals from nine families were enrolled in the study. Recorded histories and examinations focused on joint health, gait analysis, joint specific patient reported outcomes and imaging.

“We performed a detailed analysis of the musculoskeletal manifestations in patients with mutations in the aggrecan gene,” says Dr. Dauber. “We found that patients with mutations in this gene had significant short stature which worsened with age. There was a high prevalence of joint complaints and arthritis in adults, and we were able to detect pre-symptomatic joint damage in children using knee MRIs.”

Treating short stature in aggrecan-deficient patients with human growth hormone

Until now, it was unknown how to treat children with aggrecan deficiency. “Providing growth hormone therapy to children with ACAN gene mutations is relatively new in the field of pediatric endocrinology,” explains Dr. Dauber. “Previously, the assumption was that this was just short stature.”

In a new study, published in The Journal of Clinical Endocrinology and Metabolism, Dr. Dauber and colleagues reported the results of a trial that evaluated the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency.

“This is the first prospective trial of growth hormone therapy in patients with mutations in the aggrecan gene,” says Dr. Dauber. “Mutations in the gene are the cause for short stature in approximately 2% of individuals with idiopathic short stature.”

The open-label, single-arm, prospective study enrolled ten treatment-naïve patients with a confirmed heterozygous mutation in ACAN. Participants were treated with rhGH (50 µg/kg/day) over 1 year. Main outcomes measured were height velocity and change in height standard deviation score.

The authors found that growth hormone led to short term improvements in growth rate over the course of the year. The treated patients had their growth rate increase from 5.2 centimeters per year to 8.3 centimeters per year while on therapy.

In 2019, the researchers received the 2019 Human Growth Award at the Pediatric Endocrine Society’s Annual Meeting for an abstract related to this work, entitled “Clinical Characterization and Trial of Growth Hormone in Patients with Aggrecan Deficiency: 6 Month Data.”

Andrew Dauber, M.D., MMSc, caps off research success with award and reception

January 30, 2020

Unfortunately, we’ve been notified that the ENDO2020 conference has been canceled due to concerns of COVID-19. Because of this, we will not be hosting our reception in honor of Andrew Dauber, M.D., on Sunday, March 29.

We hope to see you at a future Endocrinology or Pediatric Endocrinology event.

Children’s National Hospital is incredibly proud of the work Dr. Dauber has done in the endocrinology community.

Andrew Dauber, M.D., MMSc, division chief of Endocrinology at Children’s National Hospital, will be awarded the 2020 Richard E. Weitzman Outstanding Early Career Investigator Award at ENDO 2020. The prestigious award will be presented at the annual meeting of the Endocrine Society in recognition of Dauber’s work in understanding the regulation of growth and puberty, and applying innovative genetic technologies to studying pediatric endocrinology. Dauber credits many collaborators throughout the world, as well as the team at Children’s National for the award.

With a five-year grant from the National Institutes of Health (NIH), Dauber and colleagues from the Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital and the Children’s Hospital of Philadelphia are using electronic health records to identify children who likely have rare genetic growth disorders. Using cutting-edge DNA sequencing technologies, including whole exome sequencing, the researchers are aiming to identify novel genetic causes of severe growth disorders. The first paper describing genetic findings in patients with high IGF-1 levels was published in Hormone Research in Paediatrics in December 2019.

Dauber and researchers at Cincinnati Children’s Hospital Medical Center are exploring how to treat patients with mutations in the PAPPA2 gene. In 2016, the group described the first patients with mutations in this gene who had decreased the bioavailability of IGF-1, stunting their growth and development. In their current phase of research, findings are emphasizing the importance of this gene in regulating IGF-1 bioavailability throughout childhood. The ultimate aim is to create therapies to increase IGF-1 bioavailability, thereby supporting healthy growth and development in children. Their first study to track PAPPA2 and intact IBGBP-3 concentrations throughout childhood was published in the European Journal of Endocrinology in January 2020.

Dauber is particularly interested in studying children with dominantly inherited forms of short stature. Along with collaborators in Cincinnati, he currently has an ongoing treatment trial using growth hormone in patients with Aggrecan gene mutations. Dauber hopes to announce soon a new clinical trial for children with all forms of dominantly inherited short stature.

Study upon study has shown us that there are many factors that affect an individual’s height and growth. As these studies and the conversation around how to identify and address genomic anomalies become more prevalent, the team at Children’s National is increasingly interested in engaging with other centers around the country. In the coming months, the Children’s National Research & Innovation Campus will open on the grounds of the former Walter Reed Army Medical Center, which will serve as a one-of-a-kind pediatric research and innovation hub. A critical component to this campus is the co-location of Children’s National research with key partners and incubator space.