Tag Archive for: Aggrecan

aggrecan protein

Two new papers advance aggrecan deficiency research

aggrecan protein

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

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

Andrew Dauber

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.