Posts

DNA moleucle

Genetics can’t explain mixed impact of growth hormone therapy

DNA moleucle

Growth hormone therapy is one of the most common treatments for short stature in children. However, endocrinologists report mixed outcomes, even when children have the same underlying condition as the cause of their short stature. Despite research into a variety of potential causes for this unpredictable response, there is still very little scientific evidence to help physicians predict whether children with short stature who are treated with growth hormone will respond to the treatment or not.

A study published in the Journal of Clinical Endocrinology and Metabolism took up this question with an eye to the genetic factors that might predict response by conducting the first ever genome-wide association study of response to growth hormone.

“Previous disease-specific models have been developed using multiple clinical variables such as parental height, age at treatment start, peak hormone levels and doses, and birth parameters, however, these clinical parameters only partially predict variation in response,” wrote the study authors, including Andrew Dauber, M.D., first author and chief of the division of Endocrinology at Children’s National Hospital. “Our goal was to perform a large-scale genome-wide study to provide a comprehensive assessment of how common genetic variation may play a role in growth hormone response.”

To accomplish this, the study combined five cohorts from across the world to identify 614 individuals for further review. All patients had short stature caused by conditions including growth hormone deficiency, small for gestational age, or idiopathic short stature (no previously identified cause), who received growth hormone as treatment.

Interestingly, the researchers found no overwhelming genetic predictors of response to growth hormone. They did identify a few signals that may potentially play a role in the body’s response to growth hormone but noted those signals will need further exploration. The study also ruled out the idea that genetic predictors of height in the general population might predict response to growth hormone.

“Identifying genetic predictors of how a child with short stature will respond to growth hormone would be an important step forward for clinicians and parents to make informed decisions about the right treatment approach,” says Dr. Dauber. “Though we didn’t find any specific indicators, this large-scale study has allowed us to rule out some previously held assumptions and offers several new avenues to explore.”

The study was conducted in collaboration with Pfizer and Boston Children’s Hospital.

Andrew Dauber

Growth disorder study starts by analyzing DNA

The National Institutes of Health has awarded Andrew Dauber, M.D., MMSc, the chief of endocrinology at Children’s National Health System, a five-year grant that will allow four pediatric health systems to compile and study clinical and genetic markers of severe pediatric growth disorders.

The study will use the electronic health records of large health systems combined with DNA samples from dozens of children, with the goal of enabling endocrinologists to detect children with previously undiagnosed severe genetic growth disorders.

“If you’re a pediatrician treating an 8-year-old patient who has stopped growing, the first thing you’ll want to do is determine the underlying cause, which could be due to many factors including a genetic mutation,” says Dr. Dauber. “There are many reasons why children grow poorly and it is often very difficult to figure out what is causing the problem. However, the various causes may be treated quite differently and may alert us to other medical issues that we need to watch out for. We need to be able to identify clues from the patient’s clinical presentation that may point us to the right diagnosis.”

Dr. Dauber and endocrinology researchers from Children’s National Health System, Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital and The Children’s Hospital of Philadelphia will use electronic health records to identify children who likely have rare genetic growth disorders. They will then use cutting-edge DNA sequencing technologies, whole exome sequences, to identify novel genetic causes of severe growth disorders. Patients with growth hormone resistance, resistance to insulin-like growth factor 1 (IGF-I) and severe short stature inherited from a single parent will be recruited for the initial phases of the study.

“It’s rare to find patients meeting criteria for each of these subgroups, which is why it’s critical to work collaboratively across institutions,” says Dr. Dauber. “This type of genetic sorting and sharing brings us closer to identifying new markers for severe or treatment-resistant growth disorders, which will help alert pediatricians and parents to potential risks earlier on in a child’s life.”

In addition to assessing genetic markers for short stature, the endocrinologists will conduct pilot studies of targeted interventions, such as IGF-I therapy in patients with mutations in the growth hormone pathway, based on these genetic underpinnings.

“Ideally, by identifying markers of severe growth disorders first, we’ll be able to provide targeted treatments and therapies later on to help patients throughout their lifespan,” adds Dr. Dauber.

Typical treatments for atypical growth patterns include growth hormone or less commonly insulin-like growth factor, or IGF-1, for short stature and hormone-inhibiting treatments for precocious puberty.

The multicenter clinical trial is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), under grant Ro1HD093622, and runs through June 30, 2023.