An excess of growth hormone in infancy leads to the rare yet confounding phenomenon of X-linked acrogigantism, which is known to be resistant to conventional pituitary tumor treatments in the pediatric population. However, new data suggests that pegvisomant could not only be a treatment option for these patients, but it could also improve quality-of-life measures.
When the hormonal axis that controls human growth is disrupted by a pituitary adenoma prior to epiphyseal closure (growth plate fusion), increased secretion of growth hormone and “pituitary gigantism” can result. When this condition is caused by a mutation in the GPR101 gene on chromosome Xq26.3, it is known as X-linked acrogigantism (X-LAG), or chromosome Xq26 microduplication syndrome. The GPR101 gene encodes for production of the GPR101 protein that is thought to be involved with pituitary gland cell growth or in regulating the release of growth hormone from the pituitary.
• X-linked acrogigantism (X-LAG) is characterized by infant-onset gigantism from hypersecretion of growth hormone.
• Although X-LAG does not respond to conventional pituitary tumor treatment, like octreotide, a new study is being conducted to evaluate the safety and efficacy of postsurgical pegvisomant, a growth hormone receptor antagonist, at preventing tumor recurrence.
• Secondary outcomes researchers hope to see include improvement in associated complications such as musculoskeletal problems and in quality of life.
Although X-LAG is rare, and its true prevalence is unknown, it is nevertheless thought to be responsible for 10% of cases of excessive growth in children with pituitary abnormalities. Having an X-linked dominant inheritance pattern, it is therefore more common in females.
In the May issue of the Journal of the Endocrine Society, a team of researchers led by Constantine A. Stratakis, MD, D(med)Sci, PhD(hc), senior investigator in pediatrics, endocrinology & medical genetics at the National Institutes of Health (NIH): Intramural Research Program (IRP) and former scientific director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in Bethesda, Md., announced a study they are undertaking to fill a knowledge and treatment gap.
“Safety and Efficacy of Pegvisomant in Pediatric Growth Hormone Excess” describes their open-label phase 3 study of the drug and their effort to provide data on children with growth hormone excess (GHE), also known as gigantism. To date, most available research has been done on adults.
“I don’t expect [pegvisomant] to make any residual tumor disappear, but I expect to have these patients in remission long enough to allow us to later use available modes of treatment like irradiation safely or avoid a second surgery for 10 or 20 years.”
Constantine A. Stratakis, MD, D(med)Sci, PhD(hc), senior investigator in pediatrics, endocrinology & medical genetics, National Institutes of Health: Intramural Research Program; former scientific director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.
Getting to this research question was no accident. Stratakis’s younger brother was diagnosed with a pituitary tumor at the age of nine years, and Stratakis’s career path was sealed: by high school graduation, he knew he wanted to become an endocrinologist. He chose the right path, later earning the distinction of being one of the scientists to discover the genetic cause of GHE [See Sidebar].
Making Discoveries
Published in The New England Journal of Medicine in 2014, “Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation” studied 43 children with early-onset gigantism. Inclusion criteria for the 43 study participants were pituitary lesions, height on country-specific growth charts of either more than the 97th percentile or more than two standard deviations above the mean height for age, and negative test results for mutations or deletions in genes associated with pituitary adenomas.
The team’s findings showed that this striking phenotype they named X-linked acrogigantism is likely caused by an increased dose of GPR101 on chromosome Xq26.3 and is characterized by early-onset gigantism (usually beginning by age 1 year in a normal-sized newborn) resulting from hypersecretion of growth hormone.
Though X-LAG is very rare, Stratakis explains that it accounts for 80% – 100% of pediatric GHE cases. The study also provided insight into human growth in general.
Searching for Treatment
The therapeutic picture is complicated. As the pediatrics mantra goes, children — even large-stature children — are not just little adults, so treatment approaches must be tailored to fit the pediatric population. Another consideration is that X-LAG tumors did not respond to therapy with octreotide, a somatostatin analogue and the conventional treatment for pituitary tumors.
In a study of 18 patients with X-LAG, the results of which were published in 2015 as “X-linked acrogigantism syndrome: clinical profile and therapeutic response,” in Endocrine-Related Cancers, Stratakis and team further elucidated the clinical phenotype of these patients, such as acral enlargement, coarsened facial features, acanthosis nigricans, sleep apnea, excessive perspiration, and abdominal distention. Oversecretion of insulin-like growth factor 1 (IGF1), also known as somatomedin, was another key feature, making the discovery of octreotide’s lack of efficacy somewhat surprising.
“We started studying these patients at the NIH and realized there are not many treatment options besides octreotide or surgery,” Stratakis says. “Irradiation is not really an option for very young kids. So, we started being interested in other medications that we could use.”
Importantly, they found that postoperative use of adjuvant pegvisomant, a growth hormone receptor antagonist, provided some control. “We had some evidence from patients with Carney complex, which was resistant to octreotide,” Stratakis continues. “These patients we had worked with for more than 25 years responded better to pegvisomant. And so, when we realized that patients with gigantism were not responding to octreotide, we thought pegvisomant might be a good option for them.”
Fast forward to a couple of years ago, and the team connected with Pfizer, who worked with them to establish the current protocol. In the meantime, Stratakis retired from the NIH after almost 30 years there and passed on principal investigator-ship to Christina Tatsi, MD, MHSc, PhD, also at the NIH, and they now work together on the research.
“There is currently no FDA-approved medication for this indication in children, and most of the treatments we provide are based on studies performed in adults,” Tatsi says. Recruitment is currently ongoing (the COVID-19 pandemic having slowed progress); participants will include children ages 24 months to 18 years with GHE with persistent disease after surgical or radiation therapy. These patients will receive subcutaneous injections of pegvisomant daily for one year to determine its safety and efficacy.
Quality of Life
Although X-LAG is rare, with an incidence similar to that of other genetic endocrine conditions, such as McCune-Albright syndrome, Carney complex, and neurofibromatosis type 1, these patients must cope with reduced quality of life. “Overall, health-related quality of life is impaired with growth hormone excess, with improvement but not resolution after treatment; however, there is limited data in the pediatric population,” says Meg Keil, PhD, CRNP, FAAN, a senior nurse practitioner and member of the research team at the NIH.
Stratakis agrees, citing the QOL issues associated with any pituitary tumor, such as complications of surgery like headaches or hypothalamic or partial or complete pituitary deficiencies. “All of these things affect QOL. They are common among the various patients with pituitary tumors who have had surgery or other modes of treatment that affect the function or the anatomy of the pituitary gland or the hypothalamus,” he says. “Then there are issues specific to gigantism, which is a unique disease. If we have a 4-year-old the size of a 7-year-old, this completely changes the dynamics of these kids and their relationships with their peers and their position in the family. In the eyes of other kids or family members, we have an incongruity between behavior and size, similar to but the inverse of patients with extreme short stature.”
Treatment’s Fringe Benefits
The team is clearly motivated to help these patients. “I hope the study will produce data for a safe and efficacious way for treatment of children with GH excess,” Tatsi says. Stratakis elaborates: “Every one of our patients has had surgery, so, what I expect from the study is that pegvisomant will decrease the chances for recurrence. I think that is and has been my goal.”
In many cases, the pituitary tumors cannot be completely excised, and the residual tumor causes chronic disease. “I don’t expect this medication to make any residual tumor disappear, but I expect to have these patients in remission long enough to allow us to later use available modes of treatment like irradiation safely or avoid a second surgery for 10 or 20 years,” Stratakis says.
Controlling that chronic disease also confers other benefits. “We anticipate that control of GH excess will provide also control of the complications of this disorder, such as cardiovascular changes, musculoskeletal problems, quality of life, and others,” Tatsi says.
“There are issues specific to gigantism, which is a unique disease. If we have a 4-year-old the size of a 7-year-old, this completely changes the dynamics of these kids and their relationships with their peers and their position in the family. In the eyes of other kids or family members, we have an incongruity between behavior and size, similar to but the inverse of patients with extreme short stature.”
Constantine A. Stratakis, MD, D(med)Sci, PhD(hc), senior investigator in pediatrics, endocrinology & medical genetics, National Institutes of Health: Intramural Research Program; former scientific director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.
Pegvisomant looks promising, and the team hopes the study results will bear that out. Meanwhile, Stratakis has accepted a position as chief scientific officer, at ELPEN, in Athens, Greece & director (Res. A’), Human Genetics & Precision Medicine at Foundation for Research and Technology – Hellas (FORTH). “It’s wonderful work,” he says, “and I continue my research into the genetics of endocrine diseases.”
Expect to see papers on new genes soon.
Horvath is a freelance writer based in Baltimore, Md. In the December issue, she researched, compiled, and wrote the annual Eureka! article that detailed the top endocrine science discoveries of 2021.
Like so many who enter the field of endocrinology, for Constantine A. Stratakis, MD, D(med)Sci, PhD(hc), it was personal.
Constantine A. Stratakis’s brother was diagnosed with craniopharyngioma, one of the most common pediatric brain tumors, that can be difficult to cure with most patients experiencing long-term, chronic consequences. The tumor can put pressure on the structures near the pituitary gland, causing symptoms ranging from balance and vision problems; confusion, mood swings, and behavior changes; and headache, to polydipsia and polyuria, nausea and vomiting, and slow growth.
“I am reminded how much my brother’s diagnosis changed our family when I see patients with pituitary tumors and their families,” Stratakis says. “They often tell me that their ordeal did not end with surgery even when (if) they were cured. Their quality of life in most cases changed forever, and this is certainly true for my brother as well as for my parents.” The one good outcome, he explains, is that it pushed him to go to medical school and indelibly set his career preference. “As an endocrine geneticist now, I see many patients with rare disorders, not only pituitary tumors. And I get similar responses; often, a rare disease makes somebody in the family choose a career in healthcare or life sciences.”
Stratakis grew up admiring his biologist and researcher uncle. “I loved biology in high school and was given a microscope as a teenager. This was my best gift ever; I spent hours looking at everything, from beer yeast to cheese crust. I then starting culturing microbes, to my mother’s dismay. But I had never thought of becoming a physician. My brother’s illness introduced me to medicine; furthermore, I realized that medicine was biology, and that biology could be used to investigate and even treat disease.”
Stratakis says that once on his chosen path, he never thought of doing anything else: “I love my work; it has changed many times over the years, and it keeps changing. Now that I have retired from the NIH as a Federal Researcher after 30 years, I am building a new research institute in Greece from scratch — again, in the service of disease discovery, drug design, and the development of new therapeutics. These are on the continuum of biology: from the microscope I got as a child, to medical school, to the lab where we made so many discoveries, to the research institute I led at the NIH, to the one I am building now, it is all in medicine, yet each step is so different. Every day I learn a new skill, a new thing. It’s never boring — sometimes tiring — but always exhilarating.”
The legacy he has created (and keeps expanding) encompasses teaching, administration, and research. He trained more than 200 researchers as the NIH’s scientific director, whose successes are already evident. He strove for diversity at the NIH, with more than 68% of his trainees being female, and initiated discussions for creating a program on Transgender Medicine. He also hopes the new research institute he is building will be a significant achievement and lead to scientific breakthroughs. As a researcher, he worked on 35 genes and diseases, identifying six new genes and diseases, one that is even eponymous: Carney-Stratakis syndrome.
What he most appreciates, however, is helping people. “I served so many patients, including many with the disease that my brother had. One can never fully pay back the fortune we had as a family to have my brother a heathy and productive member of our society, but part of my legacy will be that I tried to do it,” Stratakis says.
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