Monogenic Short Stature and the Promise of Identifying Genetic Etiologies: An Expert Interview

At the 2019 meeting of the Pediatric Endocrine Society (PES), held in conjunction with the Pediatric Academic Societies Meeting, April 24 to May 1, in Baltimore, Maryland, Dr Andrew Dauber, division chief of endocrinology at Children’s National Health System in Washington, DC, presented data from a trial focused on the use of growth hormone (GH) in children with aggrecan deficiency.¹

The ongoing study includes a small cohort of prepubertal children age ≥3 years who have heterozygous pathogenic mutations in the ACAN gene resulting in deficiency of aggrecan, a proteoglycan component of growth plate cartilage. Characterized by Dr Dauber and colleagues in a 2016 study published in The Journal of Clinical Endocrinology & Metabolism, aggrecan deficiency resulting from ACAN mutations causes premature fusion of the growth plates and often significant short stature.²

Interim data presented at the PES meeting showed that participants with aggrecan deficiency receiving recombinant human GH therapy for 6 months (n = 6) had improvements in height velocity (9.5 cm/yr) and mean change in height standard deviation (SD) scores (+0.46) from baseline. Patients receiving GH for 12 months (n = 4) had an even greater mean change in height SD scores (+0.67). There were no unexpected adverse events.¹

The study also investigated the extent of joint involvement in aggrecan deficiency in the pediatric patients and their affected relatives (n = 18). Of note, 2 cases of osteochondritis dissecans of the knees were reported in asymptomatic patients age 11 and 12 years and 6 cases of osteoarthritis were found in adult family members. This apparent higher risk for joint complications warrants routine evaluation in patients who have pathogenic ACAN mutations.¹

To understand the applications and future directions of this research, Endocrinology Advisor spoke with Dr Dauber about his work with aggrecan deficiency and the possible benefits of genetic testing for diagnosing short stature.

Endocrinology Advisor: You recently spoke with Endocrinology Advisor about how the emergence of genetic testing has altered the diagnosis of short stature in children, and discussed that often children have several mutations that manifest as short stature. However, there are also cases of children who have specific mutations such as those found in the aggrecan gene. How does the prognosis for growth and other comorbidities differ in patients with monogenic short stature compared with patients who have polygenic short stature?

Andrew Dauber, MD: It really depends on the underlying monogenic etiology. What we are learning is that there are multiple different subclasses of what was previously termed “idiopathic short stature,” and that within those subclasses there are a number of different monogenic etiologies. Aggrecan deficiency is one of them, but there are a number of other gene mutations that are known [to cause monogenic short stature], like NPR2, SHOX, Indian hedgehog genes, and [genes involved in] achondroplasia or hypochondroplasia.

Each of them has a different clinical manifestation and also a range of short stature severity. For example, for the aggrecan gene, we published a paper a few years ago looking at more than 100 patients with mutations in the aggrecan gene.² There was a wide range in final adult height and in the degree of short stature in that large cohort. So, I think that there is a larger potential for severe short stature in people with underlying monogenic disorders — it is rare that with “run of the mill” polygenic short stature you’d see really severe short stature — but even within an individual monogenic condition, there is a pretty significant range.

In that paper, the median adult height was -2.8 SD, but ranged from -5.9 to -0.9 SD.² So, that’s a huge range in severity in people who clearly have pathogenic mutations of the same gene. Even within families with bona fide mutations — not just in [the aggrecan gene] but in many genes — you see what is sometimes variable penetrance or differing severity of an individual’s height. I think that could be because it is not just this one gene that is the sole determinant of height, but there is a polygenic background involved. [Final adult height can depend] on that background, or there may be multiple genes with larger effects that are adding up to determine height.

Clinically, this is a really important question. People always ask: “how tall am I going to be?” And we really can’t answer that question. Pediatric endocrinologists have traditionally used a bone age x-ray to help make predictions about what somebody’s final adult height will be, but all of those bone age predictions were done in otherwise healthy children, none of whom had these underlying genetic causes. I do not think they are applicable at all to those situations. I think sometimes clinicians can make falsely reassuring or worrisome predictions based on very incomplete information.

Endocrinology Advisor: Do you see any differences in the management of monogenic vs polygenic short stature in future development?

Dr Dauber: I think for future developments, my ultimate goal, and a lot of people’s goal, is that once we have a better understanding of the underlying pathophysiology, we can start to use a more precision medicine approach with targeted treatments.

For years, people have tried to treat achondroplasia with growth hormone. It really has minimal effects and is not, I would say, accepted practice by any means. But right now, there are 2 companies conducting clinical trials of targeted treatments that focus on the pathway — the downstream of the FGFR3 gene — within the growth plate that is affected by achondroplasia. [Biomarin and Ascendis are both] using what is called a c-type natriuretic peptide agonist [in clinical trials] in patients with achondroplasia.

That molecule binds to the natriuretic peptide receptor type b, which is encoded by a gene called NPR2. Heterozygous mutations in NPR2 cause an estimated 2% of idiopathic short stature. Right now, no one is trying for that indication, although I think people are thinking about it. If we start to understand where the defects are in those pathways, maybe growth hormone will no longer be the logical treatment and there will be other targeted treatments focused on these individual pathways.

That is one view of the future. Another more common view is to do more specific trials of growth hormone therapy in a more homogenous population of patients with a specific gene mutation. That was the idea behind doing our trial in patients with aggrecan mutations so we can get a better idea with a uniform protocol in patients with individual subclasses [of short stature]. It is hard to aggregate the patients across multiple sites and do a well-controlled trial. We’re trying to start with at least a prospective data collection on a uniform protocol.

Endocrinology Advisor: Do you think data from your research can help support genetic testing early in life in regular clinical practice? You’ve mentioned before that there are often barriers to using genetic testing as part of a diagnostic workup in children with short stature.

Dr Dauber: I hope so. I think that one of the major barriers to getting genetic testing done in clinical practice currently is that insurance companies want to know there is going to be a demonstrable change in management based on obtaining a genetic diagnosis. I think that with aggrecan, for example, if you have a [patient with an] aggrecan gene mutation, we now have evidence that those patients have progressive worsening of their height SDs due to the premature growth cessation, and if we are able to generate the evidence that growth hormone therapy is an effective method for improving their height outcomes, then you could point to this work and say getting this diagnosis matters.

Not to mention the benefit of having this diagnosis for a family and avoiding further diagnostic testing, and the fact that it points [the clinician] to other comorbidities such as joint disease, which could have other important implications for people’s health. Gathering the data behind each of these subsets to show the clinical implications will help us make arguments that this needs to be part of routine testing.

Endocrinology Advisor: What are the next steps in the research being conducted by your team?

Dr Dauber: We have a number of ongoing projects going in a few different directions. One is that we’re continuing and extending the trial of growth hormone in patients with pediatric gene mutations to get a longer-term view of the effects of growth hormone and learn more about the joint comorbidities. We continue to have patients referred to us on a weekly basis who likely have aggrecan gene mutations.

Another major area of research I am working on is a multicenter study [funded by a RO1 grant from the National Institute of Child Health and Human Development] in which we are trying to use searches of the electronic health records at large children’s hospitals to identify patients with short stature who are likely to have genetic etiologies that were clinically missed. I think this idea of “how can we integrate the genetic diagnostics into routine clinical practice?” ties into “how can we harness the power of the electronic health records to pick out these children from the larger population of patients we see for short stature?”

That work is really starting now. It is a collaboration between Children’s National Health System and Boston Children’s Hospital, Children’s Hospital of Philadelphia, and Cincinnati Children’s Hospital.

Our group also has ongoing work trying to develop novel therapeutic strategies for subgroups of short stature. We are doing a lot of work on a gene called PAPPA2, a protease that cleaves insulin-like growth factor binding proteins and regulates the levels of free insulin-like growth factor 1.

So, we’re going in a number of directions to address [short stature with genetic etiologies].

References

1. Alexandrou E, Cabrera-Salcedo C, Tyzinski L, et al. Clinical characterization and trial of growth hormone in patients with aggrecan deficiency: interim data. Presented at: Pediatric Endocrine Society Presidential Poster Session; April 26, 2019; Baltimore, MD.

2. Gkourogianni A, Andrew M, Tyzinski L, et al. Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. J Clin Endocrinol Metab. 2017;102(2):460-469.