How Has Genetic Testing Changed the Diagnosis of Short Stature in Children?

Endocrinology Advisor: What are the main challenges involved in diagnosing short stature in otherwise healthy children?

Adda Grimberg, MD: There are 2 main challenges in diagnosing short stature in otherwise healthy children. First, the beauty and challenge of the endocrine system is that it is a dynamic system that is continuously responding to inputs and regulating overall homeostasis, growth, and metabolism. Thus, endocrine tests are fraught with more limitations than tests of other more static body functions and results must be interpreted within the greater context.

Second, because growth failure may be the first or only sign of various health problems, screening labs may include a number of different tests. The challenge persists in finding the right balance between broad screening for increased sensitivity and not over-testing for cost-effectiveness.

Andrew Dauber, MD: In healthy children who are short but growing at a normal rate, the likelihood of finding a pathologic condition causing their short stature is quite low. The majority of these children will have short stature from underlying genetic causes. One of the major difficulties is distinguishing kids with rare monogenic causes of short stature from kids with many common genetic variants underlying their short stature (ie, polygenic short stature).

The latter group includes children who we traditionally think about as having a familial predisposition to short stature, but the short stature does not follow a classic Mendelian pattern of inheritance such as dominantly inherited short stature from a single parent. It can be quite difficult to distinguish between these groups as many monogenic causes of short stature can have very subtle clinical presentations.

Endocrinology Advisor: What are some of the latest discoveries in this area, and what advances have there been regarding the diagnostic approach for short stature?

Dr Grimberg: The latest advances include new insights gained from genetic screening. With the increasing availability and decreasing cost of genomic screening, we are detecting more and more genes that are involved in growth regulation and growth failure. These discoveries may ultimately inform the development of new targeted therapies.

Dr Dauber: Many new genetic causes for short stature have been identified. Children previously classified as having idiopathic short stature are now being diagnosed with specific genetic subtypes. There has been a recent uptick in the use of genetic testing in the diagnosis of short stature, but the majority of practitioners — particularly endocrinologists — are not yet sufficiently familiar with how to perform a genetic workup for short stature. In addition, there are many barriers to obtaining genetic testing as part of a routine workup.

Some of these genetic causes have significant implications for height prognosis, as well as associated medical comorbidities. For example, our group described patients with mutations in the Aggrecan gene that lead to dominantly inherited short stature with premature growth cessation. These children’s height prognosis is often worse than one would think, as their growth plates prematurely fuse, leading to the lack of a significant pubertal growth spurt. Intervention is needed early in order to promote height gain. In addition, a significant percentage of people with mutations in this gene will have progressive early-onset arthritis, which can be debilitating.8

Endocrinology Advisor: What are the remaining needs in this area in terms of research, physician education, and otherwise?

Dr Grimberg: With the increasing excitement and potential of new technologies like genomic testing, I implore clinicians to not forget the basics. I am seeing a lot of malnutrition in my patients — energy mismatch between the kcals consumed by sports and high activity levels vs the kcals ingested due to unstructured meal times, fewer at-home meals, picky eating, attention-deficit/hyperactivity disorder medications, and so on — that is subtle yet sufficient to stunt linear growth.

Dr Dauber: There is a tremendous need to educate clinicians about the appropriate use of genetic testing for short stature. Endocrinologists and primary care physicians often have not received formal education on this topic. Additional research is needed regarding the clinical course of these new genetic subgroups and how each responds to available therapies such as growth hormone.

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