diagnostic testing

Stimulation Tests for Diagnosing Pediatric GHD

Growth hormone stimulation tests are among the diagnostic tools health care practitioners use when testing a pediatric patient for suspected growth hormone deficiency (GHD). However, the use of this diagnostic method is often a source of debate among practitioners, as issues persist with the standardization, validity, and replicability of these tests.

To learn more about the role of stimulation tests in the diagnosis of pediatric GHD, Consultant360 reached out to Gianluca Tornese, MD, PhD, who is a consultant in pediatrics at the Institute for Maternal and Child Health IRCCS Burlo Garofolo in Trieste, Italy.

Consultant360: Your article notes that there is no gold standard cutoff level for diagnosing GHD with stimulation tests. In your opinion, what should the cutoff level be, and should other factors be taken into consideration as well?  

Gianluca Tornese: It is not just a question of cutoffs—the lower, the better. We do know that the tests have a low sensitivity (children with normal stature and growth can have a peak GH level down to 2 ng/mL, even if pubertal) and low specificity (children with defects in the GH1 gene can have normal stimulation tests). Since we know that there is usually a scarce correlation between insulin-like growth factor 1 (IGF-1) levels and a low response to stimulation tests, a combination of the 2 probably gives a more accurate diagnosis. 

C360: You note several pitfalls that are associated with stimulation tests for the diagnosis of GHD, other than the lack of a standard cutoff level. Can you discuss those pitfalls and how they be avoided? 

GT: The first one is about the test itself, and this can hardly be avoided. The tests are nonphysiologic, with variability in GH assay results, and a physiological variability with low reproducibility because of external factors such as fasting and sleep.

The second one is about the treatment. On one side, a considerable population of patients with suspected GHD is that they are poor responders to treatment. On the other side, the majority of patients with suspected GHD are no more GH deficient at retesting. A good response to treatment, however, cannot determine the diagnosis, since other conditions may also benefit from treatment. There are several other conditions such as gonadal dysgenesis, Noonan syndrome, or SHOX deficiency where the mechanism is instead resistance to GH, even with pathological GH stimulation tests. We should be more careful not to miss them. 

C360: Are there any other diagnostic tools available to pediatric endocrinologists or other health care providers that suspect a diagnosis of pediatric GHD?

GT: I believe that we should rediscover sitting height and arm span measurements to evidence even subtle disharmonic short stature in childhood and look more carefully for phenotypic clues. We definitively should think more about genetic testing nowadays. 

Consultant360: Your article proposes an additional classification of “Short stature Unresponsive to Stimulation tests (SUS)” for patients with pathological stimulation tests but without a genetic diagnosis of GHD, multiple pituitary deficiency, pituitary abnormalities on magnetic resonance imaging scans, or acquired damage. How will this add to the treatment landscape for these patients? 

GT: The treatment, in my opinion, should be the same since we do know that they may respond well to somatropin. As for GHD patients, a re-evaluation of results after 1 year of treatment could be helpful to decide whether to discontinue the therapy. The name change to SUS would just avoid labeling children with a condition we are not entirely sure they have and expecting clinical sequelae over the years that they may not have, such as the evolution of subsequent multiple pituitary hormone deficiencies, altered body composition, or decreased bone mineral density.  

C360: What other knowledge gaps remain concerning the diagnosis of pediatric GHD?

GT: A significant knowledge gap, in my opinion, is to understand whether a “transient” or “partial” GHD really exists, especially in pre- and peripubertal boys, and how we can differentiate it from the constitutional delay in growth and puberty. This is crucial since the time could be short, and we might lose the opportunity to reach a normal stature if we miss the pubertal spurt. However, genetic studies will help us once again to understand this category of short children better.

 

Reference:

Tornese G. ‘Growth hormone deficiency’ or rather ‘short stature unresponsive to simulation tests’? Arch Dis Child. Published online January 27, 2022. doi:10.1136/archdischild-2021-323426