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  • Drew Stevens

CUL3 and Growth: Olivia's Story

I can still remember getting the news. At 26 weeks gestation, Olivia was diagnosed with intrauterine growth restriction (IUGR). In light of everything that has happened since then, it’s easy to downplay the stress and trauma of this first diagnosis. But the fact is that Olivia’s journey to a CUL3 diagnosis began with a growth issue.


Three short weeks later, following a near total cessation of movement, Olivia was delivered through an emergency c-section weighing only two pounds four ounces. In the NICU, Olivia experienced feeding difficulties and challenges gaining weight, and after three months we brought her home with an NG tube (which she pulled out a few days later).


Olivia’s bottle-feeding challenges never went away, and she never caught up on the growth charts. In fact, Olivia did not even make it onto the charts. Instead, she consistently fell below the 1st percentile for height and weight—though her head circumference was always comfortably above the 50th percentile. For a number of reasons, this led us to suspect that Olivia may have Russell-Silver Syndrome, a genetic disorder that is associated with IUGR, global developmental delays, feeding challenges, and small stature. To our surprise, however, Olivia’s genetic testing hit on something else: a de novo mutation on her CUL3 gene (de novo meaning she did not inherit it from her mother or me).


Following her genetic diagnosis, Olivia was prescribed growth hormone, which we give to her through nightly injections. While it can be a challenge to qualify for growth hormone, her endocrinologist believed that because she was IUGR and had not “caught up,” it would be approved. After more than five months of growth hormone injections, Olivia is almost three years old and weighs less than twenty pounds and has only recently entered the 1st percentile for height. Her head circumference is still in the 60th percentile. She is yet to approach the 1st percentile for weight.


What does CUL3 have to do with growth? For now, the medical literature doesn’t have a straightforward answer. But that isn’t to say there isn’t a connection between CUL3 mutations and growth problems.


A recent unpublished study of more than thirty individuals with CUL3 mutations showed that 1/3 of the individuals were diagnosed with IUGR before they were born. And at least a dozen CUL3 mutations reported in the medical literature have been connected to some form of post-natal growth failure. Then you have our group's anecdotal evidence. Olivia is but one of several children with CUL3 mutations that were either born IUGR or have experienced severe growth impairment.


One theory points to a disorder in the insulin-signaling pathway, which is a key component of normal human growth. In short, the CUL3 ubiquitin ligase (under normal circumstances) is supposed to regulate certain proteins in this pathway. For children like Olivia, however, her CUL3 ubiquitin ligase is not performing its function properly, which has led to an overaccumulation of a particular protein (the p85alpha protein). This overaccumulation then interferes with the normal function of the insulin-signaling pathway, which in turn prevents normal growth.1


But this is just a theory. So, while we will continue to give Olivia her growth hormone shots, we are also reaching out to scientists and physicians that study the insulin-signaling pathway in the hopes that we can see progress in understanding the growth disorders caused by a CUL3 diagnosis—and, one day maybe even a targeted treatment.


Find more on Olivia's story here: https://www.cul3.org/olivia-s-story


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1 See 'Comorbidities Caused by a Corrupt Cullin 3: Lessons Learned From Bedside to Bench', written by Dr. Jing Wu and Dr. Curt D. Sigmund and published in the January 2022 issue of the American Heart Association’s Journal on Hypertension (Volume 29, Issue 1; see https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.121.18430).

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