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Beyond Boundaries: The Continuous Spectrum in FGFR3-Related Conditions

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Prior to the era of molecular testing, conditions resulting from gain-of-function variants in the FGFR3 gene (e.g., thanatophoric dysplasia, TD; achondroplasia, ACH; hypochondroplasia, HCH) were diagnosed primarily by clinical and radiological imaging. Across FGFR3-related conditions, there are shared clinical characteristics with varying prominence, including disproportionate short stature (short-limbed), craniofacial features (e.g., frontal bossing andmidface hypoplasia), and other skeletal abnormalities.

Despite having a shared molecular genetic cause, driven by overactivity of the FGFR3 signaling pathway, these conditions continue to be considered distinct clinical diagnoses. In many cases, this delineation is clinically meaningful, but there is much gray area with an overlapping clinical spectrum. Although many disease-causing variants have been identified and continue to be discovered, a few specific variants account for the majority of diagnosed cases. Even within these well-characterized variants, there is a spectrum of phenotypes reported, challenging the lines between clinically defined categories. This ambiguity can lead to diagnostic challenges and delays in accessing appropriate care.

Methods:
To characterize the spectrum of phenotypes associated with FGFR3, we analyzed de-identified data collected as part of the no-cost Discover Dysplasias gene panel testing program for all patients who had one of the ACH or HCH “classic” genetic variants in FGFR3: p.Gly380Arg (ACH) and p.Asn540Lys (HCH). Data included 1) FGFR3 variant, 2) ordering clinician-reported clinical signs/symptoms, and 3) patient height/age.

Results:
A total of 385 patient results were included in the analysis, including 296 with the most common ACH-associated variant (p.Gly380Arg) and 89 with the most common HCH variant (p.Asn540Lys). A subset of patients had height Z-score reported (n=52), 20 of which had final adult height. The majority (93.2%) of patients had clinical features indicated on the order form.

Patients with a molecular diagnosis of p.Gly380Arg (ACH) and HCH (as defined by the presence of p.Asn540Lys or p.Asn540Ser) had significantly decreased Z-scores, with more prominent deficits in the ACH group. Within each group, there was a high degree of variability in Z-score and a significant overlap between ACH and HCH groups (mean [std]: -3.8 [1.7] and -3.2 [1.1], respectively). A similar trend was observed when looking at final adult height (defined as height at ≥16y).

Of the clinical features assessed, the only one exclusive to ACH was spinal stenosis. All other clinical features of interest were represented in both groups (ACH vs HCH), including trident hand (36% vs 8%), macrocephaly (54% vs 51%), rhizomelia (64% vs 43%), and frontal bossing (41% vs 29%).

Conclusion:
Despite being distinct clinical diagnoses, there is significant overlap between ACH and HCH. This overlap exists for both quantifiable measures (i.e., height) and categorical features where even “classically ACH” features are observed in HCH patients (e.g., trident hand, frontal bossing). Given overlapping clinical presentations and molecular underpinnings, FGFR3-related conditions can be conceptualized as a continuous disease spectrum, rather than a collection of discrete clinical diagnoses.

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