7297 Clinical Characterization Of FHH Patients With Functional Assessment Of Novel CaSR Variants
Bibliographic record
Abstract
Abstract Disclosure: R. Tora: None. L. Canaff: None. J. Welch: None. L. Bliss: None. L.S. Weinstein: None. W.F. Simonds: None. S.K. Agarwal: None. J. Blau: None. D. Goltzman: None. S. Jha: None. Familial Hypocalciuric Hypercalcemia (FHH) is characterized by hypercalcemia and low urinary calcium excretion from birth and its diagnosis is confirmed by the presence of a pathogenic germline heterozygous variant in CaSR, AP2S1, or GNA11. Establishing the diagnosis is important as it prevents unnecessary parathyroidectomies as surgery is not curative. We identified patients with germline variants in CaSR, AP2S1, or GNA11 seen at our institute and performed a retrospective review of available clinical parameters. 43 patients (31 kindreds) with 28 unique CaSR variants (15 pathogenic, 13 variants of uncertain significance [VUS]) and one pathogenic AP2S1 variant were identified. Median age at diagnosis was 35 [IQR: 25 - 39] years, with the youngest patient diagnosed at 4.5 months. Median serum calcium was 10.70 [10.25 - 11.00] mg/dL (ref: 8.4 - 10.2) with a median PTH of 51.7 [35.8 - 74.0] pg/mL (ref: 15 - 65). The median fractional excretion of calcium (FECa) was 1.00 [0.54 - 1.40] while median serum magnesium was 2.30 [2.19 - 2.43] mg/dL (ref: 1.6 - 2.6). 5/43 (12%) patients developed kidney stones and 6/43 (14%) men ≤ 50 years and premenopausal women developed osteoporosis with median age at diagnosis of 38 [28.50 - 45.75] years and no alternate underlying secondary cause. Longitudinal follow-up available on 9/43 patients with median duration of 14.4 ± 4.5 years showed no significant changes in serum and urine biochemistries. 23/43 (53%) patients had undergone failed parathyroidectomy prior to diagnosis, of which 20/23 (87%) had multiple glands removed including one who became hypoparathyroid. Functional characterization was performed for 8/13 CaSR VUS (p.D217G, p.C546Y, p.F563S, p.C694Y, p.A880P, p.E109Q, p.D382N, and p.A880S) in HEK293 cells by examining intracellular Ca2+ and ERK/MAPK responses to extracellular Ca2+ using NFAT-Luc and SRE-Luc constructs, respectively. Compared to the wild type (WT) receptor, p.D217G, p.C546Y, p.F563S, and p.C694Y showed less of the cell-membrane-localized mature glycosylated species in Western blots and a significant rightward shift in their concentration-response curve in both SRE- and NFAT-Luc assays. p.A880P showed a significant rightward shift in its concentration-response curve, while p.E109Q, p.D382N, and p.A880S showed no differences on Western blot or concentration-response curves as compared to WT. Further work to characterize the remaining variants (p.T14A, p.T609M, p.V268_P278del, p.G36R, and p.F589V) is ongoing. We conclude that the diagnosis of FHH is frequently missed and that patients with the disease may rarely develop target organ damage. Presentation: 6/2/2024
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".