Citations

Abstract Disclosure: K.N. Rachmasari: None. A. Osman: None. D. Toro Tobon: None. S.B. Lund: None. D.J. Merlino: None. A.R. Hsu: None. M.M. Ryder: None. Background: In low-risk papillary thyroid cancer (PTC), radioactive iodine (RAI) remnant ablation has shown no impact on disease recurrence rates, which are overall low. The role of adjuvant RAI in intermediate risk disease (i.e. T3, N1) remains unproven with no randomized clinical trials to objectively assess efficacy. Thus, in our institution, its use is highly heterogenous. We retrospectively investigated the effects of adjuvant RAI on recurrence and recurrence free survival (RFS) in patients with PTC and positive cervical lymph nodes (CLN). Methods: We performed a retrospective review of patients who underwent surgery at Mayo Clinic Rochester, MN for PTC between January 2007 and December 2016. Adult patients with Tx-T3 disease according to the 8th edition of American Joint Committee on Cancer (AJCC) were identified. Patients with positive CLN (N1) and a minimum follow up of 36 months were included. Demographics, clinicopathologic characteristics, use of RAI therapy and recurrence were analyzed. Results: A total of 367 patients with PTC, Tx-3, N1, M0 were identified, of which 187 received adjuvant RAI and 180 did not. Most patients were female (63.8%), with a median age of 44 years (IQR 34-54), and a median follow up of 77 months (IQR 58.5-101.5). There were no differences in age, type of surgery, histology, multifocality, and follow up period between the RAI and no RAI subgroups. Adjuvant Thyrogen-stimulated or thyroid hormone withdrawal-based RAI was recommended at the discretion of the treating provider and/or per patient preference. Diagnostic I-123 whole body scans were performed in all patients and mostly demonstrated remnant uptake. The median dose of I-131 was 75 mCi (range 50-100). Recurrence was defined by new occurrence of disease after at least a year of absence of clinical, biochemical, and imaging evidence of disease since initial surgery. Within the entire cohort, 35 (9.5%) developed recurrence with a median time of 41 months (28-59.5). Overall, recurrence rate and RFS were not significantly different between both subgroups (p = 0.2). A subanalysis was performed in patients with clinically detectable nodal disease (n = 161), defined by abnormal cervical lymph node on preoperative neck ultrasound with or without positive fine needle aspiration biopsy. Overall recurrence rates were 17 (10.6%) in this group. There were no differences in recurrence rates and RFS in those that received RAI versus those that did not (p = 0.8). Conclusions: In patients with intermediate risk PTC defined by nodal disease and/or T3 disease, recurrences were not different between patients that did or did not receive adjuvant I-131 therapy postoperatively. A randomized, noninferiority study of adjuvant I-131 compared to no I-131 postoperatively for N1 disease is needed to determine the benefit of near total thyroidectomy and adjuvant I-131 for this cohort. Presentation: 6/3/2024

Abstract Disclosure: S. Ahmed: None. M. Vahidi Rad: None. S.A. Westphal: None. M.D. Whitaker: None. Introduction: Painful Hashimoto thyroiditis is a rare variant of Hashimoto thyroiditis that mostly affects women. Most cases are empirically treated as subacute thyroiditis with corticosteroids, levothyroxine, or nonsteroidal anti-inflammatory drugs. However, no medical treatment may provide sustained pain resolution, so optimal treatment remains unclear. We describe the case of a 40-year-old female with longstanding throbbing anterior neck discomfort that failed medical therapy and her symptoms completely resolved with total thyroidectomy. Case Report: A 40-year-old lady with anterior neck pain centered over the thyroid for more than 16 years, shortly after she delivered her last child. The pain is described as intense, it tends to wax and wane but there is a constant throbbing with occasional radiation to the angle of the jaw. Over the years the pain has gradually worsened and during its flares, the thyroid itself is very tender to the point where she experiences difficulty in swallowing and hoarseness of voice. Complicating the issue is her underlying diagnosis of fibromyalgia, as she tends to experience discomfort in many other areas of her body. However, the neck pain appears to be of a different character. No symptoms of hyper or hypothyroidism. The anterior neck pain has been difficult to alleviate, she has used chronic opioids for it which seems to have helped to some extent, in the past she was on prednisone for 1 month however this made no difference to it. On examination, the thyroid is tender and somewhat firm without lymphadenopathy. Thyroid levels have been consistently normal and the most recent of which was a TSH: 1.48, FT4: 1.4, FT3: 3.5 with negative TPO and thyroid stimulating antibodies. ESR and CRP were unremarkable. Thyroid ultrasound showed mildly heterogeneous parenchyma with no solid nodules or lymphadenopathy. Interestingly she had an elevated thyroid uptake in her scan dated April 1st 2022, 4 hour and 24-hour uptakes were abnormal at 23% and 49% respectively which can be seen with Hashimoto's. She underwent total thyroidectomy and her surgical pathology showed benign thyroid tissue with multiple foci of chronic lymphocytic thyroiditis and hyperplastic nodules. Her pain completely resolved after total thyroidectomy. Discussion: Painful Hashimoto thyroiditis is a rare diagnosis and optimal treatment remains unclear. The painful variant of Hashimoto's thyroiditis should be considered in the differential diagnosis of pain and tenderness of the thyroid which can be managed successfully by surgical treatment. Thyroidectomy not only can lead to alleviation of symptoms but also provides the definitive diagnosis. The risks of surgical intervention must be taken into consideration, especially because painful Hashimoto thyroiditis can be associated with a small fibrous gland; hence, the importance of access to highly skilled, experienced surgeons cannot be overemphasized. Presentation: 6/1/2024

Abstract Disclosure: K. Yu: None. J. Saini: None. J.N. Farr: None. F. Vanessa: None. S. Khosla: None. I. Bancos: Advisory Board Member; Self; AstraZeneca, Adrenas, Neurocrine, Spruce, Recordati, Xeris, Novo Nordisk, HRA Pharmaceuticals, Sparrow, Diurnal, Corcept. Research Investigator; Self; HRA Pharmaceuticals, Recordati. Importance: Patients with both mild autonomous cortisol secretion (MACS) and overt Cushing syndrome (CS) demonstrated high prevalence of aging-related morbidity and an increased mortality. Objective: To determine whether p16INK4a in T cell, a cell cycle enzyme that associated with chronological aging and cell senescence, is associated with hypercortisolism and hypercortisolism-related comorbidities. Design, Setting, and Participants: In this single-center cross-sectional study, we prospectively recruited consecutive patients with hypercortisolism between July 1, 2020 and August 24 2022. Patients were included if they were diagnosed with Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS). Age- (± 2 years) and sex-matched referent subjects without known adrenal disorders were included if abdominal imaging was available. Participants on exogenous glucocorticoids within 3 months prior were excluded. Exposure: Presence of hypercortisolism (MACS and CS). Main Outcomes and Measures: Primary outcomes included p16INK4a, advanced glycation end products (AGE) reader result, Frailty Index score, frailty (defined as frailty index>0.31), and physical performances in patients and matched referents at index date. Secondary outcomes included correlation between biological age markers, hormonal workup and the risk of comorbidities. p16INK4a expression analysis was adjusted for age, sex, smoking, and alcohol use for all analyses except for associations with CVD and frailty. Results: Of 85 patients (87% women, mean age 53 years), 51 (60%) had MACS (34 had matched referents), 34 (40%) had overt CS (16 had matched referents). Patients with CS demonstrated a median 1.9-fold higher p16INK4a expression (P<.001), and patients with MACS showed a median of 1.70-fold p16INK4a expression (P=.013), when compared to referent subjects. Age- and sex-adjusted p16INK4a expression was associated with frailty index score (r=0.23, P=.035), time-up-and-go test (r=0.28, P=.048), gait speed (r=-0.36, P=.035), but not with AGE reader result, 6-minute walk test, or hand grip measurement. The p16INK4a expression was associated with history of cardiovascular disease (age-adjusted odds ratio (aOR)=3.70, 95% confidence interval (CI), 1.20-11.43) and frailty (aOR=2.27, 95%CI, 1.04-4.98). Conclusion and relevance: We demonstrated evidence of cell senescence in both patients with CS and patients with MACS. Further studies need to determine the impact of surgical, cortisol-lowering, and senolytic medical therapies in MACS on cell senescence and associated aging-related comorbidities. Presentation: 6/1/2024

Abstract Disclosure: C.A. Conover: None. L.K. Bale: None. D. Hamadi: None. M. Stan: ; Tourmaline, Genentech, Third Rock Ventures, ArgenX, Septerna, OrthoDi. ; Horizon, Immunovant, Lassen, Sling. Background: Proptosis in Thyroid Eye Disease (TED) can result in facial disfigurement and visual dysfunction. Studies revealed an interaction between thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor-I receptor (IGF-IR) that is essential in promoting TED pathogenesis. Treatment with Insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects. PAPP-A is metalloprotease that can increase pericellular IGF bioavailability through specific cleavage of inhibitory IGF binding proteins, in particular IGFBP-4. We propose that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitory antibodies attenuates IGF-IR signaling in TED with fewer side effects. Methods: Informed consent was obtained from TED patients undergoing surgery in Mayo Clinic operating suites in Rochester, MN. Retro-orbital tissue was collected from 19 TED patients and 2 control subjects for fibroblast isolation and culture and was performed in a sterile tissue culture facility. TED and control fibroblasts were treated with pro-inflammatory cytokines, and flow separation of CD34- and CD34+ orbital fibroblasts was done, the latter representing infiltrating fibrocytes into the orbit in TED. Main outcome measured were PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase/Akt pathway and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status and associated PAPP-A and IGF-IR expression. Results: Primary cultured cells showed that PAPP-A is expressed in orbital fibroblasts from TED patients but not in control subject fibroblasts and were markedly increased by pro-inflammatory cytokines stimulation. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A’s proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from TED patients. CD34+ orbital fibroblasts represent 80% of cells in culture from TED patients, and approximately 70% of these cells were accountable for PAPP-A and IGF-IR expression. Conclusion: These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis. Presentation: 6/2/2024

Abstract Disclosure: R. Sandooja: None. J. Saini: None. R. Gregg garcia: None. C. Zhang: None. S. Achenbach: None. E. Atkinson: None. J. Van Gompel: None. W.F. Young: None. I. Bancos: None. Hydrocortisone vs Prednisone During Recovery Following Surgical Cure for Endogenous Hypercortisolism: A Longitudinal Observational Study Introduction: Glucocorticoid withdrawal syndrome (GWS) is a constellation of symptoms that occurs after successful surgery for endogenous hypercortisolism. The objective of this study is to compare hydrocortisone versus prednisone on GWS symptoms. Methods: Study design: Single-center prospective longitudinal cohort study, 2019-2023. Participants: Adults with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) with post-operative adrenal insufficiency treated with either hydrocortisone or prednisone for glucocorticoid replacement. Measurements: Clinical and biochemical severity scores for hypercortisolism were calculated. Quality of life (QOL) was assessed using Short Form-36 (SF-36) and Cushing QOL surveys. GWS was assessed using weekly AddiQoL surveys for the first 12 weeks after surgery. Results: Of 131 patients, 91 (69%) patients were treated with hydrocortisone and 40 (31%) with prednisone. No differences in age (median age 51 vs 53 years, P=0.62), sex (84 vs 85% women, P=0.83), etiology of hypercortisolism (ACTH-dependent: 44% vs 48%, P=0.26), clinical severity of hypercortisolism (median score 13 vs 12, P=0.97), or biochemical severity of hypercortisolism (median score of 6 in both, P=0.31) were noted between groups. When assessed at 4-, 8-, and 12-weeks post-surgery, the prevalence and trajectory of symptoms (fatigue, myalgias/arthralgias, sleep, headaches, nausea, weakness) were similar in patients treated with hydrocortisone and prednisone (P>0.05 for all). However, patients treated with prednisone were less likely to report mood changes (8.5% vs 20.9%, P= 0.004) compared to those treated with hydrocortisone. When compared to the presurgical baseline, the overall Cushing QOL score 12 weeks post-surgery improved in both groups (mean delta 8.9 vs 13.0, P=0.21). No differences in the hydrocortisone vs prednisone treatment were found in the SF-36 physical component score (mean delta of -1.7 vs 0.3, P=0.23) and SF-36 mental component score (mean delta 2.3 vs 5.0, P=0.22). Using multivariable analysis, age (estimate 0.22, P= 0.005), clinical severity score (estimate -0.73, P<0.001), female sex (estimate -5.45, P= 0.046) but not glucocorticoid type (estimate -0.06, P=0.98) were associated with the overall GWS symptom burden at 12 weeks. Conclusion: Use of prednisone after curative surgery for hypercortisolism was associated with lower mood symptoms, but did not impact the overall severity or trajectory of other symptoms associated with GWS. Baseline clinical severity of hypercortisolism, age, and female sex were associated with GWS burden. Presentation: 6/1/2024

Abstract Disclosure: K. Gunter: Employee; Self; Inozyme Pharma. Stock Owner; Self; Inozyme Pharma. R.A. Wermers: Research Investigator; Self; Inozyme Pharma. R. Fuhr: Employee; Self; Parexel GmbH. Research Investigator; Self; Inozyme Pharma. D. Schnabel: Research Investigator; Self; Inozyme Pharma. A. Besancon: Research Investigator; Self; Inozyme Pharma. M.A. Nour: Research Investigator; Self; Inozyme Pharma. D. Wenkert: Stock Owner; Self; Inozyme Pharma. Y. Sabbagh: Employee; Self; Inozyme Pharma. Stock Owner; Self; Inozyme Pharma. Background: ENPP1 Deficiency is a rare disorder due to inactivating mutations in the ENPP1 gene that result in low levels of inorganic pyrophosphate (PPi), a critical regulator of mineralization. Subsequent pathologic soft tissue calcification results in severe vascular calcification and ∼50% infant mortality. By early adolescence the majority of survivors develop FGF-23 mediated hypophosphatemic rickets, characterized by bone deformities, short stature, joint/ligament calcification and musculoskeletal pain. No targeted therapy exists for this disease. INZ-701 is a recombinant ENPP1-Fc investigational product. Purpose: To describe the safety, tolerability, immunogenicity, and exploratory efficacy (bone and mineral metabolism biomarkers and clinical outcomes) of INZ-701 in adults with ENPP1 Deficiency through the end of the phase 2 study period (week 48). Methods: Phase 1/2, multicenter, open-label, multiple ascending dose study including three adults in each of three dose cohorts (0.2, 0.6 and 1.8 mg/kg, total N=9) with genetic variants in ENPP1 and PPi <1300 nM (NCT04686175). Participants were dosed subcutaneously on Day 1, then twice weekly from Day 8 to end of study. Data through wk 48 as of July 6, 2023 are included; topline wk 48 data will be presented. Per protocol, participants may continue to receive INZ-701 beyond wk 48. Results: Rapid increase in mean PPi from baseline of 426±407 nM was noted in all patients, reaching the healthy volunteer range within 6 hrs of the first dose with sustained elevation through wk 48. Mean PPi across the 0.2, 0.6 and 1.8 mg/kg dose cohorts from day 32 to wk 48 was 1299±131 nM, 1356±136 nM, and 1282±81 nM, respectively. There were improvements from baseline to wk 48 in mean pooled FGF-23 (-22 pg/mL) and serum phosphate (+0.18 mg/dL), with dose-dependent changes in bone specific alkaline phosphatase consistent with bone healing. DEXA revealed improvements in spine BMD and BMC. There were trends towards improvement in mean % predicted change in 6MWT from baseline to wk 48: cohort 1, 76.7% (SE 10.5) to 85.0% (SE 3.0); cohort 2, 52.2% (SE 10.9 ) to 79.0% (SE 2.9); cohort 3, wk 48 data not available. Improvements were also observed in physician and patient global impression of change score (with no patients deteriorating) and PROMIS pain intensity score. INZ-701 was well tolerated with no drug-related serious or severe (> grade 2) adverse events. Low titers of non-neutralizing anti-drug antibodies (≤160) were observed in 7/9 patients. Long half-life of approximately 126 hours suggests the potential for once-weekly dosing. Conclusions: In adults with ENPP1 Deficiency, INZ-701 was well tolerated with no related serious or severe adverse events. INZ-701 demonstrated a rapid and sustained increase in PPi levels from baseline to week 48 with corresponding improvements in bone mineral biomarkers, functional performance, and patient and physician-reported outcomes. Presentation: 6/3/2024

Abstract Disclosure: B. Salama: None. J. Saini: None. V. Fell: None. E.J. Atkinson: None. S.J. Achenbach: None. Background: Mildly autonomous cortisol secretion (MACS) can be unilateral in 80% of cases, or bilateral in 20% of cases, due to either bilateral adrenal adenomas or bilateral macronodular adrenal hyperplasia. Scarce evidence demonstrates the differences in plasma steroid profiling of patients with bilateral versus unilateral MACS, however, these findings have not been confirmed using a more comprehensive 24h urine steroid profiling. Objectives: To characterize 24h urine steroid metabolome in patients with unilateral and bilateral MACS. Methods: We conducted a single-center cross-sectional study between 2019-2022. Eligible participants included consecutive patients with MACS who provided a 24h urine sample. Urine was analyzed for 25 steroids with a high-resolution mass spectrometry assay. MACS was defined as cortisol >1.8 mcg/dL following the overnight administration of 1 mg dexamethasone (DST-cortisol). Partial cohort analysis is presented. Results: Of 72 patients with MACS included in the interim analysis, 36 (50%) had bilateral MACS. The two groups (unilateral vs bilateral) were similar in age (median 58 vs 58 years), sex (women 67% vs 61%), BMI (median 33 vs 32 kg/m2), and menopausal status (36% vs 39%), P>0.05 for all. Prevalence of comorbidities was also similar in both groups: hypertension (89% vs 89%), hyperlipidemia (69% vs 78%), and hyperglycemia (69% vs 61%), P >0.05 for all. While the DST-cortisol (median 3.0 vs 3.2 mcg/dL, P= 0.51) and dehydroepiandrosterone sulfate (DHEAS) (median 37.5 vs 55.0, P = 0.21) were similar between the 2 groups, patients with bilateral MACS had a lower ACTH (median 12.4 vs 8.2 pg/mL, P = 0.012) when compared to patients with unilateral MACS. Median adrenal mass size was similar in patients with both unilateral MACS (2.7 cm, IQR 1.7-3.9) and bilateral MACS (3.0 cm, IQR 2.2-3.6) P = 0.54. Of the 25 steroids measured, only tetrahydrocorticosterone was higher in patients with unilateral MACS (median 245 mcg/24h, IQR 165-416 vs median 184 mcg/24h, IQR 121 -278) P = 0.039. No differences in androgens (median 2229 vs 2036 mcg/24h), cortisol metabolites (median 6566 vs 5191 mcg/24h), cortisone metabolites (median 10300 vs 9429 mcg/24h), or glucocorticoid/androgen ratio (median 7.9 vs 8.9) was demonstrated between the unilateral vs bilateral MACS groups (P>0.05 for all). Conclusion: In this interim analysis of patients with unilateral vs bilateral MACS, we have found that patients had a similar post-DST cortisol and similar tumor bulk. Despite a lower ACTH in patients with bilateral MACS, no differences in androgens were found between the two groups. In addition to expanding steroid profiling analysis to the whole cohort, subgroup analyses will need to distinguish between patients with bilateral adenomas and macronodular adrenal hyperplasia, consider aldosterone co-secretion, and employ a more accurate measurement of adrenal tumor bulk. Presentation: 6/3/2024

Abstract Disclosure: J. Saini: None. C.D. Zhang: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Several studies employing computed tomography (CT) scans for body composition measurements have reported lower muscle mass and a higher proportion of visceral fat in patients with mild autonomous cortisol secretion (MACS) compared to referent subjects. While a CT scan assesses visceral adipose tissue (VAT) at a single slice level (L3), no studies have evaluated the overall VAT in patients with MACS using Dual-Energy X-ray absorptiometry (DXA). Objective: To determine the impact of MACS on VAT using DXA scan as compared to referent subjects. Methods: We conducted a single-center cross-sectional study of adults with 75 MACS and 75 referent subjects. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. All the participants underwent a full body DXA scan between 04/2019 and 07/2022. We applied the CoreScan software to estimate the (1) total lean and fat mass (2) visceral fat mass and volume (3) lean android, fat android, and android mass, and compared measurements of patients and referent subjects using linear regression models adjusted for sex and BMI. Results: A total of 75 patients with MACS (median age 57.0 years, IQR 47.8-65.6, 67% women) and 75 referent subjects (median age 57.6 years, IQR 49.1-65.8, 67% women) were included. Patients had a higher BMI compared to referent subjects (median 31.7 kg/m2, IQR 27.4-37.9 vs 28.7, IQR, 25.4-33.8, P=0.004). The median post-DST cortisol in patients was 3.1 mcg/dL (IQR, 2.2-5.2). When compared to referent subjects, and after adjustment for sex and BMI, patients had a similar total body fat (estimate=846, p-value=0.28) and lean mass (estimate=-201, p-value=0.83), similar android fat mass (estimate=59, p-value=0.64) but lower gynoid fat mass (estimate=400, 0.007). Notably, sex and BMI-adjusted analysis also showed that patients had a higher VAT fat mass (estimate= -225, p-value=0.084) and a higher VAT fat mass/total mass ratio (estimate= -0.007, p-value=0.026). Conclusions: When adjusted for BMI and sex, patients with MACS do not demonstrate differences in overall fat and lean mass. However, we showed that MACS is associated with increased visceral adiposity, a known cardiovascular risk factor. Body composition assessment by DXA could be a safer and less expensive alternative in the evaluation and follow-up of patients with MACS. Presentation: 6/2/2024

Abstract Disclosure: S.V. Rupani: None. J. Sfeir: None. L. Graeff-Armas: None. Bone microarchitecture is an important factor that impacts bone strength. Unlike other factors that affect bone strength, such as bone mineral density and bone turnover, assessment of bone microarchitecture is not yet widely accessible in clinical practice. Computed tomography is the primary method of non-invasively assessing bone microarchitecture. High-resolution peripheral quantitative CT (HR-pQCT) is an emerging imaging modality that provides a three-dimensional assessment of bone densitometry, morphometry, and microarchitecture with a low effective radiation dose. It provides a quantitative and qualitative assessment of cortical and trabecular structural and mechanical properties. We present two similar cases of osteoporosis in males, where knowledge of bone microarchitecture through HR-pQCT helped formulate two distinct and targeted therapeutic approaches. The first case is of a 46-year-old male with a history of idiopathic osteoporosis with multiple nontraumatic vertebral fractures. Given his presentation and age, anabolic therapy such as teriparatide was being considered. He underwent HR-pQCT scanning, which showed average radial trabecular parameters, but his cortical porosity was significantly above average, with similar findings in his tibial parameters. Since teriparatide has been shown to increase cortical porosity, this would not be the best option for our patient, given the risk of further weakening of the microarchitecture of his cortical bone. Therefore, denosumab, which has been shown to decrease cortical porosity, was chosen. Our second patient is a 52-year-old male with idiopathic osteoporosis with multiple nontraumatic vertebral fractures, whose HR-pQCT showed average cortical parameters at both the radius and tibia but low trabecular number and increased trabecular separation at both sites. Since teriparatide increases trabecular thickness and mass, we could confidently choose teriparatide for this patient, with less concern for significant deleterious effects on his cortical bone parameters. These case reports highlight the impact that the assessment of qualitative properties of bone, such as microarchitecture, can have in the management of osteoporosis. Currently, the lack of sufficient validated normative data for HR-pQCT limits its widespread use in the diagnosis of osteoporosis and fracture prediction. However, given that HR-pQCT can characterize the properties of trabecular and cortical bone, it may have a role in helping guide osteoporosis treatment, especially in challenging and atypical cases. Presentation: 6/3/2024

Abstract Disclosure: S.W. Ing: Advisory Board Member; Self; Ultragenyx, Amolyt. Grant Recipient; Self; Alexion Pharmaceuticals, Inc.. Research Investigator; Self; BridgeBio Pharma, Takeda, Amolyt, Radius Health, Inc, Ultragenyx. P. Harmatz: Research Investigator; Self; BridgeBio Pharma. S. Mora: Research Investigator; Self; BridgeBio Pharma. E.A. Imel: Research Investigator; Self; BridgeBio Pharma. P.J. Tebben: Research Investigator; Self; BridgeBio Pharma. M.L. Warren: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt. Speaker; Self; Ascendis. N. Ma: Research Investigator; Self; Calcilytix Therapeutics, Ultragenyx, Inozyme. Other; Self; Up To Date. A.A. Khan: Research Investigator; Self; BridgeBio Pharma, Ascendis. A. Palermo: Research Investigator; Self; BridgeBio Pharma. B. Decallonne: Research Investigator; Self; BridgeBio Pharma. S. Lemoine: Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. G. Mantovani: Research Investigator; Self; BridgeBio Pharma. A. Linglart: Consulting Fee; Self; Alexion, Novo Nordisk, Merck, Pfizer, Inc.. Research Investigator; Self; BridgeBio Pharma, Kyowa Kirin. H. Wasserman: Research Investigator; Self; BridgeBio Pharma. A.P. Barbosa: Research Investigator; Self; BridgeBio Pharma. C. Cardot-bauters: Research Investigator; Self; BridgeBio Pharma. M. Roberts: Employee; Self; BridgeBio Pharma. A. Mathew: Employee; Self; BridgeBio Pharma. S. Adler: Employee; Self; BridgeBio Pharma. M.C. Zillikens: Research Investigator; Self; BridgeBio Pharma. R.J. Clifton-Bligh: Consulting Fee; Self; Ipsen, Kyowa Kirin, Amgen Inc, Eisai. Research Investigator; Self; BridgeBio Pharma. L. Rejnmark: Research Investigator; Self; BridgeBio Pharma, Ascendis, Amolyt, Takeda, Kyowa Kirin. Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) concentrations, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. While a rare disease, ADH1 is one of the more frequently identified causes of genetic hypoparathyroidism. Conventional therapy includes calcium (Ca) and/or active vitamin D, but this regimen incompletely corrects the hypocalcemia and is associated with persistent hypercalciuria, which may result in renal complications including nephrocalcinosis (NC), nephrolithiasis (NL), and chronic kidney disease (CKD). The CLARIFY disease monitoring study [NCT05227287] is a global, multicenter, longitudinal study to understand disease burden, management, and progression in children and adults with ADH1 over a 5-year period. Here we report data on the characteristics of adult participants at study entry. As of November 2023, 45 adults (≥18 years) with ADH1 were enrolled, with a mean±SD age of 42.1±16.5 years (range 18-80). The mean±SD age of a hypocalcemia diagnosis was 19.1±19.1 years, while the mean±SD age for a diagnosis of ADH1 was 28.2±20.6 years. As reported on medical history, in decreasing order of prevalence, 36% (16) had NC, 22% (10) had intracranial calcifications, 11% (5) had history of seizures, 11% (5) had CKD, 9% (4) had cataracts, 7% (3) had NL, and 4% (2) had undergone renal transplant. Treatment data were available for 43 participants and included the following: 74% (32) Ca and active vitamin D, 9% (4) Ca alone, 9% (4) active vitamin D alone, 37% (16) magnesium, 33% (14) thiazide diuretics, 26% (11) potassium, 7% (3) phosphate binder, 7% (3) PTH, and 5% (2) no treatment. Mean±SD fasting values collected prior to conventional therapy dose are presented. PTH concentrations (10.1±8.2 pg/mL [nl 15-65]) and albumin-corrected calcium ([cCa]=7.5±1.0 mg/dL [nl 8.5-10.5]) were low. Despite the low mean cCa, the mean 24-hr urine calcium was elevated (268±183 mg/d, [nl <250 women, <300 men]). Blood phosphate was 4.8±0.8 mg/dL [nl 2.5-4.8] while blood magnesium was 1.8±0.2 mg/dL [nl 1.8-2.4]. 25-OH vitamin D was 35.0±13.5 ng/mL [nl 30-80]. Renal function as assessed by CKD-EPIcr_R showed eGFR of 86±23 mL/min/1.73m² (range 36-123). This study represents the largest cohort of adults with ADH1 described to date. These data highlight variability in therapeutic approaches in a real-world setting with some participants receiving up to 6 different medications/supplements. Despite being followed in expert centers, and treated with available therapies, patients on average have low cCa with relatively high 24-hr urine calcium excretion. The CLARIFY study provides an opportunity to better understand the progression and burden of disease in participants with ADH1. Presentation: 6/3/2024