bluuebunny/crossref_metadata_2025 huggingface dataset:
12372 A Rare Case Of Silicon Granulomatosis Induced Hypercalcemia In A Transgender Female
Authors: Aluko Oluwatomisin A , Singh Ishita
Published: October 2024

Disclosure: O.A. Aluko: None. I. Singh: None.

Introduction: Hypercalcemia has been described in patients with most granulomatous disorders, of which sarcoidosis and tuberculosis are the most common. Granuloma formation is a rare, however well known complication of silicon implants and injections. We present a case of silicon granulomatosis induced hypercalcemia in a transgender female. Case Report 60-year-old transgender female, with past medical history of HIV on HAART was referred to Endocrinology for evaluation of hypercalcemia. She Bloodwork done a few weeks prior revealed elevated calcium 12.3 and low PTH of 9. Reported symptoms include worsening abdominal pain similar to prior gastritis flare, insomnia and significant weight loss. Denied any constipation, joint pain, mood changes, no history of bone fractures or kidney stones. Admitted to significant dairy intake - half a gallon of milk within 3 days and daily yogurt consumption. Endorsed inadequate daily fluid intake and she was not taking oral calcium or Vitamin D supplementation. Quit tobacco 9 years ago. Vitals were significant for tachycardia with HR 120/min, BP stable. Patient was referred to the ER for IV hydration and further evaluation with initial suspicion of malignancy. Repeat corrected calcium was 14.7, ionized calcium 6.8, PTHrP undetectable <2, borderline high 1,25 dihydroxyvitamin D 74.5, low vitamin D 17.9 and normal free T4 1.5. ACE, SPEP, UPEP levels within normal limits. Vitamin A low. CT chest/abdomen/pelvis revealed innumerable soft tissue foci in the subcutaneous adipose tissue of the flanks and lateral gluteal areas; nodular liver, suspected cirrhosis and portal hypertension. Imaging findings prompted further discussion regarding prior procedures. She endorsed history of silicone fillers in hips and breast implants 30 years ago. Images reviewed with radiology confirmed calcification around bilateral breast implants, with intracapsular rupture. Calcium improved with IV Fluids, bisphosphonates and steroids. The most probable cause of hypercalcemia was believed to be secondary to silicone granulomatosis. Innumerable granulomas were deemed irresectable, removal of the breast implants considered however not performed. She was later diagnosed with hepatitis B, cirrhosis and succumbed to sepsis and multiorgan failure. Conclusion Eliciting a detailed history, physical exam and correlating with imaging findings is imperative to establishing an uncommon diagnosis. PTHrP was low and there were no bony metastases making the possibility of malignancy related hypercalcemia less likely. FDG-PET if performed would reveal hypermetabolic nodules, often an initial indication to the underlying etiology.

Presentation: 6/2/2024
7154 Adult Hypophosphatasia With Heterozygous Missense Mutations In ALPL Gene
Authors: Chaugule Akshata S , Cervelo Yeset , Dhillon Shabnam , Tuncay Delibasi
Published: October 2024

Disclosure: A.S. Chaugule: None. Y. Cervelo: None. S. Dhillon: None. D. Tuncay: None.

We present a case of a male in his third decade of life discovered to be a carrier of the genetic mutation associated with hypophosphatasia during routine pre-conception genetic screening. Genetic analysis revealed a heterozygous pathogenic missense variant which is c.979TC, p.F327L in the ALPL gene. A retrospective chart review after genetic diagnosis revealed that he had an alkaline phosphatase (ALP) level at 35 Units/Liter (U/L) which was considered normal as the reference range of the lab test was 31-120 U/L in 2019. The patient also had a childhood history of severely weakened enamel, dental cavities, and renal stones. After the genetic diagnosis, he was referred for a bone density scan which revealed osteoporosis of the lumbar spine. On review of symptoms, he complained of diffuse musculoskeletal pain. Current investigations revealed a low alkaline phosphatase level of 32 (U/L) and high 24-urine calcium excretion. He was started on vitamin D3 supplements and hydrochlorothiazide which led to improvement in his 24-urine calcium excretion. As an adopted individual, no family history was available. Based on laboratory and clinical findings he qualified for starting therapy with Asfotase Alfa. Hypophosphatasia is a rare and highly heterogeneous disease condition with varied mutations in the ALPL gene resulting in multiple phenotypes. Numerous studies have studied the importance of diagnosing hypophosphatasia based on clinical features, laboratory testing, radiographic findings, and family history. Fragility fractures along with age and sex-adjusted serum total ALP levels are important clinical and laboratory features respectively, promptly leading to a clue in the diagnosis of adult hypophosphatasia. ALP levels should always be corrected to the age and sex of the patient and levels less than 40 U/L should prompt a workup for hypophosphatasia. The diagnosis of hypophosphatasia for our patient was delayed due to the absence of a history of fractures, a previously recorded normal ALP and an unknown family medical history. Diagnostic criteria have been formulated to help aid the diagnosis of hypophosphatasia in childhood and include various childhood clinical manifestations and laboratory features. Diagnosis can often be missed given the wide range of clinical features. This case underscores the importance of genetic screening in symptomatic children with frequent dental problems for identifying carriers of hypophosphatasia, especially in the case of an unknown family history. Timely diagnosis and management can help improve a patient’s quality of life.

Presentation: 6/2/2024
8106 An Uncommon Cause Of Hyperparathyroidism: A Case Report
Authors: Calderon Andres , Aguilera Maria C , Kansara Abhishek
Published: October 2024

Disclosure: A. Calderon: None. M.C. Aguilera: None. A. Kansara: None.

Introduction: Parathyroid adenomas are the most common cause of primary hyperparathyroidism. Imaging techniques to locate parathyroid adenomas and hyperplasia include U/S (Sensitivity: 72%-89%), Sestamibi Tc-99 (Sensitivity of 68-95%), and 4D CT scan (Sensitivity of 80%). Combined imaging modalities increase sensitivity to 95%. We describe a case of symptomatic primary hyperparathyroidism with rapid development of hypercalcemia, and conflicting imaging findings. The final diagnosis was made after surgery and pathology review. Case presentation: A 76-year-old man with a history of hypertension, Parkinson’s disease, and prostate cancer was admitted due to a calcium level of 13 mg/dL (8.0 - 10.2 mg/dl) on routine blood tests. He had complained of progressive fatigue and constipation, attributed to Parkinson’s Disease. Five months prior his calcium was 9.7 mg/dL. Hydrochlorothiazide was discontinued due to hypotension after two months. Blood tests in the hospital showed a corrected calcium of 12.5 mg/dL, phosphorus of 1.7 (2.4 - 4.5 mg/dl), PTH of 195 (15 - 65 pg/ml), with normal vitamin D and undetectable PTHrP. A U/S of the neck showed a 0.4 x 0.5 cm cystic mass in the right-inferior pole of the thyroid. A 4D CT scan of the neck showed a non-enhancing 0.9 x 7 x 1 mm mass in the same location, and a 7 x 4.7 x 4.8 mm mildly enhancing mass in the left lower pole of the thyroid. A parathyroid nuclear scan did not identify a parathyroid adenoma. He underwent minimally invasive parathyroidectomy and was found to have a 3.2 cm enlarged and cystic right inferior parathyroid gland weighing 792 mg. Frozen section showed hypercellular parathyroid with cystic and fibrotic changes. The PTH level dropped 59% after removal of the right cystic mass. The left inferior mass identified on CT scan was identified as normal thyroid tissue. Conclusions: Parathyroid cysts are uncommon neck masses and represent less than 5% of causes of all neck masses. They can be divided into functional and non-functional. Large retrospective studies have shown that about 5% of patients manifest as classic hyperparathyroidism, whereas the most common presentation was neck mass (40%). Identification of parathyroid cysts through imaging can be challenging. In our case, the patient presented with symptomatic and rapidly progressive primary hyperparathyroidism, and imaging findings that were discordant among ultrasound, 4DCT scan and Sestamibi Tc-99 scan. The final surgical and pathology reports identified a large parathyroid cyst. This case emphasizes the variable clinical and imaging behavior of parathyroid cysts, imposing a puzzling medical challenge.

Presentation: 6/3/2024
7293 An Unusual Case Of Adult-Onset Heterozygous HHRH In A Male With Normal Phosphorus And Severe Osteoporosis
Authors: El Najjar Mayssam , Sabet Amin , Willard Devina
Published: October 2024

Disclosure: M. El Najjar: None. A. Sabet: None. D. Willard: None.

Introduction: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare genetic disorder characterized by renal phosphate wasting, which can affect bone metabolism. Although onset is typically in childhood, adult-onset forms have been described, and the manifestation depends on the zygosity of each patient. Most commonly, adults with HHRH demonstrate markedly reduced bone density and multiple fractures. Heterozygotes have milder presentations with mild hypophosphatemia, hypercalciuria, and nephrolithiasis, usually without bone disease; however, it is less well characterized. Case report: A 73-year-old man suffered an L1 vertebral compression fracture while playing golf. Bone mineral density testing revealed T-scores of -0.9 at the lumbar spine and -3.4 at the femoral neck (Z-score -2.6). He started alendronate 70 mg weekly for osteoporosis treatment. A year later, the patient sustained an L3 vertebral compression fracture while on treatment with no improvement in his bone density. His family history was remarkable for osteoporosis in his mother but no nephrolithiasis or hypercalcemia. Physical examination was unremarkable. Laboratory evaluation was notable for a 1,25-dihydroxyvitamin D of 87 pg/mL (18-72 pg/mL) , a 24-hour urine calcium of 240 mg/g Cr (30-210 mg/g),a serum PTH of 9 pg/mL (16-77 pg/ml) , but otherwise a normal serum calcium level of 9.4 mg/dL (8.6-10.3 mg/dL) and serum phosphate level of 2.2 mg/dl (2.1-4.3 mg/dl). Genetic testing revealed heterozygosity for SLC34A3 mutation, which is associated with HHRH. The patient discontinued alendronate and started 250 mg phosphorus supplementation 4 times daily. At 6 months follow up, he reported improvement in his body aches, and biochemical testing showed normalization of his 24-hour urine calcium to 171 mg/g Cr and serum PTH to 21 pg/mL. Repeat bone density scan after 1 year of phosphorus supplementation showed T-scores of -0.3 at the lumbar spine (5.8% increase) and -2.6 at the femoral neck (15.5% increase). Clinical Lesson: HHRH is an autosomal recessive hypophosphatemic rickets associated with mutations of the SLC34A3 sodium-phosphate cotransporter, where it is believed that selective phosphate wasting leads to increased calcitriol, in contrast to other forms of hypophosphatemic rickets, causing increased intestinal calcium absorption and resulting hypercalciuria. Adult-onset forms of HHRH have been described in heterozygous carriers of the SLC34A3 mutation and usually present with low to low-normal phosphate levels, hypercalciuria, and nephrolithiasis but without bone disease. However, clinical variations of heterozygous carriers have also been recognized, and therefore are likely underdiagnosed. Our patient’s serum phosphorus level was within the normal range, and hypophosphatemic rickets could have been missed if a more extensive laboratory evaluation had not been performed.

Presentation: 6/1/2024
12460 Bilateral Parietal Thinning: A Rare Condition Of Unclear Etiology
Authors: Madsen-Barbosa Thayse L , Cheikh Malek , Marcano Isabel
Published: October 2024

Disclosure: T.L. Madsen-Barbosa: None. M. Cheikh: None. I. Marcano: None.

Background: Bilateral parietal bone thinning (BPT) is an infrequent and often underdiagnosed condition characterized by the external thinning of the skull's parietal bone. The pathophysiology is unclear, but some studies suggest a link to osteoporosis. We present a case of osteoporosis diagnosed on evaluation of BPT. Case Description: A 77-year-old woman with a history of chronic kidney disease (CKD stage IV) and type 2 diabetes was referred to the Bone Health Clinic for evaluation of low bone density. She initially presented to Neurosurgery clinic for evaluation of head indentations. A dual energy x-ray absorptiometry (DEXA) scan showed values in osteopenia range (left total hip bone mineral density (BMD) 0.678 and T-score of -2.2, left femoral neck BMD 0.272 and T-score of -1.6, and left 33% radius BMD 0.577 and T-score of -2.0), leading to the referral. The patient reported painless indentations in the parietal bones that had been progressing for four years, with no history of head trauma, inflammatory disease, or prolonged steroid use. A head computed tomography (CT) scan showed symmetric thinning of the skull’s parietal bones, with an average thickness of 2.34 mm (compared to 5.1 mm four years earlier). Review of prior images also revealed a T11 compression fracture on spine X-ray from 2019. Laboratory tests showed elevated parathyroid hormone (PTH) 155 pg/mL (reference range 15-65 pg/mL), low vitamin D 25-OH 10.6 ng/mL (reference range 30-100 ng/mL), elevated alkaline phosphatase 142 units/L (reference range 46-116 units/L), and high creatinine level 2.7 mg/dL (reference range 0.5-0.8 mg/dL), other laboratory tests were normal. After discussion with the patient and Nephrology, Denosumab therapy along with Calcium and Vitamin D supplementation were started in November 2023. The patient continues the treatment with antiresorptive medication every 6 months and head CT scan to monitor the skull thinning changes. Discussion: BPT is rare, with only approximately 150 cases reported. Crucial aspects such as its etiology, pathophysiology, treatment, and prognosis remain unknown. It can result from various conditions like trauma, systemic mastocytosis, diabetes mellitus, hereditary diseases, or idiopathic causes and mainly affects women of advanced age. Osteoporosis is suggested as a possible cause based on histological findings on prior studies that propose BPT may result from osteoporosis-induced decreased bone formation rather than increased bone destruction. The reason for excessive bone resorption in the skull of osteoporotic patients remains unclear. Our case highlights progressive and symmetric BPT possibly related to systemic conditions like osteoporosis, with a focus on treatment options. Conclusion: This case sheds light on the clinical presentation, imaging findings, pathogenesis, and treatment options for the rare condition of bilateral parietal bone thinning.

Presentation: 6/3/2024
8660 Bodipy Labeled Vitamin D3 Associates With Lipid Droplets In Adipocytes
Authors: Ucar N , Deeney J T , Pickering R , Kirber M T , Fan T Y , Loo R , Holick M F
Published: October 2024

Disclosure: N. Ucar: None. J.T. Deeney: None. R. Pickering, PhD: None. M.T. Kirber: None. T. Fan: None. R. Loo, PhD: Research Investigator; Self; Carbogen Amcis BV. M.F. Holick: Grant Recipient; Self; Carbogen Amcis BV. Research Investigator; Self; Carbogen Amcis BV.

Obese patients are often found to be deficient in vitamin D, requiring higher levels of supplementation than normal weight subjects. While this has been attributed to vitamin D3‘s lipid solubility and accumulation in fat tissue, little is known about how vitamin D3 enters adipocytes and associates with the intracellular lipid droplet. The goal of this study was to investigate this association using a novel fluorescently labelled vitamin D3. Bodipy, 4,4-difluoro-1,3,5, 7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503), was covalently linked to vitamin D3 and its structure was confirmed by NMR and mass spectroscopy. Murine 3T3L1 and primary adipocytes were used for our study. Mouse 3T3L1 preadipocytes were cultured in multiwell plates or glass bottom dishes in high glucose DMEM media and differentiated for 7-14 days. Primary adipocytes were obtained by collagenase digestion after surgical extraction of adipose tissue from male/female C57BL/6J mice and attached to glass bottom dishes. The cultured adipocytes were exposed to 10 microM BODIPY labelled Vitamin D3 (vitD-B). BODIPY was added to cultured cells and served as the control. Cells were imaged at various times on a wide-field epifluorescence microscope and analysed with NIH ImageJ software. VitD-B adipocyte uptake and accumulation in lipid droplets was observed over 24 hrs. Isolated lipid droplets were also incubated with vitD-B and BODIPY. VitD-B in mature 3T3L1 cells was observed in lipid droplets after 1h incubation and increased fluorescent intensity was observed over the next 24 hrs. BODIPY was observed in the lipid droplets after 15-20 mins. As a negative control, non-differentiated 3T3L1 cells did not exhibit staining by BODIPY even after 24-hrs. When vitD-B was added to primary cultured adipocytes, it appeared in the adipocytes within 1-hr. Fluorescence intensity of primary adipocytes was increased 1.2-fold at 8 hrs and 5.7-fold at 24 hrs compared to 1 hr. For comparison the positive control treated with BODIPY exhibited rapid fluorescence uptake into primary adipocytes that was increased 29-fold higher than that of vitD-B at 1 hr. VitD-B and BODIPY both demonstrated rapid uptake into isolated lipid droplets (less than 2 min) based on fluorescence microscopy.These results hold promising implications for understanding of the interaction between vitamin D and intracellular lipid droplets. Keywords: Adipocyte, Vitamin D3, BODIPY, adipocytes, lipid droplet, fluorescent labelled vitamin D3

Presentation: 6/2/2024
7002 Building Poor Bone, A Rare Presentation Of Skeletal Fluorosis
Authors: Pham Christopher , Lopresti Jonathan S
Published: October 2024

Disclosure: C. Pham: None. J.S. Lopresti: None.

Skeletal fluorosis is a rare disease associated with osteosclerosis and fractures. Case: 26 year old male presented with a history of multiple traumatic fractures but no childhood or family history of fractures. Initial labs revealed a corrected calcium of 8.1 mg/dL (8.5-10.3), ALP 1,504 U/L (40-129), PTH 131 pg/ml (15-65), 25-OH D 14 ng/ml (30-100), PO4 3.7 mg/dl (2.5-4.5) and normal creatinine. X-Rays demonstrated osteosclerosis and cortical expansion of bone and nuclear bone scan demonstrated diffuse increased uptake. Further history revealed huffing of computer inhalants (10 cans daily) for years. Due to these findings, urine fluoride 16.88 mg/L (0.20-3.20 mg/L) and serum fluoride 0.40 mg/L (<0.05 mg/L) were obtained and vitamin D was started. 4 months later, his vitamin D level improved to 21 while calcium levels normalized despite ongoing inhalant use. ALP (878) and PTH (92) continued to be elevated albeit at improved levels. Conclusion: Exposure to fluoride leads to a rare condition called skeletal fluorosis causing accelerated osteogenesis and bone turnover leading to weak bone. Symptoms include bony pain, fractures, and osteosclerosis on radiographs. Differential diagnosis includes other conditions associated with osteosclerosis such as Paget’s disease and myelofibrosis. However, diffuse osteosclerosis and vertebral osteophytosis are noted only in skeletal fluorosis compared to other potential causes, though our patient did not have a CT spine done to assess for osteophytes. Biochemical studies can include hypocalcemia and hyperparathyroidism. It is thought that low calcium intake contributes to the hyperparathyroidism. Elevated serum and urine fluoride levels are also diagnostic and can persist for months after cessation of fluoride intake. Sodium fluoride has been posited as a treatment for osteoporosis due to its tremendous ability to build bone; however, the quality of bone made is poor leading to unacceptable fracture rates. Skeletal fluorosis should be suspected in any patient with history of diffuse osteosclerosis and hyperparathyroidism; and vitamin D supplementation should be initiated. In our case, hypocalcemia and PTH levels were improved despite active inhalant use after vitamin D supplementation. This suggests that Vitamin D deficiency and fluoride may be two independent driving factors in hyperparathyroidism in patients with fluorosis. Increased calcium absorption with vitamin D provides therapeutic benefit in both cases.

Presentation: 6/1/2024
6542 Burosumab In Unresectable/Unidentifiable Tumor-Induced Osteomalacia
Authors: Shan Der Yi , Kumar Chaubey Santosh , Kumar Sinha Ashim
Published: October 2024

Disclosure: Y. Der: None. S.K. Chaubey: None. A.K. Sinha: None.

Introduction/Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, typically arising from small, benign, slow-growing mesenchymal tumors, that secrete fibroblast growth factor (FGF23) and other phosphaturic proteins. It is characterized by hypophosphatemia, phosphaturia, reduced serum 1,25 dihydroxyvitamin D and bone demineralization. While complete resection of the causative tumor is the curative approach, unresectable or unidentifiable cases necessitate medical therapy with oral phosphate and calcitriol. Unfortunately, this option proves suboptimal, plagued by low compliance due to intolerable gastrointestinal side effects. A recent stride in treatment includes the approval of burosumab, an anti-FGF-23 monoclonal antibody, for TIO in the USA. Clinical Case: We report a perplexing TIO case where the underlying tumor remains elusive to-date. The patient, a 41-year-old former Filipino national swimmer, presented at the age of 35, wheelchair-bound, with a four-year history of progressive functional decline, secondary to diffuse osteomuscular pain and multiple fractures. Investigations revealed hypophosphatemia (0.28mmol/L; reference range: 0.75-1.5), phosphaturia, elevated ALP, low 1,25 dihydroxyvitamin D, and elevated peak FGF23 at 217ng/L (reference range: 23.2-95.4). Despite exhaustive imaging studies and stepwise venous sampling, tumor localization proved elusive. The patient experienced improvement in overall mobility and functional status on regular phosphate and calcitriol supplements. Cinacalcet was later added to reduce secondary hyperparathyroidism, FGF levels, and the need for phosphate supplements. Nevertheless, her chronic pain and limited mobility persisted, along with supplementation-associated gastrointestinal symptoms. The ionized calcium and phosphate remained low/low normal. In September 2023, the patient was commenced on subcutaneous burosumab via special access scheme, initially at 0.5mg/kg/month, subsequently uptitrated to the current 1mg/kg/month dosage. Remarkable improvements in pain and physical performance ensued, as evidenced by functional assessment and questionnaire tools. Serum phosphate levels are currently maintaining at 0.8mmol/L, with the most recent FGF level following her third burosumab injection improved to 88.4ng/L. Currently, four months into treatment, no side effects have been reported, and all previous supplementation and cinacalcet has been discontinued. Clinical Lessons/Conclusions: To our knowledge, this represents the first TIO case in Australia treated with burosumab. This case highlights favorable effects, including serum phosphate normalization and significant improvements in mobility, pain and quality of life. Thus, this case underscores the potential of burosumab in managing unresectable or unidentifiable TIO cases.

Presentation: 6/1/2024
6725 CDC’s Efforts In Standardizing Of Vitamin D Tests: Challenges And Potential Patient Misclassifications
Authors: Sugahara Otoe , Buchannan Tatiana , Danilenko Uliana , Ribera Ashley , Collins Lynn , Pokuah Fidelia , Lyle Alicia N , Vesper Hubert W
Published: October 2024

Disclosure: O. Sugahara: None. T. Buchannan: None. U. Danilenko: None. A. Ribera: None. L. Collins: None. F. Pokuah: None. A.N. Lyle: None. H.W. Vesper: None.

Accurate and reliable tests are critical for the correct diagnosis and treatment of patients, correct interpretation of research data, and effective evidence-based clinical decision-making. CDC’s Clinical Standardization Programs (CDC CSP) assist with assessing and improving the analytical performance of biomarker tests, such as vitamin D, performed in patient care, public health, and research. CDC CSP established the Vitamin D Standardization-Certification Program (VDSCP) in 2013. The program has seen improvements in calibration bias since its inception. In 2022, mass spectrometry-based assays had a mean bias of 0.55% and immunoassays had a mean bias of 0.86%, for all assays enrolled in VDSCP. This indicates that overall, the assays enrolled in the VDSCP are well-calibrated. However, with improvements in calibration, sample-specific inaccurate results became more apparent. These observations can be explained by a lack of analytical specificity and cross-reactivity, as well as incomplete analyte recovery. For example, some mass spectrometry-based assays measure C3-epi-25-hydroxyvitamin D3 in addition to 25-hydroxyvitamin D3 causing falsely elevated results in some samples. Some immunoassays appear to show cross-reactivity with 24,25-dihydroxyvitamin D3 also causing falsely elevated vitamin D concentration. These inaccuracies may result in incorrect patient classification. Preliminary assessment of data reveals evidence that could lead to patient misclassification. According to the Endocrine Society’s guideline, a vitamin D level of 50 nmol/L or less is considered as deficiency and a vitamin D level of 50-75 nmol/L is considered as insufficiency. For example, a VDSCP sample with a vitamin D reference value of 55.1 nmol/L should be classified as insufficient in vitamin D. However, 44 % of results reported would classify this sample are deficient. Another sample with a vitamin D reference value of 45.4 nmol/L should be classified as deficient in vitamin D. However, 18 % of the results reported would classify this sample as insufficient. While most vitamin D tests are effective, it is important for healthcare providers to be aware of the potential inconsistencies associated with vitamin D tests to avoid misclassification of the patients.

Presentation: 6/2/2024
7297 Clinical Characterization Of FHH Patients With Functional Assessment Of Novel CaSR Variants
Authors: Tora R , Canaff L , Welch J , Bliss L , Weinstein L S , Simonds W F , Agarwal S K , Blau J , Goltzman D , Jha S
Published: October 2024

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
12472 Clinical Features Of Adult Hypophosphatasia And Correlation Between Laboratory Findings And Patient’s Symptomatology: A Retrospective Review At The Penn Bone Center
Authors: Ocampo Mascaro Javier , Tran Richie , Kallish Staci , Berman Jessica , Al Mukaddam Mona
Published: October 2024

Disclosure: J. Ocampo Mascaro: None. R. Tran: None. S. Kallish: Consulting Fee; Self; Sanofi, Amicus. Research Investigator; Self; Ipsen, Sanofi, Incyte, Idorsia. Speaker; Self; Sanofi, Amicus. J. Berman: None. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Incyte Research Funding.

Hypophosphatasia (HPP) is an inborn error of metabolism resulting in low activity of the enzyme tissue non-specific alkaline phosphatase (ALP). It primarily involves bone and teeth mineralization. HPP has a wide clinical spectrum. It may present with rickets, fractures, failure to thrive, weakness, respiratory complications, and seizures in its more severe perinatal/infantile forms. Childhood forms tend to be milder but may have substantial musculoskeletal complications and early teeth loss. The clinical picture in adults is extremely variable too. It is usually mild with stress fractures and/or teeth loss in most individuals but can be debilitating in others due to musculoskeletal pain and recurrent fractures. This retrospective study describes the characteristics of 35 adult patients (ages 22-74 years) with HPP based on clinical presentation +/- molecular testing at the Penn Bone Center, located at a US-based large academic hospital. Out of 35 patients, 26 had an ALPL variant in genetic testing (12 pathogenic, 5 likely pathogenic, and 9 of uncertain significance), 3 were negative, and 6 did not undergo testing yet. ALP values ranged from 11 to 39 U/L (N: 38-126). Serum fasting vitamin B6 levels (off supplements) ranged from normal range to 18 times the upper limit of normal. Main symptoms reported were fractures (74%), arthralgias/myalgias (51%), diffuse bone pain (29%), atraumatic teeth loss (20%), muscle weakness (14%), and nephrolithiasis (9%). We found no significant negative correlation between ALP levels and number of symptoms (rs -0.026) or age of first symptom occurrence (rs 0.205). We also found no significant positive correlation between B6 elevation and number of symptoms (rs 0.236) or age of first symptom occurrence (rs -0.175). Six patients within our cohort had previous or current treatment with asfotase alfa. This is an FDA-approved therapy for the treatment of perinatal, infantile, and childhood HPP and has been used in adult patients if one of the presenting symptoms was before age 18 years. Response to therapy in our patient cohort was mixed. Three out of six patients discontinued treatment due to lack of clinical benefit. Continued research of the clinical characteristics of adult HPP is needed to better understand its natural history, markers of severity of disease, and how to determine who may potentially benefit from asfostase alfa therapy.

Presentation: 6/1/2024
8179 Complicated Pancreatitis Unveiled: A Case Of Untreated Primary Hyperparathyroidism
Authors: Rehan A , Al Jumaili H , Lim J
Published: October 2024

Disclosure: A. Rehan: None. H. Al Jumaili: None. J. Lim: None.

Introduction: Acute pancreatitis (AP) triggered by hypercalcemia stemming from primary hyperparathyroidism (PHPT) is an infrequent occurrence, with a prevalence of about 1.5-7%. The proposed mechanism involves deposition of calcium in the pancreatic ducts and activation of pancreatic enzymes. While a causal connection between AP and PHPT has been described, it remains controversial. Calcium levels are thought to play a major role in determining the severity of the pancreatitis. Additionally, it is thought that genetic mutations may contribute to the development of AP in PHPT. Here, we report a case of necrotizing pancreatitis in a patient with untreated PHPT. Clinical Case: Patient is a 59-year-old male with a medical history of hypertension, nephrolithiasis and PHPT secondary to parathyroid hyperplasia (scheduled for parathyroidectomy) who presented with abdominal pain, nausea, vomiting and was found to have AP. He reported no history of alcohol use, trauma or insect bites. His workup was unrevealing for cholecystitis, choledocholithiasis or hypertriglyceridemia. He represented with calcium level of 16 mg/dL (NR 8.7-10.1) due to PHPT. PHPT was deemed the likely cause of AP. Course was further complicated by necrotizing pancreatitis and pseudocyst. A few months later, patient started having coffee ground emesis, worsening epigastric pain and weight loss of 60 lbs due to poor oral intake. CT abdomen/pelvis showed walled off pancreatic necrosis with peripancreatic stranding and concern for gastric outlet obstruction. EGD with PEG-J placement was done with plans for future endoscopic drainage. Few weeks after, he had another bout of worsening abdominal pain. Labs at the time showed corrected calcium between 11-13 mg/dL, PTH 147 pg/ml (NR 5-44), phosphorus 1.6 mg/dL (NR 2.5-4.5), vitamin D 25 hydroxy 19.5 ng/ml (NR 22-110). His condition became more complex with a hemorrhagic walled off pancreatic necrosis and splenic artery pseudoaneurysm requiring ICU care. The repeated escalation of symptoms resulted in multiple delays for the scheduled parathyroidectomy. Patient was started on treatment with Cinacalcet and vitamin D while in the hospital. Due to constraints in resources, he was unable to continue Cinacalcet outpatient. He subsequently was able to undergo parathyroidectomy with pathology showing benign adenoma. Conclusion: Hypercalcemic hyperparathyroidism causing AP, although rare, is often severe and poses a greater risk of complications making it important to be aware of this association, especially when more common causes have been excluded. Imaging techniques like cervical ultrasound, CT, and scintigraphy using 99mTc-Sestambi should be utilized to confirm suspicion. Surgical resection is the mainstay treatment, and having a multidisciplinary team with gastroenterologists, endocrinologists, and surgeons helps improve outcomes.

Presentation: 6/2/2024
8063 Cystic Parathyroid Adenoma: A Rare Cause Of Severe Hypercalcemia
Authors: Owrangi M E , Hasan F
Published: October 2024

Disclosure: M. Owrangi: None. F. Hasan: None.

Introduction: Parathyroid adenomas are the most common cause of primary hyperparathyroidism, but within this category, a rare subtype exists - cystic parathyroid adenomas (CPAs). Comprising only 0.5-1% of all parathyroid lesions, CPAs present unique diagnostic and therapeutic challenges. We report a case of a female patient presenting with severe hypercalcemia caused by a CPA. Case presentation: A 44-year-old African American female with a history of nephrolithiasis presented with abdominal pain and signs of dehydration. Labs were remarkable for serum calcium 13.2 mg/dL, albumin 4.0 g/dL, phosphorus 1.8 mg/dL, iPTH 617.7 pg/mL, 25-OH vit D 12.1 ng/mL, creatinine 0.85 mg/dL. She was initially resuscitated aggressively with IV fluids resulting in an improvement in serum calcium level to 10.3 mg/dL. Thyroid US showed a cystic nodule deep to the left thyroid lobe. Sestamibi parathyroid scan was consistent with a left superior parathyroid adenoma. She underwent 2 gland parathyroidectomy 3 months after the initial presentation. Intraoperatively serum PTH decreased by 91% after resection of the 2 parathyroid adenomas. Pathology confirmed the presence of 2 parathyroid adenomas, the larger one measuring 2.8 cm and weighing 3.8 g. Discussion: We describe a case of a middle-aged female presenting with severe hypercalcemia due to CPA. Her initial presentation was concerning for parathyroid carcinoma given the severity of hypercalcemia. However, the radiologic findings, coupled with surgical pathology, indicated that she had CPA. CPAs can be either functional, causing primary hyperparathyroidism (PHPT) with elevated serum calcium levels, or non-functional, remaining asymptomatic. Clinical features of PHPT associated with CPAs are similar to those with solid adenomas and include fatigue, GI symptoms, nephrolithiasis, bone pain, and neuropsychiatric manifestations. However, CPAs may exhibit certain distinct presentations: i) higher pre-operative serum calcium levels; and ii) increased risk of symptomatic hypercalcemia. Despite their rarity, CPAs deserve special attention due to their unique presentation, challenging diagnosis, and potential for severe hypercalcemia. Surgical parathyroidectomy is the definitive treatment for functional CPAs. Accurate localization and complete excision of the adenoma are crucial to avoid recurrence. Most CPAs occur in the fourth and fifth decade of life and are more common in women (female to male ratio of 2.5:1). 65-85% of cases are located in the neck and the majority arise from the inferior parathyroid glands and are left-sided, and may very rarely be intrathyroidal.

Presentation: 6/2/2024
9236 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study
Authors: Rouach Vanessa , Gortler Hillary , Greenman Yona , Gabriel Chodick , inbalL Goldshtein
Published: October 2024

Disclosure: V. Rouach: Consulting Fee; Self; Amgen Inc. H. Gortler: None. Y. Greenman: None. C. Gabriel: None. G. inbalL: None.

Background: Anti-resorptive therapies are the mainstay of osteoporosis management, but evidence of their efficacy in the diabetic population is limited and comparison between treatments is lacking. A retrospective analysis, presented at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting, suggests that denosumab leads to greater reduction in fracture risk than zoledronic acid among treatment-naive postmenopausal women with osteoporosis. However, a comparative study recently published suggests higher mortality with denosumab versus oral bisphosphonates. Aim: To assess the association between zoledronic acid or denosumab and the risk of major osteoporotic fracture and mortality in osteoporotic patients with diabetes type 2. Methods: The study population was identified by electronic records of a diabetes registry cross-linked with an osteoporosis registry of a large provider healthcare organization in Israel. Index date was at osteoporosis registry entry. Demographics, Comorbidity Index (CCI), diabetes complications, bone mineral density (BMD) T-scores, hemoglobin A1c levels, eGFR, purchase of statins, and anti-resorptive agents were collected. Propensity score matching was performed. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 27503 diabetic osteoporotic patients were identified, 13343 (48%) patients initiated treatment; 12214 (91.5%) started an oral bisphosphonate, 627 (4.7%) zoledronic acid and 502 (3.7%) denosumab. The median follow-up was 8.9 years. The denosumab treated patients were older (75.7 vs 71.9, p<0.01), had longer diabetes duration (8.4 vs 7.2, p<0.01), were more frequently treated with insulin (29.7 vs 23.9, p=0.02) and had a lower eGFR (59.4 vs 75.3, p<0.01). Male/Female ratio, BMI, CCI, smoking status, alcohol consumption, Hip BMD, HbA1c levels, microvascular complications, hypoglycemic events and statins prescriptions were similar. After propensity weighting, we observed a significant reduced risk of death among the denosumab treated patients (RR=0.72 [0.58-0.91]) without a significant difference in the risk of fracture (RR=0.9 [0.82-1.12]). Conclusions: In this cohort of diabetic osteoporotic patients, denosumab was associated with a significantly reduced mortality compared to zoledronic acid, without a significant difference in the risk of fractures. The effect of denosumab on mortality is yet to be explored.

Presentation: 6/1/2024
8455 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study
Authors: Rouach V , Gortler H , Greenman Y , Gabriel C , inbalL G
Published: October 2024

Disclosure: V. Rouach: Consulting Fee; Self; Amgen Inc. H. Gortler: None. Y. Greenman: None. C. Gabriel: None. G. inbalL: None.

Background: Anti-resorptive therapies are the mainstay of osteoporosis management, but evidence of their efficacy in the diabetic population is limited and comparison between treatments is lacking. A retrospective analysis, presented at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting, suggests that denosumab leads to greater reduction in fracture risk than zoledronic acid among treatment-naive postmenopausal women with osteoporosis. However, a comparative study recently published suggests higher mortality with denosumab versus oral bisphosphonates. Aim: To assess the association between zoledronic acid or denosumab and the risk of major osteoporotic fracture and mortality in osteoporotic patients with diabetes type 2. Methods: The study population was identified by electronic records of a diabetes registry cross-linked with an osteoporosis registry of a large provider healthcare organization in Israel. Index date was at osteoporosis registry entry. Demographics, Comorbidity Index (CCI), diabetes complications, bone mineral density (BMD) T-scores, hemoglobin A1c levels, eGFR, purchase of statins, and anti-resorptive agents were collected. Propensity score matching was performed. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 27503 diabetic osteoporotic patients were identified, 13343 (48%) patients initiated treatment; 12214 (91.5%) started an oral bisphosphonate, 627 (4.7%) zoledronic acid and 502 (3.7%) denosumab. The median follow-up was 8.9 years. The denosumab treated patients were older (75.7 vs 71.9, p<0.01), had longer diabetes duration (8.4 vs 7.2, p<0.01), were more frequently treated with insulin (29.7 vs 23.9, p=0.02) and had a lower eGFR (59.4 vs 75.3, p<0.01). Male/Female ratio, BMI, CCI, smoking status, alcohol consumption, Hip BMD, HbA1c levels, microvascular complications, hypoglycemic events and statins prescriptions were similar. After propensity weighting, we observed a significant reduced risk of death among the denosumab treated patients (RR=0.72 [0.58-0.91]) without a significant difference in the risk of fracture (RR=0.9 [0.82-1.12]). Conclusions: In this cohort of diabetic osteoporotic patients, denosumab was associated with a significantly reduced mortality compared to zoledronic acid, without a significant difference in the risk of fractures. The effect of denosumab on mortality is yet to be explored.

Presentation: 6/1/2024
6483 Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma: A Rare Skeletal Dysplasia/Sarcoma Syndrome
Authors: Grover A , Ferreira C R , Gafni R I , Jumani S , Collins M T , Roszko K L , Hartley I R
Published: October 2024

Disclosure: A. Grover: None. C.R. Ferreira: None. R.I. Gafni: None. S. Jumani: None. M.T. Collins: None. K.L. Roszko: None. I.R. Hartley: None.

Introduction: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is a rare autosomal dominant syndrome associated with pathologic fractures, myopathy, premature hair graying, and aggressive osteosarcomas. DMS-MFH has been linked to genetic variants in the methylthioadenosine phosphorylase (MTAP) gene, which encodes an enzyme in the methionine salvage and polyamine synthesis pathway. This pathway is implicated in other skeletal fragility disorders, such as Snyder-Robinson syndrome, suggesting a still undefined role of this pathway in bone biology. We describe a kindred with DMS-MFH and identify diagnostic challenges. Case: A 53-year-old perimenopausal woman presented with four fragility fractures over one year. Relevant history included premature hair graying, esophageal strictures, and nephrolithiasis. The patient’s bone formation markers were slightly elevated; bone resorption markers were within reference range. Her only osteoporosis risk factor was perimenopausal status. Bone series showed a diffuse heterogeneous appearance of the long bones with a mixed lytic/sclerotic appearance. DEXA scan revealed osteopenia. Family history was significant for 2 sons with aggressive osteosarcomas diagnosed in their late teens; one died at age 20. The other son is currently 39-years-old with recurrent osteosarcomas in three different limbs. The family also has a multigenerational history of severe bone fragility, muscle weakness, and premature hair graying. The patient, her living son, and his father underwent genome sequencing that identified a variant in MTAP (c.885A>G; p.(R295=)) in the patient and son. This variant was previously reported in three other families with DMS-MFH and has been shown to alter splicing. Notably, commercial genetic testing did not report this as a relevant variant, and diagnosis required independent analysis of the raw sequence data. Based on these findings, the patient and her son were diagnosed with DMS-MFH. Given the bone fragility with elevated bone turnover markers we treated the patient with yearly zoledronic acid infusions with no subsequent fractures. Surveillance for osteosarcoma is also being performed with annual whole-body MRI. Conclusion: DMS-MFH has been reported in only five families to date. The sixth family described here has clinical characteristics similar to the other kindreds. Due to high risk of aggressive osteosarcoma, timely diagnosis is imperative to decrease morbidity and mortality. Commercial genome sequencing may miss this diagnosis, so targeted genetic testing should be pursued. As more cases are identified, characterization of affected families may enhance our understanding of the natural history of the disease and guide surveillance and treatment strategies.

Presentation: 6/2/2024