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ABSTRACT Degenerative osteoarthritis (OA) is recognized as an early‐onset comorbidity of X‐linked hypophosphatemia (XLH), contributing to pain and stiffness and limiting range of motion and activities of daily living. Here, we extend prior findings describing biochemical and cellular changes of articular cartilage (AC) in the phosphate‐wasting environment of XLH to determine the impact of these changes on the biomechanical properties of AC in compression and potential role in the etiology of OA. We hypothesize that despite increased proteoglycan biosynthesis, disruption of the mineralized zone of AC impacts the mechanical properties of cartilage that function to accommodate loads and that therapeutic restoration of this zone will improve the mechanical properties of AC. Data were compared between three groups: wild type (WT), Hyp, and Hyp mice treated with calcitriol and oral phosphate. EPIC microCT confirmed AC mineral deficits and responsiveness to therapy. MicroCT of the Hyp subchondral bone plate revealed that treatment improved trabecular bone volume (BV/TV) but remained significantly lower than WT mice in other trabecular microstructures (p

ABSTRACT Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24‐hydroxylase enzyme, which is responsible for the catabolism of 25‐hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH)2D). Mutations in CYP24A1 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)‐independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a CYP24A1 loss‐of‐function mutation. Case 1 presented initially with PTH‐dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (99mTc‐MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid 99mTc‐MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH‐independent hypercalcemia found to be secondary to a CYP24A1 loss‐of‐function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1 (NM_000782.5). In clinical practice CYP24A1 loss‐of‐function mutations should be considered in patients presenting with PTH‐independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a CYP24A1 loss‐of‐function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Recombinant human parathyroid hormone (1‐84), rhPTH(1‐84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1‐84). This was a phase I, open‐label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1‐84) administered subcutaneously at 25 μg BID, 50 μg BID, and 100 μg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1‐84), both BID and QD, over the short‐term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline‐adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1‐84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1‐84) dosing. Future long‐term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Inactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Dietary phosphorus restriction and phosphorus binders are commonly prescribed for patients with chronic kidney disease (CKD). However, occurrences of non‐adherence to these interventions are common. As low‐phosphorus (LP) diets have been consistently experimentally shown in vitro to increase intestinal phosphorus absorption efficiency, a bout of non‐adherence to diet or binders may cause an unintended consequence of enhanced intestinal phosphorus absorption. Thus, we aimed to determine the effect of a single bout of high‐phosphorus (HP) intake after acclimation to a LP diet. Male Sprague Dawley rats with 5/6 nephrectomy (n = 36) or sham operation (n = 36) were block‐randomized to 1 of 3 diets: LP (0.1% P w/w), HP (1.2%), or LP followed by acute HP (LPHP 0.1% then 1.2%). Phosphorus absorption tests were conducted using 33P radioisotope administrated by oral gavage or intravenously (iv). Although the overall two‐way ANCOVA model for intestinal fractional phosphorus absorption was non‐significant, exploratory comparisons showed intestinal fractional phosphorus absorption efficiency tended to be higher in rats in the LP compared with HP or LPHP groups. Rats in the HP or LPHP groups had higher plasma phosphorus compared with rats in the LP group, but the LPHP group was not different from the HP group. Gene expression of the major intestinal phosphate transporter, NaPi‐2b, was lower in the jejunum of rats in the LPHP group compared with rats in the HP group but not different in the duodenum. These results demonstrate that an acute HP load after acclimation to a LP diet does not lead to enhanced intestinal fractional phosphorus absorption efficiency in 5/6 nephrectomized male rats. These data provide evidence against the notion that dietary phosphorus restriction or binder use adversely increases absorption efficiency after a single instance of dietary or binder non‐adherence. However, other adverse consequences of fluctuating dietary phosphorus intake cannot be ruled out. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT X‐linked hypophosphatemia (XLH) is a rare genetic disorder that disrupts skeletal and dental mineralization. In addition to rickets in children, XLH patients also have frequent spontaneous dental abscesses that increase the risk of tooth loss and may lead to facial cellulitis. Hypomineralized and hypoplastic dentin is the main driver of these infections. Conventional treatment (CT) of XLH improves this tissue defect and reduces the occurrence of dental abscesses. Burosumab is a recent treatment for XLH that targets excess circulating fibroblast growth factor 23 (FGF23), and its benefits on rickets have been demonstrated. It is not yet known whether burosumab improves dental manifestations of XLH. The main objective of our study was to compare the incidence of dental abscesses with XLH treated with either CT or burosumab. In this monocentric retrospective study, we measured and compared the incidence of dental abscess in children with XLH treated with either CT or burosumab, followed at our dental center for at least 1 year. The primary endpoint was the number of dental abscesses per month of dental follow‐up. A total of 71 children were included in the study, with a mean ± standard deviation (SD) age at the start of dental follow‐up of 7.86 ± 3.76. Thirty‐eight children were treated with CT (53.5%) and 33 with burosumab (46.5%). All children treated with burosumab had previously been treated with CT. The mean number of dental abscesses per month of dental follow‐up was significantly reduced in the burosumab group compared with the CT group (0.01 versus 0.04; p = 0.04). Burosumab treatment appears to be associated with a reduction in the number of dental abscesses in XLH children, compared with CT. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate‐wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades‐old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X‐linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p

ABSTRACT In 1980, Farfel and colleagues (NEJM, 1980;303:237–42) provided first evidence for two distinct variants of pseudohypoparathyroidism (PHP) that present with hypocalcemia and impaired parathyroid hormone (PTH)‐stimulated urinary cAMP and phosphate excretion, either in the presence or absence of Albright's hereditary osteodystrophy (AHO). An “abnormal allele” and an “unexpressed allele” were considered as underlying defects, predictions that turned out to be correct for both forms of PHP. Patients affected by the first variant (now referred to as PHP1A) were later shown to be carriers of inactivating mutations involving the maternal GNAS exons encoding Gsα. Patients affected by the second variant (now referred to as PHP1B) were shown in the current study to carry a maternal 3‐kb STX16 deletion, the most frequent cause of autosomal dominant PHP1B, which is associated with loss of methylation at GNAS exon A/B that reduces or abolishes maternal Gsα expression. However, the distinct maternal mutations leading to either PHP1A or PHP1B are disease‐causing only because paternal Gsα expression in the proximal renal tubules is silenced, ie, “unexpressed.” Our findings resolve at the molecular level carefully conducted investigations reported some 41 years ago that had provided first clues for the existence of two distinct PHP variants. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Hypophosphatasia (HPP) is caused by loss‐of‐function mutations in ALPL resulting in decreased alkaline phosphatase (ALP) activity. Metatarsal stress fracture (MSF) is a common clinical feature of hypophosphatasia in adults. In this study, the primary objectives were to determine whether new cases of ALPL variants could be identified in patients with MSF and who also had serum ALP concentration below the reference range and to phenotype their clinical course. Electronic health records were queried for adult patients with MSF using International Classification of Disease codes (ICD‐9, ICD‐10CM) and ALP measurements. Patients with ALP levels below the normal limit were invited to receive mutational analysis of ALPL and to complete the following surveys: the Short Form 36 version 2 (SF36v2), the Brief Pain Inventory‐Short Form (BPI), and the Health Assessment Questionnaire Disability Index (HAQ‐DI). Cases with and controls without ALPL pathogenic variants were compared by survey scores and clinical variables relevant to fracture. In 1611 patients with MSF presenting to a podiatry clinic (10/1/2011–10/1/2017), 937 had ALP measurement, of whom 13 (1.4%) had ALP levels below the lower normal limit. In eight patients consenting to participate, two had heterozygous pathogenic ALPL variants. ALPL variants were found in 2 of 1611 patients (0.12%) with MSF, 2 patients of 937 (0.21%) in those with MSF and any ALP measurement, and 2 of 13 patients (15%) in MSF and decreased ALP level. Cases versus controls rated lower scores on eight of eight SF36v2 scales (range, 0–100); higher scores for worst pain (8.0 vs. 0.8) and average pain (6.0 vs. 0.7) on the BPI (range, 0–10); and higher standard disability score (1.4 vs. 0) on the HAQ‐DI (range, 0–3). These data provide proof‐of‐concept for HPP case identification in patients presenting to a podiatry clinic with MSF, suggesting a search for historically low ALP levels may be a useful step for consideration of HPP diagnosis, and supports a prospective study to determine an optimal case‐finding strategy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Patients with chronic inflammatory diseases (CID) experience accelerated loss of bone mineral density, which is often accompanied by increased vascular calcification. These disturbances can be attenuated by therapies for inflammation, such as the tumor necrosis factor inhibitor infliximab. Calciprotein particles (CPP) are circulating colloidal aggregates of calcium and phosphate together with the mineral‐binding protein fetuin‐A, which have emerged as potential mediators of vascular calcification. The precise origins of serum CPP are unclear, but bone turnover may be an important source. In this longitudinal observational study, we studied patients with CID undergoing treatment with infliximab to assess the temporal relationship between bone turnover and circulating CPP. Ten patients with active CID receiving infliximab induction therapy and an additional 3 patients with quiescent CID on maintenance infliximab therapy were studied for 8 weeks with repeated measures of bone turnover markers as well as CPP (calciprotein monomers [CPM], primary CPP [CPP‐I], and secondary CPP [CPP‐II]). Therapeutic response was appraised using validated disease activity scores. At baseline, those with active CID had elevated markers of bone resorption and suppressed bone formation markers as well as higher CPM and CPP‐I compared with those with quiescent CID. In responders, there was an early but transient reduction in resorption markers by week 1, but a more sustained increase in bone formation markers compared with non‐responders at week 8. This was accompanied by reductions in CPM (β = −6.5 × 103 AU [95% CI −11.1, −1.8], p = 0.006) and CPP‐I (β = −23.4 × 104 particles/mL [95% CI −34.8, −11.9], p

ABSTRACT Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder caused by mutations in FGF23, GALNT3, KLOTHO, or FGF23 autoantibodies. Prominent features include high blood phosphate and calcific masses, usually adjacent to large joints. Dental defects have been reported, but not systematically described. Seventeen patients with HFTC followed at the National Institutes of Health underwent detailed clinical, biochemical, molecular, and dental analyses. Studies of teeth included intraoral photos and radiographs, high‐resolution μCT, histology, and scanning electron microscopy (SEM). A scoring system was developed to assess the severity of tooth phenotype. Pulp calcification was found in 13 of 14 evaluable patients. Short roots and midroot bulges with apical thinning were present in 12 of 13 patients. Premolars were most severely affected. μCT analyses of five HFTC teeth revealed that pulp density increased sevenfold, whereas the pulp volume decreased sevenfold in permanent HFTC teeth compared with age‐ and tooth‐matched control teeth. Histology revealed loss of the polarized odontoblast cell layer and an obliterated pulp cavity that was filled with calcified material. The SEM showed altered pulp and cementum structures, without differences in enamel or dentin structures, when compared with control teeth. This study defines the spectrum and confirms the high penetrance of dental features in HFTC. The phenotypes appear to be independent of genetic/molecular etiology, suggesting hyperphosphatemia or FGF23 deficiency may be the pathomechanistic driver, with prominent effects on root and pulp structures, consistent with a role of phosphate and/or FGF23 in tooth development. Given the early appearance and high penetrance, cognizance of HFTC‐related features may allow for earlier diagnosis and treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Treatment with asfotase alfa has transformed the prognosis of hypophosphatasia in children and improves the bone and muscle signs in adults. The doses used in adults are the same as in children, whereas bone remodeling is different between them. We report on the cases of two patients treated with 1 mg/kg/day of asfotase alfa who developed spinal cord compression from spinal ossifications during treatment. The first patient, 50 years old, presented after 2 years of treatment with quadraparesis secondary to an increase in ossifications of the cervical vertebral ligaments. The neurological damage was resolved after laminectomy, and the patient was then treated for 18 months with doses of 80 mg per week, without recurrence of the bone and muscle signs. The second patient, 26 years old, 78 kg, developed pain and cervical stiffness with pyramidal tract irritation secondary to ossifications of the vertebral ligaments. This improved with a reduction of doses to 80 mg/week, which then, after 6 months of follow‐up, enabled maintained improvement of the bone and muscle pain that was initially obtained. To our knowledge, these are the first reported cases of increased spinal ligamentous ossifications with neurological complications. Biological monitoring in adults does not seem to enable asfotase alfa doses to be adjusted. The levels of serum alkaline phosphatase (ALP) while on the recommended treatment of 1 mg/kg/day are significantly supraphysiological (5000 to 20,000 IU) and the assays of pyrophosphate and pyridoxal phosphate are not correlated with clinical efficacy. In both of our patients, the treatment with 80 mg of asfotase alfa per week, which was proposed after the occurrence of spinal complications, seemed as effective, after a follow‐up of 18 months and 6 months, as the initial treatment for improving the bone and muscle signs, and could be provided as “attack” doses after healing of the pseudoarthroses. © 2021 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Tumor‐induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte‐derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45‐year‐old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44–215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate‐regulating endopeptidase homolog, X‐linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Osteitis fibrosa cystica is a rare presentation of both primary and secondary hyperparathyroidism. In this perspective, we provide a historical backdrop to this form of parathyroid disease and contend that this clinical presentation of excess parathyroid hormone, particularly in primary hyperparathyroidism, is still seen today. In view of its rarity and the way it typically presents, the diagnosis of metastatic cancer is often the first diagnostic impression. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Prolonged signaling at the parathyroid hormone receptor 1 (PTHR1) correlates with the capacity of a ligand to bind to a G protein‐independent receptor conformation (R0). As long‐acting PTH (LA‐PTH) ligands hold interest as potential treatments for hypoparathyroidism (HP), we explored the structural basis in the ligand for stable R0 binding and prolonged cAMP signaling. A series of PTH/PTHrP hybrid analogs were synthesized and tested for actions in vitro and in vivo. Of the series, [Ala1,3,12,Gln10,Arg11,Trp14]‐PTH(1‐14)/PTHrP(15–36) (M‐PTH/PTHrP) bound with high affinity to R0, induced prolonged cAMP responses in UMR106 rat osteoblast‐derived cells, and induced the most prolonged increases in serum calcium (sCa) in normal rats. Daily s.c. injection of M‐PTH/PTHrP into thyroparathyroidectomized (TPTX) rats, a model of HP, normalized sCa without raising urine Ca. In contrast, oral alfacalcidol, a widely used treatment for HP, normalized sCa, but induced frank hypercalciuria. M‐PTH/PTHrP exhibited low solubility in aqueous solutions of neutral pH; however, replacement of Leu18, Phe22, and His26 with the less hydrophobic residues, Ala, Ala, and Lys, at those respective positions markedly improved solubility while maintaining bioactivity. Indeed, we recently showed that the resultant analog [Ala18,22,Lys26]‐M‐PTH/PTHrP or LA‐PTH, effectively normalizes sCa in TPTX rats and mediates prolonged actions in monkeys. These studies provide useful information for optimizing PTH and PTHrP ligand analogs for therapeutic development. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Benign parathyroid adenoma is the most common cause of primary hyperparathyroidism, whereas malignant parathyroid carcinoma is exceedingly rare. Distinguishing parathyroid carcinoma from benign adenoma is often difficult, and may be considerably delayed even after surgical resection until the rigorous diagnostic criteria of local invasion of surrounding tissues and/or distant metastases are fulfilled. Thus, new insights into their respective molecular bases may potentially aid in earlier diagnostic discrimination between the two, as well as informing new directions for treatment. In two recent studies, gain‐of‐function mutations in PIK3CA, a recognized driver oncogene in many human malignancies, have been newly identified in parathyroid carcinoma. To assess the potential specificity for malignant, as opposed to benign parathyroid disease, of PIK3CA hotspot mutations, we PCR‐amplified and Sanger sequenced codons 111, 542/545, and 1047 and the immediate flanking regions in genomic DNA from 391 typical, sporadic parathyroid adenomas. Four parathyroid adenomas (1%) had subclonal, somatic, heterozygous, activating PIK3CA mutations. The rarity of PIK3CA activating mutations in benign parathyroid adenomas suggests that tumorigenic activation of PIK3CA is strongly associated with malignant parathyroid neoplasia. However, it does not appear that such mutations, at least in isolation, can be relied upon for definitive molecular diagnosis of parathyroid carcinoma. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Familial hypocalciuric hypercalcemia (FHH) is a group of autosomal dominant disorders caused by dysfunction of the calcium sensing receptor (CaSR) and its downstream signaling proteins, leading to generally asymptomatic hypercalcemia. During pregnancy, distinguishing FHH from primary hyperparathyroidism (PHPT) is important, as the latter is associated with adverse outcomes and can be treated surgically during pregnancy, whereas the former is benign. This case report highlights the difficulties in diagnosing FHH during pregnancy. A 32‐year‐old woman was found to have asymptomatic hypercalcemia at 14‐weeks’ gestation. Investigations showed a corrected calcium (cCa) of 2.61 mmol/L (2.10 to 2.60), ionized Ca (iCa) of 1.40 mmol/L (1.15 to 1.28), 25OHD of 33 nmol/L (75 to 250), and PTH of 9.5 pmol/L (1.5 to 7.0). The patient was treated with 2000 IU cholecalciferol daily with normalization of 25OHD. The urine calcium / creatinine clearance ratio (CCCR) was 0.0071, and neck US did not visualize a parathyroid adenoma. Upon a retrospective review of the patient's biochemistry from 2 years prior, hypercalcemia was found that was not investigated. The patient was monitored with serial iCa levels and obstetric US. She delivered a healthy boy at 38‐weeks’ gestation. Postnatal iCa was 1.48 mmol/L and remained elevated. Her son had elevated iCa at birth of 1.46 mmol/L (1.15 to 1.33), which rose to 1.81 mmol/L by 2 weeks. He was otherwise well. Given the familial hypercalcemia, a likely diagnosis of FHH was made. Genetic testing of the son revealed a missense mutation, NM_000388.3(CASR):c.2446A > G, in exon 7 of the CaSR, consistent with FHH type 1. To our knowledge, there are only three existing reports of FHH in pregnancy. When differentiating between FHH and PHPT in pregnancy, interpretation of biochemistry requires an understanding of changes in Ca physiology, and urine CCCR may be unreliable. If the decision is made to observe, clinical symptoms, calcium levels, and fetal US should be monitored, with biochemistry and urine CCCR performed postpartum, once lactation is completed © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.