Jansen metaphyseal chondrodysplasia: analysis of craniofacial manifestations.

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by constitutive activation of parathyroid hormone type 1 receptor (PTH1R). We sought to characterize the craniofacial phenotype of patients with the disease. Six patients with genetically confirmed JMC underwent comprehensive craniofacial phenotyping revealing a distinct facial appearance that prompted a cephalometric analysis demonstrating a pattern of mandibular retrognathia.

Treatment Advances in Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by hypersecretion of fibroblast growth factor 23 (FGF23) by typically benign phosphaturic mesenchymal tumors (PMTs). FGF23 excess causes chronic hypophosphatemia through renal phosphate losses and decreased production of 1,25-dihydroxy-vitamin-D. TIO presents with symptoms of chronic hypophosphatemia including fatigue, bone pain, weakness, and fractures.

Ocular findings in Jansen metaphyseal chondrodysplasia.

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans.

Structural and molecular imaging-based characterization of soft tissue and vascular calcification in hyperphosphatemic familial tumoral calcinosis.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. Here, we systematically characterized and quantified macro- and micro-calcification in a HFTC cohort using CT and 18F-sodium fluoride PET/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on 4 phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite.

Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of encoding for Gα and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gα activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gα activation in the BMSC transcriptome and secretome.

Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

Background: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals.

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in , encoding for Gα, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gα activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gα activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors.

Hypoparathyroidism: Genetics and Diagnosis.

This narrative report summarizes diagnostic criteria for hypoparathyroidism and describes the clinical presentation and underlying genetic causes of the nonsurgical forms. We conducted a comprehensive literature search from January 2000 to January 2021 and included landmark articles before 2000, presenting a comprehensive update of these topics and suggesting a research agenda to improve diagnosis and, eventually, the prognosis of the disease. Hypoparathyroidism, which is characterized by insufficient secretion of parathyroid hormone (PTH) leading to hypocalcemia, is diagnosed on biochemical grounds.

Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia.

Fibroblast growth factor-23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23-mediated hypophosphatemia, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), in whom pathology-driving FGF23 levels can be in the "normal range.

Infigratinib Reduces Fibroblast Growth Factor 23 (FGF23) and Increases Blood Phosphate in Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25-dihydroxy-vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1-fibroblast growth factor receptor 1 (FN1-FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs.

PTH 1-34 Replacement Therapy Has Minimal Effect on Quality of Life in Patients With Hypoparathyroidism.

In addition to hypocalcemia, patients with hypoparathyroidism report poor quality of life (QOL), complaining of fatigue and "brain fog." Parathyroid hormone (PTH) therapy can effectively manage hypocalcemia; however, the effects of PTH treatment on QOL are unclear. Thirty-one patients with hypoparathyroidism were treated in an open-label study with full replacement subcutaneous PTH 1-34 twice daily for up to 5.

Genotype-Phenotype Correlation in Fibrous Dysplasia/McCune-Albright Syndrome.

Context: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine.

C-Terminal, but Not Intact, FGF23 and EPO Are Strongly Correlatively Elevated in Patients With Gain-of-Function Mutations in HIF2A: Clinical Evidence for EPO Regulating FGF23.

Fibroblast growth factor 23 (FGF23) is a key phosphate- and vitamin D-regulating hormone. FGF23 circulates as an intact 251 amino acid protein or N- and C-terminal degradation products. Hormone activity resides in the intact molecule, but it has been suggested that high levels of the C-terminal protein can interfere with intact FGF23 (iFGF23) activity.

Successful Intravascular Treatment of an Intraosseous Arteriovenous Fistula in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a benign bone disease characterized by expansile lesions that typically stabilize with age. Rarely, FD can undergo malignant transformation, presenting with atypical, rapid growth and destruction of adjacent bone. Other potential causes of rapid FD expansion include secondary lesions, such as aneurysmal bone cysts.

Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) , which encodes a protein responsible for FGF23 glycosylation; and (3) , the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling.

Approach to patients with hypophosphataemia.

Phosphate metabolism is an evolving area of basic and clinical research. In the past 15 years, knowledge on disturbances of phosphate homoeostasis has expanded, as has the discovery of new targeted therapies. Hypophosphataemia might be the biochemical finding in several diseases, and its clinical evaluation should initially focus on the assessment of pathophysiological mechanisms leading to low serum phosphate concentrations.

When Low Bone Mineral Density and Fractures Is Not Osteoporosis.

Purpose Of Review: To review the differential diagnosis of low bone mineral density (BMD).

Recent Findings: Osteoporosis is the most common cause of low BMD in adults; however, non-osteoporotic causes of low BMD should be considered in the differential diagnosis of patients with low BMD. Mild osteogenesis imperfecta, osteomalacia, and mineral and bone disorder of chronic kidney disease as well as several other rare diseases can be characterized by low BMD.