低ホスファターゼ症

Pycnodysostosis (PYCD) is a rare genetic bone disease characterized by impaired osteoclastic bone resorption. The inability to resorb bone leads to sclerosis, with increased bone mineral density (BMD) but paradoxically increased bone fragility. We report a case of a young female with PYCD with multiple fragility fractures including bilateral atypical femur fractures (AFF). Areal and volumetric bone density were supranormal, measured by dual-energy x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT), respectively. However, bone disorganization was prominent, observed on visual assessment of HR-pQCT images, with microfractures and sclerotic intramedullary lesions. ALIGNOGRAM1.0 is an artificial intelligence (AI) powered disorganization quantifier. It detected femoral lesions (including microfractures) on femoral radiographs up to two years prior to atypical femoral fractures at those sites. These microcracks were not visible on routine hip radiographs without the ALIGNOGRAM1.0 software. We postulate that disorganized bone, including microfractures, may be an underrecognized mechanism of bone fragility in patients with PYCD that could contribute to complications such as delayed fracture healing. Visual assessment via HR-pQCT may detect gross abnormalities but may miss subtle, subclinical changes - e.g., early sclerotic changes - that predate severe lesions and are not visible on routine HR-pQCT analysis. Quantitative tools such as ALIGNOGRAM1.0 may be particularly valuable in disorders characterized by paradoxical skeletal fragility despite normal or elevated bone density and apparently preserved microarchitecture. By quantifying bone disorganization on standard radiographs, these approaches may provide complementary information beyond conventional assessments of bone mass and structure. The paradox of severe fragility despite supranormal bone density has long remained unexplained. This diagnostic paradox is not unique to pycnodysostosis and is encountered across a range of genetic, metabolic, and treatment-related skeletal disorders in which fracture risk appears disproportionate to conventional measures of bone density or structure. Consequently, there is a need for complementary approaches capable of identifying abnormalities that are not captured by standard assessments. In genetic and metabolic bone disorders (e.g., pycnodysostosis or hypophosphatasia) that evade conventional assessments of bone health (e.g., DXA and HR-pQCT), we demonstrate how disorganization may act as a causative mechanism as an independent biomarker of fragility.

PURPOSE: Hypophosphatasia (HPP) is a multi-system genetic disorder that affects mineralization of the skeleton and dentition. Despite the success of postnatal enzyme replacement therapy (ERT), children with life-threatening presentations (LT-HPP) experience significant morbidity, decreased quality of life, and risk of death. Recent evidence suggests that in-utero ERT (IU-ERT) may further improve outcomes; however, acceptability within the HPP community has not been assessed. This study aimed to explore patient and caregiver attitudes toward IU-ERT for LT-HPP. METHODS: We surveyed adults with lived experience with HPP. The survey was distributed through patient advocacy organizations. RESULTS: Ninety-two individuals completed the survey. Most participants supported availability of IU-ERT following prenatal detection of LT-HPP and further research in this area. Predominant concerns were potential risks for the baby or mother, long-term side effects, and uncertainty regarding treatment effectiveness. Frequent reasons cited for one to pursue IU-ERT were reduced disease severity, a potential cure, and reduced mortality. Potential barriers included perceived risks, uncertainty regarding safety or benefits, and financial burden. CONCLUSIONS: Participants were supportive of further research and clinical trials for IU-ERT for LT-HPP. These results provide preliminary evidence that can be used to inform the development and implementation of IU-ERT for LT-HPP.

Hypophosphatasia (HPP) is a rare metabolic bone disease caused by deficient alkaline phosphatase activity, leading to impaired mineralization. While total knee arthroplasty (TKA) is a common treatment for end-stage knee arthritis, its outcomes in patients with metabolic bone disorders like HPP are poorly documented.

Adult-onset hypophosphatasia manifests after age 18, and is characterised by reduced tissue-nonspecific alkaline phosphatase activity. This can lead to fractures, pseudo-fractures, osteomalacia, decreased bone density (bone loss), muscle weakness, myalgia, arthralgia, headache, dental symptoms (loss of permanent teeth, periodontal disease), and pseudogout. Over 480 distinct genetic mutations have been identified to date, with eight cases reported for the c.572A > G (p.Glu191Gly) mutation. However, all reported cases involved compound heterozygous mutations, and there have been no previous reports of cases of a single heterozygous mutation. We report the case of a 40-year-old woman with persistent hypophosphatasia, elevated urinary phosphoethanolamine levels suggesting adult-onset hypophosphatasia, and a heterozygous missense mutation (c.572A > G p.Glu191Gly) in the ALPL gene according to genetic testing. Treatment with subcutaneous injections of aspartate phosphatase alpha was initiated, which was followed by significant improvement of the pain, enhanced range of motion in both upper limbs, and improved gait. This patient's case differed from previously reported cases in that it involved a heterozygous c.572A > G (p.Glu191Gly) mutation alone in adult-onset hypophosphatasia. Adult-onset hypophosphatasia is an extremely rare disorder. However, its symptoms resemble those of systemic rheumatic diseases such as polymyalgia rheumatica and fibromyalgia, and rheumatologists may encounter this condition in routine clinical practice. Importantly, it can be detected based on low serum ALP levels.

A woman in her late 40s presented with a 1 year history of progressive symmetrical rest tremor, bradykinesia, rigidity, hypophonia and postural instability (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III 41) without musculoskeletal symptoms or family history. Routine investigations were unremarkable except low-normal serum alkaline phosphatase (41 U/L, range 35-104), mild anaemia and vitamin D insufficiency; brain MRI showed blooming in bilateral globus pallidi. Minimal to no improvement observed at 1 month on modest dopaminergic dosing (MDS-UPDRS III 38). Whole-exome sequencing identified a heterozygous pathogenic frameshift variant c.388del (p.Val130Cysfs*1) in ALPL (alkaline phosphatase, liver/bone/kidney) gene. In the absence of classical skeletal features and without substrate testing, this finding is suggestive of a possible mild adult hypophosphatasia phenotype. This case highlights a potential association between ALPL variants and parkinsonism and underscores the role of genetic testing in atypical presentations.