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Background: Hypophosphatasia (HPP) is a rare disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (ALP), encoded by the ALPL gene. The primary objective was to explore novel ALPL variants by whole genome sequencing (WGS) in patients with HPP who previously tested negative by standard methods for ALPL variants. The secondary objective was to search for genes beyond ALPL that may reduce ALP activity or contribute to HPP symptoms. Methods and results: WGS was performed in 16 patients clinically diagnosed with HPP who had ALP activity below the normal range and tested negative for ALPL variants. Genetic variants in ALPL and genes possibly associated with low ALP activity or phenotypic overlap with HPP were assessed. All 16 patients had ALP activity below the normal range. WGS did not identify any novel disease-causing ALPL variants. Positive findings for other gene variants were identified in 4 patients: 1 patient presented with variants in COL1A1, NLRP12, and SCN9A, coding for collagen, type, I alpha-1 chain, nod-like receptor pyrin domain containing 12, and sodium voltage-gated channel alpha subunit 9, respectively; 1 presented with a heterozygous, likely pathogenic variant in P3H1 coding for prolyl 3 hydroxylase 1; 1 presented with a heterozygous pathogenic variant in SGCE, coding for sarcoglycan epsilon; and 1 presented with a heterozygous variant of uncertain significance in VDR, encoding vitamin D receptor. Conclusion: Genomic analysis did not identify novel ALPL variants or a pattern of disease-causing variants in genes other than ALPL to explain the HPP phenotype in these patients. Registration: Clinicaltrials.gov identifier: NCT04925804. [ABSTRACT FROM AUTHOR]

Summary: Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. Purpose: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. Methods: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. Results: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. Conclusion: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF. [ABSTRACT FROM AUTHOR]

To provide an evidence-based resource for paleopathologists to consider multiple skeletal indicators of pathology associated with early tooth loss in children to aid in diagnosis. Three databases (Cochrane Library, MedLine, and Scopus) were used for a review. According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, a systematic review guideline, 85 articles were selected. A total of 189 children had a syndrome or disease associated with early tooth loss. Our review, based on 25 diseases, lists the bone and dental lesions observable in archeological remains. Based on a review of the literature, a synthesis of 25 diseases and syndromes that may be associated with premature loss of permanent or deciduous teeth in children was developed for paleopathologists. It highlights the importance of a thorough dental examination by paleopathologists to further assess past health conditions. This paper provides an extensive resource addressing early tooth loss in childhood to assist researchers with differential diagnosis. The articles included in this review are case reports based on living populations. Further studies into diseases and their association with early tooth loss would complement this work, as would utilizing the differential diagnoses on archeological individuals to clarify its value and limitations. [ABSTRACT FROM AUTHOR]

Stage IV grade C localized periodontitis (pre-puberal localized aggressive periodontitis/LPP), an extremely rare form of periodontal disease, occurs in otherwise healthy individuals (no signs of dental plaque/calculus) due a hyper-aggressive auto-immune response to high periodontopathic bacteria levels. Methods: A 4-year-old Caucasian girl with unusually high mobility of the deciduous lower left canine and localized gingival inflammation was misrecognized by multiple clinicians (initially diagnosed with hypophosphatasia, genetic and metabolic disorders, all turning negative), over a period of 4–6 months, despite initial radiographs showing clear pathognomonic signs. The LPP diagnostic was made by the last clinician, but by then the tooth was lost. Similar inflammation signs appeared around the lower deciduous right canine. X-ray examination showed similar bone and periodontal loss as previously seen, while periodontopathic bacteria tested highly positive. The patient received both mechanical cleaning and ten days of systemic antibiotic treatment (Augmentin and Metronidazole). Results: Two months later, inflammation signs disappeared, with periodontal regeneration radiologically present, and only small periodontopathic bacteria precursor concentrations. Conclusions: Despite initial periodontal loss, an adequate treatment can keep under control an LPP disease. Moreover, bone and periodontal regeneration appears if periodontopathic bacteria scores are kept lower, showing the importance of fast adequate diagnostic and treatment. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the role of pyridoxal-5-phosphate (PLP) level on the oral health status as a predictive marker in patients with hypophosphatasia (HPP). Materials and methods: Throughout a systematic retrospective assessment both bone metabolism and oral health status were analyzed. The oral health status was assessed by the decayed/missing/filled teeth index (DMFT), clinical attachment level (CAL), probing pocket depth (PPD), and the periodontal screening index (PSI). Results: A total of 48 HPP patients (81.3% female) with a mean age of 42.21 years was included in this retrospective study. The study population was divided into two groups using the mean PLP level (87 µg/l) as a cut-off. Patients with a PLP level ≥ 87 µg/l (n = 14) showed a significantly poorer oral health status regarding DMFT index, CAL, PPD and PSI compared to patients with a PLP level < 87 µg/l (n = 34). No significant group differences for tooth loss were found. Conclusion: The results of the present study indicate that the PLP level is a suitable diagnostic predictor for the oral health status in HPP patients. HPP patients with PLP levels ≥ 70 µg/l should be included into a regular dental preventive program. Clinical Relevance: The oral health status in HPP and its correlation with laboratory parameters (i.e. PLP) has been understudied. For clinical practice, the findings of the present study clearly demonstrated that high PLP levels correlate with a worse oral health status in HPP patients. Therefore, these patients should receive an intensive dental treatment and/or inclusion in a strict maintenance program in a specialized dental practice/university hospital with a PLP level ≥ 70 µg/l. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a rare, inherited, and systemic disorder characterized by impaired skeletal mineralization and low tissue nonspecific serum alkaline phosphatase (TNSALP) activity. It is caused by either autosomal recessive or dominant‐negative mutations in the gene that encodes TNSALP. The phenotype of HPP is very broad including abnormal bone mineralization, disturbances of calcium and phosphate metabolism, pain, recurrent fracture, short stature, respiratory impairment, developmental delay, tooth loss, seizures, and premature death. Other than supportive care, there has been no disease‐specific treatment available for those with HPP. Asfotase alfa is a fully humanized, recombinant enzyme replacement therapy for the management of HPP. It is available in several countries for the treatment of the more severe forms of HPP, namely perinatal and infantile HPP. This review will summarize the preclinical data on asfotase alfa and highlight the data from clinical trials and case reports. These data show the transformative nature of asfotase alfa when administered as part of an interdisciplinary treatment model. [ABSTRACT FROM AUTHOR]

Abstract Background Early-onset bone dysplasia is a common manifestation of hypophosphatasia (HPP), an autosomal inherited disease caused by ALPL mutation. ALPL ablation induces prototypical premature bone ageing characteristics, resulting in impaired osteogenic differentiation capacity of human bone marrow mesenchymal stem cells (hBMMSCs). As angiogenesis is tightly coupled with osteogenesis, it also plays a necessary role in sustaining bone homeostasis. We have previously observed a decrease in expression of angiogenesis marker gene CD31 in the metaphysis of long bone in Alpl +/− mice. However, the role of ALPL in regulation of angiogenesis in bone has remained largely unknown. Methods Exosomes derived from Normal and HPP hBMMSCs were isolated and identified by ultracentrifugation, transmission electron microscopy, and nanoparticle size measurement. The effects of ALPL on the angiogenic capacity of hBMMSCs from HPP patients were assessed by immunofluorescence, tube formation, wound healing and migration assay. exo-ELISA and Western Blot were used to evaluate the exosomes secretion of hBMMSCs from HPP, and the protein expression of VEGF, PDGFBB, Angiostatin and Endostatin in exosomes respectively. Results We verified that ALPL ablation resulted in impaired pro-angiogenic capacity of hBMMSCs, accounting for reduced migration and tube formation of human umbilical vein endothelial cells, as the quantities and proteins composition of exosomes varied with ALPL expression. Mechanistically, loss of function of ALPL enhanced ATP release. Additional ATP, in turn, led to markedly elevated level of ATP receptor P2X7, which consequently promoted exosomes secretion, resulting in a decreased capacity to promote angiogenesis. Conversely, inhibition of P2X7 increased the angiogenic induction capacity by preventing excessive release of anti-angiogenic exosomes in ALPL deficient-hBMMSCs. Conclusion The ALPL–ATP axis regulates the pro-angiogenic ability of hBMMSCs by controlling exosomes secretion through the P2X7 receptor. Thus, P2X7 may be proved as an effective therapeutic target for accelerating neovascularization in ALPL–deficient bone defects.

Familial Hypophosphatasia presents a complex diagnostic challenge due to its wide-ranging clinical manifestations and genetic heterogeneity. This study aims to elucidate the molecular underpinnings of familial Hypophosphatasia within a Tunisian family harboring a rare c.896 T > C mutation in the ALPL gene, offering insights into genotype–phenotype correlations and potential therapeutic avenues. The study employs a comprehensive approach, integrating biochemical examination, genetic analysis, structural modeling, and functional insights to unravel the impact of this rare mutation. Genetic investigation revealed the presence of the p.Leu299Pro mutation within the ALPL gene in affected family members. This mutation is strategically positioned in proximity to both the catalytic site and the metal-binding domain, suggesting potential functional consequences. Homology modeling techniques were employed to predict the 3D structure of TNSALP, providing insights into the structural context of the mutation. Our findings suggest that the mutation may induce conformational changes in the vicinity of the catalytic site and metal-binding domain, potentially affecting substrate recognition and catalytic efficiency. Molecular dynamics simulations were instrumental in elucidating the dynamic behavior of the tissue-nonspecific alkaline phosphatase isozyme (TNSALP) in the presence of the p.Leu299Pro mutation. The simulations indicated alterations in structural flexibility near the mutation site, with potential ramifications for the enzyme's overall stability and function. These dynamic changes may influence the catalytic efficiency of TNSALP, shedding light on the molecular underpinnings of the observed clinical manifestations within the Tunisian family. The clinical presentation of affected individuals highlighted significant phenotypic heterogeneity, underscoring the complex genotype–phenotype correlations in familial Hypophosphatasia. Variability in age of onset, severity of symptoms, and radiographic features was observed, emphasizing the need for a nuanced understanding of the clinical spectrum associated with the p.Leu299Pro mutation. This study advances our understanding of familial Hypophosphatasia by delineating the molecular consequences of the p.Leu299Pro mutation in the ALPL gene. By integrating genetic, structural, and clinical analyses, we provide insights into disease pathogenesis and lay the groundwork for personalized therapeutic strategies tailored to specific genetic profiles. Our findings underscore the importance of comprehensive genetic and clinical evaluation in guiding precision medicine approaches for familial Hypophosphatasia. [ABSTRACT FROM AUTHOR]

Mutations in dental hypophosphatasia (HPP) have been reported less than those in other types of HPP because the symptoms are mild or the dental lesions are only partial manifestations of other types of HPP. In this case, we observe the clinical manifestation of dental hypoalkaline phosphatase by analyzing the genetic mutation and biochemical parameters in child. The clinical data of the child with odonto HPP were collected and analyzed. The blood samples of the child and his parents were sequenced and verified using Sanger through a specific probe capture and high-throughput second-generation sequencing technology. Major clinical manifestations in the patient were early loss of deciduous teeth, significantly lower serum alkaline phosphatase (ALP) levels, lower active vitamin D, and increased blood phosphorus, but no abnormality was observed in the oral X-ray. Two missense mutations—c.542C>T (p. ser181leu) and c.644 T> C (p.Ile215Thr)—were found in exon 6 of the ALPL gene from the father and mother, respectively. The clinical manifestations of odonto hypophosphatasia were early loss of deciduous teeth and significantly reduced serum ALP levels. Of 2 mutations—c.542C>T (p.ser181leu) and c.644 T> C (p.Ile215Thr)—in the ALPL gene, c.644 T> C (p.Ile215Thr) was a new mutation. [ABSTRACT FROM AUTHOR]

Background: A balanced diet rich in calcium and protein is recommended for bone-healthy people and osteoporosis patients, but it may also be important for rare bone disease (RBD). Little data is available on RBD and diet. Therefore, the aim of this study was to evaluate the nutritional behavior of patients with RBD. Methods: This single-center, cross-sectional, questionnaire-based study assessed the nutritional behavior of RBD patients (X-linked hypophosphatemia (XLH), osteogenesis imperfecta (OI), hypophosphatasia (HPP)), osteoporosis (OPO) patients and healthy controls (CTRL). The nutritional questionnaire comprised 25 questions from seven nutritional areas. The associations between socioeconomic factors and BMI were assessed by age-adjusted univariate analysis of covariance (ANCOVA). Results: Fifty patients with RBD (17 OI, 17 HPP, 16 XLH; mean age of 48.8 ± 15.9, 26.0% male, mean BMI 26.2 ± 5.6), 51 with OPO (mean age 66.6 ± 10.0, 9.8% male, mean BMI 24.2 ± 3.9) and 52 CTRL (mean age 50.8 ± 16.3, 26.9% male, mean BMI 26.4 ± 4.7) participated. Twenty-six (52.0%) RBD, 17 (33.4%) OPO and 24 (46.1%) CTRL were overweight or obese according to BMI. Only a minority of RBD, OPO and CTRL had a daily intake of at least three portions of milk or milk products (17.3% RBD, 15.6% OPO, 11.6% CTRL, p = 0.453). In general, similar nutritional behavior was observed between the three subgroups. However, significant differences were found in caffeine consumption (p = 0.016), fruit/vegetable juice consumption (p = 0.034), portions of fish per week (p = 0.044), high-fat meals per week (p = 0.015) and consumption of salty snacks (p = 0.001). Conclusion: Nutritional counseling, controlling BMI and ensuring sufficient calcium and protein intake are crucial in patients with osteoporosis as well as in rare bone diseases. Vitamin D does not appear to be sufficiently supplied by the diet, and therefore supplementation should be considered in patients with bone diseases. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to better understand the clinical profiles of children with hypophosphatasia (HPP) prior to treatment with enzyme replacement therapy (ERT). Methods: Pretreatment demographics and medical histories of ERT-treated children (aged <18 years) enrolled in the Global HPP Registry (2015–2020) were analyzed overall, by age at first HPP manifestation (<6 months vs. 6 months to 18 years), and by geographic region (USA/Canada, Europe, and Japan). Results: Data from 151 children with HPP were analyzed. Sex distribution was balanced overall (52.3% female; 47.7% male) but differed in Japan (63.0% female; 37.0% male). Prior to ERT initiation, common manifestations were skeletal (67.5%) and extraskeletal, with the foremost types being muscular (48.3%), constitutional/metabolic (47.0%), and neurologic (39.7%). A high proportion of children who first presented at <6 months of age (perinatal/infantile period) had a history of bone deformity (59.3%) and respiratory failure (38.3%), while those aged 6 months to 18 years at first manifestation had a predominance of early loss of primary teeth (62.3%) and gross motor delay (41.0%). Those from Japan were reported to have a younger median age overall, the highest proportion of skeletal manifestations (80.4%) and growth impairment, while European data reported the highest proportion of muscular manifestations (70.7%). In the USA/Canada, skeletal and muscular manifestations were reported at the same frequency (57.4%). Conclusion: Prior to ERT, skeletal and extraskeletal manifestations were commonly reported in children with HPP, with differences by age at first HPP manifestation and geographical region. Comprehensive assessments of children with HPP are warranted prior to ERT initiation. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is a rare genetic disease characterized by abnormal alkaline phosphatase activity and deficiency of bone and teeth mineralization. Hypophosphatasia is well known in pediatrics with typical presentations in children, but mild forms can also be present in adults and are difficult to detect. We present the case of a 50-year-old woman referred for pain management, with a previous diagnosis of fibromyalgia. The association of clinical features (diffuse pain syndrome, early dental loosening, personal history of two fractures with osteoporosis, and family history of osteoporosis) with radiographic (heterotopic calcifications of the yellow and interspinous lumbar ligaments) and biological (low levels of total alkaline phosphatase) indices was suggestive of hypophosphatasia, which was confirmed by genetic analysis. We review and discuss the association between hypophosphatasia, musculoskeletal pain, and calcium pyrophosphate deposition and the importance of raising the diagnosis of adult-onset hypophosphatasia when facing these two rheumatologic entities. [ABSTRACT FROM AUTHOR]

Summary: Hypophosphatasia (HPP) is a rare bone disease with limited scientific evidence on the tolerability and safety of its novel treatment, Asfotase Alfa (AA). We report 7 HPP patients' heterogenous presentations and the significant improvement in various clinical outcomes attained with AA shedding light on this highly effective and safe therapy. Introduction: Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder characterized by a deficiency in the tissue non-specific alkaline phosphatase (TNSALP) due to loss of function mutation in the ALPL gene. HPP is associated with impaired skeletal mineralization due to elevations in inorganic pyrophosphate and altered phosphate : pyrophosphate ratio. Asfotase alfa (AA) "enzyme replacement" was approved for treatment of HPP in 2015. We present 7 patients with HPP, 5 with pediatric-onset, and 2 with adult-onset, who have been treated with AA and describe the efficacy and safety in these patients. Methods: 7 patients (4 females, 3 males) aged 19–68 years with HPP were included in this study. Diagnosis of HPP was confirmed by DNA analysis. AA was administered in doses of 6mg/kg/week with a mean follow-up of 6 months (SD= 5). Results: Subjective improvement in muscle strength, muscle pain, walking ability, and walking distance with a reduction in the use of gait aids was seen "with AA in HPP patients." Muscle strength and pain improved by up to 70% from baseline as quantified subjectively by patients. Walking distance improved by up to 100%. Patients also reported improved cognition, mood, and energy levels, with up to 90% improvement in mood and 75% improvement in energy levels. 4 out of 6 patients first noted clinical signs of improvement after 3 months of being on therapy. 1 out of the 7 patients sustained a toe fracture 10 months from being on AA. AA was well-tolerated with injection site reactions being the most reported adverse effect. Conclusion: HPP treatment with AA in individuals with both pediatric and adult-onset forms resulted in significant subjective improvement in musculoskeletal and cognitive manifestations in addition to patients' quality of life. The drug was well tolerated in 6 patients. 1 patient discontinued therapy because of minor adverse effects with myalgias. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is a rare inherited metabolic disorder caused by the deficiency of tissue-nonspecific alkaline phosphatase. More severe and early onset cases present symptoms of muscle weakness, diminished motor coordination, and epileptic seizures. These neurological manifestations are poorly characterized. Thus, it is urgent to discover novel differentially expressed genes for investigating the genetic mechanisms underlying the neurological manifestations of hypophosphatasia. RNA-sequencing data offer a high-resolution and highly accurate transcript profile. In this study, we apply an empirical Bayes model to RNA-sequencing data acquired from the spinal cord and neocortex tissues of a mouse model, individually, to more accurately estimate the genetic effects without bias. More importantly, we further develop two integration methods, weighted gene approach and weighted Z method, to incorporate two RNA-sequencing data into a model for enhancing the effects of genetic markers in the diagnostics of hypophosphatasia disease. The simulation and real data analysis have demonstrated the effectiveness of our proposed integration methods, which can maximize genetic signals identified from the spinal cord and neocortex tissues, minimize the prediction error, and largely improve the prediction accuracy in risk prediction. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a rare genetic condition associated with poor bone mineralization, low serum alkaline phosphatase, high urinary pyrophosphate excretion, and nephrocalcinosis. Nephrocalcinosis is thought to develop due to the increased filtered loads associated with hypercalcemia and hyperphosphatemia, but the composition of these calcifications is incompletely understood. We report the first ever magnesium pyrophosphate (MgPPi) urinary stone, which prompted the new diagnosis of HPP in a 12-year-old boy. Stone analysis labs should include infrared spectra of PPi salts in their reference libraries to facilitate identification of these rare but clinically important stones.

Malignant infantile osteopetrosis is a rare inherited disease of bone metabolism, in which osteoclast dysfunction and diminished bone turnover lead to diffuse sclerosis with obliteration of the medullary cavities and narrowing of the skull base neural foramina. We report a case of malignant infantile osteopetrosis with bone marrow failure and optic atrophy that co-occurred with hypophosphatasia, another rare inherited bone disease, in a 6-year-old boy. Key imaging signs of these rare diseases are discussed.

(1) Background: The use of complementary and alternative medicine (CAM) has seen a notable increase in popularity. However, there is an absence of data regarding the prevalence of CAM use in patients with rare bone diseases (RBDs). (2) Methods: This monocentric, cross-sectional study was carried out in a reference hospital for RBDs. RBD patients included individuals with osteogenesis imperfecta, hypophosphatasia and X-linked hypophosphatemia, and their data were compared with those of patients with osteoporosis (OPO) and of healthy controls (CON). This study utilized the German version (I-CAM-G) of the I-CAM questionnaire. (3) Results: This study comprised 50 RBD patients [mean age (SD) of 48.8 (±15.9), 26% male], 51 OPO patients [66.6 (±10.0), 9.8% male] and 52 controls [50.8 (±16.3), 26.9% male]. Treatments by naturopaths/healers were more prevalent in the RBD group (11.4%) compared with OPO (0%) and CON (5.8%) (p = 0.06). More than half of the OPO (60.8%) and CON (63.5%) patients and 46% of the RBD patients reported vitamin/mineral intake within the past 12 months (p = 0.16). Individuals with tertiary education had a significantly higher odds ratio of 2.64 (95% CI: 1.04–6.70, p = 0.04) for visiting any CAM provider. Further, OPO patients were significantly less likely to use self-help techniques compared with the CON group (OR = 0.42, 95% CI: 0.19–0.95; p = 0.04). (4) Conclusions: Herbal medicine, vitamin and mineral supplements, and self-help techniques were the most common forms of CAM reported by patients with RBDs. However, the use of CAM was generally low. [ABSTRACT FROM AUTHOR]

Background: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. Methods: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. Results: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60–632 m) at baseline (n = 31) to 484 m at Month 12 (range 240–739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from − 0.72 (95% CI: − 1.23, − 0.21; n = 38) to − 1.13 (95% CI: − 1.76, − 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. Conclusions: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. Registration: NCT02306720; EUPAS13514. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults. [ABSTRACT FROM AUTHOR]

Background: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. Methods: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. Results: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. Conclusion: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children. [ABSTRACT FROM AUTHOR]

Introduction: Hypophosphatasia (HPP) is an inborn metabolic error caused by mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP) and leading to decreased alkaline phosphatase (ALP) activity. Although the main characteristic of this disease is bone involvement, it presents a great genetic and clinical variability, which makes it a systemic disease. Methods: Patients were recruited based on biochemical assessments. Diagnosis was made by measuring serum ALP and pyridoxal 5-phosphate levels and finally by Sanger sequencing of the ALPL gene from peripheral blood mononuclear cells. Characterization of the new variants was performed by transfection of the variants into HEK293T cells, where ALP activity and cellular localization were measured by flow cytometry. The dominant negative effect was analyzed by co-transfection of each variant with the wild-type gene, measuring ALP activity and analyzing cellular localization by flow cytometry. Results: Two previously undescribed variants were found in the ALPL gene: leucine 6 to serine missense mutation (c.17T>C, L6S) affecting the signal peptide and threonine 167 deletion (c.498_500delCAC, T167del) affecting the vicinity of the active site. These mutations lead mainly to nonpathognomonic symptoms of HPP. Structural prediction and modeling tools indicated the affected residues as critical residues with important roles in protein structure and function. In vitro results demonstrated low TNSALP activity and a dominant negative effect in both mutations. The results of the characterization of these variants suggest that the pleiotropic role of TNSALP could be involved in the systemic effects observed in these patients highlighting digestive and autoimmune disorders associated with TNSALP dysfunction. Conclusions: The two new mutations have been classified as pathogenic. At the clinical level, this study suggests that both mutations not only lead to pathognomonic symptoms of the disease, but may also play a role at the systemic level. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts. The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present. [ABSTRACT FROM AUTHOR]

Background and Objectives: Stage IV grade C localized periodontitis (pre-puberal localized aggressive periodontitis/LPP) is a rare form of inflammatory periodontal disease occurring in clinically healthy individuals (no/small calculus/dental plaque traces), due a hyper-aggressive auto-immune response to high amounts of bacteria present in the oral cavity. Case Presentation: This case report describes a 4-year-old Caucasian girl with localized gingival inflammation and advanced bone loss around the temporary lower left canine. The first diagnostic assumption was hypophosphatasia, and the patient was sent for further genetic and metabolic investigations (which turned out to be negative). The LPP diagnosis was made during the family's summer holidays due to her parents' concerns about persistent gingival inflammation and tooth mobility. Results: The diagnosis of LPP was supported by clinical oral examination results, earlier X-rays, earlier blood tests, and a periodontal bacterial test. The treatment was limited to avoid spreading inflammation to other teeth (via topical antibiotic treatment) due to our limited time frame, while the main problem of excessive amounts of periodontal bacteria in the oral cavity was not addressed. The tooth was eventually lost. Conclusions: The ability to early recognize radiological and clinical LPP signs correlated with understanding of its pathological auto-immune mechanism is extremely important for expanding treatment options, since bone preservation and reducing amounts of bacteria are strictly correlated with therapeutic speed. [ABSTRACT FROM AUTHOR]

Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 – December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5′-phosphate (PLP) and genetic study of ALPL gene. Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder. [ABSTRACT FROM AUTHOR]

Context Impairments in musculoskeletal and mental health are common in adults with Hypophosphatasia (HPP). Restricted phosphorus intake has been suggested to positively affect symptoms in HPP, but there is a lack of interventional evidence. Objective This work aimed to evaluate the effect of a phosphorus-restricted, calcium-adjusted diet on musculoskeletal and mental health in HPP. Methods A prospective, noncontrolled, single-center interventional study (NuSTEPS II) was conducted among outpatients at the Osteology Department, University of Wuerzburg, Germany. A total of 26 adults with an established HPP diagnosis received a standardized diet with a defined daily intake of phosphorus (1160-1240 mg/d) and calcium (870-930 mg/d) over 8 weeks. Main outcome measures were functional testing and patient-reported outcome measures. Results At 8 weeks, significant improvements were observed in usual gait speed (P =.028) and the chair-rise test (P =.019), while no significant changes were seen in the 6-minute walk test (P =.468) and the timed up-and-go test (P =.230). Pain was not significantly reduced according to the visual analog scale (VAS) (P =.061), pain subscale of the 36-Item Short-Form Health Survey (SF-36) (P =.346), and Pain Disability Index (P =.686). Further, there was a significant improvement in the SF-36 vitality subscale (P =.022) while all other subscales as well as the Lower Extremity Functional Scale (P =.670) and the Fatigue Assessment Scale (P =.392) did not change significantly. Adjustments of mineral intake were not associated with relevant alterations regarding the intake of energy and energy-supplying nutrients or body composition. Conclusion Adjusting phosphorus and calcium intake may positively affect individual symptoms in adults with HPP, but overall clinical effectiveness regarding major issues like pain and endurance appears limited. [ABSTRACT FROM AUTHOR]

Background/Objective: Hypophosphatasia (HPP) is a rare disease associated with low serum alkaline phosphatase (ALP) activity. Here, we present a case of a patient with normal serum ALP levels diagnosed with HPP. Case Report: A 36-year-old woman presented with progressive fatigue, weakness, and joint pain. She had been evaluated in the past for genetic disorders due to these symptoms and was found to have a history of several total ALP levels within normal limits but elevated vitamin B6 levels. She also reported having loose teeth and “gray gums” during her childhood. Bone-specific ALP was tested for suspicion of HPP and returned at 4.4 μ/L (reference range, 5.3-19.5 μg/L), which prompted genetic testing. Genetic testing confirmed a positive pathogenetic variant of the ALPL gene, the c.542C>T (p.Ser181Leu) variant. She started asfotase alfa treatment to improve her symptoms. Discussion: HPP was diagnosed based on clinical suspicion supported by laboratory findings, which can cause it to be underdiagnosed or misdiagnosed. Current literature reports that a low total ALP level is the main biochemical marker of HPP and the only level needed to diagnose the disease. However, bone-specific ALP, a common marker used for bone turnover, has not been required to be tested. Conclusion: This case highlights a patient with normal total ALP, but low bone-specific ALP diagnosed with HPP confirmed by genetic testing. This case warrants future investigation into the diagnostic approach to HPP and the diagnostic utility between ALP and bone-specific ALP.

Hypophosphatasia (HPP) is a rare condition characterized by abnormal bone mineralization. The manifestations of HPP vary from no symptoms to intrauterine fetal death; short stature is another indication of HPP. A 3 ½-year-old boy presented with short stature, transient hypercalcemia, and mild gait disturbance without definite bony deformity. Laboratory examination revealed transient hypercalcemia, normal phosphorous and 25-hydroxy vitamin D levels, and mildly low alkaline phosphatase levels. A targeted next-generation sequencing panel associated with inborn errors of metabolism revealed a pathogenic heterozygous mutation in the ALPL gene, c.979T>C (p.Phe327Leu). When a child visits a hospital with short stature, decreased height velocity, and low alkaline phosphatase level, clinicians should consider the possibility of HPP even if definite skeletal dysplasia is not evident.

Stage IV grade C localized periodontitis (pre-puberal localized aggressive periodontitis/LPP), an extremely rare form of periodontal disease, occurs in otherwise healthy individuals (no signs of dental plaque/calculus) due a hyper-aggressive auto-immune response to high periodontopathic bacteria levels. Methods: A 4-year-old Caucasian girl with unusually high mobility of the deciduous lower left canine and localized gingival inflammation was misrecognized by multiple clinicians (initially diagnosed with hypophosphatasia, genetic and metabolic disorders, all turning negative), over a period of 4–6 months, despite initial radiographs showing clear pathognomonic signs. The LPP diagnostic was made by the last clinician, but by then the tooth was lost. Similar inflammation signs appeared around the lower deciduous right canine. X-ray examination showed similar bone and periodontal loss as previously seen, while periodontopathic bacteria tested highly positive. The patient received both mechanical cleaning and ten days of systemic antibiotic treatment (Augmentin and Metronidazole). Results: Two months later, inflammation signs disappeared, with periodontal regeneration radiologically present, and only small periodontopathic bacteria precursor concentrations. Conclusions: Despite initial periodontal loss, an adequate treatment can keep under control an LPP disease. Moreover, bone and periodontal regeneration appears if periodontopathic bacteria scores are kept lower, showing the importance of fast adequate diagnostic and treatment.