Hypophosphatasia (HPP) is characterized by low activity of tissue nonspecific alkaline phosphatase (TNSALP). The enzyme replacement therapy asfotase alfa has been approved for childhood-onset forms of HPP. MicroRNAs (miRNAs) have emerged as a novel disease biomarker, with potential application in therapy monitoring. Circulating miRNAs were analyzed at baseline, months 1, 2, 4, and 16 in a 49-yr-old woman with childhood-onset HPP, chronic musculoskeletal pain, and non-traumatic fractures prior to enzyme replacement therapy. Serum RNA was extracted and sequenced using miRNeasy Mini Kit (Qiagen, Germany), RealSeq Biosciences Kit (Santa Cruz, US) together with miND spike-in control kit (TAmiRNA, Austria) and Illumina NovaSeq 6000 SP1 flow cell (San Diego, US). Brief Pain Inventory Severity and Interference scores (BPI-S/BPI-I), fatigue severity scale (FSS), Patient Global Impression of Improvement (PGI-I), Western Ontario and McMaster university hip disability and osteoarthritis outcome score (WOMAC), fibromyalgia impact questionnaire (FIQ), 6-Minute Walking Test (6-MWT), chair-rise-test (CRT), and handgrip dynamometry (HD) were performed at baseline and different timepoints during the therapy. Out of >800 screened, 84 miRNAs were selected based on differences in expression profiles between 24 HPP patients and 24 healthy controls. Six miRNAs showed a clear graphic trend and were up- or downregulated by ≥50% reads per million (rpm). These included hsa-let-7i-5p (+50%), hsa-miR-1-3p (-66.66%), hsa-miR-1294 (+63.63%), hsa-miR-206 (-85.57%), hsa-miR-375-3p (-71.43%), and hsa-miR-624-5p (+69.44%). hsa-miR-1-3p and hsa-miR-206 were identified as muscle-specific miRNAs. hsa-mir-375-3p, which negatively regulates osteogenesis, was significantly downregulated. In terms of patient-reported outcomes, BPI-S, BPI-I, FSS, PGI-I, WOMAC, and FIQ showed a reduction by -58.62%, -68.29%, -33.33%, -75.00%, -63.29%, and -43.02%, respectively. 6-MWT improved by +33.89% and CRT by -44.46%. Mean hand grip strength of the right/left hand measured by HD improved by +12.50% and + 23.53%, respectively. miRNA profile changes during the therapy with asfotase alfa, accompanying improvements in functionality tests and quality of life scores.

Rare diseases are an often an overlooked public health problem. Although they are infrequent, occurring on average in 100-500 people per million, these diseases represent a significant challenge in paediatric dentistry due to their complex manifestations and the need for specialised care. Conditions such as X-linked hypophosphatemic rickets (XLH), hypophosphatasia (HPP), and osteogenesis imperfecta (OI) exemplify the intersection of systemic health issues and oral health, requiring a multidisciplinary approach for their effective management. Dentists frequently play a crucial role in identifying genetic alterations through their dental manifestations and then referring patients to the geneticist for a definitive diagnosis. X-linked hypophosphatemia is the most common genetic form of rickets, with a prevalence of 1/20,000 - 1/60,000. XLH is characterised by stunted growth with disproportionate short stature, bowing of the lower limbs associated with reduced motor skills, osteoarticular pain, hypotonia, and dental and periodontal anomalies. XLH is due to inactivating mutations in the PHEX gene which cause excessive production of fibroblast growth factor 23 (FGF23). Increased concentration of FGF23 represents the main pathogenetic mechanism of XLH, stimulating urinary phosphate loss and renal 24-hydroxylase activity, and reducing renal 1α-hydroxylase activity with insufficient production of 1,25 -dihydroxy-vitamin D (1,25(OH)2D). PHEX protein is also expressed in osteoblasts, osteocytes, and odontoblasts. Regardless of FGF23\'s systemic effects on phosphate homeostasis, odontoblast differentiation, and dentin formation, its overexpression directly reduces osteoblast differentiation and matrix mineralisation. In patients with XLH, the deficit of 1,25(OH)2D induced by FGF23 causes poor enamel mineralisation with presence of cracks on teeth surface. XLH patients have recurrent dental abscesses with fistulas. Radiographic investigations highlight a generalised enlargement of the pulp chambers, molars with short roots, and a taurodontic appearance. Hypophosphatasia (HPP) is another condition in which dental manifestations precede systemic symptoms; it is a rare genetic disease (1/300,000 for severe forms, 1/100,000 for moderate forms. The incidence is perhaps underestimated due to missed diagnosis of moderate forms of the disease). It mainly affects bone and dental mineralisation. It is caused by pathogenic variant mutations in the ALPL gene which is located on the short arm of chromosome 1 and encodes the non-tissue-specific alkaline phosphatase (TNSALP) enzyme. TNSALP deficiency results in vitamin B6 (pyridoxine) deficiency and pathological accumulation of alkaline phosphatase substrates which may be responsible for extra-osseous manifestations, such as neurologic ones (pyridoxine sensitive seizures) as well as involvement of muscles and joints (arthropathies, muscle fatigue/hypotonia). Early non-traumatic loss of primary teeth between the ages of 2 and 4 years (and sometimes earlier) with an intact, non-resorbed root is a sign of disease. Tooth mobility precedes exfoliation of the tooth/teeth, most often without associated gum inflammation or pain. The primary incisors are the most affected teeth, and the number and type of primary teeth lost are proportional to the severity of the disease. From a radiologic perspective, characteristic signs include localised or generalised horizontal alveolar bone loss, large pulp chambers, intrapulpal calcifications, and reduced enamel thickness. Osteogenesis imperfecta, or brittle bone disease, is a rare condition characterised by bone fragility and osteopenia. It combines skeletal signs of varying severity (mainly fractures, hyperlaxity, and ligament deformities) and extra skeletal signs (bluish sclera, deafness, vascular fragility). It may also involve dentinogenesis imperfecta. The severity of clinical manifestations is highly variable, ranging from moderate forms that can go unnoticed to major forms that are lethal in the perinatal period. The birth prevalence of osteogenesis imperfecta is approximately 1 in 10,000 people. In approximately 90% of cases, it is an autosomal dominant disease due to monoallelic mutations in the COL1A1, COL1A2 or IFITM5 genes. Ten percent of cases are recessive forms characterised by dentinogenesis imperfecta, where the dental manifestations include teeth discoloration and weakness. The timely recognition of dental manifestations of these rare genetic diseases can allow providers to make an early diagnosis even prior to the development of systemic complications, and for this reason paediatric dentists have a key role in the recognition and management of these patients. Once the diagnosis is suspected, the dentist should refer patients for a genetic evaluation so as to ensure multidisciplinary management and initiation of medical therapies with the collaboration of paediatricians, endocrinologists and other health specialists. The role of dental professionals is not limited to the diagnosis of these rare diseases, but it also encompasses delivering specific, patient-tailored treatments, encouraging preventive care with regular dental visits and educating patients with the ultimate goal to promote not only oral health but the patient\'s overall wellbeing.

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.

Idiopathic juvenile osteoporosis (IJO) is a rare condition presenting with vertebral and metaphyseal fractures that affects otherwise healthy prepubertal children. Bone mineral density (BMD) measurements are very low. The primary problem appears to be deficient bone formation, with a failure to accrue bone normally during growth. The onset in childhood suggests IJO is a genetic disorder, and a number of reports indicate that some children carry heterozygous pathogenic variants in genes known to be associated with defective osteoblast function and low bone mass, most commonly LRP5 or PLS3. However, a positive family history is unusual in IJO, suggesting the genetic background can be complex. We describe a young man with classical IJO who was investigated with a bone fragility gene panel and whole genome sequencing. The proband was found to carry four variants in three different genes potentially affecting osteoblast function. From his mother he had inherited mutations in ALPL (p.Asn417Ser) and LRP5 (p.Arg1036Gln), and from his father mutations in LRP5 (p.Asp1551Alsfs*13) and activating transcription factor 4 (ATF4) (p.Leu306Ile). His sister had also inherited the LRP5 (p.Asp1551Alsfs*13) from her father, but not the ATF4 mutation. Their spinal BMD z-scores differed substantially (sister -1.6, father -3.2) pointing to the potential importance of the ATF4 mutation. Activating transcription factor 4 acts downstream from RUNX2 and osterix and plays an important role in osteoblast differentiation and function. This case, together with others recently published, supports the view that IJO can result from clustering of mutations in genes related to osteoblast development and function. Novel genes in these pathways may be involved. Our case also emphasizes the value of detailed study of other family members. After a bone biopsy had excluded a mineralization defect due to hypophosphatasia, the proband was treated with zoledronate infusions with good clinical effect.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of efzimfotase alfa. Fifteen adults (five per cohort) with HPP received efzimfotase alfa 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one i.v. dose followed by 3 weekly s.c. doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5\'-phosphate [PLP]), and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2 days. Peak and total exposures of efzimfotase alfa increased in a greater than dose-proportional manner over 15-90 mg after i.v. and s.c. dosing. Arithmetic mean elimination t½ was approximately 6 days; absolute bioavailability ranged from 28.6% to 36.8% over the s.c. dose range of 15-90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4 weeks after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), three of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants were positive for neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients.
BACKGROUND: NCT04980248.
Hypophosphatasia (HPP) is a rare metabolic disease caused by low activity of tissue non-specific alkaline phosphatase (TNSALP), which is an enzyme involved in the formation and healing of bone and function of other body systems. People with HPP experience fractures, difficulty moving and walking, muscle weakness, pain, fatigue (tiredness), and teeth problems. Babies with HPP often have life-threatening breathing problems, craniosynostosis (early closure of skull bones), seizures that respond to treatment with vitamin B6, failure to thrive (inability to gain weight), and weak and abnormally shaped bones. Enzyme replacement therapy (ERT) for HPP was developed to supplement defective TNSALP with active enzyme, thus improving bone health and the symptoms of HPP. Asfotase alfa, the first ERT approved for the treatment of HPP is given by subcutaneous injection either 3 or 6 times per week. Efzimfotase alfa is a second-generation ERT that is being developed for the treatment of HPP. While similar to asfotase alfa, efzimfotase alfa has incorporated several changes that have the potential to require lower doses and reduce injection volume and dosing frequency, thereby potentially improving the treatment experience for patients. This first-in-human study investigated the safety, tolerability, pharmacokinetics (how a drug is absorbed into, distributed throughout, and removed from the body), pharmacodynamics (effects of the drug within the body), and immunogenicity (ability of a drug to provoke an undesirable immune response) of four injections of efzimfotase alfa when given by intravenous and subcutaneous routes of administration to adults with HPP. Our results showed that efzimfotase alfa has acceptable safety and pharmacokinetics and is effective for reducing biomarkers (measurable substances that reflect underlying disease) when given once weekly by subcutaneous injection, supporting further evaluation of efzimfotase alfa in planned clinical trials in adult and pediatric patients with HPP.

Hypophosphatasia is a rare inherited metabolic disease leading to inhibition of bone and teeth mineralization that can be complicated by multiple insufficiency fractures. Treatment is currently limited to enzyme replacement therapy using bone-targeting recombinant human alkaline phosphatase, or asfotase alfa. Romosozumab is a monoclonal anti-sclerostin antibody originally indicated for the treatment of osteoporosis in postmenopausal women with high-risk of fracture. Recently its indication had been expanded to other metabolic bone disorders such as osteogenesis imperfecta. We report a unique case of a 67-yer-old female with hypophosphatasia complicated by multiple delayed-union and nonunion insufficiency fractures of the pelvis. After 12-month therapy with Romosozumab to address her osteoporosis, the patient healed her fractures and increased her bone mass density. Our case report shows interesting effects of Romozumab in an adult patient with hypophosphatasia. It not only helped increase bone density, but also help in the healing process of delayed-union and nonunion insufficiency fractures of the pelvis and prevented the occurrence of new fractures during the treatment period. To our knowledge, this is the first report describing the potential effect of Romosozumab on insufficiency fractures in patients with hypophosphatasia.

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.

BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder characterized by defective bone mineralization, leading to skeletal abnormalities and systemic complications. Asfotase alfa, a recombinant human tissue-nonspecific alkaline phosphatase (TNSALP) enzyme replacement therapy, has emerged as a promising treatment for HPP. However, a comprehensive evaluation of its efficacy and safety is warranted to guide clinical practice effectively.
METHODS: The study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in Prospective Register of Systematic Reviews (PROSPERO). A search strategy across databases found studies on asfotase alfa for HPP. Two researchers independently extracted and assessed data. This systematic review examined how the drug impacted clinical outcomes such as survival rates, musculoskeletal symptoms, respiratory function, growth measurements, dental health, quality of life, and laboratory results.
RESULTS: This systematic review included 15 articles with a total of 455 HPP patients. Asfotase alfa was predominantly administered at a dose of 6 mg per kg per week among the reviewed studies. Notable findings included enhanced survival rates, relief from musculoskeletal pain, improvements in respiratory outcomes, growth parameters, dental health, and quality of life. Changes in laboratory variables indicated positive responses to treatment, including changes such as increase in alkaline phosphatase (ALP), decline in pyridoxal 5\'-phosphate (PLP) and inorganic pyrophosphate (PPi) levels.
CONCLUSIONS: Asfotase alfa demonstrates efficacy in improving clinical outcomes and safety in patients with HPP. Its therapeutic benefits extend across various domains. However, Larger, age-stratified comparative studies are needed to further investigate the drug\'s effects in HPP patients.

OBJECTIVE: 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.
METHODS: Three databases (Cochrane Library, MedLine, and Scopus) were used for a review.
METHODS: According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, a systematic review guideline, 85 articles were selected.
RESULTS: 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.
CONCLUSIONS: 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.
CONCLUSIONS: This paper provides an extensive resource addressing early tooth loss in childhood to assist researchers with differential diagnosis.
CONCLUSIONS: The articles included in this review are case reports based on living populations.
UNASSIGNED: 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.

OBJECTIVE: The objective of this study was to analyse an individual whose remains are characterised by early deciduous tooth loss and multi-focal lesions on the post-cranial skeleton.
METHODS: Skeletal remains of an immature individual buried between 1770 and 1849 in London.
METHODS: The remains were examined by visual macroscopic inspection, supplemented by radiographic examination of the mandible and maxillae. A differential diagnosis with possible conditions, frequent in this archaeological context, was conducted. A comprehensive examination of dental lesions was performed to investigate the aetiologies of deciduous tooth loss.
RESULTS: The individual exhibited a mosaic of skeletal and dental pathological changes, including premature loss of deciduous dentition, premature eruption of permanent teeth generalised bone loss in both the mandible and maxilla; osteomyelitis of the left radius; osteolytic lesion on the body of the second lumbar vertebra, and marked expansions of the rib shafts due to sub-periosteal new bone formation.
CONCLUSIONS: A differential diagnosis considered indicates that the pathological changes of the individual were most likely associated with a comorbidity involving hypophosphatasia and tuberculosis.
CONCLUSIONS: We present in this study several oral signs that could alert paleopathologists and bioarcheologists to systematically consider the potential of a condition that is rarely encountered in archaeological contexts.
CONCLUSIONS: Due to poor preservation, this study was confined to the analysis of a partial maxilla and mandible, a left radius shaft and the axial skeleton (rib heads and vertebrae) of the individual.
UNASSIGNED: Further radiographic, histological and genetic analyses would confirm the diagnosis.