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Toshimi Michigami
Congenital skeletal dysplasias have been considered to be fundamentally untreatable diseases. However, molecular diagnosis by genetic testing has become more prevalent, and efforts are being made to develop novel therapies based on the pathogenesis. As treatments for osteogenesis imperfecta, in addition to anti-resorptive agents, neutralizing antibodies against sclerostin and transforming growth factor(TGF)-β and chemical chaperones can be beneficial. Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has been recently developed to treat hypophosphatasia and has much improved the prognosis of the patients affected with severe forms of the disease...
2018: Clinical Calcium
S Ursprung
Today, public opinion and the French authorities are more aware of rare diseases, in particular due to the implementation of national plans for rare diseases (PNMR I: 2005-2008 and PNMR II: 2011-2016), the existence of national networks and the current organization of the reference expert centers for rare diseases. While the management of rare diseases is now better structured, it remains long for the patients to be diagnosed. It is not always easy for physicians to clearly identify one of the 7,000 rare diseases even though they increasingly ask themselves the question: is this a rare disease? A person diagnosed with a rare disease lives in a familial, social and professional environment that has not prepared him or her, suddenly or after years of uncertainty, for such an experience...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
J Bacchetta
Renal impairment in hypophosphatasia (HPP) has been described but remains poorly understood: hypercalciuria, nephrocalcinosis and sometimes even chronic kidney failure secondary to chronic hypercalcemia/hypercalciuria or exposure to toxic agents. The objectives of this review are to describe the different renal lesions observed in HPP, and the therapeutic measures that can be applied (in particular, thiazide diuretics).
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
F Di Rocco, G Baujat, V Cormier-Daire, A Rothenbuhler, A Linglart
Hypophosphatasia (HPP) when diagnosed at a young age may induce premature fusion of one or several cranial sutures, resulting in a craniocerebral disproportion. The main forms of craniosynostosis associated with HPP are loss of the sagittal suture (scaphocephaly), alone or associated with loss of the coronal sutures (oxycephaly) or associated with loss of the coronal and lambdoid sutures (pansynostosis). Craniosynostosis is accompanied by putatively functional consequences. Diagnosis must thus be early and lead to management by a specialized team...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
C Fonta, J-P Salles
The pathophysiology of the neuromuscular manifestations of hypophosphatasia (HPP) remains unknown. Pyridoxine-sensitive seizures characterize severe forms of infantile HPP. Young children and infants affected with severe forms of HPP, but also adults often present with myopathy characterized by hypotonia or muscle weakness. Chronic pain, of unclear mechanism is also often present. Tissue-non-specific alkaline phosphatase (Alkaline Phosphatase-Liver/Bone/Kidney [ALPL]) is expressed in brain neuronal cell and in muscle cells during development and adulthood...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
A Bloch-Zupan, F Vaysse
Dental anomalies exist in every subtype of hypophosphatasia (HPP), from the most severe to the most moderate, called odontohypophosphatasia. The forms are defined by the age at onset of the initial symptoms. These anomalies affect all dental mineralized tissues from enamel, dentin and cementum to alveolar bone in a gradient proportional to the severity of the disease. Early loss of the deciduous teeth, before 3 years of age, and then possibly of the permanent teeth, is due to an abnormality of the cementum, the tissue attaching the teeth to alveolar bone, and is the most frequent abnormality...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
A Linglart, J-P Salles
Radiography and imaging are necessary for the diagnosis of hypophosphatasia (HPP) at all stages of life, from the antenatal period to the complications of adulthood, and in the forms of variable severity. The consequences of alkaline phosphatase activity deficiency, namely defective mineralization and bone fragility, may be detected by radiological tools and share features that distinguish them from other diseases responsible for mineralization defects. Radiography and imaging are also fundamental for the screening and diagnosis of the complications of HPP, some of which are related to the episodes of hypercalcemia and hyperphosphatemia (nephrocalcinosis)...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
K Briot, C Roux
In adults, hypophosphatasia (HPP) may be revealed by fractures, mainly metatarsal and femoral, and by crystal-related joint diseases. Low alkaline phosphatase levels are often overlooked. There is no established treatment for adults but the diagnosis is important to prevent the use of therapies that promote bone resorption in this context of bone fragility.
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
A Rothenbuhler, A Linglart
Hypophosphatasia (HPP) is a rare genetic disease due to loss of function mutations in the gene that encodes for Alkaline Phosphatase-Liver (ALPL) that encodes for tissue non-specific alkaline phosphatase (TNSALP) or ALP. Juvenile HPP is, by definition, diagnosed between 6 months of age and adulthood. The clinical signs and symptoms of juvenile HPP are very heterogeneous in their presentation, severity and course. The bone (impaired bone mineralization, leg deformations, pain, rickets, growth abnormalities) and dental (premature loss of deciduous teeth) abnormalities are the best known...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
G Baujat, C Michot, K H Le Quan Sang, V Cormier-Daire
Hypophosphatasia (HPP) is a rare hereditary disease characterized by defective skeletal mineralization, and with a broad severity spectrum. The perinatal forms, lethal and non-lethal, are associated with severe neonatal respiratory distress, potential seizures, hypotrophy and marked hypotonia. The diagnosis is rapidly suggested by a combination of typical radiological signs, hypercalcemia, hyperphosphatemia and low alkaline phosphatase (ALP) activity. In the infantile form, the clinical signs appear before the age of six months, but the patients usually have no or very mild signs at birth...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
I Gennero, F Conte-Auriol, J-P Salles
The laboratory diagnosis of hypophosphatasia (HPP) is primarily based on the precise analysis of circulating serum alkaline phosphatase (ALP) activity, determined by biochemical assays. This analysis requires specific conditions of implementation and interpretation and should always be viewed in the light of the clinical and radiological data. Concerns regarding the normal ranges of ALP with respect to age, regarding ALP values that may overlap those of normal subjects in HPP patients, regarding apparently normal ALP values in cases of proven HPP, regarding differential diagnoses that may be responsible for low ALP values outside of HPP will be discussed...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
E Mornet
Hypophosphatasia (HPP) is a rare inherited disorder primarily affecting bone and dental mineralization. Although there is a continuum in the severity of the disease, clinical forms may be arbitrarily distinguished on the basis of age at onset and the presence or absence of bone symptoms: perinatal, infantile, juvenile, adult, prenatal benign, and odontological. Severe forms (perinatal and infantile) are autosomally recessively inherited while less severe forms may be autosomally recessively or dominantly inherited...
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
J-P Salles, A Linglart
No abstract text is available yet for this article.
May 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
Michael P Whyte, Stephen P Coburn, Lawrence M Ryan, Karen L Ericson, Fan Zhang
Hypophosphatasia (HPP) is the inborn-error-of-metabolism due to loss-of-function mutation(s) of the ALPL (TNSALP) gene that encodes the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). TNSALP represents a family of cell-surface phosphohydrolases differing by post-translational modification that is expressed especially in the skeleton, liver, kidney, and developing teeth. Thus, the natural substrates of TNSALP accumulate extracellularly in HPP including inorganic pyrophosphate (PPi), a potent inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6...
January 19, 2018: Bone
John E Lawrence, Danish Saeed, Jonathan Bartlett, Andrew D Carrothers
We report the case of a 55-year-old woman who presented to the emergency department having woken from sleep with right sided thigh swelling. Pelvic radiographs revealed bilateral atypical subtrochanteric femoral fractures (ASFFs). In the two years leading up to this admission, the patient had experienced gradually increasing pain and weakness in her legs which had resulted in a decrease in her mobility from fully mobile to bed-bound. During this time a neurologist had organised a magnetic-resonance imaging (MRI) scan of the brain and spine which was normal...
September 2017: Clinical Cases in Mineral and Bone Metabolism
Francesca Marini, Maria Luisa Brandi
Hypophosphatasia (HPP) is a congenital, rare and heterogeneous bone disorder, characterized by a deficit of calcified tissue mineralization, leading to skeletal deformities and osteomalacia in adults, rickets in infants and children, and fragility fractures and premature loss of dentition in children and adults. The disease is caused by a reduced or absent expression and activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, derived from inactivating mutations of the alkaline phosphatase (ALPL) gene...
September 2017: Clinical Cases in Mineral and Bone Metabolism
Siobhan Bacon, Rachel Crowley
In the last decade, there have been a number of significant advances made in the field of rare bone diseases. In this review, we discuss the expansion of the classification system for osteogenesis imperfecta (OI) and the resultant increase in therapeutic options available for management of OI. Bisphosphonates remain the most widely used intervention for OI, although the effect on fracture rate reduction is equivocal. We review the other therapies showing promising results, including denosumab, teriparatide, sclerostin, transforming growth factor β inhibition and gene targeted approaches...
January 2018: Therapeutic Advances in Chronic Disease
Michael P Whyte, Kenji P Fujita, Scott Moseley, David D Thompson, William H McAlister
Hypophosphatasia (HPP) is the heritable metabolic disease characterized by impaired skeletal mineralization due to low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. Although HPP during growth often manifests with distinctive radiographic skeletal features, no validated method was available to quantify them, including changes over time. We created the Radiographic Global Impression of Change (RGI-C) scale to assess changes in the skeletal burden of pediatric HPP. Site-specific pairs of radiographs of newborns, infants, and children with HPP from 3 clinical studies of asfotase alfa, an enzyme replacement therapy for HPP, were obtained at Baseline and during treatment...
January 3, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Morgane Righetti, Jean Wach, Romain Desmarchelier, Fabienne Coury
Atypical femoral fractures are defined as atraumatic fractures located in the subtrochanteric region or femoral shaft. They have been mainly reported in patients taking bisphosphonates. We report the case of a 67-year-old female with osteoporosis treated by alendronate during ten years. Radiographies showed atypical femoral fractures. Serum levels of total and bone-specific alkaline phosphatase were low. In order to accelerate bone healing, teriparatide was introduced. After one year of teriparatide treatment, pain and functional difficulty have decreased, and alkaline phosphatase levels were normalized...
December 12, 2017: Joint, Bone, Spine: Revue du Rhumatisme
Agnès Taillandier, Christelle Domingues, Annika Dufour, Françoise Debiais, Pascal Guggenbuhl, Christian Roux, Catherine Cormier, Bernard Cortet, Valérie Porquet-Bordes, Fabienne Coury, David Geneviève, Jean Chiesa, Thierry Colin, Elaine Fletcher, Agnès Guichet, Rose-Marie Javier, Michel Laroche, Michael Laurent, Ekkehart Lausch, Bruno LeHeup, Cédric Lukas, Georg Schwabe, Ineke van der Burgt, Christine Muti, Brigitte Simon-Bouy, Etienne Mornet
Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain...
December 13, 2017: Journal of Bone and Mineral Metabolism
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