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ABSTRACT Background Objective Methods Results Conclusion Hypophosphatasia (HPP) is a rare inherited disease that affects multiple organ systems including bone and teeth. Limited knowledge exists on dental and oral health in patients with adult‐onset HPP (aHPP).The aim of this study was to investigate oro‐dental characteristics in patients with aHPP compared to healthy controls.This case‐control study included 20 patients with aHPP compared to 31 healthy controls. Oro‐dental manifestations were examined by standardised interviews, clinical examinations as well as radiological registrations on panoramic radiograph (OP) and cone‐beam computed tomography (CBCT) scans.The subjective experience of tooth fractures (p = 0.010), caries in permanent teeth (p = 0.032) and early loss of permanent teeth (p = 0.002) was significantly higher in patients with aHPP compared to the controls. In the aHPP group, the presence of specific teeth (p ≤ 0.045) and attrition of 11 were significantly lower (p = 0.012) compared to the controls. Opacity of a few teeth (p ≤ 0.049), presence of denticles (p = 0.024), the distance between the enamel–cement junction (CEJ) and the marginal bone level at specific sites (p ≤ 0.021) and crown height of 11 (p = 0.017) were significantly higher in patients with aHPP than in healthy controls.The results indicate that patients with aHPP have a subjective experience of having poorer dental health. Loss of permanent teeth, less attrition, tooth opacities, denticles and larger distance between CEJ and marginal bone level are possible oro‐dental findings in patients with aHPP. [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]

Hypophosphatasia (HPP) is an underrecognized, complex bone mineralization disorder with variable manifestations caused by one or two deleterious variants in the alkaline phosphatase (ALPL) gene. Expanded carrier screening (ECS), inclusive of ALPL, intends to inform reproductive risk but may incidentally reveal an HPP diagnosis with 50% familial risks. We sought to investigate at‐risk individuals and develop a multidisciplinary referral and evaluation protocol for ECS‐identified ALPL heterozygosity. A retrospective database query of ECS results from 8 years to 1 month for heterozygous pathogenic/likely pathogenic ALPL variants was completed. We implemented a clinical protocol for diagnostic testing and imaging, counseling, and interdisciplinary care management for identified patients, and outcomes were documented. Heterozygous ALPL variants were identified in 12/2248 unrelated patients undergoing ECS (0.53%; heterozygote frequency 1/187). Of 10 individuals successfully contacted, all demonstrated symptomatology and/or alkaline phosphatase values consistent with HPP. ECS may reveal incidental health risks, including recognition of missed HPP diagnoses in ALPL heterozygotes. In our cohort, all ECS‐identified ALPL heterozygotes with clinical and/or biochemical data available demonstrated features of HPP. Referral to a genetics professional familiar with HPP is indicated for family history assessment, genetic counseling, cascade testing, and long‐term bone health management. [ABSTRACT FROM AUTHOR]

Aim: This study evaluated the oral health status of adult patients with hypophosphatasia (HPP). Materials and Methods: Parameters of oral health assessment comprised decayed/missing/filled teeth (DMFT) index, probing pocket depth and clinical attachment level (CAL) as well as documentation of tooth loss and periodontal health status according to CCD/AAP criteria. Findings were compared with national reference data (DMS V survey) reporting oral health status in age‐related controls. Within‐group comparisons were made between the HPP patients harbouring one versus two alkaline phosphatase liver/bone/kidney type (ALPL) gene variants. Results: Of 80 HPP patients (64 female) with a mean age of 46.4 years (range 24–78) and one (n = 55) or two (n = 18) variants (n = 7 lacking testing) within the ALPL gene, those with two variants displayed substantially higher tooth loss rate (14.0 ± 9.3) than those affected by only one ALPL variant (4.1 ± 5.4), who did not differ substantially from healthy DMS V controls. While DMFT score and severe periodontal diseases (PDs) of HPP patients with one variant only increased with progressing age, the two‐variant sub‐cohort age independently exhibited increased DMFT scores and a higher rate of severe PDs. Conclusions: HPP patients affected by two variants of the ALPL gene exhibited a higher risk of periodontitis and tooth loss than the general population, while patients with one variant developed clinically relevant oral disease symptoms with progressing ageing. Clinicaltrials.gov identifier: NCT02291497. [ABSTRACT FROM AUTHOR]

We report a 48‐year‐old female patient with various stress fractures of extremities, musculoskeletal pain, and tooth loss. Hypophosphatasia was diagnosed based on clinical and laboratory findings and ALPL genetic results. This case highlights the importance of early diagnosis of hypophosphatasia in adults and appropriate treatment to prevent further complications. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is a rare inherited disease defined by teeth and bone mineralization impairment leading to depletion of tissue non‐specific alkaline phosphatase. We define a young woman diagnosed with hypophosphatasia (after several times alkaline phosphatase levels were low) was discovered following femoral fracture. A 30‐year‐old woman who presented for a history of early permanent teeth loss during the last 5 years and HPP‐like symptoms in family history and bone radiograph verified bowing, deficient mineralization, and symmetrical subtrochanteric stress fractures of femurs was referred to our clinic for further management. Blood test findings defined raised phosphorus levels on two occasions at 6.2 and 5.7 mg/dl and insufficient 25‐hydroxy vitamin D level. HPP early diagnosis and adequate treatment, depending on the clinical symptoms along with laboratory tests, could be effective in decreasing the suffering of the disease and side effects. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is a rare metabolic inherited dento‐osseous disorder. Although there is some available literature on various dental characteristics of hypophosphatasia patients, few reports focus on the effects of hypophosphatasia on the permanent dentition and prosthodontic rehabilitation, particularly in relation to the use of dental implants. This paper reports a case with hypophosphatasia and prosthodontic rehabilitation using dental implants with 7‐year follow‐up. [ABSTRACT FROM AUTHOR]

Introduction: Tumour‐induced osteomalacia (TIO) is a rare paraneoplastic condition characterised by decreased tubular phosphate reabsorption. The purpose of this study is to evaluate bone mineral density (BMD) and microarchitecture in six TIO patients, compared with 18 healthy controls. Methods: Volumetric BMD and microarchitecture were evaluated by high‐resolution peripheral quantitative computed tomography (HR‐pQCT), and areal BMD by dual‐energy X‐ray absorptiometry (DXA). Differences between groups were significant for p <.05. Results: All TIO subjects were healthy until the development of diffuse bone pain and multiple skeletal fractures and deformities. At baseline, sPi and TmPi/GFR were low and patients were on vitamin D and phosphate replacement at the study. Compared with controls, TIO patients had lower aBMD at lumbar spine and hip, and lower vBMD at trabecular, cortical and entire bone, at distal radius (R) and distal tibia (T): trabecular vBMD (R = 118.3 × 177.1; T = 72.3 × 161.3 gHA/cm3); cortical vBMD (R = 782.3 × 866.5; T = 789.1 × 900.9 gHA/cm3); total region vBMD (R = 234.5 × 317; T = 167.1 × 295.8 gHA/cm3). Bone microarchitecture was very heterogeneous among patients and significantly different from controls: lower cortical thickness (R = 0.59 × 0.80; T = 0.90 × 1.31 mm), bone volume‐to‐total volume ratio (R = 0.09 × 0.14; T = 0.06 × 0.13) and Tb.N (R = 1.46 × 2.10; T = 0.93 × 1.96 mm−1) and also higher Tb.Sp (R = 0.70 × 0.41; T = 1.28 × 0.45 mm) and Tb.1/N.SD (R = 0.42 × 0.18; T = 0.87 × 0.20 mm). Conclusion: In this original study of TIO patients, DXA and HR‐pQCT evaluation identified lower areal and volumetric BMD and severely impaired microarchitecture at cortical and trabecular bones, which probably contribute to bone fragility and fractures. [ABSTRACT FROM AUTHOR]

The most frequent dental signs of hypophosphatasia in children are premature loss of primary teeth, decrease in height of alveolar bone, and malocclusions. Enzyme replacement therapy with Asfotase alfa might be associated with stabilization of dental status. [ABSTRACT FROM AUTHOR]

The article presents a case study of a female infant with perinatal severe hypophosphatasia (HPP) undergoing high-setting ventilation and enzyme replacement therapy, who developed chylous ascites. Topics discussed include the diagnosis of perinatal severe HPP, the challenges in respiratory management due to chest deformities and lung hypoplasia, and the previously unreported complication of chylous ascites in HPP patients on high-setting ventilation.

The lack of awareness of patient risk factors, failure to obtain adequate family history, was discussed by clinical experience in prenatal testing of hypophosphatasia with a novel variant in the ALPL gene identified in the index case of the family. [ABSTRACT FROM AUTHOR]

The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno‐Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. The entire 19th century collection was described in full detail by Eduard Sandifort (1742–1814) and his son Gerard Sandifort (1779–1848). Efforts were made to re‐describe, re‐diagnose and re‐categorize all present human teratological specimens, and to match them with historical descriptions. In the extant collection a total of 642 human teratological specimens were identified, including exceptional conditions such as faciocranioschisis and conjoined twins discordant for cyclopia, and sirenomelia. Both father and son Sandifort differed in their opinion regarding the causative explanation of congenital anomalies. Whereas, their contemporaries Wouter Van Doeveren (1730–1783) and Andreas Bonn (1738–1817) both presented an interesting view on how congenital anomalies were perceived and explained during the 18th and 19th centuries; the golden age of descriptive teratology. Although this enormous collection is almost 400 years old, it still impresses scientists, (bio)medical students, and laymen visiting and exploring the collections of the Museum Anatomicum in Leiden, The Netherlands. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates. [ABSTRACT FROM AUTHOR]

Objective Hypophosphatasia ( HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa ( AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan. Design Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015. Patients Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1). Measurements Safety determined from adverse events ( AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development. Results Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved. Conclusion Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients. [ABSTRACT FROM AUTHOR]

Background and Objective Hypophosphatasia is a rare inherited skeletal disorder characterized by defective bone mineralization and deficiency of tissue non-specific alkaline phosphatase ( TNSALP) activity. The disease is caused by mutations in the liver/bone/kidney alkaline phosphatase gene ( ALPL) encoding TNSALP. Early exfoliation of primary teeth owing to disturbed cementum formation, periodontal ligament weakness and alveolar bone resorption are major complications encountered in oral findings, and discovery of early loss of primary teeth in a dental examination often leads to early diagnosis of hypophosphatasia. Although there are no known fundamental treatments or effective dental approaches to prevent early exfoliation of primary teeth in affected patients, several possible treatments have recently been described, including gene therapy. Gene therapy has also been applied to TNSALP knockout mice ( Alpl−/−), which phenocopy the infantile form of hypophosphatasia, and improved their systemic condition. In the present study, we investigated whether gene therapy improved the dental condition of Alpl−/− mice. Material and Methods Following sublethal irradiation (4 Gy) at the age of 2 d, Alpl−/− mice underwent gene therapy using bone marrow cells transduced with a lentiviral vector expressing a bone-targeted form of TNSALP injected into the jugular vein ( n = 3). Wild-type ( Alpl+/+), heterozygous mice ( Alpl+/−) and Alpl−/− mice were analyzed at 9 d of age ( n = 3 of each), while Alpl+/+ mice and treated or untreated Alpl−/− mice were analyzed at 1 mo of age ( n = 3 of each), and Alpl+/− mice and Alpl−/− mice with gene therapy were analyzed at 3 mo of age ( n = 3 of each). A single mandibular hemi-section obtained at 1 mo of age was analyzed using a small animal computed tomography machine to assess alveolar bone formation. Other mandibular hemi-sections obtained at 9 d, 1 mo and 3 mo of age were subjected to hematoxylin and eosin staining and immunohistochemical analysis of osteopontin, a marker of cementum. Results Immunohistochemical analysis of osteopontin, a marker of acellular cementum, revealed that Alpl−/− mice displayed impaired formation of cementum and alveolar bone, similar to the human dental phenotype. Cementum formation was clearly present in Alpl−/− mice that underwent gene therapy, but did not recover to the same level as that in wild-type ( Alpl+/+) mice. Micro-computed tomography examination showed that gene therapy improved alveolar bone mineral density in Alpl−/− mice to a similar level to that in Alpl+/+ mice. Conclusions Our results suggest that gene therapy can improve the general condition of Alpl−/− mice, and induce significant alveolar bone formation and moderate improvement of cementum formation, which may contribute to inhibition of early spontaneous tooth exfoliation. [ABSTRACT FROM AUTHOR]

Tissue non-specific alkaline phosphatase ( TNAP) is a key player of bone mineralization and TNAP gene ( ALPL) mutations in human are responsible for hypophosphatasia ( HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However, TNAP's role in the nervous system remains poorly understood. To investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used 1H- and 31P NMR to analyze the brain metabolome of Alpl ( Akp2) mice null for TNAP function, a well-described model of infantile HPP. Among 39 metabolites identified in brain extracts of 1-week-old animals, eight displayed significantly different concentration in Akp2 −/− compared to Akp2 +/+ and Akp2 +/− mice: cystathionine, adenosine, GABA, methionine, histidine, 3-methylhistidine, N-acetylaspartate ( NAA), and N-acetyl-aspartyl-glutamate, with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto-nucleotide levels and of pyridoxal phosphate-dependent enzymes. Some of these metabolites are involved in neurotransmission ( GABA, adenosine), in myelin synthesis ( NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP. [ABSTRACT FROM AUTHOR]

A series of isonicotinohydrazide derivatives was synthesized and tested against recombinant human and rat ecto-5′-nucleotidases ( h-e5′ NT and r-e5′ NT) and alkaline phosphatase isozymes including both bovine tissue-non-specific alkaline phosphatase ( b- TNAP) and tissue-specific calf intestinal alkaline phosphatase ( c- IAP). These enzymes are implicated in vascular calcifications, hypophosphatasia, solid tumors, and cancers, such as colon, lung, breast, pancreas, and ovary. All tested compounds were active against both enzymes. The most potent inhibitor of h-e5′ NT was derivative (E)-N′-(1-(3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1 H-pyrazol-1-yl)ethylidene)isonicotinohydrazide ( 3j), whereas derivative ( E)- N′-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide ( 3g) exhibited significant inhibitory activity against r-e5′ NT . In addition, the derivative (E)-N′-(4′-chlorobenzylidene)isonicotinohydrazide ( 3a) was most potent inhibitor against calf intestinal alkaline phosphatase and the derivative ( E)- N′-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide ( 3g) was found to be most potent inhibitor of bovine tissue-non-specific alkaline phosphatase. Furthermore, putative binding modes of potent compounds against e5′ NT (human and rat e5′ NT) and AP (including b- TNAP and c- IAP) were determined computationally. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene ( ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Hypophosphatasia ( HPP) is a rare inherited metabolic disease in which mutations in the ALPL gene (encoding tissue-nonspecific alkaline phosphatase) result in varying degrees of enzyme deficiency. HPP manifests in a spectrum of symptoms, including early primary tooth loss (root intact) and alveolar bone mineralisation defects. Objective To provide an overview of HPP for dental professionals to help recognise and differentially diagnose patients for appropriate referral to a specialist team. Methods A non-systematic review of publications on HPP was performed. Results Different forms of HPP are described, along with characteristic symptoms and laboratory findings. Diagnosis is challenging due to the rareness and variable presentation of symptoms. Low alkaline phosphatase levels are a signature of HPP, but reference ranges vary according to gender and age. Key features are defined and management strategies discussed, focusing on enzyme replacement therapy. Finally, a patient registry aimed at better defining the prevalence of HPP and raising awareness is described. Conclusions HPP is a rare disease with a wide spectrum of manifestations, with orodental symptoms featuring prominently in the natural history. Dental professionals may be positioned at the beginning of the diagnostic pathway; thus, recognition of HPP features for timely referral and optimal disease management is important. [ABSTRACT FROM AUTHOR]

Tissue-nonspecific alkaline phosphatase ( TNSALP) is a membrane glycoprotein with a proposed role in bone mineralization. Indeed, mutations in TNSALP have been identified in patients with hypophosphatasia ( HPP), a genetic disease characterized by hypomineralization of bone and teeth and a deficiency in serum ALP activity. TNSALP has five potential N-glycosylation sites at N140, N230, N271, N303 and N430 by standard nomenclature. A mutation at one of these sites, N430, was recently detected in a patient with infantile HPP. Using site-directed mutagenesis, we demonstrated that TNSALP has five N-glycans in transfected COS-1 cells and that individual single N-glycan deletion mutants of TNSALP retain the dimeric structure required for ALP activity, excluding the possibility that any single N-glycan plays a vital role in the structure and function of TNSALP. However, we found that TNSALP (N430Q) and TNSALP (N430E) mutants, but not a TNSALP (N430D) mutant, failed to form dimers. The TNSALP (N430S) mutant linked to infantile HPP was glycosylation-defective and unable to dimerise, similar to TNSALP (N430Q) and TNSALP (N430E) mutants; therefore, TNSALP (N430S) was established as a severe allele without strong ALP activity. By contrast to individual single N-glycan deletion mutants, TNSALP devoid of all five N-glycans was present to a much lesser extent than wild-type TNSALP in transfected cells, possibly reflecting its instability. A comprehensive analysis of a series of multiple N-glycan depletion mutants in TNSALP revealed that three N-glycans on N230, N271 and N303 were the minimal requirement for the structure and function of TNSALP and a prerequisite for its stable expression in a cell. [ABSTRACT FROM AUTHOR]

Background: Inactivating mutations in tissue-nonspecific alkaline phosphatase (TNAP) cause hypophosphatasia (HPP), which is commonly characterized by decreased bone mineralization. Infants and mice with HPP can also develop craniosynostosis and craniofacial shape abnormalities, although the mechanism by which TNAP deficiency causes these craniofacial defects is not yet known. Manifestations of HPP are heterogeneous in severity, and evidence from the literature suggests that much of this variability is mutation dependent. Here, we performed a comprehensive analysis of craniosynostosis and craniofacial shape variation in the Alpl−/− mouse model of murine HPP as an initial step toward better understanding penetrance of the HPP craniofacial phenotype. Results: Despite similar deficiencies in alkaline phosphatase, Alpl−/− mice develop craniosynostosis and a brachycephalic/acrocephalic craniofacial shape of variable penetrance. Only those Alpl−/− mice with a severe bone hypomineralization defect develop craniosynostosis and an abnormal craniofacial shape. Conclusions: These results indicate that variability of the HPP phenotype is not entirely dependent upon the type of genetic mutation and level of residual alkaline phosphatase activity. Additionally, despite a severity continuum of the bone hypomineralization phenotype, craniofacial skeletal shape abnormalities and craniosynostosis occur only in the context of severely diminished bone mineralization in the Alpl−/− mouse model of HPP. Developmental Dynamics 245:175-182, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth - where calcium phosphate crystals are deposited and grow within an extracellular matrix - is essential for dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition in which teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibers ( Sharpey's fibers) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth-suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here, with clinical examples given, namely tissue-nonspecific alkaline phosphatase and phosphate-regulating gene with homologies to endopeptidases on the X chromosome. Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia and X-linked hypophosphatemia, respectively, where the levels of local and systemic circulating mineralization determinants are perturbed. In X-linked hypophosphatemia, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating small integrin-binding ligand N-linked glycoproteins, such as matrix extracellular phosphoglycoprotein and osteopontin, and the phosphorylated peptides proteolytically released from them, such as the acidic serine- and aspartate-rich-motif peptide, may accumulate locally to impair mineralization in this disease. [ABSTRACT FROM AUTHOR]

Bone marrow ( BM) transplantation (BMT) is one of the treatment strategies for congenital metabolic disease, but leukemia secondary to intensive cytoreductive treatment is a major concern. Besides BM cells, mesenchymal stem cells ( MSC) are also used for transplantation. An 8-month-old girl with hypophosphatasia underwent transplantation of haploidentical BM cells followed by two transplants of MSC obtained from her father to facilitate osteogenesis. Fludarabine( Flu)/cyclophosphamide ( CPA)/anti-thymocyte globulin were used for myeloablative conditioning, but the patient developed therapy-related leukemia harboring t(9;22)(q34;q11.2); minor BCR-ABL (t-leukemia with Ph) at the age of 32 months. At the age of 40 months she underwent a second BM and third MSC transplant from the same donor. Thereafter, she achieved complete histological and molecular remission. The present case suggests that the combination of cytotoxic agents ( Flu/ CPA) and MSC led to t-leukemia with Ph as a consequence of chromosome instability and suppression of host anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Mutations in the tissue-nonspecific alkaline phosphatase ( TNSALP) gene cause hypophosphatasia ( HPP), an inborn error of metabolism characterized by defects in bone and teeth mineralization accompanying subnormal levels of serum alkaline phosphatase activity. Missense mutations at position 420 of TNSALP (standard nomenclature), which convert glycine to serine [ TNSALP ( G420 S)] or alanine [ TNSALP ( G420 A)], have been reported in perinatal and childhood HPP, respectively. When expressed in COS-1 cells, both TNSALP mutants were indistinguishable from wild-type TNSALP [ TNSALP ( W)] as evidenced by immunofluorescence and western blotting. Nevertheless, the two TNSALP mutants did not show substantial alkaline phosphatase activity. In agreement with transiently transfected cells, TNSALP ( G420 S) expressed in a Tet- On inducible expression system lacked its alkaline phosphatase activity, although this mutant was anchored to the cell surface lipid bilayers by glycosylphosphatidylinositol as an 80 kDa mature form bearing complex-type oligosaccharides like TNSALP ( W). Importantly, TNSALP ( G420 S) was found to largely fail to assemble into the homodimer in contrast to TNSALP ( W). Taken together, these results demonstrate that the glycine residue at position 420 is crucial for the subunit interaction of TNSALP and hence its catalytic function without affecting trafficking of monomeric TNSALP. We conclude that the dimerization defect is the molecular basis for perinatal HPP associated with the genotype G420 S/ G420 S. [ABSTRACT FROM AUTHOR]

Background: Mutations in the liver/bone/kidney alkaline phosphatase (ALPL) gene in hypophosphatasia (HPP) reduce the function of tissue non-specific alkaline phosphatase (ALP), resulting in increased pyrophosphate (PPi) and a severe deficiency in acellular cementum. We hypothesize that exogenous phosphate (Pi) would rescue the in vitro mineralization capacity of periodontal ligament (PDL) cells harvested from HPPdiagnosed patients, by correcting the Pi/PPi ratio and modulating expression of genes involved with Pi/PPi metabolism. Methods: Ex vivo and in vitro analyses were used to identify mechanisms involved in HPP-associated PDL/tooth root deficiencies. Constitutive expression of PPi-associated genes was contrasted in PDL versus pulp tissues obtained from healthy individuals. Primary PDL cell cultures from patients with HPP (monozygotic twin males) were established to assay ALP activity, in vitro mineralization, and gene expression. Exogenous Pi was provided to correct the Pi/PPi ratio. Results: PDL tissues obtained from healthy individuals featured higher basal expression of key PPi regulators, genes ALPL, progressive ankylosis protein (ANKH), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), versus paired pulp tissues. A novel ALPL mutation was identified in the twin patients with HPP enrolled in this study. Compared to controls, HPP-PDL cells exhibited significantly reduced ALP and mineralizing capacity, which were rescued by addition of 1 mM Pi. Dysregulated expression of PPi regulatory genes ALPL, ANKH, and ENPP1 was also corrected by adding Pi, although other matrix markers evaluated in our study remained downregulated. Conclusion: These findings underscore the importance of controlling the Pi/PPi ratio toward development of a functional periodontal apparatus and support Pi/PPi imbalance as the etiology of HPP-associated cementum defects. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is characterized by deficiency of serum alkaline phosphatase with defective bone and teeth mineralization. We report on an 11-month-old boy who developed a complex clinical picture characterized by bulging anterior fontanelle, growth failure, nephrocalcinosis and impaired bone mineralization during high-dose calcium and vitamin D supplementation. This therapy had been started 5 months earlier for a presumed diagnosis of nutritional rickets established on the grounds of isolated widened anterior fontanelle. However, laboratory investigations revealed reduced alkaline phosphatase levels associated with hypercalcemia, hypercalciuria, low PTH and normal 25-hydroxy vitamin D levels. Genetic testing detected a compound heterozygote for the novel mutation (c.262G>A) and the described mutation (c.920C>T) in the ALPL gene. High calcium and vitamin D supplementation should not be started in the presence of isolated signs of nutritional rickets without assessing calcium-phosphate metabolism. In fact, in rare bone-mineralizing disorders, this combined therapy might induce severe clinical complications. [ABSTRACT FROM AUTHOR]

The prevalence of hypophosphatasia (HP), a rare metabolic disorder due to loss-of-function mutations in the ALPL gene, has never been estimated in the European population. Only one published study evaluated the incidence of severe HP at 1/100,000 in Canada 53 years ago. Moderate forms of hypophosphatasia (mHP), including HP with moderate bone features and the mildest form odontohypophosphatasia, reflect both recessive and dominant inheritance, and are therefore expected to be more frequent than severe forms of HP. Here we estimated both the prevalences of severe and mHP in European populations. The prevalence of severe HP was estimated at 1/300,000 on the basis of the number of cases tested in our laboratory and originating from France during the period 2000-2009. The prevalence of mHP was then estimated by using the proportion of dominant mutations among severe alleles and by estimating the penetrance of the disease in heterozygotes for dominant mutations. According to a genetic model with four alleles resulting in 10 distinct genotypes, the prevalence of dominant mHP in the European population was estimated to be 1/6370, pointing out that mHP is much more frequent than severe HP. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is the instructive rickets or osteomalacia caused by loss-of-function mutation(s) within TNSALP, the gene that encodes the “tissue nonspecific” isoenzyme of alkaline phosphatase (TNSALP). HPP reveals a critical role for this enzyme in skeletal mineralization. Increased extracellular levels of pyridoxal 5′-phosphate and inorganic pyrophosphate (PPi) demonstrate that TNSALP is a phosphomonoester phosphohydrolase and a pyrophosphatase that hydrolyzes much lower concentrations of natural substrates than the artificial substrates of laboratory assays. Clearly, TNSALP acts at physiological pH and “alkaline phosphatase” is a misnomer. Aberrations of vitamin B6 metabolism in HPP revealed that TNSALP is an ectoenzyme. PPi excesses cause chondrocalcinosis and sometimes arthropathy. The skeletal disease is due to PPi inhibition of hydroxyapatite crystal growth extracellularly so that crystals form within matrix vesicles but fail to enlarge after these structures rupture. Trials of alkaline phosphatase replacement therapy for HPP suggest that TNSALP functions at the level of skeletal tissues. [ABSTRACT FROM AUTHOR]

There are reports in the literature of the various dental features of hypophosphatasia, especially where it affects the deciduous dentition. The descriptions include both the manifestations of the disorder and the subsequent patterns of tooth loss. There are fewer descriptions of the effects of hypophosphatasia on the permanent dentition and little information on the subsequent prosthodontic management of these patients, particularly in relation to the use of dental implants. The aim of this paper was to review the literature on the dental effects of hypophosphatasia, present two cases and describe how one of those patients, a young adult, was successfully rehabilitated using dental implants. That latter patient’s pattern of tooth loss as well as some histological and scanning electron microscopic findings of root cementum from the other case is also described. [ABSTRACT FROM AUTHOR]

Hypophosphatasia, a congenital metabolic disease related to the tissue-nonspecific alkaline phosphatase gene (TNSALP), is characterized by reduced serum alkaline phosphatase levels and defective mineralization of hard tissues. A replacement of valine with alanine at position 406, located in the crown domain of TNSALP, was reported in a perinatal form of hypophosphatasia. To understand the molecular defect of the TNSALP (V406A) molecule, we examined this missense mutant protein in transiently transfected COS-1 cells and in stable CHO-K1 Tet-On cells. Compared with the wild-type enzyme, the mutant protein showed a markedly reduced alkaline phosphatase activity. This was not the result of defective transport and resultant degradation of TNSALP (V406A) in the endoplasmic reticulum, as the majority of newly synthesized TNSALP (V406A) was conveyed to the Golgi apparatus and incorporated into a cold detergent insoluble fraction (raft) at a rate similar to that of the wild-type TNSALP. TNSALP (V406A) consisted of a dimer, as judged by sucrose gradient centrifugation, suggestive of its proper folding and correct assembly, although this mutant showed increased susceptibility to digestion by trypsin or proteinase K. When purified as a glycosylphosphatidylinositol-anchorless soluble form, the mutant protein exhibited a remarkably lower Kcat/ Km value compared with that of the wild-type TNSALP. Interestingly, leucine and isoleucine, but not phenylalanine, were able to substitute for valine, pointing to the indispensable role of residues with a longer aliphatic side chain at position 406 of TNSALP. Taken together, this particular mutation highlights the structural importance of the crown domain with respect to the catalytic function of TNSALP. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is a rare inherited bone disease caused by mutations in the alkaline phosphatase liver-type gene (ALPL) gene, with extensive allelic heterogeneity leading to a range of clinical phenotypes. We report here a patient who died from severe lethal hypophosphatasia, who was compound heterozygous for the mutation c.1133A>T (D361V) and the newly detected missense mutation c791A>G, and whose parents were both healthy. Because the c.1133A>T (D361V) mutation was previously reported to have a dominant-negative effect and to be responsible for the uncommon perinatal benign form of the disease, we studied the expression of the ALPL gene in this family. Analysis at the messenger RNA (mRNA) level, both quantitative and qualitative, showed that the paternal c.1133A>T (D361V) mutation was associated with over-expression of the ALPL gene and that the maternal c.791A>G mutation lead to complete skipping of exon 7. The results provide an explanation of the lethal phenotype in the patient where the two ALPL alleles are non-functional and in the asymptomatic father where over-expression of the normal allele could counteract the effect of the c.1133A>T (D361V) mutation by providing an increased level of normal mRNA. This may also explain the variable expression of hypophosphatasia observed in parents of patients with the perinatal benign form. [ABSTRACT FROM AUTHOR]

The article offers information on recent advances in the diagnosis and treatment of hypophosphatasia. It states that this disease is an inborn error of mineral and bone metabolism that was first identified more than 50 years ago. Relative to this, the fifth International Alkaline Phosphatase Symposium was conducted in May 2007 in Huningue, France to further the understanding of this disease.

Structured Abstract Authors – Hu JC-C, Simmer JP The synthesis of tooth development biology with human studies focusing on inherited conditions that specifically interfere with tooth development is improving our understanding of normal and pathological tooth formation. The type of inherited dental malformations observed in a given kindred relate to when, during odontogenesis, the defective gene is critically expressed. Information about the protein encoded by the defective gene and the resulting dental phenotype helps us understand the major processes underway at different stages during tooth development. Genes affecting early tooth development ( PAX9, MSX1, and AXIN2) are associated with familial tooth agenesis or oligodontia. Genes expressed by odontoblasts ( COL1A1, COL1A2, and DSPP), and ameloblasts ( AMELX, ENAM, MMP20, and KLK4) during the crown formation stage, are associated with dentinogenesis imperfecta, dentin dysplasia, and amelogenesis imperfecta. Late genes expressed during root formation ( ALPL and DLX3) are associated with cementum agenesis (hypophosphatasia) and taurodontism. Understanding the relationships between normal tooth development and the dental pathologies associated with inherited diseases improves our ability to diagnose and treat patients suffering the manifestations of inherited dental disorders. [ABSTRACT FROM AUTHOR]

Various mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene are responsible for hypophosphatasia characterized by defective bone and tooth mineralization; however, the underlying molecular mechanisms remain largely to be elucidated. Substitution of an arginine at position 433 with a histidine [TNSALP(R433H)] or a cysteine [TNSALP(R433C)] was reported in patients diagnosed with the mild or severe form of hypophosphatasia, respectively. To define the molecular phenotype of the two TNSALP mutants, we sought to examine them in transient (COS-1) and conditional (CHO-K1 Tet-On) heterologous expression systems. In contrast to an 80 kDa mature form of the wild-type and TNSALP(R433H), a unique disulfide-bonded 160 kDa molecular species appeared on the cell surface of the cells expressing TNSALP(R433C). Sucrose density gradient centrifugation demonstrated that TNSALP(R433C) forms a disulfide-bonded dimer, instead of being noncovalently assembled like the wild-type. Of the five cysteine residues per subunit of the wild-type, only Cys102 is thought to be present in a free form. Replacement of Cys102 with serine did not affect the dimerization state of TNSALP(R433C), implying that TNSALP(R433C) forms a disulfide bridge between the cysteine residues at position 433 on each subunit. Although the cross-linking did not significantly interfere with the intracellular transport and cell surface expression of TNSALP(R433C), it strongly inhibited its alkaline phosphatase activity. This is in contrast to TNSALP(R433H), which shows enzyme activity comparable to that of the wild-type. Importantly, addition of dithiothreitol to the culture medium was found to partially reduce the amount of the cross-linked form in the cells expressing TNSALP(R433C), concomitantly with a significant increase in enzyme activity, suggesting that the cross-link between two subunits distorts the overall structure of the enzyme such that it no longer efficiently carries out its catalytic function. Increased susceptibility to proteases confirmed a gross conformational change of TNSALP(R433C) compared with the wild-type. Thus, loss of function resulting from the interchain disulfide bridge is the molecular basis for the lethal hypophosphatasia associated with TNSALP(R433C). [ABSTRACT FROM AUTHOR]

Strontium is used in the treatment of osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as isotope. At very high doses and in certain conditions, it can lead to osteomalacia characterized by impairment of bone mineralization. The osteomalacia symptoms resemble those of hypophosphatasia, a rare inherited disorder associated with mutations in the gene encoding for tissue-nonspecific alkaline phosphatase (TNAP). Human alkaline phosphatases have four metal binding sites-two for zinc, one for magnesium, and one for calcium ion-that can be substituted by strontium. Here we present the crystal structure of strontium-substituted human placental alkaline phosphatase (PLAP), a related isozyme of TNAP, in which such replacement can have important physiological implications. The structure shows that strontium substitutes the calcium ion with concomitant modification of the metal coordination. The use of the flexible and polarizable force-field TCPEp (topological and classical polarization effects for proteins) predicts that calcium or strontium has similar interaction energies at the calcium-binding site of PLAP. Since calcium helps stabilize a large area that includes loops 210-228 and 250-297, its substitution by strontium could affect the stability of this region. Energy calculations suggest that only at high doses of strontium, comparable to those found for calcium, can strontium substitute for calcium. Since osteomalacia is observed after ingestion of high doses of strontium, alkaline phosphatase is likely to be one of the targets of strontium, and thus this enzyme might be involved in this disease. [ABSTRACT FROM AUTHOR]

In the majority of hypophosphatasia patients, reductions in the serum levels of alkaline phosphatase activity are caused by various missense mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. A unique frame-shift mutation due to a deletion of T at cDNA number 1559[TNSALP (1559delT)] has been reported only in Japanese patients with high allele frequency. In this study, we examined the molecular phenotype of TNSALP (1559delT) usingin vitrotranslation/translocation system and COS-1 cells transiently expressing this mutant protein. We showed that the mutant protein not only has a larger molecular size than the wild type enzyme by≈ 12 kDa, reflecting an 80 amino acid-long extension at its C-terminus, but that it also lacks a glycosylphosphatidylinositol anchor. In support of this, alkaline phosphatase activity of the cells expressing TNSALP (1559delT) was localized at the juxtanucleus position, but not on the cell surface. However, only a limited amount of the newly synthesized protein was released into the medium and the rest was polyubiquitinated, followed by degradation in the proteasome. SDS/PAGE and analysis by sucrose-density-gradient analysis indicated that TNSALP (1559delT) forms a disulfide-bonded high-molecular-mass aggregate. Interestingly, the aggregate form of TNSALP (1559delT) exhibited a significant enzyme activity. When all three cysteines at positions of 506, 521 and 577 of TNSALP (1559delT) were replaced with serines, the aggregation disappeared and instead this modified mutant protein formed a noncovalently associated dimer, strongly indicating that these cysteine residues in the C-terminal region are solely responsible for aggregate formation by cross-linking the catalytically active dimers. Thus, complete absence of TNSALP on cell surfaces provides a plausible explanation for a severe lethal phenotype of a homozygote hypophosphatasia patient carrying TNSALP (1559delT). [ABSTRACT FROM AUTHOR]

A patient with infantile hypophosphatasia was treated with calcitonin, chlorothiazide and the bisphosphonate, sodium clodronate. She suffered progressive skeletal demineralization and died at 14 mo. We suspect that such treatment has little impact on this disease and that the outcome depends primarily on the severity of the genetic defect. [ABSTRACT FROM AUTHOR]

A kindred with dominant hypophosphatasia resulting from an alanine to threonine substitution at position 99 of the alkaline phosphatase protein is described. The clinical findings of individual members of the kindred were assessed by oral and physical examinations, or from the descriptions of multiple family members. The proband displayed enamel hypoplasia and premature loss of fully rooted primary anterior teeth, which were shown by histological examination to lack cementum. Serum alkaline phosphatase (ALP) and a vitamin B6 panel, and urine phosphoethanolamine (PEA) were measured on 21 family members. Based upon the clinical and laboratory tests, affected and unaffected status was assigned. Parametric linkage analysis of the kindred using different dominant models and frequency distributions for the disease allele and the mutation gave lodscores 44.2 and confirmed the strong linkage between the disease and the mutation. Assuming the defined mutation causes the disease, the reliability of clinical and laboratory tests is assessed. [ABSTRACT FROM AUTHOR]

A pregnant woman of 14 weeks' gestation was sonographically examined due to large-for-dates uterine size. The ultrasound examination showed poor ossification of all bony structures. All limbs were shortened with no evidence of fractures. The echodensity approximated that of the surrounding organs. No acoustic shadowing was observed. Based on these sonographic findings, skeletal dysplasia and short-limb dwarfism were diagnosed, the most likely condition being congenital hypophosphatasia. Early cordocentesis was successfully performed at 15 weeks' gestation to determine fetal alkaline phosphatase concentration. This was undetectable. The prenatal diagnosis of congenital hypophosphatasia was made. After counselling, the woman decided to opt for termination of pregnancy which was performed vaginally. Post-abortion findings confirmed the prenatal diagnosis. To our knowledge, this is the earliest sonographic diagnosis of this condition reported. [ABSTRACT FROM AUTHOR]

We report on two families in which one or two children had a severe disorder of skeletal development detected by prenatal ultrasonography. The children died postnatally and showed typical radiological and biochemical findings of perinatal hypophosphatasia. Biochemical analysis revealed a low activity of alkaline phosphatase (AP) and a high value of pyridoxal-5-phosphate (PLP), one of its natural substrates. The screening for mutations of the tissue nonspecific alkaline phosphatase (TNSALP) gene showed homozygosity for a point mutation (G 317→D) in the two affected children of the first family. The affected child of the second family was homozygous for a nonsense mutation (R 411→X). Family screening revealed that the determination of AP and PLP is helpful for detection of heterozygotes. However, heterozygote children had values of AP in the lower normal range during phases of rapid growth. The determination of PLP proved to be more sensitive in these cases. It should be kept in mind that during the last trimester of gestation there is an increase in maternal AP activity and a normalization of PLP due to placental AP, which is not affected. Therefore, in the course of a prenatal diagnosis in an index case, paternal blood should be analyzed in parallel. For detailed genetic counseling and early prenatal diagnosis in following pregnancies, the possibility of mutation analysis should be used. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HOPS) is an inherited disorder characterized by the defect of skeletal mineralization due to tissue-nonspecific alkaline phosphatase (TNSALP) deficiency. In this study we analyzed the TNSALP gene from a Japanese patient with HOPS, his parents, his brother, and unstated normal controls. The proband is a 25-year-old Japanese male diagnosed with childhood hypophosphatasia. The patient reported premature exfoliation of the deciduous teeth and severe periodontal destruction of the permanent dentition. Genomic DNA was extracted from peripheral leukocytes of subjects. Eleven pairs of the polymerase chain reaction (PCR) primers were used to amplify the coding exons according to the published sequence data of the TNSALP gene. The PCR amplified samples were subjected to PCR-single strand conformation polymorphism (SSCP) analysis and PCR-allele specific oligonucleotide (ASO) analysts, in PCR-SSCP analysis of the patient's genomic DNA, the fragments containing exons 9 and 10 revealed abnormal mobilities. These abnormal mobilities (exons 9 and 10) were also found from his mother and father's genomic DNA, respectively. The sequencing analysis of the abnormal bands extracted from the SSCP gel showed a T to C transition at nucleotide position 1155 (T1155C) in exon 9 and G1320A in exon 10. PCR-ASO analysis confirmed these missense point mutations. PCR-ASO analysis also confirmed that mutation-specific oligonucleotides corresponded to the new mutations and did not hybridize with PCR products from normal control genomic DNAs. These results indicated that the proband was a compound heterozygote who inherited T1155C mutation in exon 9 from the mother and G1320A mutation in exon 10 from the father. Both of them are new missense point mutations and appear to cause significant changes in the structure and function of TNSALP. [ABSTRACT FROM AUTHOR]

In the present retrospective study different dental and medical parameters have been analyzed in 17 Swedish children with established hypophosphatasia (HP). It was demonstrated that the basis for the establishment of the diagnosis varied among different dentists and physicians, and that the diagnostic parameters studied among the children varied. The most reliable parameters for HP included raised levels of phosphoethanolamine in urine, and clinical and radiologic findings associated with the legs. These findings were found among the children more often than lowered values of alkaline phosphatase in serum. Histologic analysis of an extracted both made a valuable diagnostic complement. It is concluded that a better diagnostic uniformity is recommended. In a well functioning collaboration with well defined tasks, both dentists and physicians can contribute to a reliable diagnosis. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is an inherited disorder characterized by defective mineralization of the skeletal and dental structures of the body and deficient liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. There has been a tremendous advance in our knowledge of this condition over the last decade due to the advent of highly specific DNA probes and novel microanalytic techniques. The purpose of this paper is threefold: to review the dental aspects of current literature about this rare condition; to present a case (and family study) that was diagnosed in a 5-yr-old boy from 0.14 microliters of gingival crevicular fluid, using a new ultrasensitive chemiluminescent assay for the enzyme alkaline phosphatase; and to provide strong evidence for an autosomal dominant mode of inheritance. [ABSTRACT FROM AUTHOR]

The changes in a permanent central incisor of a patient suffering from hypophosphatasia, were investigated light microscopically and compared with those of two of his primary teeth. In addition his other central incisor was studied with transmission and scanning EM. The changes in permanent teeth were similar to those of the primary dentition, including loss of cementum and the presence of deep resorption areas in dentin. Afibrillar cementum was detected with EM, and was attached to dentin surface. The presence of a thick layer of bacterial plaque was a prominent feature in all the teeth examined. A large number of bacteria was also found in resorption bays. It is suggested that bacteria may play an important role in the destruction of soft and hard tissues leading to loss of teeth in hypophosphatasia. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is a rare inherited disease, the 1st clinical sign of which is often a premature loss of deciduous teeth. We describe clinical, histological and SEM findings of 2 cases of hypophosphatasia from a single family and discuss the pathological mechanisms with reference to the literature. [ABSTRACT FROM AUTHOR]

Hypophosphatasia is rare enzymopathy that normally presents within the first few years of life and often has profound effects upon the periodontium. It is a heritable disorder characterised by defective mineralisation of the skeletal and dental structures of the body and a deficiency in the liver/bone/kidney (L/B/K) isoenzyme of alkaline phosphatase (ALP). There has been a tremendous advance in our knowledge of this condition over the last decade due to the advent of highly specific DNA probes and novel microanalytical techniques. This paper aims to review current literature about hypophosphatasia with special reference to the dental aspects of the condition and to shed light upon the controversial area of its mode of genetic inheritance. It is concluded that hypophosphatasia may result from the existence of 2 defective alleles, which alone or in combination may cause the condition. One allele is expressed in an autosomal dominant mariner producing milder phenotypic characteristics, whilst the other is expressed in an autosomal recessive manner producing the more severe clinical form that often results in neonatal death. The milder phenotypes may go undiagnosed and the consequence of this in genetic counselling terms is extremely important. [ABSTRACT FROM AUTHOR]

In a previous publication, we described the clinical and radiographic findings of a family in which the children manifested premature exfoliation of the deciduous teeth. We now report for the same family the results of extensive laboratory studies performed on blood and urine, analysis of periodontal microflora, and a family pedigree. We demonstrated the presence of putative periodontal pathogens in the subgingival microflora, elevated levels of serum antibodies reacting to Bacteroides gingivalis, Capnocytophaga gingivalis, and C. sputigena in 2 of the children, and significantly suppressed monocyte chemotaxis in all 3 children. Phosphoethanolamine was found in the urine of the father and all 3 children, but not in the mother. Likewise, serum alkaline phosphatase was abnormally low for all 3 children, and was at the extreme low end of normal range for the father, but was normal for the mother. On the basis of the alkaline phosphatase and phosphoethanolamine measurements, we assigned a diagnosis of hypophosphatasia to the 3 children, Phosphoethanolamine and alkaline phosphatase were also abnormal in the paternal grandmother and her brother. The son of this brother who was deceased had a daughter manifesting premature loss of the primary teeth. The data are consistent with an autosomal dominant mode of transmission. In the light of our findings, hypoplastic cementum must be considered in the etiology of some forms of early-onset periodontitis. [ABSTRACT FROM AUTHOR]

Reports on dental abnormalities in connection with hypophosphatasia almost exclusively describe changes in primary teeth. A 23-year-old man with hypophosphatasia, first diagnosed at the age of 8 months, is described; histologically and radiographically verified signs of the condition were present in the permanent dentition. The findings included a reduced level of the marginal alveolar bone supporting the upper central incisors, which had to be extracted. The molars displayed large coronal pulp chambers. Histologically, the upper incisors demonstrated abnormal root cementum, with areas of dentin resorption, as well as disturbances of the mineralization of the coronal dentin. The patient also had signs of abnormal root resorption of molars. The potential involvement of permanent teeth puts children with hypophosphatasia at risk of developing oral complications during adolescent and adult life. [ABSTRACT FROM AUTHOR]

The article discusses the effects of retinoic acid on alkaline phosphatase activity (ALP) and tissue-non-specific alkaline phosphatase gene expression in human periodontal ligament cells and gingival fibroblasts. Topics discussed include patients with hypophosphatasia; the human periodontal ligament cells; and the ALP activity in osteoblastic and fibroblastic cells.