Hypophosphatasia in Adults: Clinical Spectrum and Its Association With Genetics and Metabolic Substrates.

BACKGROUND: Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium. METHODOLOGY: Adults with HPP were identified through medical record review. Inclusion criteria were: (1) age ≥ 16 yr; (2) consecutively low ALP levels not explained by secondary causes; (3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation. RESULTS: Nineteen patients met our inclusion criteria (n = 2 infantile, n = 6 childhood, n = 10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n = 7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N = 7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p = 0.013) and significantly higher pyridoxal-5'-phosphate (p = 0.0018) and urinary phosphoethanolamine (p = 0.0001) concentrations. CONCLUSIONS: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.

Low serum alkaline phosphatase activity due to asymptomatic hypophosphatasia in a teenage girl.

OBJECTIVE: The case report details an unusual presentation of a teenage patient with hypophosphatasia. PATIENT AND METHODS: A 17 year-old female patient presented to endocrinology for the evaluation of fatigue and possible adrenal insufficiency. In the course of her clinical evaluation she was noted to have a low serum alkaline phosphatase activity. Relatively few conditions are associated with a low serum alkaline phosphatase including Wilson's disease, hypophosphatasia, pernicious anemia and untreated hypothyroidism. RESULTS: Laboratory testing for hypothyroidism were unrevealing, as were the results for vitamin B12 and vitamin D. Testing for Wilson's disease revealed a ceruloplasmin concentration of 165 mg/L (Reference Interval, 160-450 mg/L), however sequencing of the ATP7B gene revealed no deleterious mutations. Measurement of serum pyridoxal phosphate and urine phosphoethanolamine for the diagnosis of hypophosphatasia revealed concentrations of 541.5 nmol/L (reference interval: 29.6-295.5) and 707 mmol/mol creatinine (reference interval: <778 mmol/mol creatinine), respectively, consistent with a diagnosis of hypophosphatasia. CONCLUSIONS: Hypophosphatasia was initially considered an unlikely diagnosis for this patient given her lack of characteristic skeletal abnormalities. This diagnosis of hypophosphatasia in this case was complicated by a serum ceruloplasmin concentration at the lower end of the reference interval leading to the genetic testing for Wilson's disease.

Asfotase alfa treatment for 1 year in a 16 year-old male with severe childhood hypophosphatasia.

We describe the clinical outcome of asfotase alfa therapy in a 16-year-old boy with severe childhood hypophosphatasia (HPP), who began therapy at age 15 years. The patient was diagnosed with HPP at age 2 years when he presented with genu varum and premature loss of primary teeth. He had a history of multiple fractures requiring 16 orthopedic surgeries with rod and pin placement in his lower extremities. He had chronic skeletal pain and used cane to ambulate with great difficulty. His height Z score at age 15 years was - 5. He had severe scoliosis and deformity of both legs. Bone radiograph showed hypomineralization and characteristic "tongues" of radiolucency in the distal radius and ulna. His serum alkaline phosphatase level was stable, with elevated serum pyridoxal 5'-phosphate and urine phosphoethanolamine, consistent with HPP. He was started on asfotase alfa 2 mg/kg given subcutaneously thrice weekly. He had marked clinical improvement in mobility with no report of pain after 3 months of treatment. At 6 month, he walked without cane and participated in outdoor activities with peers. Bone radiograph at 6 months showed striking improvement in previous radiolucent areas. At 9 months, his annualized growth velocity was 9.5 cm/year, while growth velocity of arm span was 12 cm/year. However, at 12 months, he was noted to have worsening scoliosis from 60 degrees before therapy to 110 degrees, with a slight decrease in height, necessitating a spinal fusion surgery. In conclusion, treatment with asfotase alfa significantly improved physical function, pain, overall quality of life, and skeletal radiographic findings in this patient. Close monitoring for progression of scoliosis in adolescents with HPP treated with asfotase alfa is recommended.

Dental Manifestations of Pediatric Bone Disorders.

PURPOSE OF REVIEW: Several bone disorders affecting the skeleton often are manifest in the maxillofacial region. This review presents the most common bone disorders in children and their dental-oral manifestations: fibrous dysplasia, Paget's disease, osteogenesis imperfecta, renal osteodystrophy, hypophosphatasia, and osteoporosis. The specific intraoral characteristics will reviewed in detail. RECENT FINDINGS: Recent studies confirmed the close relationship between the mandible and the maxilla with the most prevalent systemic bone disorders in children. This review will help practitioners to integrate the oral health into the systemic health and improve the multidisciplinary approach of pediatric patients between medicine and dentistry.

Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys.

BACKGROUND: Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutation(s) in the tissue-nonspecific alkaline (TNSALP) phosphatase gene, which manifests as rickets and/or osteomalacia with systemic complications and affects patients of all ages. The burden of disease is poorly characterized in adult patients. AIMS: We assessed patient-reported burden of disease using two surveys reasonably specific for HPP symptomatology, the Hypophosphatasia Impact Patient Survey (HIPS) and the Hypophosphatasia Outcomes Study Telephone interview (HOST). METHODS: Patients with HPP were invited to participate via patient advocacy groups or their medical provider. Survey questions captured demography, HPP-related medical history, mobility, and health-related quality of life (using Short Form 12 [version 2] Health Survey [SF-12v2]) via internet report (HIPS) or telephone interview (HOST). RESULTS: One hundred twenty-five adults responded (mean [standard deviation, SD] age: 45 [14.3] years). Eighty-four patients (67%) reported pediatric-onset of their symptoms. Common clinical features in the study population included pain (95% of patients), fractures (86% of patients) muscle weakness (62%) and unusual gait (52%). Use of assistive devices for mobility (60%) was also prevalent. Twenty-six percent of patients reported more than 10 fractures. Seventy-four percent of patients had undergone orthopedic/dental surgical procedures. The health profile of patients responding on the SF-12 showed a broad and substantial impact of HPP on health-related quality of life, with domains related to physical ability showing the greatest decrement compared to normative data. CONCLUSIONS: In aggregate, these data indicate that HPP can confer a high burden of illness in adulthood.

Hypophosphatasia: Natural history study of 101 affected children investigated at one research center.

Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Resultant extracellular accumulation of inorganic pyrophosphate, a TNSALP substrate and potent inhibitor of mineralization, typically leads to tooth loss and sometimes to rickets or osteomalacia. HPP's remarkably broad-ranging severity is largely explained by autosomal dominant versus autosomal recessive transmission from among several hundred usually missense mutations positioned throughout the gene that encodes TNSALP. In 2015, our cross-sectional investigation of 173 affected children validated and expanded the clinical nosology commonly used for pediatric HPP. Herein, for the 101 patients in that cohort with longitudinal data, we explored the natural history of pediatric HPP by assessing their z-scores for height and then for weight, grip strength, and bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DXA) also after adjusting for patient height. Eighteen patients contributed to "across" puberty evaluation. According to increasing HPP severity, there were 28 odonto HPP, 28 mild childhood HPP, 37 severe childhood HPP, and 8 infantile HPP patients typically studied from early to mid-childhood. The individual values for each parameter were wide-ranging within, and overlapping between, the four successive patient groups. Final mean/median z-scores, like the published initial values, paralleled the nosology. Longitudinal findings were similar for the boys versus girls and across puberty. Mean/median height z-scores remained constant for all four patient groups. In contrast, mean/median weight z-scores increased with aging, including after height-adjustment, resembling the recent trend for American children. However, excessive weight gain was typically not observed and mean/median values became average for height. Mean/median z-scores calculated routinely for chronologic age did not change for grip strength or for lumbar spine or total hip BMD. However, height-correction of the cohort suggested some worsening of grip strength z-scores and indicated improvement in spine BMD z-scores. Overall, in affected children and adolescents, HPP represents a clinically stable but chronic disorder.

Physical therapy management of infants and children with hypophosphatasia.

Hypophosphatasia (HPP) is a rare inborn error of metabolism resulting in undermineralization of bone and subsequent skeletal abnormalities. The natural history of HPP is characterized by rickets and osteomalacia, increased propensity for bone fracture, early loss of teeth in childhood, and muscle weakness. There is a wide heterogeneity in disease presentation, and the functional impact of the disease can vary from perinatal death to gait abnormalities. Recent clinical trials of enzyme replacement therapy have begun to offer an opportunity for improvement in survival and function. The role of physical therapy in the treatment of the underlying musculoskeletal dysfunction in HPP is underrecognized. It is important for physical therapists to understand the disease characteristics of the natural history of a rare disease like HPP and how the impairment and activity limitations may change in response to medical interventions. An understanding of when and how to intervene is also important in order to optimally impact body function, lessen structural impairment, and facilitate increased functional independence in mobility and activities of daily living. Individualizing treatment to the child's needs, medical fragility, and setting (home/school/hospital), while educating parents, caregivers, and school staff regarding approved activities and therapy frequency, may improve function and development in children with HPP.

Neurodevelopmental alterations and seizures developed by mouse model of infantile hypophosphatasia are associated with purinergic signalling deregulation.

Hypomorphic mutations in the gene encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme, ALPL in human or Akp2 in mice, cause hypophosphatasia (HPP), an inherited metabolic bone disease also characterized by spontaneous seizures. Initially, these seizures were attributed to the impairment of GABAergic neurotransmission caused by altered vitamin B6 (vit-B6) metabolism. However, clinical cases in human newborns and adults whose convulsions are refractory to pro-GABAergic drugs but controlled by the vit-B6 administration, suggest that other factors are involved. Here, to evaluate whether neurodevelopmental alterations are underlying the seizures associated to HPP, we performed morphological and functional characterization of postnatal homozygous TNAP null mice, a model of HPP. These analyses revealed that TNAP deficient mice present an increased proliferation of neural precursors, an altered neuronal morphology, and an augmented neuronal activity. We found that these alterations were associated with a partial downregulation of the purinergic P2X7 receptor (P2X7R). Even though deficient P2X7R mice present similar neurodevelopmental alterations, they do not develop neonatal seizures. Accordingly, we found that the additional blockage of P2X7R prevent convulsions and extend the lifespan of mice lacking TNAP. In agreement with these findings, we also found that exogenous administration of ATP or TNAP antagonists induced seizures in adult wild-type mice by activating P2X7R. Finally, our results also indicate that the anticonvulsive effects attributed to vit-B6 may be due to its capacity to block P2X7R. Altogether, these findings suggest that the purinergic signalling regulates the neurodevelopmental alteration and the neonatal seizures associated to HPP.

Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment.

Hypophosphatasia is the inborn error of metabolism characterized by low serum alkaline phosphatase activity (hypophosphatasaemia). This biochemical hallmark reflects loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, extracellular accumulation of TNSALP natural substrates includes inorganic pyrophosphate, an inhibitor of mineralization, which explains the dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Severely affected infants sometimes also have hypercalcaemia and hyperphosphataemia due to the blocked entry of minerals into the skeleton, and pyridoxine-dependent seizures from insufficient extracellular hydrolysis of pyridoxal 5'-phosphate, the major circulating form of vitamin B6, required for neurotransmitter synthesis. Autosomal recessive or dominant inheritance from ~300 predominantly missense ALPL (also known as TNSALP) mutations largely accounts for the remarkably broad-ranging expressivity of hypophosphatasia. High serum concentrations of pyridoxal 5'-phosphate represent a sensitive and specific biochemical marker for hypophosphatasia. Also, phosphoethanolamine levels are usually elevated in serum and urine, though less reliably for diagnosis. TNSALP mutation detection is important for recurrence risk assessment and prenatal diagnosis. Diagnosing paediatric hypophosphatasia is aided by pathognomic radiographic changes when the skeletal disease is severe. Hypophosphatasia was the last type of rickets or osteomalacia to await a medical treatment. Now, significant successes for severely affected paediatric patients are recognized using asfotase alfa, a bone-targeted recombinant TNSALP.

Osteomalacia with low alkaline phosphatase: a not so rare condition with important consequences.

Hypophosphatasia is a genetic disorder, characterised by a dysfunctional tissue-non-specific isoenzyme of alkaline phosphatase that impacts bone metabolism and predisposes to osteomalacia or rickets. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease. Several forms of hypophosphatasia are recognised. We present a case of a 50-year-old woman with low impact fractures and loss of teeth at a young age. She also had a low alkaline phosphatase and was diagnosed with adult hypophosphatasia. Although the severe forms of hypophosphatasia are rather rare, the adult form is thought to occur quite frequently. As this condition is not well known by healthcare professionals, the time to diagnosis and initiation of adequate treatment is often postponed. When encountering a patient with low alkaline phosphatase, low bone density or a history of bone fractures, the possibility of hypophosphatasia should be considered.

Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing.

Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients.

Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) within the gene TNSALP that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). In HPP, inorganic pyrophosphate, an inhibitor of mineralization and substrate for TNSALP, accumulates extracellularly often leading to rickets or osteomalacia and tooth loss, and sometimes to craniosynostosis and calcium crystal arthropathies. HPP's remarkably broad-ranging expressivity spans stillbirth from profound skeletal hypomineralization to adult-onset dental problems or arthropathies without bone disease, which is largely explained by autosomal recessive versus autosomal dominant transmission from among several hundred, usually missense, TNSALP mutations. For clinical purposes, this expressivity has been codified according to absence or presence of skeletal disease and then patient age at presentation and diagnosis. Pediatric patients are reported principally with "odonto", "childhood", "infantile", or "perinatal" HPP. However, this nosology has not been tested using a cohort of patients, and the ranges of the clinical and laboratory findings have not been defined and contrasted among these patient groups. To evaluate the extant nosology for HPP in children, we assessed our 25 years experience with 173 pediatric HPP patients. Data were exclusively from inpatient studies. The childhood form of HPP was further designated "mild" or "severe". Here, we focused on demographic, clinical, and dual-energy X-ray absorptiometry parameters compared to data from healthy American children. The 173-patient cohort comprised 64 individuals with odonto HPP, 38 with mild childhood HPP, 58 with severe childhood HPP, and 13 with infantile HPP. None was a survivor of perinatal HPP. TNSALP analysis revealed a mutation(s) in all 105 probands tested. Thirteen mutations were unique. Most patients represented autosomal dominant inheritance of HPP. Mutant allele dosage generally indicated the disorder's severity. Gender discordance was found for severe childhood HPP; 42 boys versus 16 girls (p=0.006), perhaps reflecting parental concern about stature and strength. Key disease parameters (e.g., height, weight, numbers of teeth lost prematurely, grip strength, spine and hip bone mineral density) were increasingly compromised as HPP was designated more severe. Although data overlapped successively between the four patient groups, body size (height and weight) differed significantly. Thus, our expanded nosology for HPP in children organizes the disorder's broad-ranging expressivity and should improve understanding of HPP presentation, natural history, complications, and prognosis.

Calcific periarthritis as the only clinical manifestation of hypophosphatasia in middle-aged sisters.

Hypophosphatasia (HPP) is the inborn error of metabolism that features low serum alkaline phosphatase (ALP) activity caused by loss-of-function mutation(s) within the gene for the tissue nonspecific isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate (PPi), a TNSALP substrate and inhibitor of mineralization, leads frequently to premature tooth loss and often to rickets or osteomalacia. In affected adults, the excess PPi sometimes also causes calcium pyrophosphate dihydrate (CPPD) deposition, PPi arthropathy, or pseudogout, or seemingly paradoxical deposition of hydroxyapatite crystals in ligaments or around joints when the condition is called calcific periarthritis (CP). We report three middle-aged sisters with CP as the only clinical manifestation of HPP. Each presented during early adult life with recurrent episodes of pain principally around the shoulders, elbows, wrists, hips, or Achilles tendon. Otherwise, they were in good health, including no history of unusual dental disease, fractures, or pseudofractures. Calcific deposits were identified in symptomatic areas principally by ultrasonographic assessment but also confirmed radiographically. All three sisters had low serum levels of total and bone-specific ALP, hyperphosphatemia, and increased serum concentrations of the TNSALP substrate pyridoxal 5'-phosphate together characteristic of HPP. Mutation analysis revealed that each carried a single unique 18-bp duplication within TNSALP (c.188_205dup18, p.Gly63_Thr68dup) as did two of their healthy sons and their mother, who was without signs of CPPD deposition or CP but had knee osteoarthritis. We find that CP can be the only complication of HPP in adults. Thus, multiple juxta-articular deposits of hydroxyapatite causing CP may be a useful sign of HPP, especially when the CP is familial.

Acute severe hypercalcemia after traumatic fractures and immobilization in hypophosphatasia complicated by chronic renal failure.

CONTEXT: Hypophosphatasia (HPP) features deficient activity of the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP) due to loss-of-function mutation(s) within the TNSALP gene. Consequently, inorganic pyrophosphate, a TNSALP substrate and inhibitor of mineralization, accumulates extracellularly. This can cause rickets or osteomalacia. OBJECTIVE: We report a 55-year-old man with HPP and chronic renal failure (CRF) requiring hemodialysis who developed severe hypercalcemia acutely after traumatic fractures and immobilization. He manifested HPP in childhood and in middle age received hemodialysis for CRF attributed to hypertension and anti-inflammatory medication. He took 2 g of calcium carbonate orally each day to bind dietary phosphorus, but never aluminum hydroxide or any form of vitamin D. Pretrauma serum levels of calcium spanned 8.4-10.7 mg/dL (normal [Nl], 8.6-10.3), inorganic phosphate 5.8-6.4 mg/dL (Nl, 2.5-4.5), and PTH 63-75 pg/mL (Nl, 10-55). RESULTS: Rapid succession falls fractured multiple major bones. Six hours later, he became confused. Serum calcium was 14.9 mg/dL, ionized calcium was 7.4 mg/dL (Nl, 4.5-5.1), and PTH was 16 pg/mL. Hemodialysis quickly corrected his hypercalcemia and confusion. Low serum alkaline phosphatase persisted, and follow-up skeletal histopathology showed that his osteomalacia was severe. CONCLUSION: Hemodialysis does not heal the skeletal disease of HPP. During sudden fracture immobilization in HPP, sufficient calcium can emerge from bone, perhaps from a rapidly exchangeable calcium pool, to cause acute severe hypercalcemia if the kidneys cannot compensate for the mineral efflux. Hence, we worry that acute hypercalcemia might accompany sudden immobilization in CRF patients without HPP if they have adynamic bone disease.

Tooth root dentin mineralization defects in a mouse model of hypophosphatasia.

Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PP(i) ), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PP(i) , resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in Alpl(-/-) mice, a model for infantile HPP. In Alpl(-/-) mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in Alpl(-/-) mice. TNAP was found to be highly expressed by mature odontoblasts, and Alpl(-/-) molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in Alpl(-/-) dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in Alpl(-/-) mice, was present in the generally unmineralized Alpl(-/-) mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in Alpl(-/-) mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to Alpl(-/-) mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PP(i) during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients.

[Genetic basis for skeletal disease. Clinical characteristics of hypophosphatasia and its treatment].

Hypophosphatsia is caused by the defect of tissue-nonspecific alkaline phosphatase (ALP), and exhibits hypomineralization of skeleton and rachitic change of bone. The most severe form of hypophosphatasia is a perinatal form, which is also called a lethal form. However, some patients of this form can survive due to advances in neonatology. Other forms consist of infantile, childhood, adult and odonto types. Conventional therapies for hypophosphatasia are administration of vitamin B6 for convulsion and low calcium-containing milk for hypercalcemia. Bone marrow transplantation has been reported to treat several patients with hypophosphatasia. However, the method must be developed which improves the survival of donor mesenchymal cells in patients. Recombinant bone-targeted ALP therapy is now on clinical trial in Canada and U.S.A and expected to be available in near future.

Systemic disorders and their influence on the development of dental hard tissues: a literature review.

OBJECTIVES: This report highlights the influence of a number of disorders with systemic physiological effects that impact on the development of dental hard tissues. It focuses in particular, on the pathological effects of systemic conditions with less well recognised, but no less important, impacts on dental development. Such conditions, include cystic fibrosis, HIV/AIDS, leukaemia, Alstrom syndrome, hypophosphatasia, Prader-Willi syndrome, Tricho-dento-osseous syndrome, tuberous sclerosis, familial steroid dehydrogenase deficiency and epidermolysis bullosa. These, along with developmental and environmental causes of enamel and dentine defects, are discussed and the possible aetiology of such effects are proposed. Furthermore, the dental management and long-term dental care of these patients is outlined. SOURCES: MEDLINE/PubMed. CONCLUSIONS: Enamel and dentine defects can present with a wide spectrum of clinical features and may be caused by a variety of factors occurring throughout tooth development from before birth to adulthood. These may include host traits, genetic factors, immunological responses to cariogenic bacteria, saliva composition, environmental and behavioural factors and systemic diseases. These diseases and their spectrum of clinical manifestations on the organs affected (including the dentition) require an increased knowledge by dental practitioners of the disease processes, aetiology, relevant treatment strategies and prognosis, and must encompass more than simply the management of the dental requirements of the patient. It is important that the impact of the disease and its treatment, particularly in respect of immunosuppression where dental interventions may become life-threatening, is also taken into consideration.

New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia.

Mesenchymal stem cells (MSCs) can show osteogenic differentiation capability when implanted in vivo, as well as cultured in vitro; therefore we attempted to use allogeneic MSCs for an 8-month-old patient with hypophosphatasia. MSCs were obtained by culture expansion of fresh marrow from the patient's father. Some of the MSCs were further cultured under osteogenic conditions on a culture dish or porous hydroxyapatite ceramics, resulting in cultured osteoblasts and osteogenic constructs, respectively. The MSCs and osteoblasts were injected into the patient, and the constructs were implanted locally. After traditional bone marrow transplantation, the MSCs, osteoblasts, and osteogenic constructs were used for treatment and to improve the patient's respiratory condition and skeletal abnormality. The condition worsened again, and an MSC booster shot was administered. At the same time, the construct was retrieved. The respiratory condition improved, and the retrieved construct showed de novo bone derived from both donor and patient cells. We demonstrated the importance of allogeneic MSC transplantation for hypophosphatasia and the constructs as an alternative to bone fragments that provided further osteogenic capability in the patient.

Orodental phenotype and genotype findings in all subtypes of hypophosphatasia.

BACKGROUND: Hypophosphatasia (HP) is a rare inherited disorder characterized by a wide spectrum of defects in mineralized tissues and caused by deficiency in the tissue non-specific alkaline phosphatase gene (ALPL). The symptoms are highly variable in their clinical expression, and relate to numerous mutations in this gene. The first clinical sign of the disease is often a premature loss of deciduous teeth, mostly in the moderate forms. AIM: The purpose of this study was to document the oral features of HP patients and to relate theses features to the six recognized forms of HP in 5 patients with known genotype and to investigate the genotype-phenotype correlations. METHODS: Clinical and radiographic examinations were carried out. We collected medical and dental history in the kindred and biochemical data. Finally, mutations in the ALPL gene were tested by DNA sequencing in SESEP laboratory. RESULTS: We have for the first time related the known dental anomalies which occur as integral features of HP to the recognized clinical forms of HP. We also pointed out striking dental abnormalities which were never described in association with this rare disease. Accurate genotype-phenotype severity correlations were observed. CONCLUSION: This work allowed us to compare orodental manifestations in all the clinical forms of HP within the patient's sample. According to the severity of the disorder, some dental defects were infrequent, while other were always present. The long term prognosis of the permanent teeth varies from a patient to another. As premature loss of primary teeth is often the first, and sometimes the only visible symptom of the milder forms, the paediatric dentist plays a critical role in the detection and diagnosis of the disease.

Case report: multiple fractures in a patient with mutations of TWIST1 and TNSALP.

Hypophosphatasia is a rare inherited disorder characterized by defective skeletal mineralization and low alkaline phosphatase activities in the serum. The genetic cause of hypophosphatasia is believed related to inactivating mutations in the TNSALP gene, encoding tissue-nonspecific alkaline phosphatase. Another rare inheritable disease, Saethre-Chotzen syndrome, leads to premature fusion of the cranial sutures caused by heterozygous mutations of the human TWIST1 gene. Because the two disorders apparently are not genetically related (only reported individually) yet both involve defective skeletal formation, we believe it is important to report our findings on a patient harboring mutations of TNSALP and TWIST1.