RESUMO
Hypophosphatasia (HPP) is an inherited disease caused by a low activity of tissue-nonspecific alkaline phosphatase, a hydrolase that removes phosphate groups from many molecules. Decreased alkaline phosphatase activity leads to the accumulation of three main metabolites, i.e., pyridoxal 5´-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine. Impairment in PLP dephosphorylation induces seizures, while PPi accumulation inhibits bone mineralization. Clinically, HPP has a wide spectrum of presentations, ranging from neonatal death to an apparent lack of symptoms. This disease is classified into six subtypes according to the age at onset of first signs or symptoms. The clinical manifestations of the disease include rickets-like bone changes, bone demineralization, fragility fractures, reduced muscular strength, chest deformity, pulmonary hypoplasia, nephrolithiasis, nephrocalcinosis, and chondrocalcinosis. Treatment of HPP consists of enzyme replacement therapy. Before this therapy was approved, treatment was palliative and associated with high morbidity and mortality. Asfotase alfa has changed the prognosis of the disease by reducing bone deformity and improving bone mineralization, lung function, and muscle weakness, among other benefits. In adults, teriparatide and anti-sclerostin antibody have been used off-label in selected cases, demonstrating benefit in accelerating fracture healing and in concomitant treatment of osteoporosis. This review summarizes the main aspects of HPP and identifies the particularities of the disease in adult patients.
Assuntos
Hipofosfatasia , Osteoporose , Adulto , Recém-Nascido , Humanos , Fosfatase Alcalina/metabolismo , Hipofosfatasia/terapia , Hipofosfatasia/tratamento farmacológico , Osteoporose/tratamento farmacológico , Terapia de Reposição de EnzimasRESUMO
OBJECTIVE: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. STUDY DESIGN: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6-dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator-free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life. RESULTS: Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6-dependent seizures and respiratory distress and failure were associated significantly (P < .05) with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4] U/L) was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator-free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. CONCLUSIONS: Patients with perinatal or infantile hypophosphatasia and vitamin B6-dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01419028.
Assuntos
Fosfatase Alcalina/sangue , Causas de Morte , Terapia de Reposição de Enzimas/métodos , Hipofosfatasia/mortalidade , Hipofosfatasia/terapia , Fosfatase Alcalina/uso terapêutico , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Terapia de Reposição de Enzimas/mortalidade , Feminino , Seguimentos , Humanos , Hipofosfatasia/sangue , Hipofosfatasia/diagnóstico , Lactente , Internacionalidade , Estimativa de Kaplan-Meier , Masculino , Gravidez , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de TempoRESUMO
La hipofosfatasia (HP) es una enfermedad congénita, causada por mutaciones con pérdida de función en el gen ALPL que codifica la isoenzima no específica de tejido de la fosfatasa alcalina (TNSALP). Su expresión clínica es muy variable, desde casos de muerte intraútero por alteración grave de la mineralización ósea, hasta casos solo con caída prematura de la dentición. Se presenta el caso clínico de un varón al que se le diagnosticó odontohipofosfatasia a los 30 meses por pérdida temprana de piezas dentarias y niveles anormalmente bajos de fosfatasa alcalina, sin signos de raquitismo ni deformidades óseas. Durante su seguimiento, hasta los 13 años, presentó síntomas compatibles con HP infantil leve, como cansancio al caminar, incoordinación en la marcha y dolor en miembros inferiores que aumentaban con la actividad física. Ante la aparición de edema bimaleolar y poca respuesta al tratamiento con calcitonina y antiinflamatorios, se descartaron patologías infecciosas o reumáticas o ambas y se diagnosticó, por biopsia de tibia y peroné, periostitis sin detección de cristales de pirofosfato. Los controles radiológicos durante su evolución mostraron ensanchamiento metafisario en muñeca, falta de remodelado de metacarpianos, hojaldrado perióstico en tibia y peroné e hipomineralización en metáfisis tibiales, con "lenguas radiolúcidas" características de HP. Como conclusión, la hipofosfatasia debe considerarse como una entidad clínica para descartar en niños que presentan pérdida temprana de dientes. La presencia de este cuadro clínico es en general suficiente para realizar el diagnóstico de HP de la niñez. (AU)
Hypophosphatasia (HP) is a congenital disease, caused by mutations with loss of function in the gene ALPL that encodes the non-specific tissue isoenzyme of alkaline phosphatase (TNSALP). Its clinical expression displays considerable variability, from cases of intrauterine death due to severe alteration of bone mineralization, to cases with only early loss of teeth. We report the case of a male, diagnosed as odontohypophosphatasia at 30 months of age due to early loss of teeth and abnormally low levels of alkaline phosphatase, without signs of rickets or bone deformities. During follow-up, up to 13 years of age, he presented symptoms consistent with mild infantile HP such as tiredness when walking, lack of gait coordination, and pain in lower limbs, especially after physical activity. Due to the appearance of bimalleolar edema and poor response to treatment with calcitonin and anti-inflammatory drugs, infectious and / or rheumatic pathologies were ruled out. Periostitis without pyrophosphate crystal detection was diagnosed by tibial and fibular biopsy. Radiological controls during follow up showed metaphyseal wrist enlargement, lack of remodeling of metacarpals, periosteal flaking in the tibia and fibula and hypomineralization in the tibial metaphysis, with "radiolucent tongues"; characteristic of HP. In conclusion, hypophosphatasia should be considered as a clinical entity in children who present early loss of teeth. The presentation of this clinical case is generally sufficient to make the diagnosis of childhood HP. (AU)
Assuntos
Humanos , Masculino , Pré-Escolar , Criança , Adolescente , Fosfatase Alcalina/genética , Hipofosfatasia/diagnóstico , Periostite/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Fluoreto de Sódio/administração & dosagem , Tíbia/diagnóstico por imagem , Anormalidades Dentárias/genética , Complexo Vitamínico B/uso terapêutico , Calcitonina/administração & dosagem , Carbamazepina/uso terapêutico , Fosfatase Alcalina/sangue , Fíbula/diagnóstico por imagem , Hidroxicolecalciferóis/efeitos adversos , Hipofosfatasia/patologia , Hipofosfatasia/sangue , Hipofosfatasia/terapia , Sulfato de Magnésio/uso terapêutico , Anti-Inflamatórios/uso terapêuticoRESUMO
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.
Assuntos
Hipofosfatasia/terapia , Transplante de Células-Tronco Mesenquimais , Osteogênese , Fosfatase Alcalina/sangue , Densidade Óssea , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Hipofosfatasia/metabolismo , Hipofosfatasia/fisiopatologia , Lactente , Infusões Intraósseas , Infusões Intravenosas , Osteoblastos/transplante , Respiração Artificial , Engenharia Tecidual , Transplante HomólogoRESUMO
OBJETIVO: Relatar uma série de casos de hiperfosfatasemia transitória benigna da infância (HTBI). DESCRIÇÃO: São descritas quatro meninas. A faixa etária variou de 11-45 meses (mediana: 13 meses). Ao diagnóstico, a fosfatase alcalina sérica estava aumentada de 1,1-6,1 vezes (mediana: 1,36 vezes) o valor de referência. O retorno à normalidade ocorreu entre 7-11 meses (mediana: 9 meses). Não havia evidência de doenças ósseas, hepáticas, endócrinas, ou uso de medicamentos associados à elevação da fosfatase alcalina. Uma paciente apresentou infecções de vias aéreas superiores precedendo o diagnóstico da hiperfosfatasemia. Alanina aminotransferase, aspartato aminotransferase, cálcio, fósforo e magnésio estavam normais em todos. O paratormônio foi dosado em três crianças, estando normal em todas. Em dois pacientes, a investigação para hepatites A, B e C foi negativa. A fosfatase alcalina estava normal em três dos quatro pares de pais testados. COMENTÁRIOS: HTBI é uma patologia autolimitada, benigna e de resolução espontânea, que acomete crianças abaixo de cinco anos, sem evidência clínica ou laboratorial de doença óssea, hepática ou endócrina subjacente. A etiologia é desconhecida. Esta possibilidade deve ser considerada no diagnóstico diferencial da hiperfosfatesemia para evitar exames e procedimentos desnecessários.
OBJECTIVE: To report a case series of benign transient hyperphosphatasemia of infancy (BTHI). DESCRIPTION (CASE REPORT): A series of four girls with BTHI is described. The age range was 11-45 months (median: 13 months). At diagnosis, the serum alkaline phosphatase was 1.1- 6.1 times (median: 1.36) above the reference values. Return to normal values occurred between 7-11 months (median: 9 months). There was no evidence of bone, liver, or endocrine disease, and none of the patients were using medications that could lead to serum alkaline phosphatase level rise. One of the patients presented with upper airway infection before the hyperphosphatasemia was diagnosed. Aspartate-aminotransferase, alanine-aminotransferase, calcium, phosphorus and magnesium levels were normal in all children. Parathyroid hormone was normal in the three patients tested. In two patients, the investigation for hepatitis A, B and C was negative. Alkaline phosphatase was normal in three of four parent couples tested. COMMENTS: BTHI is a self-limited and benign disease with spontaneous resolution affecting children younger than five years old, without clinical or laboratorial evidence of osseous, hepatic and endocrine disorders. The etiology remains unclear. BTHI potential should be considered in the diagnostic evaluation of hyperphosphatasemia in order to avoid unnecessary tests.
Assuntos
Humanos , Feminino , Lactente , Doenças do Desenvolvimento Ósseo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Hipofosfatasia/terapia , Desenvolvimento Infantil/fisiologia , Doenças Metabólicas/etiologiaRESUMO
After a 3-month course of weekly intravenous infusions of pooled normal plasma in an attempt at enzyme replacement therapy, we observed gradual and prolonged normalization of circulating alkaline phosphatase (AP) activity in a boy with infantile hypophosphatasia. During this 4-month period, when hypophosphatasemia had been corrected, electrophoretic and heat denaturation studies suggested that the AP in serum was skeletal in origin. Serial radiographic and histologic studies of bone demonstrated skeletal remineralization and the appearance of AP activity in osteoblasts and chondrocytes after the infusions. Considerable clinical improvement coincided with the skeletal remineralization. Our observations indicate that in one patient with infantile hypophosphatasia the structural gene for the tissue-nonspecific (bone/liver/kidney) AP isoenzyme was intact and could be expressed with marked physiologic effect. Infantile hypophosphatasia may result from absence or inactivation of a circulating factor(s) that regulates the expression of the gene for tissue nonspecific AP.
Assuntos
Fosfatase Alcalina/metabolismo , Osso e Ossos/metabolismo , Hipofosfatasia/terapia , Minerais/metabolismo , Fosfatase Alcalina/sangue , Fosfatase Alcalina/genética , Transfusão de Sangue , Osso e Ossos/enzimologia , Pré-Escolar , Genes , Humanos , Isoenzimas/genética , Masculino , Fatores de TempoRESUMO
After biochemical and radiographic studies, enzyme replacement therapy in three patients with the infantile form of hypophosphatasia was attempted by weekly intravenous infusions of bone alkaline phosphatase-rich (BAP) plasma from patients with Paget bone disease. Subsequently, circulating BAP activity was substantially increased in each patient, and in one was maintained in the normal range for nearly 2 months. Despite partial or complete correction of the deficiency of circulating BAP activity, we observed no radiographic evidence for arrest of progressive osteopenia or improvement in rachitic defects in any of the patients. Failure of infants with hypophosphatasia to show significant healing of rickets on correction of circulating BAP activity supports the hypothesis that this isoenzyme functions in situ during normal skeletal mineralization.