Hypophosphatasia: from birth to adulthood

ABSTRACT 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.

Diagnostic challenges in hypophosphatasia in adult patients / Desafios do diagnóstico da hipofosfatasia em adultos

Introdução: Hipofosfatasia é um distúrbio metabólico que afeta a mineralização óssea e dentária, causada por mutações no gene ALPL, levando à deficiência enzimática da fosfatase alcalina tecido não-específica. A forma adulta caracteriza-se por fraturas atípicas do fêmur, osteomalácia, osteoporose, grave osteoartropatia, condrocalcinose e artralgia. Objetivo: Demonstrar desafios diagnósticos relacionados à hipofosfatasia através do relato de dois casos. Paciente 1: feminino, 59 anos, encaminhada para avaliação clínica devido às fraturas patológicas de difícil consolidação e osteoporose generalizada de causa genética. Relata perda dentária precoce da arcada superior, fraturas na coluna, em ombro esquerdo e no fêmur. Atualmente, queixa-se de dor crônica intensa, com uso de múltiplos medicamentos. Achados clínicos, laboratoriais e radiológicos foram compatíveis com o diagnóstico de hipofosfatasia. Paciente 2: masculino, 31 anos, filho da paciente 1, encaminhado para avaliação clínica por fratura patológica precoce em fêmur esquerdo e osteoporose não esclarecida. Atualmente relata dor e claudicação importante em membro inferior esquerdo, associado à lombalgia crônica. Confirmação do diagnóstico de hipofosfatasia por exames laboratoriais e radiológicos e sequenciamento do gene ALPL, aliados ao diagnóstico da sua genitora. Discussão: Hipofosfatasia é uma doença rara de herança autossômica dominante e recessiva. Pacientes acometidos apresentam fraturas constantes, densidade mineral óssea baixa, cicatrização óssea deficitária. É comum a hipofosfatasia ser diagnosticada erroneamente como osteopenia e/ou osteoporose primária, acarretando prejuízos ao paciente. Ressalta-se a importância da história clínica completa e dos antecedentes familiares a fim de se obter um diagnóstico precoce, garantindo, por sua vez, o adequado acompanhamento e manejo terapêutico (AU)

Introduction: hypophosphatasia is a metabolic disorder affecting bone and tooth mineralization, caused by mutations in the ALPL gene leading to enzymatic deficiency of tissue non-specific alkaline phosphatase. The adult form is characterized by atypical femur fractures, osteomalacia, osteoporosis, severe osteoarthropathy, chondrocalcinosis, and arthralgia. Objective: to demonstrate diagnostic challenges related to hypophosphatasia through the report of two cases. Patient 1: female, 59 years old, referred for clinical evaluation due to pathological fractures of difficult consolidation and generalized osteoporosis of genetic cause. She reports early tooth loss in the upper arch, fractures in the spine, left shoulder and femur. Currently, he complains of severe chronic pain, with use of multiple medications. Clinical, laboratory, and radiological findings were compatible with the diagnosis of hypophosphatasia. Patient 2:male, 31 years old, son of patient 1, referred for clinical evaluation due to an early pathological fracture in the left femur and unclear osteoporosis. He currently reports pain and significant claudication in the left lower limb, associated with chronic low back pain. Confirmation of the diagnosis of hypophasatasia by laboratory and radiological tests and sequencing of the ALPL gene combined with the diagnosis of his mother. Discussion: hypophosphatasia is a rare disease of autosomal dominant and recessive inheritance. Affected patients have constant fractures, low bone mineral density, and impaired bone healing. It is common for hypophosphatasia to be misdiagnosed as osteopenia and/or primary osteoporosis, which can be harmful to the patient. The importance of a complete clinical history and family history is emphasized in order to obtain an early diagnosis, ensuring adequate follow-up and therapeutic management (AU)

Un caso de hipofosfatasia perinatal grave con una mutación novedosa / Severe perinatal hypophosphatasia case with a novel mutation

La hipofosfatasia es un trastorno hereditario raro causado por mutaciones en el gen ALPL. Causa defectos en la mineralización ósea y dental, función respiratoria anormal, convulsiones, hipotonía, dolor óseo y nefrocalcinosis. Las formas clínicas se reconocen según la edad al diagnóstico y la gravedad. Presentamos el caso de una lactante con fontanela anterior agrandada, bóveda craneal blanda, fracturas, dificultad respiratoria y convulsiones. El análisis bioquímico mostró hipercalcemia, fosfato sérico normal y fosfatasa alcalina sérica baja. La radiografía mostró hipomineralización, fracturas y callos. La concentración plasmática de piridoxal-5'-fosfato era de 762 mg/l (intervalo normal: 5-50) y la concentración de fosfoetanolamina en orina era de 1015 mmol/l (intervalo normal: 15-341). El análisis del gen ALPL mostró dos mutaciones heterocigotas compuestas, una de las cuales es novedosa. El diagnóstico y tratamiento tempranos de la hipofosfatasia perinatal podría mejorar los resultados y tener un impacto positivo en la sobrevida.

Hypophosphatasia (HPP) is a rare inherited disorder caused by mutations in the ALPL gene. Mineralization defect in bones and teeth, abnormal respiratory function, seizures, hypotonia, bone pain, and nephrocalcinosis can be observed. Clinical forms are usually recognized based on age at diagnosis and severity of features. We present an infant with an enlarged anterior fontanelle, soft calvarium, fractures, respiratory distress, and seizures. Biochemical analysis showed hypercalcemia, normal serum phosphate, and low serum alkaline phosphatase (ALP) levels. X-ray showed hypomineralization, fractures, and callus formations. Plasma pyridoxal 5'-phosphate (PLP) was 762 mg/L (NV : 5-50) and urine phosphoethanolamine (PEA) was 1015 mmol/L (NV : 15-341) and ALPL gene analysis showed two compound heterozygous mutations, one of which is a novel one. Early diagnosis and treatment of perinatal HPP may improve outcomes and might have a positive impact on survival.

Desafios do diagnóstico da hipofosfatasia em adultos / Diagnostic challenges in hypophosphatasia in adult patients

RESUMO:Introdução: Hipofosfatasia é um distúrbio metabólico que afeta a mineralização óssea e dentária, causada por mutações no gene ALPL, levando à deficiência enzimática da fosfatase alcalina tecido não-específica. A forma adulta caracteriza-se por fraturas atípicas do fêmur, osteomalácia, osteoporose, grave osteoartropatia, condrocalcinose e artralgia. Objetivo: Demonstrar desafios diagnósticos relacionados à hipofosfatasia através do relato de dois casos. Paciente 1: feminino, 59 anos, encaminhada para avaliação clínica devido às fraturas patológicas de difícil consolidação e osteoporose generalizada de causa genética. Relata perda dentária precoce da arcada superior, fraturas na coluna, em ombro esquerdo e no fêmur. Atualmente, queixa-se de dor crônica intensa, com uso de múltiplos medicamentos. Achados clínicos, laboratoriais e radiológicos foram compatíveis com o diagnóstico de hipofosfatasia. Paciente 2: masculino, 31 anos, filho da paciente 1, encaminhado para avaliação clínica por fratura patológica precoce em fêmur esquerdo e osteoporose não esclarecida. Atualmente relata dor e claudicação importante em membro inferior esquerdo, associado à lombalgia crônica. Confirmação do diagnóstico de hipofosfatasia por exames laboratoriais e radiológicos e sequenciamento do gene ALPL, aliados ao diagnóstico da sua genitora. Discussão: Hipofosfatasia é uma doença rara de herança autossômica dominante e recessiva. Pacientes acometidos apresentam fraturas constantes, densidade mineral óssea baixa, cicatrização óssea deficitária. É comum a hipofosfatasia ser diagnosticada erroneamente como osteopenia e/ou osteoporose primária, acarretando prejuízos ao paciente. Ressalta-se a importância da história clínica completa e dos antecedentes familiares a fim de se obter um diagnóstico precoce, garantindo, por sua vez, o adequado acompanhamento e manejo terapêutico. (AU)

ABSTRACT: Introduction: hypophosphatasia is a metabolic disorder affecting bone and tooth mineralization, caused by mutations in the ALPL gene leading to enzymatic deficiency of tissue non-specific alkaline phosphatase. The adult form is characterized by atypical femur fractures, osteomalacia, osteoporosis, severe osteoarthropathy, chondrocalcinosis, and arthralgia. Objective: to demonstrate diagnostic challenges related to hypophosphatasia through the report of two cases. Patient 1: female, 59 years old, referred for clinical evaluation due to pathological fractures of difficult consolidation and generalized osteoporosis of genetic cause. She reports early tooth loss in the upper arch, fractures in the spine, left shoulder and femur. Currently, he complains of severe chronic pain, with use of multiple medications. Clinical, laboratory, and radiological findings were compatible with the diagnosis of hypophosphatasia. Patient 2:male, 31 years old, son of patient 1, referred for clinical evaluation due to an early pathological fracture in the left femur and unclear osteoporosis. He currently reports pain and significant claudication in the left lower limb, associated with chronic low back pain. Confirmation of the diagnosis of hypophasatasia by laboratory and radiological tests and sequencing of the ALPL gene combined with the diagnosis of his mother. Discussion: hypophosphatasia is a rare disease of autosomal dominant and recessive inheritance. Affected patients have constant fractures, low bone mineral density, and impaired bone healing. It is common for hypophosphatasia to be misdiagnosed as osteopenia and/or primary osteoporosis, which can be harmful to the patient. The importance of a complete clinical history and family history is emphasized in order to obtain an early diagnosis, ensuring adequate follow-up and therapeutic management. (AU)

Case report of pediatric systemic lupus erythematosus combined with hypophosphatasia / 中华实用儿科临床杂志

The clinical data of a child with systemic lupus erythematosus (SLE) and hypophosphatasia (HPP) admitted to the Department of Pediatrics, the Second Hospital of Jilin University in December 2015 were retrospectively analyzed.The patient was a 10-year-old boy who was hospitalized because of fever and facial rashes in the past 4 days.He had a history of HPP for 7 years.His clinical manifestations included skeletal and dental dysplasia, oral ulcers, buccal erythema and renal lesions.Laboratory examination showed a low level of serum alkaline phosphatase, whole blood cell count decreased, antinuclear antibody(ANA) 1∶1 000, anti-double strand DNA antibodies positive, anticardiolipin antibodies positive, complement 3 (C 3) and C 4 decreased.Therefore, he was diagnosed with SLE.After glucocorticoid, immunosuppressant and symptomatic treatment, the child′s condition improved and he discharged from the hospital.He was followed up regularly, and died 2 years after the diagnosis of SLE.SLE complicated with HPP is extremely rare in clinical practice, and the symptoms may overlap.Hence these two diseases should be differentiated.

Case report of pediatric systemic lupus erythematosus combined with hypophosphatasia / 中华实用儿科临床杂志

The clinical data of a child with systemic lupus erythematosus (SLE) and hypophosphatasia (HPP) admitted to the Department of Pediatrics, the Second Hospital of Jilin University in December 2015 were retrospectively analyzed.The patient was a 10-year-old boy who was hospitalized because of fever and facial rashes in the past 4 days.He had a history of HPP for 7 years.His clinical manifestations included skeletal and dental dysplasia, oral ulcers, buccal erythema and renal lesions.Laboratory examination showed a low level of serum alkaline phosphatase, whole blood cell count decreased, antinuclear antibody(ANA) 1∶1 000, anti-double strand DNA antibodies positive, anticardiolipin antibodies positive, complement 3 (C 3) and C 4 decreased.Therefore, he was diagnosed with SLE.After glucocorticoid, immunosuppressant and symptomatic treatment, the child′s condition improved and he discharged from the hospital.He was followed up regularly, and died 2 years after the diagnosis of SLE.SLE complicated with HPP is extremely rare in clinical practice, and the symptoms may overlap.Hence these two diseases should be differentiated.

A Case of Adult Hypophosphatasia with Non-specific Symptoms / 日本プライマリ・ケア連合学会誌

A 40-year-old female visited our hospital because of malaise. She had no history of early loss of primary teeth nor family history of skeletal dysplasia. Laboratory examination showed low serum alkaline phosphatase levels of 18 U/L. In addition, hypozincemia was also observed, but alkaline phosphatase level did not increase after zinc replacement. Mediators, including calcium and phosphorus metabolism, were within normal range. X-ray examination showed no evidence of osteomalacia, but mineral bone density was slightly decreased compared with the young adult mean. Urine phosphoethanolamine level was increased, and we then suspected hypophosphatasia. Genetic tests detected ALPL gene heterozygous missense mutation (c.529G>A p.Ala177Thr and c.670A>G p.Lys224Glu) and adult-onset hypophosphatasia was finally diagnosed. It is important to evaluate alkaline phosphatase levels in the screening of patients with non-specific symptoms.

Study on genetic etiology of two cases with hypophosphatasia(HPP) using whole-exome sequencing / 中华内分泌代谢杂志

Objective:Clinical and genetic analysis were conducted in 2 patients with hypophosphatasia(HPP) and their families to explore the pathogenic mechanism of HPP.Methods:The genomic DNA was extracted from peripheral blood of two patients with HPP and their family members. Sanger sequencing and pedigree verification were performed on the pathogenic variants identified using whole-exome sequencing. Then the function of the mutation sites was analyzed with bioinformatics software.Results:Proband 1 presented with developmental retardation, pectus funnel and premature loss of deciduous tooth, of which the serum alkaline phosphatase level was slightly lower than the bound of the normal range. Two complex heterozygous missense variants c. 1120G>A and c. 1334C>G of ALPL gene were detected in the proband 1 which were inherited from his parents respectively, showing an autosomal recessive inheritance. Both the variants were predicted to inflict deleterious effects on ALPL gene function by multiple bioinformatics program, and were classified as likely pathogenetic variants according to American College of Medical Genetics and Genomics(ACMG) guidelines. Proband 2 showed three missing permanent teeth and the significantly lower level of serum alkaline phosphatase than normal range. A heterozygous variant c. 1190-3C>G of ALPL gene was detected in proband 2 whose pattern of inheritance was unknown. The clinical significance of this variant was unknown according to ACMG standards and guidelines. All of these variants were considered as novel since none of them has been reported. Along with the above combined results, proband 1 and 2 were diagnosed as childhood HPP and Odontohypophosphatasia, respectively.Conclusion:This study reinforced the relationship between HPP and variants in ALPL gene. Two variants, c. 1120G>A and c. 1334C>G, were located in the homodimer interface and crown domain of tissue-nonspecific alkaline phosphatase(TNSALP), respectively, while c. 1190-3C>G were located in the splice sites, which might result in low TNSALP activity.

Active search of adult patients with persistently low serum alkaline phosphatase levels for the diagnosis of hypophosphatasia

ABSTRACT Objectives: Alkaline phosphatase (ALP) is the main laboratory marker of hypophosphatasia (HPP), a rare disease unknown to most physicians. The prevalence of HPP has been widely discussed in the literature due to the diverse phenotypes of HPP. The purpose of this study was to search for patients with hypophosphatasemia based on previous biochemistry tests and reevaluate them to confirm the diagnosis of HPP. Subjects and methods: A total of 289,247 biochemical tests for ALP in adults were performed from 2015 to 2019 in two tertiary hospitals in Rio de Janeiro were reviewed (Clementino Fraga Filho University Hospital - HUCFF - and Bonsucesso Federal Hospital - BFH). Results: A total of 1,049 patients were identified with ALP levels below 40 U/L, and 410 patients had hypophosphatasemia confirmed by at least two exams. After the active search of medical reports and/or interviews based on structured questionnaires, 398 subjects were excluded due to secondary causes of reduced ALP. The remaining 12 patients were invited to attend the medical consultation at HUCFF, accompanied by at least one first-degree relative. None of the patients or their relatives had a history or clinical manifestations consistent with HPP. Serum ALP was within reference values in all relatives, but persistently low in further laboratory evaluation in all the 12 patients, in whom secondary causes were ruled out. Thus, we cannot exclude the possibility that they might carry the mutations associated with HPP. Conclusion: Further image evaluations and genetic testing would be appropriate to confirm this asymptomatic adult form of HPP.

Hipofosfatasemia crónica persistente de causa no determinada y su repercusión músculo-esquelética / Persistent hypophosphatasemia and its musculoskeletal repercussion

La fosfatasa alcalina baja o hipofosfatasemia, ya sea debida a causas genéticas (hipofosfatasia) o secundarias, presenta correlato clínico. Nuestro objetivo es estimar la prevalencia de hipofosfatasemia crónica persistente y describir sus hallazgos osteometabólicos. Se realizó una búsqueda electrónica de afiliados adultos al Hospital Italiano de Buenos Aires, entre 2013 y 2017, con al menos 2 determinaciones de fosfatasa alcalina igual a 30 UI/l o menor y ninguna mayor de 30 UI/l (rango de referencia 30-100 UI/l). Se excluyeron aquellos con causas secundarias diagnosticadas y se analizaron los correlatos clínico y bioquímico. Se detectó hipofosfatasemia crónica persistente en 78 de 105.925, 0,07% (0,06-0,09) de los afiliados. Solo uno fue excluido por tener causa secundaria. Eran 61,1% mujeres de 44 (34-56) años, fosfatasa alcalina 24 (20-27) UI/L, fosfatemia 4,1 (3,8-4,6) mg/dl. Se observaron osteoartritis, calcificaciones vasculares y fracturas, menos frecuentemente litiasis renal, calcificación del ligamento longitudinal común anterior, pérdida dental y convulsiones. El 63,6% tenían al menos una de las características clínico-radiológicas evaluadas, pero en solo 5,2% fue mencionado el diagnóstico de hipofosfatasemia en la historia clínica. La densitometría evidenció algún grado de afección (osteopenia u osteoporosis) en 76,2%. Se constataron 19 fracturas, con predominio en radio. La prevalencia de hipofosfatasemia fue similar a lo previamente reportado. El reconocimiento fue bajo; sin embargo, se observaron variadas manifestaciones músculo-esqueléticas, similares a las descriptas en la hipofosfatasia del adulto, por lo cual ­ante una hipofosfatasemia sin causa secundaria­ se sugiere considerar este diagnóstico. (AU)

Low alkaline phosphatase (ALP) or hypophosphatasemia either due to genetic (hypophosphatasia) or secondary causes, presents a clinical correlate. Our objectives are to estimate the prevalence of persistent hypophosphatasemia and to describe the clinical findings. We performed a search using the electronic medical records of the members of the Hospital Italiano de Buenos Aires health care system, between 2013 and 2017. Adult members with ≥ 2 ALP ≤ 30 IU/l, no ALP >30 IU/l (normal range 30-100 UI/l) and without diagnosed secondary causes were analyzed. Persistent hypophosphatasemia was detected in 78 of 105.925, 0.07% (0.06-0.09) of members. Only one was excluded due to a secondary cause, 61.1% were women, 44 (34-56) year-old, ALP 24 (20-27) IU/l and phosphatemia 4.1 (3.8-4.6) mg/dl. Osteoarthritis, vascular calcifications and fractures were detected, and nephrolithiasis, DISH (Diffuse idiopathic skeletal hyperostosis), tooth loss, and seizures were less frequently observed. At least one of the mentioned characteristics were present in 63.6 %, but only 5.2% had hypophosphatasemia registered in their clinical record. Densitometry showed osteopenia or osteoporosis in 76.2%. There were 19 fractures, most of them in radius. The prevalence of hypophosphatasemia was similar to what has been previously reported. Hypophosphatasemia finding in medical records was low, but far from being asymptomatic, clinical manifestations were observed. In the presence of hypophosphatasemia without a secondary cause, adult hypophosphatasia should be uspected. (AU)

Genetic diagnosis for a case of hypophosphatasia and the prenatal diagnosis of his sibling / 中华内分泌外科杂志

Hypophosphatasia is a rare hereditary metabolic bone disease caused by ALPL gene mutation.This papaer report the genetic diagnosis of a child with childhood hypophosphatasia,and the prenatal diagnosis of his sibling.We hope it can provide reference for clinical diagnosis and prenatal diagnosis of this disease.

Skeletal mineralization: mechanisms and diseases

Skeletal mineralization is initiated in matrix vesicles (MVs), the small extracellular vesicles derived from osteoblasts and chondrocytes. Calcium and inorganic phosphate (Pi) taken up by MVs form hydroxyapatite crystals, which propagate on collagen fibrils to mineralize the extracellular matrix. Insufficient calcium or phosphate impairs skeletal mineralization. Because active vitamin D is necessary for intestinal calcium absorption, vitamin D deficiency is a significant cause of rickets/osteomalacia. Chronic hypophosphatemia also results in rickets/osteomalacia. Excessive action of fibroblast growth factor 23 (FGF23), a key regulator of Pi metabolism, leads to renal Pi wasting and impairs vitamin D activation. X-linked hypophosphatemic rickets (XLH) is the most common form of hereditary FGF23-related hypophosphatemia, and enhanced FGF receptor (FGFR) signaling in osteocytes may be involved in the pathogenesis of this disease. Increased extracellular Pi triggers signal transduction via FGFR to regulate gene expression, implying a close relationship between Pi metabolism and FGFR. An anti-FGF23 antibody, burosumab, has recently been developed as a new treatment for XLH. In addition to various forms of rickets/osteomalacia, hypophosphatasia (HPP) is characterized by impaired skeletal mineralization. HPP is caused by inactivating mutations in tissue-nonspecific alkaline phosphatase, an enzyme rich in MVs. The recent development of enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has improved the prognosis, motor function, and quality of life in patients with HPP. This links impaired skeletal mineralization with various conditions, and unraveling its pathogenesis will lead to more precise diagnoses and effective treatments.

Caso clínico: hipofosfatasia de la niñez. Seguimiento clínico / Clinical case: childhood hypophosphatasia. Clinical follow-up

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)

Adult hypophosphatasia caused by ALPL mutation: one pedigree study / 中华内分泌代谢杂志

An adult patient with hypophosphatasia caused by compound heterozygous mutations in alkaline phosphatase,liver /bone /kidney(ALPL)gene was investigated through comprehensively reviewing the medical history and clinical records of the proband and her family members in order to better understand the disease.The proband and her older sister had mild decreased serum alkaline phosphatase level accompanied with frequently nontraumatic fractures at limbs and all the teeth fell off at the age of 20 and 7, respectively.Both of them carried a missense mutation c.407G>A(p.Arg136His)in exon 5 and a deletion mutation c.1318_1320delAAC(p.Asn440del)in exon 12 simultaneously.Other four family members were p.Arg136His mutation carriers and two members were p.Asn440del mutation carriers.We found that p.Asn440del mutation was associated with the oral disorders.In this family, compound heterozygous manifested more serious symptoms, while heterozygous showed relatively mild symptoms.In addition, it is necessary to differentiate it from primary osteoporosis and other diseases of disturbed bone mineralization.

Prenatal diagnosis of hypophosphatasia congenita using ultrasonography

Congenital hypophosphatasia is a rare fatal skeletal dysplasia. Antenatal determinants of Epub ahead of print lethality include small thoracic circumference with pulmonary hypoplasia and severe micromelia. These features were present in the fetus of a 25-year-old female who came for an anomaly scan in her second trimester of pregnancy. Additional findings of generalized demineralization and osteochondral spurs led to the diagnosis of hypophosphatasia congenita. The pregnancy was terminated, and the findings were confirmed on autopsy. Common differential diagnoses with clues to diagnose the above mentioned condition have been discussed here. Early and accurate detection of this medical condition is important as no treatment has been established for this condition. Therefore, antenatal ultrasonography helps in diagnosing and decision making with respect to the current pregnancy and lays the foundation for the genetic counseling of the couple.

The radiological manifestation of hypophosphatasia / 中华放射学杂志

ObjectiveTo explore the radiological features of hypophosphatasia.MethodsFive cases of hypophosphatasia were definitely diagnosed,which included 3 males and 2 females aged from 5 months to 23 years.The laboratory assays were analyzed,radiological appearances of bone were determined and differential diagnoses were made.ResultsThe alkaline phosphatase in blood serum of five patients decreased,which were 8,20,13,21,and 18 U/L respectively.Phosphoethanolamine increased in blood serum of the five patients,which were 16.5,13.5,21.6,18.7,and 28.9 μmol/L respectively.Phosphoethanolamine also increased in urine,which were 2350,9120,3520,5280,and 1820 μmol/L respectively.Calcium in blood serum increased,which were 4.2,5.6,4.9,6.1,and 3.5 mmol/L respectively.X-ray images displayed that the density of bone decreased in 5 cases,the metaphyses exhibited widening and cupping in 4 cases,the provisional calcification zone of the metaphysis became thinning or disappearing in 4 cases,long bone bended in 4 cases and pathologically fractured in 1 case.Conclusion Hypophosphatasia can be indicated by its relatively special radiological appearance,and it can be diagnosed and differentiated from rickets,osteomalacia and osteogenesis imperfect by the laboratory examination combined with its clinical presentation.

Hiperfosfatasemia transitória benigna da infância / Benign transient hyperphosphatasemia of childhood

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.

Bilateral Transverse (Bowdler) Fibular Spurs with Hypophosphatasia in an Adolescent Girl

Hypophosphatasia is a clinically heterogeneous inheritable disorder characterized by defective bone mineralization and the deficiency of serum and tissue liver/bone/kidney alkaline phosphatase activities. Due to the mineralization defect of the bones, various skeletal findings can be radiologically observed in hypophosphatasia. Bowing and Bowdler spurs of long bones are the characteristic findings. The Bowdler spurs reported on in the previous pertinent literature were observed in the perinatal aged patients and these lesions have rarely involved adolescents. We herein report on a 14-year-old girl with fibular Bowdler spurs.

Study on dental pulp stem cells from patients with hypophosphatasia / 北京大学学报(医学版)

Objective:To find out whether the dentin formation of hypophosphatasia children is affec-ted;to study the biological difference of cultured human dental pulp cells from deciduous teeth between hypophosphatasia and normal healthy children.Methods: Anterior deciduous teeth were collected from hypophosphatasia(experiment group)and normal healthy children(control group)respectively.Grounding sections of the affected and healthy deciduous teeth were made to observe their roots;the den-tal pulp cells were separated and cultured.The characteristics of cell proliferation,differentiation and calcification were studied and compared between the two groups of children.MTT assay was performed to study the growth curves of the cells;RT-PCR was performed to evaluate the expression of tissue nonspecific alkaline phosphatase(TNSALP)at different stages;von Kosssa staining was used to test formed calcification nodules after 3 weeks of induction.Results: From the grounding sections,the root surface of the experiment group was not smooth with absorbed areas,cementum was absent.For proliferation activity and the expression of TNSALP,the dental pulp cells from experiment group was obviously lower than control group.Calcified nodules could be seen in both groups,but the nodules were less and the sizes were smaller in experiment group than in control group.Conclusion: In hypophosphatasia patients,not only the cementum but also the dentin were affected.The proliferation,TNSALP expression and calcification capability of the dental pulp cells were influenced in hypophosphatasia patients,and this may be related to the tooth calcification defect.