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)

Evaluación de la densidad mineral ósea y de los parámetros de 3D-Shaper en la hipofosfatasia congénita del adulto / Agitated/inattentive children: explanatory models

Objetivo: Evaluar la densidad mineral ósea (DMO) y parámetros de 3D-Shaper a nivel de fémur proximal (FP) en adultos con hipofosfatasia (HPP) confirmada genéticamente y compararlos en aquellos sujetos con y sin fracturas. Material y métodos: Análisis transversal de datos densitométricos y de arquitectura ósea de la visita basal de un estudio longitudinal en el que se incluyeron pacientes con HPP. Se realizó un estudio densitométrico (Lunar Prodigy, GE iDXA) en FP y se empleó el software 3D-Shaper (version 2,7. Galgo Medical). Resultados: Se incluyeron 33 adultos con HPP con mutaciones en heterocigosis. Un 63,6% (21/33) fueron mujeres (42,9% postmenopáusicas), y 8 de los varones (66,6%) fueron mayores de 50 años. La media de edad fue 50,56±15,08 años, el 30,3% (10/33) tuvieron fracturas previas traumáticas, y un 15,2% (5/33), de estrés. La prevalencia de osteoporosis en CF fue del 11,8% (2/17) y de osteopenia, 82,4% (14/17). En premenopáusicas y varones jóvenes se detectó baja masa ósea para la edad en un 12,5% (2/16). Al comparar sujetos con fracturas de estrés y sin ellas, así como con traumáticas, no hubo diferencias en DMO. El 3D-Shaper mostró disminución del grosor cortical (mm) en pacientes con fracturas de estrés [1,8 (1,77-1,89)] frente a sujetos sin ellas [1,94 (1,87-2,03, p=0,03)] y en comparación con los que tuvieron fracturas traumáticas [1,97 (1,88-2,04), p=0,03]. Conclusión: Estos datos reflejan una discreta repercusión densitométrica en formas más leves del adulto. Estudios de arquitectura ósea pudieran resultar de interés para determinar pacientes susceptibles de presentar fracturas de estrés. (AU)

Objetivo: To evaluate bone mineral density (BMD) and 3D-Shaper parameters at the proximal femur (FP) level in adults with genetically confirmed hypophosphatasia (HPP) and to compare them in those subjects with and without fractures. Material and methods: Crosssectional analysis of densitometric data and bone architecture from the baseline visit of a longitudinal study in which patients with HPP were included. A densitometric study (Lunar Prodigy, GE iDXA) was carried out in FP using 3D-Shaper software (version 2.7. Galgo Medical). Results: 33 adults with HPP with heterozygous mutations were included. 63.6% (21/33) were women (42.9% postmenopausal), and 8 of the men (66.6%) were older than 50 years. The mean age was 50.56±15.08 years, 30.3% (10/33) had previous traumatic fractures and 15.2% (5/33) presented stress fractures. The prevalence of osteoporosis in CF was 11.8% (2/17) and of osteopenia, 82.4% (14/17). In premenopausal women and young men, low bone mass was detected for age in 12.5% (2/16). When comparing subjects with and without stress fractures, as well as traumatic ones, there were no differences in BMD. The 3D-Shaper showed a decrease in cortical thickness (mm) in patients with stress fractures [1.8 (1.77-1.89)] compared to subjects without them [1.94 (1.87-2.03, p=0.03)] and compared to those with traumatic fractures [1.97 (1.88-2.04), p=0.03]. Conclusions: These data reflect a discrete densitometric impact in milder forms of the adult. Bone architecture studies could be of interest in determining patients susceptible to stress fractures. (AU)

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)

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)

[Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options]. / Hipofosfatasia: manifestaciones clínicas, recomendaciones diagnósticas y opciones terapéuticas.

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options.

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.