Freitas Thiago Quadrante, Franco André Silva, Pereira Rosa Maria Rodrigues
Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
Medicine (Baltimore). 2018 Nov;97(48):e13210. doi: 10.1097/MD.0000000000013210.
Hypophosphatasia is an inborn error of metabolism that can appear any time in life, mainly with bone manifestations due to low alkaline phosphatase activity. Asfotase alfa is a specific enzyme reposition treatment that has shown promising results in children; however, there are few reports about the outcomes in adult patients.
A 36-year-old male presented with an early history of craniosynostosis, short stature, and multiple fractures since the age of 13 years-which needed numerous surgical corrections. He was admitted with a previous diagnosis of osteogenesis imperfecta, taking alendronate, calcium carbonate, cholecalciferol, and calcitriol. Bone mineral density was low (lumbar spine Z-score = -3.0 SD), with impairment of all parameters of high-resolution peripheral quantitative computed tomography (HR-pQCT). Kidney impairment was also observed with reduced creatinine clearance, nephrolithiasis, and nephrocalcinosis.
Alkaline phosphatase was unexpectedly low (6 U/L, reference value: 30-120 U/L), with high serum vitamin B6 (260 mcg/L, reference value: 5.2-34.1). Genetic testing showed a homozygous missense mutation in ALPL gene c.443 C>T: p.Thr148Ile.
Asfotase alfa was requested due to important bone deterioration, ambulatory disability, and kidney impairment. It was given subcutaneously 2 mg/kg per dose, 3 times a week, for 12 months before reassessment.
Bone mineral densities of the lumbar spine and whole body, besides almost all HR-pQCT microstructural parameters of the distal tibia, showed improvements and the patient was able to walk without assistant device. Kidney function did not further deteriorate.
Hypophosphatasia should be considered as a differential diagnosis in young patients with multiple fractures and kidney impairment, since the use of antiresorptive drugs, calcium and vitamin D, commonly used to treat fractures, worsen its symptoms and prognosis. A 12-month asfotase alfa treatment improved bone density and structural parameters even in an adult patient with late diagnosis.
低磷酸酯酶症是一种先天性代谢紊乱疾病，可在生命中的任何时候出现，主要表现为由于碱性磷酸酶活性降低而导致的骨骼症状。阿法骨化醇是一种特定的酶替代疗法，已在儿童中显示出有前景的结果；然而，关于成年患者治疗结果的报道很少。
一名36岁男性，自13岁起就有颅缝早闭、身材矮小和多处骨折的病史，需要多次手术矫正。他因之前诊断为成骨不全症入院，正在服用阿仑膦酸钠、碳酸钙、胆钙化醇和骨化三醇。骨密度较低（腰椎Z值=-3.0标准差），高分辨率外周定量计算机断层扫描（HR-pQCT）的所有参数均受损。还观察到肾功能损害，表现为肌酐清除率降低、肾结石和肾钙质沉着症。
碱性磷酸酶意外降低（6 U/L，参考值：30-120 U/L），血清维生素B6升高（260 mcg/L，参考值：5.2-34.1）。基因检测显示ALPL基因c.443 C>T存在纯合错义突变：p.Thr148Ile。
由于严重的骨质恶化、行动不便和肾功能损害，使用了阿法骨化醇。在重新评估前，每周皮下注射3次，每次2 mg/kg，持续12个月。
腰椎和全身的骨密度，以及几乎所有胫骨远端的HR-pQCT微观结构参数均有所改善，患者能够在无辅助设备的情况下行走。肾功能没有进一步恶化。
对于有多处骨折和肾功能损害的年轻患者，应考虑低磷酸酯酶症作为鉴别诊断，因为常用于治疗骨折的抗吸收药物、钙和维生素D会加重其症状和预后。即使是诊断较晚的成年患者，12个月的阿法骨化醇治疗也能改善骨密度和结构参数。
