Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP in healthy individuals is on cell surfaces richly in bone, liver, and kidney. Thus, TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation and growth. Superabundance of extracellular PPi (ePPi) in HPP impairs mineralization of bones and teeth, often leading to rickets during childhood and osteomalacia in adult life and to tooth loss at any age. HPP's remarkably broad-ranging severity is largely explained by nearly four hundred typically missense mutations throughout the ALPL gene that are transmitted as an autosomal dominant or autosomal recessive trait. In the clinical laboratory, the biochemical hallmark of HPP is low serum ALP activity (hypophosphatasemia). However, our experience indicates that hyperphosphatemia from increased renal reclamation of filtered inorganic phosphate (Pi) is also common. Herein, from our prospective single-center study, we document throughout the clinical spectrum of non-lethal pediatric HPP that hyperphosphatemia reflects increased renal tubular threshold maximum for phosphorus adjusted for the glomerular filtration rate (TmP/GFR). To explore its pathogenesis, we studied mineral metabolism and quantitated circulating levels of three phosphatonins [fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (sFRP4), and fibroblast growth factor 7 (FGF7)] in 41 pediatric patients with HPP, 73 with X-linked hypophosphatemia (XLH), and 15 healthy pediatric control (CTR) subjects. The HPP and XLH cohorts had normal serum total and ionized calcium and parathyroid hormone levels (Ps > 0.10) and uncompromised glomerular filtration. In XLH, serum FGF23 was characteristically elevated (P < 0.0001) and despite hypophosphatemia sFRP4 was normal (P > 0.4) while FGF7 was low (P < 0.0001). In HPP, despite hyperphosphatemia serum FGF23 and sFRP4 were normal (Ps > 0.8) while FGF7 was low (P < 0.0001). Subsequently, in rats, we confirmed that FGF7 is phosphaturic. Thus, hyperphosphatemia in non-lethal pediatric HPP is associated with phosphatonin insufficiency together with, as we discuss, ePPi excess and diminished renal TNSALP activity.

中文翻译：

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循环中 FGF7 低且 FGF23 和 sFRP4 水平正常的高磷血症是小儿低磷酸酯酶症的特征

低磷酸酯酶症 (HPP) 是由编码碱性磷酸酶的组织非特异性同工酶 (TNSALP) 的 ALPL 基因功能丧失突变引起的先天性代谢错误。健康个体的 TNSALP 位于富含骨骼、肝脏和肾脏的细胞表面。因此，TNSALP 天然底物在 HPP 中细胞外积累，包括无机焦磷酸盐 (PPi)，一种有效的羟基磷灰石晶体形成和生长抑制剂。HPP 中过多的细胞外 PPi (ePPi) 会损害骨骼和牙齿的矿化，通常会导致儿童时期的佝偻病和成年期的骨软化症以及任何年龄的牙齿脱落。高压泵' ALPL 基因中近 400 个典型的错义突变在很大程度上解释了这种异常广泛的严重性，这些突变作为常染色体显性或常染色体隐性性状传播。在临床实验室中，HPP 的生化标志是低血清 ALP 活性（低磷酸血症）。然而，我们的经验表明，由于过滤的无机磷酸盐 (Pi) 的肾脏回收增加而导致的高磷血症也很常见。在此，从我们的前瞻性单中心研究中，我们记录了非致死性儿科 HPP 的整个临床范围，即高磷血症反映了肾小管最大磷阈值增加，针对肾小球滤过率 (TmP/GFR) 进行了调整。探究其发病机制，我们研究了 41 名患有 HPP 的儿科患者、73 名患有 X-相关联的低磷血症 (XLH) 和 15 名健康儿科对照 (CTR) 受试者。HPP 和 XLH 队列具有正常的血清总钙和离子钙和甲状旁腺激素水平（P > 0.10）和未受损的肾小球滤过。在 XLH 中，血清 FGF23 的特征性升高（P < 0.0001），尽管有低磷血症，sFRP4 正常（P > 0.4）而 FGF7 低（P < 0.0001）。在 HPP 中，尽管存在高磷血症，但血清 FGF23 和 sFRP4 正常（Ps > 0.8），而 FGF7 较低（P < 0.0001）。随后，在大鼠中，我们证实 FGF7 是磷酸盐尿剂。因此，