Supplementary Material for: A de novo PRPF8 pathogenic variant in transient severe hypophosphatemia with delayed puberty and growth failure

Introduction: Childhood hypophosphatemia is a rare condition and may be caused by malabsorption, malignancies, or genetic factors. Prolonged hypophosphatemia leads to impaired growth and radiographic signs of rickets.
Methods: We performed a detailed clinical and genetic evaluation of an adolescent boy with repeatedly low plasma phosphate concentrations (below 0.60 mmol/L), and growth failure.
Results: At 14 years, the patient presented with decelerating growth and delayed puberty. Biochemistry showed hypophosphatemia due to increased urinary phosphate loss; kidney function and vitamin D status were normal. Radiographs showed mild metaphyseal changes. A gene panel for known genetic hypophosphatemias was negative. Trio exome analysis followed by Sanger sequencing identified a pathogenic heterozygous de novo stop gain variant in PRPF8 gene, c.5548C>T p.(Arg1850*)., in the conserved RNase H homology domain. PRPF8 encodes the pre-RNA protein 8, which has a role in RNA processing. Heterozygous PRPF8 variants have been associated with retinitis pigmentosa and neurodevelopmental disorders but not with phosphate metabolism. The patient underwent growth hormone (GH) stimulation tests which confirmed GH deficiency. Head MRI indicated partially empty sella. GH treatment was started at 15 years. Surprisingly, phosphate metabolism normalized during GH treatment, suggesting that hypophosphatemia was at least partly secondary to growth hormone deficiency.
Conclusion: In conclusion, the evaluation of an adolescent with profound long-term hypophosphatemia revealed a pituitary developmental defect associated with a stop gain variant in PRPF8. Hypophosphatemia alleviated with GH treatment. The pathological PRPF8 variant may contribute to abnormal pituitary development; however, its role in phosphate metabolism remains uncertain.

引言：儿童低磷血症是一种罕见疾病，其病因可包括吸收不良、恶性肿瘤或遗传因素。长期低磷血症可导致生长发育受损，并出现佝偻病的影像学特征。
方法：本研究对一名反复出现血浆磷酸盐浓度低于0.60 mmol/L且生长发育迟缓的青春期男性患者开展了详细的临床与遗传学评估。
结果：该患者14岁时表现为生长减速与青春期延迟。生化检测提示低磷血症由尿磷丢失增加所致，肾功能与维生素D水平均正常。影像学检查可见轻度干骺端改变。针对已知遗传性低磷血症的基因检测面板结果为阴性。通过三人组外显子组测序联合桑格测序，在保守的核糖核酸酶H（RNase H）同源结构域中，于PRPF8基因中发现了一处致病性杂合新发终止获得变异c.5548C>T p.(Arg1850*)。PRPF8基因编码前RNA蛋白8，该蛋白参与RNA加工过程。既往研究显示，杂合PRPF8变异与色素性视网膜炎及神经发育障碍相关，但尚未见其与磷代谢异常相关的报道。该患者接受生长激素（growth hormone，GH）激发试验，结果证实存在生长激素缺乏症。头部磁共振成像（MRI）提示部分空蝶鞍。患者于15岁时开始接受GH治疗。令人意外的是，GH治疗期间患者的磷代谢恢复正常，提示低磷血症至少部分继发于生长激素缺乏症。
结论：综上，对1例存在长期重度低磷血症的青春期患者进行评估后，发现其存在垂体发育缺陷，该缺陷与PRPF8基因的终止获得变异相关。GH治疗可缓解患者的低磷血症。致病性PRPF8变异可能参与垂体发育异常的发生过程，但其在磷代谢中的具体作用仍有待明确。