儿童果糖-1，6-二磷酸酶缺乏症4例临床特征与文献复习

doi:10.12372/jcp.2026.25e1355

摘要/Abstract

摘要：

目的总结FBP1基因变异所致果糖-1，6-二磷酸酶缺乏症（FBP1D）患儿的临床特征和基因变异特点。方法选取2019年1月至2025年6月收治的4例FBP1D患儿作为研究对象，回顾性分析其临床表现、实验室检查、基因检测结果、治疗及预后。对已报道的中国FBP1D患者资料进行文献复习与总结。结果 4例患儿来自4个不同家系，男1例，女3例，诊断年龄分别为2岁3月龄、3岁5月龄、2岁11月龄、4岁4月龄，主要临床表现为发热、呕吐、食欲欠佳时出现嗜睡、乏力、多汗及精神萎靡；实验室检查提示低血糖、代谢性酸中毒、乳酸升高及血酮体升高。所有患者均检出FBP1基因纯合或复合杂合变异，其中发现3个位点为首次报道（c.242T>C、c.469G>C、c.115C>A）。随访6个月至6年，在严格饮食管理和密切血糖监测下，所有患儿疾病均控制良好，身心发育水平均基本正常。截至2025年12月20日，国内共报道38例FBP1D患者，其中男23例、女15例，最常见表现为低血糖、代谢性酸中毒及抽搐；81.6%的患者智力与运动发育正常，无神经系统后遗症。最常见的FBP1基因变异位点为c.960dup、c.960del、c.490G>A、c.704del、c.355G>A。结论酮症性低血糖同时伴有代谢性酸中毒和乳酸升高，需警惕FBP1D可能，建议进行基因检测。FBP1D患儿通过合理的饮食管理及血糖监测，可有效避免低血糖频繁发作；随年龄增长，低血糖发作逐渐减少，大多数患儿预后良好。

关键词: 酮症性低血糖, FBP1基因, 果糖-1, 6-二磷酸酶缺乏症, 儿童

Abstract:

Objective To summarize the clinical features and genetic variation characteristics of children with fructose-1,6-bisphosphatase deficiency (FBP1D) caused by FBP1 gene variations. Methods Four pediatric patients with FBP1D admitted from January 2019 to June 2025 were enrolled as study subjects. Their clinical manifestations, laboratory findings, genetic testing results, treatment strategies, and prognosis were analyzed retrospectively. Additionally, a literature review was conducted to summarize data of previously reported Chinese FBP1D patients. Results The four patients were from four unrelated families, including 1 male and 3 females, with ages at diagnosis of 2 years and 3 months, 3 years and 5 months, 2 years and 11 months, and 4 years and 4 months, respectively. Core clinical presentations included fever, vomiting, anorexia, accompanied by drowsiness, fatigue, hyperhidrosis, and lethargy. Laboratory tests revealed hypoglycemia, metabolic acidosis, elevated lactate, and increased blood ketone bodies. All patients carried homozygous or compound heterozygous FBP1 gene variants, among which three novel variants were identified (c.242T>C, c.469G>C, c.115C>A). During a follow-up period of 6 months to 6 years, all patients achieved well-controlled disease under strict dietary management and close blood glucose monitoring, with essentially normal physical and mental development. As of December 20, 2025, a total of 38 FBP1D cases had been reported in China (23 males, 15 females), with the most common manifestations being hypoglycemia, metabolic acidosis, and convulsions. Approximately 81.6% of patients exhibited normal intellectual and motor development without neurological sequelae. The most frequent FBP1 gene variants were c.960dup, c.960del, c.490G>A, c.704del, and c.355G>A. Conclusion Ketotic hypoglycemia accompanied by metabolic acidosis and elevated lactate should raise suspicion of FBP1D, and genetic testing is recommended in such cases. Rational dietary management and blood glucose monitoring can effectively reduce the frequency of hypoglycemic episodes in FBP1D children. Hypoglycemic attacks tend to decrease with age, and most patients have a favorable prognosis.

Key words: ketotic hypoglycemia, FBP1 gene, fructose-1, 6-bisphosphatase deficiency, child

中图分类号:

黄书越, 程明, 王稀欧, 宋弋, 杜牧, 宋福英, 曹冰燕. 儿童果糖-1，6-二磷酸酶缺乏症4例临床特征与文献复习[J]. 临床儿科杂志, 2026, 44(5): 438-444.

HUANG Shuyue, CHENG Ming, WANG Xi′ou, SONG Yi, DU Mu, SONG Fuying, CAO Bingyan. Clinical features of fructose-1,6-bisphosphatase deficiency in 4 children and literature review[J]. Journal of Clinical Pediatrics, 2026, 44(5): 438-444.

图/表 2

表1

表2

参考文献 30

[1]	Baker L, Winegrad AI. Fasting hypoglycemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-bisphosphatase activity[J]. Lancet, 1970, 2: 13-16. pmid: 4193749
[2]	Bijarnia-Mahay S, Bhatia S, Arora V. Fructose-1,6-bisphosphatase deficiency[EB/OL]. Seattle (WA): University of Washington, 1993-2025. https://www.ncbi.nlm.nih.gov/books/.
[3]	Piziak VK, Cryar AK. Hypoglycemic disorders[J]. N Engl J Med, 1995, 332(17): 1154.
[4]	Metwalley KA, Farghaly HS. Idiopathic ketotic hypoglycemia in children: an update[J]. Ann Pediatr Endocrinol Metab, 2024, 29(3): 152-155. doi: 10.6065/apem.2346156.078
[5]	Li N, Chang G, Xu Y, et al. Clinical and molecular characterization of patients with fructose-1,6-bisphosphatase deficiency[J]. Int J Mol Sci, 2017, 18(4): 857. doi: 10.3390/ijms18040857
[6]	刘颖文, 闫露露, 张玉鑫, 等. FBP1基因变异致果糖-1, 6-二磷酸酶缺乏症患儿1例的临床及遗传学分析并文献复习[J]. 中华医学遗传学杂志, 2025, 42(6): 719-728.
	Liu YW, Yan LL, Zhang YX, et al. Clinical and genetic analysis of a child with fructose-1,6-bisphosphatase deficiency caused by FBP1 gene variation and literature review[J]. Zhonghua Yixue Yichuanxue Zazhi, 2025, 42(6): 719-728.
[7]	王华, 薛峰, 熊复, 等. 果糖-1,6-二磷酸酶缺乏症基因型-表型相关性研究: 一例报告及文献复习[J]. 国际生殖健康/计划生育杂志, 2025, 44(5): 377-382.
	Wang H, Xue F, Xiong F, et al. Genotype-phenotype correlation study of fructose-1,6-bisphosphatase deficiency: a case report and literature review[J]. Guoji Shengzhi Jiankang/Jihua Shengyu Zazhi, 2025, 44(5): 377-382..
[8]	张赟健, 路通, 王艺. FBP1基因突变致果糖-1,6-二磷酸酶缺乏的癫痫持续状态1例并文献复习[J]. 中国循证儿科杂志, 2018, 13(3): 219-223.
	Zhang YJ, Lu T, Wang Y. Status epilepticus caused by FBP1 gene mutation in fructose-1,6-bisphosphatase deficiency: a case report and literature review[J]. Zhongguo Xunzheng Erke Zazhi, 2018, 13(3): 219-223.
[9]	杨蒙洁, 卢一丽, 吴慧平, 等. 一例延迟诊断7年的果糖-1,6-二磷酸酶缺乏症报道及文献复习[J]. 中华内分泌代谢杂志, 2021, 37(5): 457-461.
	Yang MJ, Lu YL, Wu HP, et al. A case report of fructose-1,6-bisphosphatase deficiency with delayed diagnosis for 7 years and literature review[J]. Zhonghua Neifenmi Daixie Zazhi, 2021, 37(5): 457-461.
[10]	Doğruel H, Aydemir M, Yılmaz N, et al. An extremely rare case of hypoglycemia with a novel mutation and review of the literature: fructose1,6 bisphosphatase deficiency in an adult man[J]. Ir J Med Sci, 2024, 193(3): 1267-1273. doi: 10.1007/s11845-024-03614-8
[11]	Visser G, Bakker H, Klerk JD, et al. Natural history and treatment of fructose-1,6, bisphosphatase deficiency in the Netherlands[J]. J Inherit Metab Dis, 2004, 27(1 Suppl): 207.
[12]	Lebigot E, Brassier A, Zater M. et al. Fructose-1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients[J]. J Inherit Metab Dis, 2015, 38(5): 881-887. doi: 10.1007/s10545-014-9804-6 pmid: 25601412
[13]	Pinheiro FC, Sperb-Ludwig F, Ligabue-Braun R. et al. Genetic analysis of patients with fructose-1,6- bisphosphatase deficiency[J]. Gene, 2019, 699: 102-109. doi: 10.1016/j.gene.2019.03.007
[14]	Ni Q, Tang M, Chen X. et al. Fructose-1,6- bisphosphatase deficiency: estimation of prevalence in the Chinese population and analysis of genotype-phenotype association[J]. Front. Genet, 2024, 15:1296797. doi: 10.3389/fgene.2024.1296797
[15]	Emecen Sanli M, Cengiz B, et al. Fructose 1,6 bisphosphatase deficiency: outcomes of patients in a single center in Turkey and identification of novel splice site and indel mutations in FBP1[J]. J Pediatr Endocrinol Metab, 2022, 35(4): 497-503. doi: 10.1515/jpem-2021-0732 pmid: 35179010
[16]	Kılıç M, Kasapkara ÇS, Yılmaz DY. Exon 2 deletion represents a common mutation in Turkish patients with fructose-1,6-bisphosphatase deficiency[J]. Metab Brain Dis, 2019, 34: 1487-1491. doi: 10.1007/s11011-019-00455-8 pmid: 31278438
[17]	Santer R, du Moulin M, Shahinyan T, et al. A summary of molecular genetic findings in fructose-1,6-bisphosphatase deficiency with a focus on a common long-range deletion and the role of MLPA analysis[J]. Orphanet J Rare Dis, 2016, 11: 44. doi: 10.1186/s13023-016-0415-1 pmid: 27101822
[18]	Bhai P, Bijarnia-Mahay S, Puri RD, et al. Clinical and molecular characterization of Indian patients with fructose-1, 6- bisphosphatase deficiency: identification of a frequent variant (E281K)[J]. Ann Hum Genet, 2018, 82(5): 309-317. doi: 10.1111/ahg.2018.82.issue-5
[19]	Yasir Zahoor M, Cheema HA, Ijaz S, et al. Genetic analysis of tyrosinemia type 1 and fructose-1, 6 bisphosphatase deficiency affected in Pakistani cohorts[J]. Fetal Pediatr Pathol, 2020, 39(5): 430-440. doi: 10.1080/15513815.2019.1672224
[20]	Ijaz S, Zahoor MY, Imran M, et al. Genetic analysis of fructose-1,6-bisphosphatase (FBPase) deficiency in nine consanguineous Pakistani families[J]. J Pediatr Endocrinol Metab 2017, 30: 1203-1210. doi: 10.1515/jpem-2017-0188 pmid: 29016355
[21]	Matsuura T, Chinen Y, Arashiro R, et al. Two newly identified genomic mutations in a Japanese female patient with fructose-1, 6-bisphosphatase (FBPase) deficiency[J]. Mol Genet Metab, 2002, 76: 207e10. doi: 10.1016/S1096-7192(02)00038-0
[22]	Salih RM, Mohammed EA, Alhashem AM, et al. Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis. An important cause of hypoglycemia in children[J]. Saudi Med J, 2020, 41(2): 199-202 doi: 10.15537/smj.2020.2.24885 pmid: 32020156
[23]	王霞, 邱文娟. 糖原累积病I型研究进展[J]. 国际儿科学杂志, 2008, 35(5): 436-438.
	Wang X, Qiu WJ. Research progress of glycogen storage disease type I[J]. Guoji Erkexue Zazhi, 2008, 35(5): 436-438.
[24]	el-Maghrabi MR, Lange AJ, Jiang W, et al. Human fructose-1,6-bisphosphatase gene (FBP1): exonintron organization, localization to chromosome bands 9q22.2q22.3, and mutation screening in subjects with fructose-1,6-bisphosphatase deficiency[J]. Genomics, 1995, 27: 520-525. pmid: 7558035
[25]	喻菱, 陈晓红. 1例FBP1基因突变导致的果糖-1,6-二磷酸酶缺乏症的临床及遗传学分析[J] .标记免疫分析与临床, 2025, 32(5): 1089-1097.
	Yu L, Chen XH. Clinical and genetic analysis of a case with fructose-1,6-bisphosphatase deficiency caused by FBP1 gene mutation[J]. Biaoji Mianyi Fenxi Yu Linchuang, 2025, 32(5): 1089-1097.
[26]	寇睿, 陈志红. 果糖-1,6-二磷酸酶缺乏症诊疗进展[J]. 国际儿科杂志, 2019, 44(8): 535-538.
	Kou R, Chen ZH. Advances in diagnosis and treatment of fructose-1,6-bisphosphatase deficiency[J]. Guoji Erke Zazhi, 2019, 44(8): 535-538.
[27]	程燕丽, 王丽, 韩乐, 等. 先天性果糖代谢缺陷病的研究进展[J]. 生理科学进展, 2020, 51(6): 469-474.
	Cheng YL, Wang L, Han L, et al. Research progress of congenital fructose metabolism defects[J]. Shengli Kexue Jinzhan, 2020, 51(6): 469-474.
[28]	Pinto A, Alfadhel M, Akroyd R, et al. International practices in the dietary management of fructose 1-6 biphosphatase deficiency[J]. Orphanet J Rare Dis, 2018, 25, 13(1): 21. doi: 10.1186/s13023-018-0760-3 pmid: 29370874
[29]	Ferguson C, Madison A, Hamosh A, et al. Metabolic management of a successful pregnancy and postpartum complications in fructose-1,6-bisphosphatase deficiency[J]. JIMD Rep, 2024, 65(6): 401-405 doi: 10.1002/jmd2.12453 pmid: 39512430
[30]	Gorce M, Lebigot E, Arion A, et al. Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up[J]. J Inherit Metab Dis, 2022, 45(2): 215-222. doi: 10.1002/jimd.v45.2

项目	例1	例2	例3	例4
性别	女	女	男	女
起病年龄	1岁8月龄	2岁9月龄	2岁11月龄	1岁4月龄
诊断年龄	2岁3月龄	3岁5月龄	2岁11月龄	4岁4月龄
确诊时身高/cm 体重/kg	92.5(P₇₅~P₉₀) 16.5(>P₉₇)	96.5(P₂₅~P₅₀) 16.4(P₇₅~P₉₀)	90(P₃~P₁₀) 11.7(P₃~P₁₀)	100(P₁₀) 15(P₁₀~P₂₅)
红细胞/10¹²·L^-1	5.10	4.18	4.03	4.21
血红蛋白/g·L^-1	136	107	118	115
血气pH值	7.16	7.2	7.28	7.07
HCO^-₃/mmol·L^-1	7.8	7.3	17	6.5
BE/mmol·L^-1	-19.1	-17.1	-6.3	-24.8
乳酸/mmol·L^-1	12.10	3.82	2.70	7
葡萄糖/mmol·L^-1	1.20	2.66	2.63	<1.10
胰岛素/μIU·mL^-1	<0.20	0.30	<0.20	0.25
C肽/ng·mL^-1	0.198	0.204	0.133	0.960
D3羟丁酸/mmol·L^-1	1.58	2.67	3.49	5.48
HbA1C	5.2	5.0	5.2	5.0
皮质醇/μg·dL^-1	23.90	25.31	20.49	16.49
ACTH/pg·mL^-1	88.6	45.6	74.1	26.6
ALT/U·L^-1	65.6	15.1	29.7	58.4
AST/U·L^-1	56.2	25.9	28.4	28.3
三酰甘油/mmol·L^-1	0.49	1.03	0.73	2.30
肌酐/μmol·L^-1	21.2	22	24.8	32
尿素氮/mmol·L^-1	3.7	5.3	4.3	5.6
尿酸/mmol·L^-1	667	494	747	720
K⁺/mmol·L^-1	3.8	3.5	4.7	3.4
Na⁺/mmol·L^-1	136	133	139	131
Cl^-/mmol·L^-1	105	95	107	92
尿液有机酸分析	乳酸、酮体、双羧酸、丙氨酸升高	酮体、甘油升高	酮体、甘油稍高	乳酸、酮体升高
血氨基酸及酯酰肉碱谱	乳酸，丙酮酸升高	乳酸升高	未见明显异常	丙氨酸升高
腹部超声	脂肪肝，肝大	未见明显异常	未见明显异常	肝实质密度减低，肝大
头颅鞍区MRI	未见明显异常	未见明显异常	未见明显异常	-

患儿	核苷酸改变	氨基酸改变	变异状态	变异类型	来源	外显子/ 遗传方式	ACMG证据	变异评级
例1	c.861C>A	p.Tyr287Ter	复合杂合	错义突变	母亲	exon7/AR	PVS1_Strong+PM2_Supporting+PM3_Strong+PP4	P
例1	c.242T>C	p.Leu81Pro	复合杂合	错义突变	父亲	exon2/AR	PM2_Supporting+PM3+PP3_Moderate+PP4	LP
例2	c.490G>A	p.Gly164Ser	复合杂合	错义突变	母亲	exon4/AR	PS3_Supporting+PM2_Supporting+ PM3_VeryStrong+PP1+PP3_Moderate	P
例2	c.469G>C	p.Gly157Arg	复合杂合	错义突变	父亲	exon4/AR	PM2_Supporting+PM3+PP3_Moderate	VUS
例3	c.490G>A	p.Gly164Ser	纯合	错义突变	父母	exon4/AR	PS3_Supporting+PM2_Supporting+ PM3_VeryStrong+PP1+PP3_Moderate	P
例4	c.155C>A	p.Ala52Glu	纯合	错义突变	母亲	exon1/AR	PM2_Supporting+PP3_Moderate	VUS
例4	c.155C>A	p.Ala52Glu	纯合	错义突变	自发变异	exon1/AR	PM2_Supporting+PP3_Moderate	VUS