背景:范可尼-比克尔综合征(FBS)是一种罕见的常染色体隐性遗传疾病,其特征是葡萄糖和半乳糖利用受损以及近端肾小管功能障碍。
方法:临床,生物化学,遗传,治疗,对11例FBS患儿的随访数据进行回顾性分析.
结果:肝肿大(10/11),身材矮小(10/11)和低磷血症性病(7/11)是最常见的初始症状。诊断时,所有患者空腹血糖(FBG)均下降,血浆碳酸氢盐(HCO3-)和血清磷,以及肝转氨酶升高,碱性磷酸酶(AKP)和近端肾小管功能障碍。2例患儿误诊为短暂性新生儿糖尿病。经过未煮熟的玉米淀粉和常规的病治疗,在所有患者中观察到肝肿大的缓解,随着餐前血糖的显著改善,肝转氨酶,甘油三酯,血浆HCO3-和AKP(p<0.05)。在最后一次随访中,5/7AKP升高的患者有肾钙质沉着症。8名接受常规治疗的患者的平均身高标准差评分(HtSDS)从-4.1增加到-3.5(p=0.02)。重组人生长激素(rhGH)给予4/9患者,但他们的HtSDS没有明显改善(p=0.13)。确定了SLC2A2基因的14种变体,六个是小说,其中1例复发:c.1217T>G(p.L406R)(等位基因频率:4/22,18%)。具有双等位基因错义变异的患者比具有无效变异的患者表现出更轻的代谢性酸中毒。来自罕见纯合变异的非近亲家庭的五名患者中,有两名在变异周围显示出5.3Mb和36.6Mb的纯合性,分别;涉及覆盖SLC2A2基因的整个3号染色体的纯合性区域(ROH),提示在一名患者中检测到单亲二组3。
结论:由于初始症状的异质性,FBS的早期诊断很困难。虽然身材矮小是FBS治疗的主要问题,在有正常GH刺激试验的FBS患者中不推荐使用rhGH。具有双等位基因无效变体的患者可能需要补充碱,因为尿碳酸氢盐的损失是遗传相关的。ROH是非近亲家族中罕见的FBS纯合变体的机制。
BACKGROUND: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction.
METHODS: Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed.
RESULTS: Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient.
CONCLUSIONS: Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.