非典型染色体22q11.2缺失导致成人起病甲状旁腺功能减退症家系及文献分析

Atypical deletion of chromosome 22ql1.2 caused an adult-onset hypoparathyroidism:A case report and literature review

目的分析1例以成人起病的甲状旁腺功能减退症患者及其家系的临床特征及致病基因。方法先证者成年起病,以反复手足麻木3年余,意识不清6 d为主要表现的患者,总结其与家系成员的临床特征。采用多重连接探针扩增技术(multiplex ligation-dependent probe amplification assay,MLPA)及基于二代全基因组测序技术的基因组拷贝数变异测序(copy number variation sequencing,CNV-seq)分析本例家系染色体22q11.2区域的拷贝数变异。结果先证者主要表现为反复手足麻木,血钙及甲状旁腺素水平明显降低,头颅CT示基底节区钙化,临床诊断考虑为甲状旁腺功能减退症。由于患者具有宽眼距及小下颌面容特征,心脏超声提示房间隔膨出瘤,因此考虑22q11.2缺失综合征可能。使用MLPA检测到先证者及其次子染色体22q11.2区域存在杂合性缺失,进一步CNV-seq证实缺失片段位置为chr22:19217940_19879956(hg38),长度约0.66 Mb。缺失片段的断裂点均位于低拷贝重复序列(low copy repetitives,LCRs)以外,即LCR22A+至LCR22B-,为一种非典型缺失,目前尚未见文献报道。结论22q11.2缺失综合征临床异质性大,为遗传性甲状旁腺功能减退症常见病因,通过对患者甲状旁腺外临床表现及分子遗传学分析,可提高该病的诊治水平。

Objective To analyze the phenotype of a patient with adult-onset hypoparathyroidism and detect its pathogenic mutation.Methods A 26-year-old female was included who suffered from repeated numbness of hands and feet for more than 3 years and unconsciousness for 6 days.Clinical characteristics,biochemical features and imaging manifestations of the proband and her family members were evaluated.Multiplex ligation-dependent probe amplification assay(MLPA)and copy number variation sequencing(CNV-seq)based on next generation sequencing were used to analyze the copy number of chromosome 22q11.2.Results The main symptom of the proband was repeated numbness of the hands and feet.The serum calcium and parathyroid hormone levels were significantly decreased,and the head CT showed calcification in the basal ganglia.The clinical diagnosis was considered to be hypoparathyroidism.Because the proband showed facial features of ocular hypertelorism and micrognathia and echocardiography suggested atrial septal aneurysm,the possibility of 22ql1.2 deletion syndrome was considered.The proband and her younger son were found to harbor a heterozygosity loss in the chromosome 22ql1.2 region by MLPA.Further CNV-seq based on next generation sequencing confirmed that the deletion fragment was located at chr22:19217940_19879956(hg38),with a length of about 0.66 Mb.The breakpoint of the deletion fragment was located outside the low copy repetitive sequences(LCRs),namely LCR22A+to LCR22B-.The above atypical deletion of 22ql1.2 region has not been reported in the literature.Conclusions The 22ql1.2 deletion syndrome has great clinical heterogeneity and is a common cause of hereditary hypoparathyroidism.Analyzing the clinical manifestations outside of the parathyroid and molecular genetics could improve the knowledge of the disease and avoid misdiagnosis.