1例3β-羟类固醇脱氢酶缺乏症临床特点及基因突变结果分析
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摘要
为探索3β-羟类固醇脱氢酶(3β-HSD)缺乏症患儿的临床特点和基因突变特点,为临床诊治提供思路,本文对1例在广州市妇女儿童医疗中心遗传与内分泌科门诊就诊的3β-HSD缺乏症患儿的临床特点、激素水平检测结果及基因突变进行分析,并复习相关文献。本例患儿因皮肤色素沉着,阴蒂肥大就诊。B超显示子宫、卵巢组织。染色体核型为46XX。激素水平显示血促肾上腺皮质激素(ACTH)水平升高,血皮质醇(F)水平下降,硫酸脱氢表雄酮(DHEAs)水平增高,HSD3B2基因纯合错义突变,为第228位氨基酸由缬氨酸变为甲硫氨酸。3β-HSD缺乏症患儿可表现有失盐型及男性化型,与其他类型的先天性肾上腺皮质增生症不容易鉴别,△5类固醇增高及△5/△4类固醇比例增高提示3β-HSD缺乏症的可能,基因检测可进一步确诊。
To explore the clinical characteristics and gene mutation features of 3β-hydroxysteroid dehydrogenase(3β-HSD) deficiency in children to provide ideas for clinical diagnosis and treatment, this paper analyzes the clinical characteristics, hormone levels detection results and gene mutations of a child with 3β-HSD deficiency in the department of genetics and endocrinology of Guangzhou Women and Children Medical Center, and relevant literatures were reviewed. In this case, the child visited doctor for skin hyperpigmentation and clitorimegaly. B-ultrasound showed uterine, ovarian tissue. The karyotype is 46 XX. The hormone levels showed rising of blood adrenocorticotrophic hormone(ACTH), decrease of blood cortisol(F), and increase of dehydroepiandrosterone sulfate(DHEAs). HSD3 B2 gene homozygous missense mutation was due to the amino acid at position 228 changing from valine to methionine. Children with 3β-HSD deficiency may exhibit salt wasting phenotype and masculinization, which are not easily differentiated from other types of congenital adrenal hyperplasia. Increased △5 steroids and increase of △5/Δ4 steroids suggest possible 3β-HSD deficiency, which can be further confirmed by genetic testing.
To explore the clinical characteristics and gene mutation features of 3β-hydroxysteroid dehydrogenase(3β-HSD) deficiency in children to provide ideas for clinical diagnosis and treatment, this paper analyzes the clinical characteristics, hormone levels detection results and gene mutations of a child with 3β-HSD deficiency in the department of genetics and endocrinology of Guangzhou Women and Children Medical Center, and relevant literatures were reviewed. In this case, the child visited doctor for skin hyperpigmentation and clitorimegaly. B-ultrasound showed uterine, ovarian tissue. The karyotype is 46 XX. The hormone levels showed rising of blood adrenocorticotrophic hormone(ACTH), decrease of blood cortisol(F), and increase of dehydroepiandrosterone sulfate(DHEAs). HSD3 B2 gene homozygous missense mutation was due to the amino acid at position 228 changing from valine to methionine. Children with 3β-HSD deficiency may exhibit salt wasting phenotype and masculinization, which are not easily differentiated from other types of congenital adrenal hyperplasia. Increased △5 steroids and increase of △5/Δ4 steroids suggest possible 3β-HSD deficiency, which can be further confirmed by genetic testing.
引文
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[9]刘彦玲,孙首悦,秦雪艳,等.2例3β-羟类固醇脱氢酶缺陷症的临床特点及分子遗传学研究[J].中华内分泌代谢杂志,2016,32(2):98-102.
[10]Bizzarri C,Massimi A,Federici L,et al.A new homozygous frameshift mutation in the HSD3B2 gene in an apparently nonconsanguineous Italian family[J].Horm Res Paediatr,2016,86(1):53-61.
[11]黄永兰,郑纪鹏,谢婷,等.HSD3B2基因p.E25X新纯合突变致失盐型3β-羟类固醇脱氢酶缺乏症一例及文献复习[J].中华儿科杂志,2014,52(12):948-951.
[12]陈瑞敏,李云斐,袁欣.先天性肾上腺皮质增生症罕见类型[J].中华实用儿科临床杂志,2015,30(8):570-574.
[13]Rabbani B,Mahdieh N,Haghi Ashtiani MT,et al.In silico structural,functional and pathogenicity evaluation of a novel mutation:an overview of HSD3B2 gene mutations[J].Gene,2012,503(2):215-221.
[14]Birkebaek NH,Hougaard DM,Cohen AS.Monitoring steroid replacement therapy in children with congenital adrenal hyperplasia[J].J Pediatr Endocrinol Metab,2017,30(1):85-88.
[15]Speiser PW,White PC.Congenital adrenal hyperplasia[J].NEngl J Med,2003,349(8):776-788.
[2]Benkert AR,Young M,Robinson D,et al.Severe salt-losing3β-hydroxysteroid dehydrogenase deficiency:treatment and outcomes of HSD3B2 c.35G>A homozygotes[J].J Clin Endocrinol Metab,2015,100(8):E1105-E1115
[3]Flück CE,Pandey AV.Steroidogenesis of the testis-new genes and pathways[J].Ann Endocrinol(Paris),2014,75(2):40-47.
[4]Simard J,Ricketts ML,Gingras S,et al.Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family[J].Endocr Rev,2005,26(4):525-582.
[5]Moisan AM,Ricketts ML,T ardy V,et al.New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency:identification of eight mutations in the HSD3B2gene eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes[J].J Clin Endocrinol Metab,1999,84(12):4410-4425.
[6]Pang S,Wang W,Rich B,et al.A novel nonstop mutation in the stop codon and a novel missense mutation in the typeⅡ3beta-hydroxysteroid dehydrogenase(3beta-HSD)gene causing,respectively,nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia[J].J Clin Endocrinol Metab,2002,87(6):2556-2563.
[7]Katsumata N,Tanae A,Yasunaga T,et al.A novel missense mutation in the typeⅡ3 beta-hydroxysteroid dehydrogenase gene in a family with classical salt-wasting congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency[J].Hum Mol Genet,1995,4(4):745-746.
[8]Zhang L,Mason JI,Naiki Y,et al.Characterization of two novel homozygous missense mutations involving codon 6and 259 of typeⅡ3beta-hydroxysteroid dehydrogenase(3betaHSD)gene causing,respectively,nonsalt-wasting and salt-wasting 3betaHSD deficiency disorder[J].J Clin Endocrinol Metab,2000,85(4):1678-1685.
[9]刘彦玲,孙首悦,秦雪艳,等.2例3β-羟类固醇脱氢酶缺陷症的临床特点及分子遗传学研究[J].中华内分泌代谢杂志,2016,32(2):98-102.
[10]Bizzarri C,Massimi A,Federici L,et al.A new homozygous frameshift mutation in the HSD3B2 gene in an apparently nonconsanguineous Italian family[J].Horm Res Paediatr,2016,86(1):53-61.
[11]黄永兰,郑纪鹏,谢婷,等.HSD3B2基因p.E25X新纯合突变致失盐型3β-羟类固醇脱氢酶缺乏症一例及文献复习[J].中华儿科杂志,2014,52(12):948-951.
[12]陈瑞敏,李云斐,袁欣.先天性肾上腺皮质增生症罕见类型[J].中华实用儿科临床杂志,2015,30(8):570-574.
[13]Rabbani B,Mahdieh N,Haghi Ashtiani MT,et al.In silico structural,functional and pathogenicity evaluation of a novel mutation:an overview of HSD3B2 gene mutations[J].Gene,2012,503(2):215-221.
[14]Birkebaek NH,Hougaard DM,Cohen AS.Monitoring steroid replacement therapy in children with congenital adrenal hyperplasia[J].J Pediatr Endocrinol Metab,2017,30(1):85-88.
[15]Speiser PW,White PC.Congenital adrenal hyperplasia[J].NEngl J Med,2003,349(8):776-788.