1例肾单位肾痨12型的临床特点及TTC21B基因型研究
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摘要
肾单位肾痨(NPHP)是一组常染色隐性遗传,主要累及肾小管间质的囊性肾病。该文报道1例TTC21B基因突变所致的NPHP 12型。患儿女,起病隐匿,3岁6个月首次就诊时即存在中量蛋白尿、肾功能损害、高血压2期,并伴有内脏反位、短指/趾,4岁前进展到终末期肾病。尿蛋白电泳以肾小球性蛋白尿为主。尿β2-微球蛋白、尿α1-微球蛋白等肾小管指标均明显增高。基因检测显示TTC21B基因存在c.1552T>C(p.C518R)、c.752T>G(p.M251R)复合杂合突变,前者来自父亲,后者来自母亲。c.752T>G为新发突变。TTC21B基因突变患儿的肾脏病理除了NPHP典型的肾小管改变外,多同时存在显著的肾小球损害。[中国当代儿科杂志,2019,21(6):580-584]
Nephronophthisis(NPHP) is a group of autosomal recessive tubulointerstitial cystic kidney disorders. This article reports a case of NPHP type 12 caused by TTC21 B mutations. The girl had an insidious onset, with moderate proteinuria, renal dysfunction, stage 2 hypertension, situs inversus, and short phalanges when she visited the hospital for the first time at the age of 3 years and 6 months. The renal lesions progressed to end-stage renal disease(ESRD) before she was 4 years old. Urine protein electrophoresis showed glomerular proteinuria. There were significant increases in urinary β2-microglobulin and α1-microglobulin. Gene detection revealed two compound heterozygous mutations, c.1552 T>C(p.C518 R) and c.752 T>G(p.M251 R), in the TTC21 B gene, which came from her father and mother respectively. The c.752 T>G mutation was a novel mutation. It is concluded that besides typical tubular changes of NPHP, marked glomerular damage is also observed in patients with TTC21 B gene mutations.[Chin J Contemp Pediatr, 2019, 21(6): 580-584]
Nephronophthisis(NPHP) is a group of autosomal recessive tubulointerstitial cystic kidney disorders. This article reports a case of NPHP type 12 caused by TTC21 B mutations. The girl had an insidious onset, with moderate proteinuria, renal dysfunction, stage 2 hypertension, situs inversus, and short phalanges when she visited the hospital for the first time at the age of 3 years and 6 months. The renal lesions progressed to end-stage renal disease(ESRD) before she was 4 years old. Urine protein electrophoresis showed glomerular proteinuria. There were significant increases in urinary β2-microglobulin and α1-microglobulin. Gene detection revealed two compound heterozygous mutations, c.1552 T>C(p.C518 R) and c.752 T>G(p.M251 R), in the TTC21 B gene, which came from her father and mother respectively. The c.752 T>G mutation was a novel mutation. It is concluded that besides typical tubular changes of NPHP, marked glomerular damage is also observed in patients with TTC21 B gene mutations.[Chin J Contemp Pediatr, 2019, 21(6): 580-584]
引文
[1]Hildebrandt F,Attanasio M,Otto E.Nephronophthisis:disease mechanisms of a ciliopathy[J].J Am Soc Nephrol,2009,20(1):23-35.
[2]管娜,张宏文,丁洁,等.家族性少年型肾单位肾痨的临床和基因诊断[J].临床儿科杂志,2008,26(4):287-290.
[3]孙良忠,林宏容,岳智慧,等.少年型肾单位肾痨13例临床特点和基因突变分析[J].中华儿科杂志,2016,54(11):834-839.
[4]Richards S,Aziz N,Bale S,et al.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J].Genet Med,2015,17(5):405-424.
[5]Zhang H,Su B,Liu X,et al.Mutations in TTC21B cause different phenotypes in two childhood cases in China[J].Nephrology(Carlton),2018,23(4):371-376.
[6]Waldherr R,Lennert T,Weber HP,et al.The nephronophthisis complex.A clinicopathologic study in children[J].Virchows Arch A Pathol Anat Histol,1982,394(3):235-254.
[7]Potter DE,Holliday MA,Piel CF,et al.Treatment of end-stage renal disease in children:a 15-year experience[J].Kidney Int,1980,18(1):103-109.
[8]Bullich G,Vargas I,Trujillano D,et al.Contribution of the TTC21B gene to glomerular and cystic kidney diseases[J].Nephrol Dial Transplant,2017,32(1):151-156.
[9]Schueler M,Halbritter J,Phelps IG,et al.Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies[J].J Med Genet,2016,53(3):208-214.
[10]Kang HG,Lee HK,Ahn YH,et al.Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy[J].Exp Mol Med,2016,48:e251.
[11]McInerney-Leo AM,Harris JE,Leo PJ,et al.Whole exome sequencing is an efficient,sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies[J].Clin Genet,2015,88(6):550-557.
[12]Neuhaus TJ,Stallmach T,Leumann E,et al.Familial progressive tubule-interstitial nephropathy and cholestatic liver disease-a newly recognized entity?[J].Eur J Pediatr,1997,156(9):723-726.
[13]Huynh Cong E,Bizet AA,Boyer O,et al.A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS[J].J Am Soc Nephrol,2014,25(11):2435-2443.
[14]Otto EA,Ramaswami G,Janssen S,et al.Mutation analysis of18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy[J].J Med Genet,2011,48(2):105-116.
[15]Davis EE,Zhang Q,Liu Q,et al.TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum[J].Nat Genet,2011,43(3):189-196.
[16]Halbritter J,Porath JD,Diaz KA,et al.Identification of 99novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy[J].Hum Genet,2013,132(8):865-884.
[2]管娜,张宏文,丁洁,等.家族性少年型肾单位肾痨的临床和基因诊断[J].临床儿科杂志,2008,26(4):287-290.
[3]孙良忠,林宏容,岳智慧,等.少年型肾单位肾痨13例临床特点和基因突变分析[J].中华儿科杂志,2016,54(11):834-839.
[4]Richards S,Aziz N,Bale S,et al.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J].Genet Med,2015,17(5):405-424.
[5]Zhang H,Su B,Liu X,et al.Mutations in TTC21B cause different phenotypes in two childhood cases in China[J].Nephrology(Carlton),2018,23(4):371-376.
[6]Waldherr R,Lennert T,Weber HP,et al.The nephronophthisis complex.A clinicopathologic study in children[J].Virchows Arch A Pathol Anat Histol,1982,394(3):235-254.
[7]Potter DE,Holliday MA,Piel CF,et al.Treatment of end-stage renal disease in children:a 15-year experience[J].Kidney Int,1980,18(1):103-109.
[8]Bullich G,Vargas I,Trujillano D,et al.Contribution of the TTC21B gene to glomerular and cystic kidney diseases[J].Nephrol Dial Transplant,2017,32(1):151-156.
[9]Schueler M,Halbritter J,Phelps IG,et al.Large-scale targeted sequencing comparison highlights extreme genetic heterogeneity in nephronophthisis-related ciliopathies[J].J Med Genet,2016,53(3):208-214.
[10]Kang HG,Lee HK,Ahn YH,et al.Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy[J].Exp Mol Med,2016,48:e251.
[11]McInerney-Leo AM,Harris JE,Leo PJ,et al.Whole exome sequencing is an efficient,sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies[J].Clin Genet,2015,88(6):550-557.
[12]Neuhaus TJ,Stallmach T,Leumann E,et al.Familial progressive tubule-interstitial nephropathy and cholestatic liver disease-a newly recognized entity?[J].Eur J Pediatr,1997,156(9):723-726.
[13]Huynh Cong E,Bizet AA,Boyer O,et al.A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS[J].J Am Soc Nephrol,2014,25(11):2435-2443.
[14]Otto EA,Ramaswami G,Janssen S,et al.Mutation analysis of18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy[J].J Med Genet,2011,48(2):105-116.
[15]Davis EE,Zhang Q,Liu Q,et al.TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum[J].Nat Genet,2011,43(3):189-196.
[16]Halbritter J,Porath JD,Diaz KA,et al.Identification of 99novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy[J].Hum Genet,2013,132(8):865-884.