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A Chinese tuberous sclerosis complex family and a novel tuberous sclerosis complex-2 mutation.

Luo R, Cai Q, Mu D - Chin. Med. J. (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, West China Second University Hospital; Key Laboratory of Obstetric and Gynecologic and Pediatric Dieases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan 610041, China.

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The incidence of TSC in Chinese population is still unknown although case reports of Chinese TSC patients were documented... Two causative genes for TSC, TSC1 gene on chromosome 9q34 and TSC2 gene on chromosome16p13, have been identified in 1997 and 1993 respectively... Chinese TSC patients are more likely to have TSC2 missense and frame shift mutations... The proband, a 16-year-old male, first presented with frequent focal motor seizures at age of 6 years and was clinically diagnosed as TSC at age of 9 years... Physical examination found forehead fibrous plaque, facial angiofibromas [Figure 1a], hypopigmented macules, and shagreen patches on his back. [Figure 1b]... He has shown moderate mental retardation and failed to pass any academic examinations... Tuberous sclerosis complex 1 and TSC2 genes, the pathogenic genes of TSC, are indicated as tumor suppressor genes due to their function in regulation of cell growth and differentiation by inhibiting the mammalian target of rapamycin (mTOR) in the Akt-mTOR-S6kinase cell growth pathway... Mutations including nonsense mutations, small deletions, splice site changes, missense mutations, and sometimes large deletions or rearrangements can occur over the entire regions of TSC1 and TSC2... However, no hotspots have been found... In this report, the family had a frame-shift mutation (c. 3576_3577insA) in exon 29 of TSC2 gene detected by Sanger sequencing, the gold standard to detect gene mutations... The fact that this mutation was observed only in the patients of the family but not in other healthy family members and the 100 unrelated normal controls suggests that this mutation is pathogenic... This mutation cannot be found in the leiden open variation database, suggesting the sequence aberration is novel... The phenomenon of mosaicism can explain the difference in severity between the father and his children, but cannot explain that between the two children... Therefore, whether TSC caused by the same mutation would aggravate itself when transmitted to the next generation and result in severity differences between siblings needs to be further explored.

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(a) Forehead fibrous plaque and facial angiofibromas of the proband. (b) Shagreen patches on the back of the proband. (c) Heart ultrasound of the younger brother detects multiple cardiac rhabdomyoma. (d) Brain computed tomography of the father shows multiple subependymal calcifications. (e) Brain magnetic resonance imaging (MRI) of the proband reveals subependymal nodules along the lateral walls of the lateral ventricles. (f) Brain MRI of the proband demonstrates multiple cortical tubers.
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Figure 1: (a) Forehead fibrous plaque and facial angiofibromas of the proband. (b) Shagreen patches on the back of the proband. (c) Heart ultrasound of the younger brother detects multiple cardiac rhabdomyoma. (d) Brain computed tomography of the father shows multiple subependymal calcifications. (e) Brain magnetic resonance imaging (MRI) of the proband reveals subependymal nodules along the lateral walls of the lateral ventricles. (f) Brain MRI of the proband demonstrates multiple cortical tubers.

Mentions: One TSC family was identified through a proband from Sichuan province of China. The proband, a 16-year-old male, first presented with frequent focal motor seizures at age of 6 years and was clinically diagnosed as TSC at age of 9 years. Physical examination found forehead fibrous plaque, facial angiofibromas [Figure 1a], hypopigmented macules, and shagreen patches on his back. [Figure 1b]. He has shown moderate mental retardation and failed to pass any academic examinations. Electroencephalogram (EEG) revealed multifocal spike wave and spike-slow wave complex discharges. Cardiac ultrasound was normal, but renal ultrasound detected multiple small nodular hamartomas. His seizure was successfully controlled by sodium valproate and oxcarbazepine. The father of the proband is 48-years-old without epilepsy or mental retardation. However, physical examination revealed facial angiofibromas, shagreen patches on his back, and confetti-like hypopigmented patches on his legs. Renal ultrasound revealed multiple hamartomas obviously larger than the proband. The third patient of the family was the younger brother of the proband. He was born when the proband was 11-year-old without any prenatal molecular diagnosis. At the age of 1 month, he began to experience frequent focal motor seizures, which could not be controlled by the combined treatment of sodium valproate, oxcarbazepine and topiramate, and demonstrated severe mental retardation. Physical examination was almost the same as the proband. EEG revealed focal and generalized epileptiform discharges. Multiple cardiac rhabdomyoma [Figure 1c] and nodular renal hamartomas were identified by ultrasound. In all the three patients, brain computed tomography showed multiple subependymal calcifications [Figure 1d] and brain magnetic resonance imaging detected multiple cortical tubers as well as subependymal nodules along the lateral walls of the lateral ventricles [Figure 1e and f].


A Chinese tuberous sclerosis complex family and a novel tuberous sclerosis complex-2 mutation.

Luo R, Cai Q, Mu D - Chin. Med. J. (2015)

(a) Forehead fibrous plaque and facial angiofibromas of the proband. (b) Shagreen patches on the back of the proband. (c) Heart ultrasound of the younger brother detects multiple cardiac rhabdomyoma. (d) Brain computed tomography of the father shows multiple subependymal calcifications. (e) Brain magnetic resonance imaging (MRI) of the proband reveals subependymal nodules along the lateral walls of the lateral ventricles. (f) Brain MRI of the proband demonstrates multiple cortical tubers.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4837808&req=5

Figure 1: (a) Forehead fibrous plaque and facial angiofibromas of the proband. (b) Shagreen patches on the back of the proband. (c) Heart ultrasound of the younger brother detects multiple cardiac rhabdomyoma. (d) Brain computed tomography of the father shows multiple subependymal calcifications. (e) Brain magnetic resonance imaging (MRI) of the proband reveals subependymal nodules along the lateral walls of the lateral ventricles. (f) Brain MRI of the proband demonstrates multiple cortical tubers.
Mentions: One TSC family was identified through a proband from Sichuan province of China. The proband, a 16-year-old male, first presented with frequent focal motor seizures at age of 6 years and was clinically diagnosed as TSC at age of 9 years. Physical examination found forehead fibrous plaque, facial angiofibromas [Figure 1a], hypopigmented macules, and shagreen patches on his back. [Figure 1b]. He has shown moderate mental retardation and failed to pass any academic examinations. Electroencephalogram (EEG) revealed multifocal spike wave and spike-slow wave complex discharges. Cardiac ultrasound was normal, but renal ultrasound detected multiple small nodular hamartomas. His seizure was successfully controlled by sodium valproate and oxcarbazepine. The father of the proband is 48-years-old without epilepsy or mental retardation. However, physical examination revealed facial angiofibromas, shagreen patches on his back, and confetti-like hypopigmented patches on his legs. Renal ultrasound revealed multiple hamartomas obviously larger than the proband. The third patient of the family was the younger brother of the proband. He was born when the proband was 11-year-old without any prenatal molecular diagnosis. At the age of 1 month, he began to experience frequent focal motor seizures, which could not be controlled by the combined treatment of sodium valproate, oxcarbazepine and topiramate, and demonstrated severe mental retardation. Physical examination was almost the same as the proband. EEG revealed focal and generalized epileptiform discharges. Multiple cardiac rhabdomyoma [Figure 1c] and nodular renal hamartomas were identified by ultrasound. In all the three patients, brain computed tomography showed multiple subependymal calcifications [Figure 1d] and brain magnetic resonance imaging detected multiple cortical tubers as well as subependymal nodules along the lateral walls of the lateral ventricles [Figure 1e and f].

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, West China Second University Hospital; Key Laboratory of Obstetric and Gynecologic and Pediatric Dieases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan 610041, China.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The incidence of TSC in Chinese population is still unknown although case reports of Chinese TSC patients were documented... Two causative genes for TSC, TSC1 gene on chromosome 9q34 and TSC2 gene on chromosome16p13, have been identified in 1997 and 1993 respectively... Chinese TSC patients are more likely to have TSC2 missense and frame shift mutations... The proband, a 16-year-old male, first presented with frequent focal motor seizures at age of 6 years and was clinically diagnosed as TSC at age of 9 years... Physical examination found forehead fibrous plaque, facial angiofibromas [Figure 1a], hypopigmented macules, and shagreen patches on his back. [Figure 1b]... He has shown moderate mental retardation and failed to pass any academic examinations... Tuberous sclerosis complex 1 and TSC2 genes, the pathogenic genes of TSC, are indicated as tumor suppressor genes due to their function in regulation of cell growth and differentiation by inhibiting the mammalian target of rapamycin (mTOR) in the Akt-mTOR-S6kinase cell growth pathway... Mutations including nonsense mutations, small deletions, splice site changes, missense mutations, and sometimes large deletions or rearrangements can occur over the entire regions of TSC1 and TSC2... However, no hotspots have been found... In this report, the family had a frame-shift mutation (c. 3576_3577insA) in exon 29 of TSC2 gene detected by Sanger sequencing, the gold standard to detect gene mutations... The fact that this mutation was observed only in the patients of the family but not in other healthy family members and the 100 unrelated normal controls suggests that this mutation is pathogenic... This mutation cannot be found in the leiden open variation database, suggesting the sequence aberration is novel... The phenomenon of mosaicism can explain the difference in severity between the father and his children, but cannot explain that between the two children... Therefore, whether TSC caused by the same mutation would aggravate itself when transmitted to the next generation and result in severity differences between siblings needs to be further explored.

Show MeSH
Related in: MedlinePlus