Clinical Features and Genetic Analysis of Tuberous Sclerosis Complex in a Chinese Family Caused by c.2677-2678del Mutation on TSC2 Gene
KE Lai-shun, JIANG Hua, QU Xiu-xiu, ZHENG De-quan, WU Xin-yu, LU Wu-sheng*
Department of Neurology, The Affiliated Dongnan Hospital of Xiamen University, Zhangzhou, Fujian, 363000, China
*Corresponding Author: LU Wu-sheng, E-mail:

The clinical data of patients from a Chinese family with tuberous sclerosis complex (TSC) were collected and the gene mutation type of TSC2 of proband in pedigree one was determined by polymerase chain reaction (PCR) and direct genes sequencing. There were 2 cases with TSC in the family, both of whom had facial angiofibromas, one case with ungual fibromas, the other with mental retardation. The MRI and CT showed multiple intracranial nodules together. What’s more, gene mutation analysis of TSC2 demonstrated the c.2677-2678del mutation in both and the genetic manner deduced with autosomal dominant inheritance.

Key words: Tuberous sclerosis complex; Genes; Dominant trait; Next-generation sequencing; Tomography; X-ray computed tomography; Magentic resonance imaging; Pedigree

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to the mutation of the TSC1 or TSC2 genes, involving hamartoma or tumor development in multiple organs [1], where cellular differentiation and proliferation result in hamartoma formation in the skin, brain, eye, kidney, and heart [2]. Northrup et al.[3]estimated a frequency of 1/6 000 to 1/10 000 live births and a population prevalence of around 1 in 20 000. TSC is transmitted as an autosomal dominant trait but 60%-70% of cases are sporadic, apparently representing new mutations [4, 5]. Heterozygous pathogenic variants can be identified with 75%-90% of individuals that meet the clinical diagnostic criteria for TSC [6]. It has not been reported that the gene c.2677-2678del (coding region nucleotide deletion No. 2677-2678) in the TSC2 can cause TSC. Hence, in this article, the clinical data are reported on this gene mutation in a Chinese TSC family, and their genes are also analyzed.

Case Report

Patient (proband), a 37-year old female, came to see a doctor in our hospital because of recurrent dizziness, headache for over 10 days. The pink lumps of the big feet hallux nail were found stripped after birth, with no pain, swelling and other discomforts, thus without any diagnosis and treatment by a doctor. Then the nail strips mass gradually developed. At the age of 20, she had her first child, and the flaky erythem, papules, and plaques began appearing, and gradually increased much more on her face and neck. The patient had gone to several hospitals for examinations many times, but the diagnosis still remained unclear. She had no special past history. Examinations showed normal intelligence, normal brain nerve function, normal muscle tone and strength, normal sensory system, negative dystaxia, negative pathological signs and meningeal irritation. Some pinhead-sized pink papules and light brown translucent waxy papules scattered on her face and neck, without any changes under pressure (Figure 1). Family history: her son showed similar skin damage, mental retardation, childish behavior and impulsiveness, etc. But her father, mother and sister did not have similar manifestations. The Subependymal nodules in magnetic resonance imaging (MRI) revealed high signals in T1WI, while low signals in T2WI, and mixed signals in FLAIR. And the contrast-enhanced T1-weighted MR (CE-MR) scans showed ring enhancement around the subependymal nodules. Otherwise, CT scans showed multiple calcifications in the subependymal area. Genetic Testing: first, take peripheral blood 2 mL of all the family members, and then detect each specimen using the next-generation sequencing of the Lllumina Company NexSep500 sequencer. The test results: 1. TSC1 and TSC2 genes did not experience a large variation (Figure 3). 2. C.2677-2678del heterozygous nucleotide variation existed in sample TSC2 genes of the index-patient and her son (Figure 4). The results of family genetic tests are shown in the figure 5. EEG, chest radiographs, echocardiography, abdominal ultrasound showed no abnormalities. Blood count, electrolytes, liver and kidney function, autoimmune antibodies were all normal.

Figure 1 a: Ungual fibromas, b: Facial angiofibromas, c: Angiofibromas and hypopigmented macules the neck, d: Facial angiofibromas of the index-patient’ s son.

Figure 2 A, B, C The subependymal nodules in magnetic resonance imaging (MRI) revealed high signals in T1WI, while low signals in T2WI, and mixed signals in FLAIR. D: The contrast-enhanced T1-weighted MR (CE-MR) scans showed ring enhancement around the subependymal nodules. E: CT scans showed multiple calcifications in the subependymal area.

Figure 3 The result of the index-patient TSC gene sequencing is that TSC1 and TSC2 gene did not exist a large Variation.

Figure 4 A: The index-patient sample, B: The index-patient, s son sample. The TSC2 gene detection of the index-patient and her son’ s result is that the point mutations: chr16:2126106, Gene mutations: c.2677-2678del heterozygous mutation.

Figure 5 Index-patient and her son experienced her first seizure within 1 year of age


TSC is an autosomal dominant disorder due to the mutation of the TSC1 or TSC2 gene. In addition to skeletal muscle, peripheral nerve and spinal cord, all differentiation in tissues or organs from three germ layers, such as brain, skin, kidneys, eyes, lungs, heart, liver, bones etc. can be affected by TSC. In population-based studies, Yates et al. [9]found that 81%-95% patients diagnosed with TSC had one of the characteristic skin lesions, which showed a variety of clinical symptoms, such as the face fibroma, depigmentation spots, finger (toe) fibroma, shark spots etc.. Facial angiofibromas are the most visible and unsightly of all the cutaneous manifestations of TSC, and often results in a negative psychological impact on pediatric patients and stigmatization of their families [10]. Although TSC affects many organ systems, the neurological symptoms (i.e., seizures, mental retardation, autism, and a variety of behavioural disorders) account for the most significant mortality and morbidity [4, 11]. Epilepsy occurs in 80%-90% of all patients, often with medically refractory seizures [12]. The angiofibroma on face and neck and the ungual fibromas are significant manifestation on the Chinese family. Her CT and MR also show the multiple subependymal calcified nodules. According to the recommendations of the 2012 international tuberous sclerosis complex consensus conference [3], it can be diagnosed with TSC.

TSC gene mutation can be identified with a vast majority of individuals that meet the clinical diagnostic criteria for TSC, among whom pathogenic variants can be identified, with 31% of that in TSC1 and 69% in TSC2 [6]. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin)[13]. The TSC2 gene encodes a 200 kDa proteingene encodes a 200 kDa protein, tuberin [4, 14]. The genetic test results have showed that TSC2 genes c.2677-2678del heterozygous nucleotide variation exist in the index-patient and her son. It can be found that the variation is the frameshift mutationmay begining from the Ile in No. 893 amino acids and terminating in the first 21 amino acid, which leads to the change of the amino acid synthesis after the termination. Some studies have showed inactivating mutations in Tsc1 or Tsc2 result in the accumulation of the GTP-bound form of Rheb, which activates mammalian target of rapamycin complex 1 (mTORC1)[15, 16]. The mTOR is a serine/threonine protein kinase that stimulates translation initiation processes involving eukaryotic initiation factor 4E (eIF4E)-binding protein (4EBP) and p70S6 kinase/ribosomal S6 protein, integrates intracellular and extracellular signals to regulate vital cellular processes such as growth, proliferation and metabolism [17]. In Summary, Tsc1 and Tsc2 are negative regulators of Rheb, an activator of mTOR signaling [18]. The loss of Tsc1 or Tsc2 leads to hyperactivation of mTOR pathways, which results in a higher translation rate and formation of the cell abnormal proliferation and hamartomas [19, 20]. Therefore, we suggest that the TSC2 gene mutations of the family lead to the Rheb formation disorder or dysfunction, which enables the inhibition of mTOR protein complexes more weakened. And the abnormal activation of mTOR leads to abnormal cell proliferation, which causes such clinical manifestations on the skin and nervous system as fibroma on the face and neck, ngual fibromas, angiofibromas, hypopigmented macules, and the multiple subependymal calcified nodules.

The parents and sister had no skin lesions and neurological damage symptoms, and TSC2 mutations were not found in genetic testing. These above data support the fact that patient gene mutation is spontaneous mutation. Because the skin lesions of the patient increased after birth, we suggest that the breeding history may induce or promote the expression of the mutant gene. According to the similar skin damages and mental retardation, childish behavior, impulsiveness as the main clinical symptoms, her son can be diagnosed with tuberous sclerosis too, consistent with autosomal dominant inheritance, while her daughter does not have similar clinical symptoms and mutation genetic testing. The offspring pathogenic was 50% in the family, which is consistent with the literature that is the offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant [6]. It is curious that the patient and her son haven’ t suffered from epilepsy, and the heart, kidney and lung damages. We concerned that the causative gene is a spontaneous mutation type and has its unique clinical symptoms, or related to its complex and diverse clinical manifestations. And we can follow up the changes of the further clinical symptoms.


In all, it is highly suggestive of tuberous sclerosis for patients with skin lesions as the initial symptoms when the imaging examination showed intracerebral tuberous calcified points. As for the family, c.2677-2678del is the spontaneous mutant gene of TSC2, which is consistent with autosomal dominant inheritance. Genetic testing is helpful for further diagnosis and genetic counseling for the members of the family.

About this research, we haven’ t seen any similar reports on such gene mutation at present yet. This report has enriched TSC2 gene mutation database, enhanced the awareness of the disease, and provided evidence for the diagnosis before onset and genetic counseling for the patients with the genetic mutation.

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