A child with tuberous sclerosis having Novel NRAS gene mutation

ABSTRACT

Tuberous sclerosis (TS) is a rare genetic disorder of autosomal-dominant inheritance. Mutations on either of the two genes Tuberous Sclerosis Complex 1 (TSC1) or Tuberous Sclerosis Complex 2 (TSC2) will lead to hamartomas formation involving many organs, such as the brain, heart, kidneys, skin, lungs, and liver. This case report is about an 11-month-old boy with epilepsy and hypomelanotic macules. MRI of the brain showed cortical tubers and subependymal nodule which confirms the diagnosis of Tuberous Sclerosis. Genetic analysis by Whole Exome Sequencing showed a novel genetic mutation in NRAS gene suggestive of Noonan syndrome-6.

Introduction

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder with high penetrance, a prevalence ranging from 1 in 6,000–10,000.[1] It is caused by mutations of tumour suppressor genes either TSC1 or TSC2, which cause upregulation of the mechanistic target of rapamycin1 (mTOR1) signalling pathway.[2] Disinhibition of this pathway accelerates cell growth and proliferation, subsequently leading to growth of hamartomatous tumours in the brain, heart, kidneys, eyes, skin, and lungs. It can be diagnosed clinically, or by presence of a pathogenic TSC1 or TSC2 variant, or both.[3] With the recent advancement, the diagnosis, treatment, and surveillance of tuberous sclerosis have improved markedly.

Case Report

An 11-month-old boy born out of nonconsanguineous marriage was presented to paediatric emergency with complaints of generalized epilepsy and mild developmental delay. The child was born at term gestation by normal vaginal delivery, cried immediately after birth with birth weight of 2.2 kg. Antenatal and perinatal period were uneventful. The child is fully immunised for his age. There was a history of seizure since the child was 4 months of age. The child is on antiepileptic medications including phenobarbitone and levetiracetum for seizure control. He is the second child of the 2 siblings, and there is family history of global developmental delay and seizure in elder sibling.

Physical examination showed hypomelanotic macules (ash leaf macule) Figure 1 on the cheeks, trunk and left sided leg, so provisional diagnosis of Tuberous Sclerosis was kept. Subependymal nodule with cortical tuber were seen on MRI of the brain [Figure 2a and b] confirming the diagnosis. EEG showed seizure activity in the form of subtle seizure. Fundus examination was done which showed macula tessellations. 2D Echocardiogram was conducted to rule out rhabdomyoma, and CT of the abdomen was conducted to rule out renal angiomyolipoma and other abdominal tumors which came out to be normal. One unusual finding on physical examination was massive hepatosplenomegaly for which bone marrow examination was conducted to rule out any associated malignancy which turned out to be unremarkable. To confirm the same, genetic analysis was performed by Whole Exome Sequencing [Figure 3] whereby a novel genetic mutation in NRAS gene was present which is usually seen in Noonan Syndrome-6. Literature search showed that being both conditions are caused by gene variations in RAS family of genes, they could present a single spectrum. After confirmation of diagnosis, child was started on Tab Vigabatrin 250 mg twice a day with iron folic acid and calcium supplements. Child is still on regular follow up and had no repeat episodes of seizures. Parents’ consent was obtained for publication purpose as patient is minor.

Figure 1.

(a-c) Showing clinical picture of hypomelanotic macule on leg and cheek region

Figure 2.

(a) MRI brain showing sub ependymal nodules, and (b) cortical tubers

Figure 3.

Whole exome sequencing report showing NRAS gene mutation suggestive of Noonan syndrome-6

Discussion

In tuberous sclerosis, seizure is present in about 80–90% of patients which usually occur within the first year of life. Seizure control should be considered a medical emergency in infants with tuberous sclerosis because refractory epilepsy is strongly correlated with poor developmental and cognitive outcome. It can be infantile spasms, focal seizures, or both, and infantile spasms are frequently not accompanied by hypsarrhythmia.[4] Hypomelanotic macule is present in about 90% of patients which are seen at birth and within the first two years of life. Diagnosis of tuberous sclerosis was based on 2 major features or 1 major feature with 2 minor features.[5] Our patient was presented with 3 major features of subependymal nodules, cortical tubers and hypomelanotic macules, hence confirming the diagnosis.

As per the literature, TSC2 variants were ten times more common than TSC1 and its mutation produce a more severe phenotype than TSC1 mutations and more than 1000 gene mutation site have been reported.[6] Another study reported that PTPN11 mutation characterising Noonan syndrome was found in a patient fulfilling criteria for tuberous sclerosis.[4] In our patient, genetic analysis by WholeExome Sequencing showed a novel gene mutation in NRAS gene suggestive of Noonan syndrome-6. This variant lies in the RAS family domain of the NRAS protein and it is pathogenic.

The first line of treatment for tuberous sclerosis associated epilepsy is Vigabatrin, which is more effective if introduced early and the clinical study was found that early treatment with Vigabatrin can delayed the onset and reduced the occurrence of infantile spasms in infants with tuberous sclerosis. However, this preventive effect was not observed for focal seizures or drug-resistant epilepsy, and the prevention of infantile spasms did not result in measurable improvements in cognitive outcomes.[7] Our patient was started on Vigabatrin and there was no repeat episode of seizure.

A multidisciplinary clinical evaluation by paediatricians, paediatric surgeons, cardiologists, dermatologist and medical geneticists is imperative for complete assessment. Genetic counselling plays a pivotal role in the management of tuberous sclerosis. Although, the diagnosis of tuberous sclerosis is mostly clinical, genetic testing is helpful in managing the genetic implications for the family. Therefore, genetic prenatal diagnosis is advised in subsequent pregnancies.[8]

Conclusion

A case of tuberous sclerosis with Noonan syndrome gene mutation has been rarely reported making it a unique case. To the authors’ knowledge, no case has been reported in literature until date. It is a lifelong condition requiring multidisciplinary treatment programs. A proper health education and counselling to the parents should be emphasized. Preconceptional counselling and prenatal testing can prevent the risk of recurrence in further pregnancy.

Conflicts of interest

There are no conflicts of interest..

Funding Statement

Nil.