How early is too early? Diagnosis of tuberous sclerosis complex in a neonateRR Prashanth1, S Nair1, A Haribalakrishna1, H Thakkar2
1 Department of Neonatology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India
2 Department of Radiology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.jpgm_326_23
Source of Support: None, Conflict of Interest: None
A 30-year-old third gravida mother with previous two normal live births delivered vaginally a male neonate at 38 weeks of gestation with a birth weight of 2,590 gm. Neonate had appearance, pulse, grimace, activity, and respiration (APGAR) scores of 9/10 at both 1 and 5 minutes, and no resuscitation was required. The antenatal scan was suggestive of multiple cardiac rhabdomyomas diagnosed at 28 weeks of gestation with the rest of the scan findings including amniotic fluid index being normal. Parents were counseled for post-natal evaluation for the cause and further genetic workup. Examination showed normal head circumference, four hypopigmented macules measuring 4–5 mm with well-defined margins over the left thigh and left flank suggestive of ash leaf macules [Figure 1]. The rest of the examination was normal.
A diagnosis of tuberous sclerosis was suspected and evaluation with echocardiography revealed rhabdomyomas: 1 cm × 0.6 cm over the anterior mitral valve leaflet and interventricular septum and 0.7 cm × 0.4 cm attached to the anterior leaflet of the tricuspid valve [Figure 2]. Ultrasound abdomen showed cysts measuring 2.3 mm in bilateral kidneys. Renal function tests were normal. Multiple nodules suggestive of astrocytoma were seen in both eyes on fundoscopy [Figure 2].
Neurosonogram showed a few tiny sub-ependymal nodules along the frontal horn and body of the right lateral ventricle with an irregular bumpy outline. Magnetic Resonance Imaging (MRI) brain revealed cortical tubers, radial migration bands in the frontoparietal region, and subependymal nodules in the right parietal periventricular area [Figure 2].
There were no clinical seizures and video electroencephalographic (EEG) monitoring at birth and 4 weeks postnatally was normal. The clinical exome showed a TSC2 mutation which confirmed the diagnosis of tuberous sclerosis. The neonate was on exclusive breastfeeding, and multidisciplinary care and was discharged on day 29 with normal growth and continues to be on close follow-up.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with variable expression. The current consensus is to diagnose at the earliest and start treatment before the onset of clinical seizures. However, in the majority of infants, the workup often begins after the seizure onset. Here we have described the clinical course of a neonate who had been antenatally detected to have multiple cardiac rhabdomyomas; and then a post-natal diagnosis of TSC had been made in the neonatal period, well before the onset of seizures.
Inactivation mutations in TSC1 or TSC2 lead to the disinhibition serotonin/threonine pathway mammalian protein kinase of rapamycin. TSC2 mutation as in the present case is responsible for early onset and more severe disease manifestations, reemphasizing the need for early genetic diagnosis.
In the order of frequency of clinical features, cardiac rhabdomyoma is the earliest detectable sign of TSC. They can be diagnosed from the twentieth week of gestation. This is followed by hypomelanotic macules, retinal hamartomas, and renal cysts. The present neonate had all the above-mentioned clinical features and these were detected as early as the first week of life and identified by a thorough evaluation.
Cortical tubers and cerebral white matter radial migration lines as seen in the present case are common forms of cortical dysplasia. Subependymal nodules need to be carefully looked for in the neonatal period, since it is widely accepted that subependymal giant cell astrocytoma typically arises from the subependymal nodule.
A seizure can occur as initial presentation in 15–35% of infants and 73% of them can develop epilepsy within the first year of life indicating a higher risk in TSC2 patients. There is a delay of more than three months between the detection of EEG abnormalities and the first clinical seizures. This allows for preventive treatment. In the present patient, the EEG done at birth and four weeks of life was normal. We plan to repeat EEG every four weeks in the first six months, and every six weeks thereafter and start preventive treatment with vigabatrin upon diagnosis of abnormal EEG, as per the recent evidence from the prevention of epilepsy in infants with tuberous sclerosis complex (EPISTOP) trial. Phase 3 of EXiST-3 trial has shown that the addition of everolimus to the multiple antiepileptics significantly reduces the refractoriness of seizures.
Future trials comparing the role of vigabatrin before the onset of epileptogenesis on EEG and comparing vigabatrin and everolimus for the prevention of seizures are required. Genetic counseling, multidisciplinary care, parental education, and management right from the neonatal period as per the current consensus about seizure recognition are imperative for optimal neurodevelopment.
Declaration of patient consent
The authors certify that appropriate patient consent was obtained.
The authors thank Dr. Ashish Doshi Consultant Ophthalmologist K.B.Haji Bachooali Charitable Ophthalmic and ENT Hospital, Mumbai for providing the ophthalmology image.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]