De novo mutation of the TSC2 gene in patient with Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND) Phenotype: a case report

Abstract

Tuberous sclerosis complex (TSC) is a neurocutaneous disease caused by a mutation in the TSC1 or TSC2 gene. There are several neuropsychiatric manifestations associated with TSC known as TSC-associated neuropsychiatric disorder (TAND). This article concerns neuropsychiatric manifestations in children with the TSC2 gene mutation, with genetic analysis findings using whole-exome sequencing.

Case: A 17-year-old girl presented with TSC, absence and focal epilepsy, borderline intellectual functioning, organic psychosis, and renal angiomyolipoma. She was emotionally unstable and preoccupied with irrelevant fears. In the physical examination, we found multiple hypomelanotic maculae, angiofibroma, and a shagreen patch. The intellectual assessment result with the Wechsler Adult Intelligence Scale at 17 was borderline intellectual functioning. Brain MRI showed cortical and subcortical tubers in the parietal and occipital lobes. Whole-exome sequencing was conducted, and the result was a missense mutation in exon 39 of the TSC2 gene [NM_000548.5:c.5024C>T (NP_000539.2:p.Pro1675Leu)]. The Sanger sequencing of the patient's parents revealed no mutations in the TSC2 gene, confirming the patient's de novo mutation. The patient was given several antiepileptic and antipsychotic drugs.

Clinical discussion: Neuropsychiatric manifestation is a common phenotype in the TSC variant, and psychosis is one of the rare TAND symptoms in children.

Conclusions: The neuropsychiatric phenotype and genotype in TSC patients are rarely reported and evaluated. We reported a female child with epilepsy, borderline intellectual functioning, and organic psychosis associated with a de novo mutation of the TSC2 gene. Organic psychosis is a rare symptom of TAND which also manifested in our patient.

Keywords: case report; de novo missense mutation of TSC2 gene; tuberous sclerosis complex–associated neuropsychiatric disorders; whole-exome sequencing.

Figure 1

Features of tuberous sclerosis in the patient. Multiple angiofibroma (A), multiple hypomelanotic macules on the back (B), Shagreen patch (ash leaf marks) over the leg region (C), and ungual fibromas on her digits (D).

Figure 2

Electroencephalogram showed diffuse epileptiform abnormalities on the left hemisphere (A). Sagittal T1-weighted image flair sequence, and axial T2- weighted image flair sequence (B), and brain MRI (C) showed cortical and subcortical tubers in parietal and occipital lobes (red arrow). Coronal T2-weighted image sequence with fat-saturated in the abdominal MRI showed a hypointense lesion (red arrow) with size 3.46 × 3.60 × 4.20 cm at the upper pole of the left kidney (D).

Figure 3

Sanger sequencing of TSC2 gene from father (A) and mother (B).