Contributed by Christopher C. Griffith MD, PhD and Jeffrey A. Kant MD, PhD
The patient is a 5 month old male born to a G2P1 mother at 36 weeks gestation by Cesarean section. The infant was discharged home on day 4 of life.
At 4 months the patient presented with new onset seizures. The parents described the seizures as flexor spasms occurring only during sleeping hours over a two to three week period prior to hospital admission. These seizures were felt to be consistent with infantile spasms, and this was consistent with an electroencephalogram showing hypsarrhythmia.
Physical examination showed scattered hypopigmented macular (ash leaf) lesions on the trunk and a connective tissue nevus (Shagreen patch) on the left arm. Ophthalmologic examination did not reveal any retinal hamartomas or other ocular lesions. Renal ultrasound showed a dilated collecting duct system but no glomerular disease or renal masses. Chest x-rays and echocardiogram were negative. MRI of the head showed multiple subependymal nodules, a left frontoparietal cortical tuber, occipital and posterior parietal cortical tubers (Image), and multiple radial glial lines.
The patient's family history is significant only for a paternal cousin with epilepsy as an adult. The patient has one older sibling who is alive and well.
Based on these findings the patient was thought to have tuberous sclerosis complex (TSC) and peripheral blood was sent for genetic testing.
MOLECULAR GENETIC STUDIES
Complete tuberous sclerosis evaluation including TSC1 sequencing, TSC1 deletion/duplication analysis, TSC2 sequencing and TSC2 deletion/duplication analysis was requested by the treating physician. 4 ml of blood in EDTA was sent for testing.
A single heterozygous nucleotide deletion of cytosine at position 1628 (c.1628delC) in the coding sequence of TSC2 was detected. This results in a frameshift at amino acid position 543 which normally codes for Proline (p.Pro543fs). While not previously reported, this variant is of the type predicted to cause disease due to the introduction of a frameshift in the coding sequence. This variant is therefore considered a category 2 variant by the American College of Medical Genetics (ACMG) 2007 recommendations1. No other abnormal DNA sequences were detected in the TSC1 or TSC2 genes.
With this confirmation of TSC in the patient the treating physicians are now considering additional genetic testing in the parents and older sibling. This testing of the parents and sibling can help determine whether one of the parents is mosaic for the mutation or whether the mutation is de novo and thus aid in family planning.