Tuberous sclerosis complex

Case history #1

Six-month-old adopted fraternal twins present to their paediatrician for a first healthcare visit. There is no available family history. Each child is healthy and twin A appears developmentally on target, whereas twin B is not as vocal, is less visually interactive, is not sitting, and has been noted to have frequent startles. Their examinations are normal; however, both twins have several hypopigmented macules. Upon careful inspection under Wood's lamp illumination, there is one large macule (3 cm) and four smaller ones (<1.5 cm) on the skin of each child. Ophthalmological examination reveals two small retinal hamartomas in the eyes of twin B. A brain CT scan of each child identifies calcified subependymal nodules, and an MRI shows these as well as several cortical tubers. An electroencephalogram (EEG) is normal for twin A, but is severely abnormal in twin B, demonstrating hypsarrhythmia with concurrent infantile spasms. Each child has a normal echocardiogram and renal ultrasound. They each have a definite diagnosis of TSC.

Case history #2

A healthy 28-year-old woman presents for a routine fetal ultrasound at 6 months of gestation. The ultrasound identifies a cardiac mass in the fetus. She later undergoes a fetal MRI, which discloses two cardiac masses within the ventricular septum not obstructing cardiac outflow. The infant is born at term without perinatal complications. The cardiac masses remain asymptomatic and an electrocardiogram (ECG) is normal. There are no hypomelanotic macules. The infant undergoes brain MRI, which identifies periventricular nodules and cortical tubers. Ophthalmological examination is normal, as is a subsequent renal ultrasound. A definite diagnosis of TSC is made. The mother is examined and is found to have facial angiofibromas, no hypomelanotic macules, and a normal ophthalmological examination. Subsequent brain MRI is normal, but she has several bilateral renal angiomyolipomas and is diagnosed with definite TSC. There are no other maternal family members with symptoms or signs of TSC.

Other presentations

A diagnosis of autosomal dominant polycystic kidney disease (APKD) may be made in infants with bilateral palpable flank/abdominal masses and confirmatory renal imaging. Affected infants have multiple large cysts with little remaining normal renal parenchyma. APKD can be part of a large, contiguous gene deletion syndrome identified in 3% to 5% of TSC patients, because the gene for APKD is adjacent to and continuous with the TSC2 gene.

An initial evaluation for developmental delays and/or autism in children may reveal hypomelanotic macules, which should prompt further investigation and a definitive diagnosis of TSC. The incidence of cognitive impairment in patients with TSC varies widely according to different studies, but is estimated to be as high as 64%, with up to 50% of patients having autism spectrum disorder.[6]de Vries PJ, Wilde L, de Vries MC, et al. A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):309-20. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.c.31637 http://www.ncbi.nlm.nih.gov/pubmed/30117265?tool=bestpractice.com [7]de Vries PJ, Belousova E, Benedik MP, et al. TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J Rare Dis. 2018 Sep 10;13(1):157. https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0901-8 http://www.ncbi.nlm.nih.gov/pubmed/30201051?tool=bestpractice.com [8]Tye C, Mcewen FS, Liang H, et al. Long-term cognitive outcomes in tuberous sclerosis complex. Dev Med Child Neurol. 2020 Mar;62(3):322-29. https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14356 http://www.ncbi.nlm.nih.gov/pubmed/31538337?tool=bestpractice.com ​​​​

Spontaneous pneumothorax in young women with previously unrecognised lymphangioleiomyomatosis of the lung is an uncommon presentation.

Occasionally, the hallmark calcified subependymal nodules will be incidental findings on brain imaging, leading to the diagnosis of TSC in the absence of epilepsy.