Diagnosing TSC by Making Clinical Connections

TSC = tuberous sclerosis complex. Diagnosing tuberoussclerosis complex: b a If yousee≥1dermatologiclesionassociatedwiththisdisease,alsoconsideraskingthefollowingtargetedquestions: Suspect TSC? Acombination ofthe2clinicalfeatures (LAMandangiomyolipomas) without otherfeatures does notmeetcriteria foradefinitediagnosis. Includes tubersand cerebralwhitematterradialmigrationlines. Definite Diagnosisof Tuberous Sclerosis Complex (TSC)

Genetic • •

Major Criteria with≥2minorfeatures or1majorfeature ≥2 majorfeatures Either a Criteria Does the patient have any majordermatologicmanifestationsof TSC?(seereverse)Does thepatienthaveany ManifestationsDermatologic Does thepatientexperience progressivedyspneaonexertion andrecurrentpneumothoraces? ManifestationsPulmonary According tomedicalhistory, hasthepatienthadacardiacrhabdomyoma? Cardiovascular Manifestations Has thepatientshownevidenceorbeendiagnosedwithepilepsyneuropsychiatricdisorders? of Neurologic Manifestations TSC Has thepatientbeendiagnosedwithretinalhamartomas? Retinal Manifestations grandparents? parents, or familyDoes thepatienthaveany memberswithsimilarsymptoms Angiomyolipomas (≥2) TSC1 pathogenic mutation mutation pathogenic Subependymal nodules(SENs) Subependymal Subependymal giantcellastrocytomasSubependymal (SEGAs) Lymphangioleiomyomatosis (LAM) Cardiac rhabdomyoma Cortical dysplasias Multiple retinalhamartomas ofeithera Identification or TSC2 mutation isdetectedinnormaltissue mutation a

b TSC1

or TSC2 b

MORECLUES 10%to25%of identified nomutation have TSC patients • Seenin80%of oftendetected prenatally TSC patients; • Corticaltubersareseenin90%of TSC patients • Normalgenetictestingresultdoesnotexclude TSC • • Skin lesions are seen in ≥90% of patients with Skin lesionsareseenin≥90% ofpatients TSC • • Fat-containing angiomyolipomasareseenin80%of • specificto Relatively TSC • • Seenin30%to40%offemale TSC patients • Incidenceof5%to15%;cancauseserious • Finding ishighlyspecificto TSC • 50%of Seenin30%to TSC patients • Possible DiagnosisofTSC TSC patients by genetictesting neurologic compromise birth or at dialysis andnephrectomy/transplantation to80%of (up 40) TSC femalesbyage Can causeseriousissueswith bleeding;mayleadto Lung involvementmayincreasewithage • Either 1 major feature or≥2minorfeatures Either 1majorfeature — especially siblings, Diagnosing tuberoussclerosis complex: If yousee≥1dermatologiclesionassociatedwiththisdisease,alsoconsideraskingthefollowingtargetedquestions: Suspect TSC? Definite Diagnosisof Tuberous Sclerosis Complex (TSC) • • Relevant diagnostictesting ≥2 major features or1majorfea ≥2 majorfeatures Either a Kidney Brain Eye Heart Teeth Skin Lung Genetics Test Minor Features TSC1 Does the patient have evidence of any ofthefollowingminorfeaturesTSC? Does thepatienthaveevidenceofany Recommendation • • • • • • • • • • • or Assess forangiomyolipomasandrenalcysts byMRI Retinalachromicpatch • “Confetti” skinlesions • 24-h EEGrecommendedifabnormalor neurologicchangesareevident TSC-associated cannot beclinically confirmed Complete ophthalmologicexam pa Echocardiograms inpediatric Detailed clinical dentalinspection inspection Detailed dermatologic functiontesting Baseline pulmonary Screen forhypertension, determineglomerularfiltra (EEG)forallpedia Electroencephalography (CT)orheadultrasound( Computed tomography (MRI)fortubers, resonanceimaging Magnetic SEN, SEGA suspected but genetictestingrecommendedwhendiagnosis familyhistory; 3-generation TSC2 mutation isdetectedinnormaltissue mutation ture with≥2minorfeatures 1

tients andelectrocardiogramsforallages MORECLUES tric patients (even in absence of apparent seizures); (eveninabsenceofapparent tric patients Possible DiagnosisofTSC Multiplerenalcysts • Dentalenamelpits • in neonates/infants withopen fontanels) in neonates/infants • Either 1 major feature or≥2minorfea Either 1majorfeature tion rate (cont) > 3

Nonrenalhamartomas • Intraoralfibromas • tures > 2 Diagnosing tuberous sclerosis complex: LEARNINGS THROUGH LESIONS

Skin lesions are present in ≥90% of patients with TSC. Knowing how to differentiate TSC-associated lesions from other skin disorders may help you diagnose TSC. The following table summarizes dermatologic symptoms that are considered major clinical diagnostic criteria for TSC.2

Test 1: Physical exam: Look for skin abnormalities and differential diagnoses Image Skin Lesion Age at Onset Consideration • Observed in about 90% of individuals with TSC Hypomelanotic • At birth or infancy • ≥3 lesions at least 5 mm in macules diameter must be present (1 or 2 lesions is relatively common in general population) Differential Image

Hypomelanotic macules

Nevus anemicus Nevus depigmentosus Piebaldism Early vitiligo

Image Skin Lesion Age at Onset Consideration

• Occur in 75% of TSC patients Angiofibromas • Ages 2 to 5 • ≥3 lesions must be present (1 or 2 isolated sporadic lesions often present in general population)

Differential Image

Angiofibromas

Acne vulgaris Rosacea Multiple trichoepithelioma

Image Skin Lesion Age at Onset Consideration

• Occurs in 25% of TSC patients Fibrous cephalic • Most specific skin finding for TSC • Ages 2 to 5 plaque • Most common on forehead, but may occur on other parts of face or scalp Fibrous cephalic plaque Diagnosing tuberous sclerosis complex: LEARNINGS THROUGH LESIONS (cont)

Test 1: Physical exam: Look for skin abnormalities and differential diagnoses Image Skin Lesion Age at Onset Consideration

• Occur in 20% of TSC patients overall, • Second decade Ungual fibromas but in up to 80% of older adults or later • > 2 must be present

Differential Image

Ungual fibromas

Epithelial inclusion cysts Verruca vulgaris Infantile digital fibromatosis

Image Skin Lesion Age at Onset Consideration

Shagreen patch • First decade • Occurs in 50% of TSC patients

Differential Image

Shagreen patch

Connective tissue nevi

Worth noting...minor dermatologic/dental features of TSC include “confetti” skin lesions, multiple (>3) dental enamel pits, and multiple (≥2) intraoral fibromas. References 1. Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:255-265. 2. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243-254.