1. Tuberous Sclerosis Complex Criteria and Surveillance
TSC
Criteria and Surveillance
Márcio A. Sotero de Menezes
Swedish Pediatric Neuroscience Center – SMC
Tuberous Sclerosis Alliance Clinic
Clinical Associate Professor Neurology and Pediatrics
University of Washington Dept of Neurology
Seattle Children’s Hospital

2. Autosomal dominant inheritance Age dependent phenotype
Tuberous Sclerosis Complex
Multisystem disease v
Autosomal dominant inheritance v
Age dependent phenotype
-Neonate cardiac disease
-Infant (and beyond) seizures
-Teenage (and beyond) renal disease
-Adult pulmonary manifestations v
Sotero 2000

3. Tuberous Sclerosis Complex – History
Von Recklinghausen 1862
Newborn with multiple cardiac tumors
Many “cerebral scleroses”
Bourneville introduced the term
Sclérose Tubéreuse (~ potatoes)
A/w renal tumors (Bourneville & Brissard 1900)
Acne rosacea and molluscum (significance?)
Vogt 1908 – “classic triad”
MR (ID), intractable epilepsy, adenoma sebaceum
Allowed the diagnosis in life
Gomez
~50% of TSC cases normal cognition
Vogt’s triad present in 29%, all 3 absent 6%
Sotero 2015

4. ~ 1/3 cases familial autosomal dominant
Tuberous Sclerosis Complex
Frequency 1/5,800 to 1/10,000 v
High
penetrance
(close to 100%) v
~ 1/3 cases familial autosomal dominant v
~ 2/3 due to new (de novo) mutations v
Genetic heterogeneity (2 genes)
-9q34 - TSC1- Hamartin
-17p13 - TSC2 -Tuberin
Osborne 1991; Northrup 1999; Jozwiak S, Ktolska K 2006

5. TSC Clinical Consensus Conference Update recommended diagnosis, surveillance, & management
June 14-15, 2012, in Washington, DC
Co-organizers Hope Northrup and Darcy Krueger
79 experts 14 countries

6. Clinical Diagnostic Criteria For TSC
MAJOR FEATURES
MINOR FEATURES 1
Hypomelanotic macules (≥3, at least 5mm)
“Confetti” skin lesions 2
Angiofibromas (≥3) or fibrous cephalic plaque
Dental enamel pits (≥3) 3
Ungual fibromas (≥2)
Intraoral fibromas (≥2) 4
Shagreen patch
Retinal achromic patch 5
Multiple retinal hamartomas
Multiple renal cysts 6
Cortical dysplasias (≥3)*
Nonrenal hamartomas 7
Subependymal nodules (≥2) 8
Subependymal giant cell astrocytomas 9
Cardiac rhabdomyoma 10
Lymphangioleiomyomatosis (LAM)** 11
Angiomyolipomas (≥2)**
* Includes tubers and cerebral white matter radial migration lines.
** A combination of the two major clinical features LAM and angiomyolipomas without other features does not meet criteria for a Definite Diagnosis. DEFINITE DIAGNOSIS: 2 major features or 1 major feature with 2 minor features POSSIBLE DIAGNOSIS: Either 1 major feature, 1 major and 1 minor, or ≥ 2 minor features

7. Tuberous Sclerosis - Diagnostic Criteria Major Features
When pulmonary lymphangiomatosis and renal
angiomyolipomata occur in the same patient they be
considered as a single major feature.
When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they are counted as one rather than two features of TSC.

8. TSC- Diagnostic Criteria by DNA testing
Definite TSC = TSC1 or 2 mutation*
Since 15% of individuals with TSC have no mutation identified by conventional genetic testing, and a normal result does not exclude TSC or have any effect on the use of Clinical Diagnostic Criteria to diagnose TSC.
Consensus conference in July 1998 sponsored by the Tuberous Sclerosis Alliance

9. Genetic Diagnostic Criteria For TSC
A TSC1 or TSC2 pathogenic mutation is sufficient to make a Definite Diagnosis of TSC.
A pathogenic mutation is defined as a sequence variant that clearly prevents TSC1 or TSC2 protein production.
Additionally, some mutations compatible with protein production (e.g., some missense changes) are well established as disease-causing and as sufficient to make a Definite Diagnosis of TSC. Other variants should be considered with caution.

10. TSC- Diagnostic Criteria by DNA testing
Definite TSC = TSC1 or 2 mutation*
*A pathogenic mutation if it clearly inactivates the function of the TSC1 or TSC2 proteins (out of frame insertion or deletion or nonsense mutation), prevents protein synthesis (large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment.
Consensus conference in July 1998 sponsored by the Tuberous Sclerosis Alliance
Orlova KA. Crino PB Ann. N.Y. Acad. Sci (2010) 87–105

11. Tuberous Sclerosis - Diagnostic Criteria Major Features
1- Facial angiofibroma or plaque
2- Ungal or periungual fibroma
3- Hypomelanotic macules (three or more)
4- Shagreen patch
5- Multiple retinal hamartoma
6- Cortical dysplasia tuber, migration line,
7- Subependymal nodule
8- Subependymal giant cell astrocytoma
9- Cardiac rhabdomyoma
10-Lymphangioleiomyomatosis
11-Renal angiomyolipoma S K I N
EYE C N S
HEART
LUNGS
KIDNEYS

12. Surveillance Recommendations For Newly Diagnosed Or Suspected TSC
Skin Periodic examination (yearly)
Teeth Periodic examination (yearly)
Brain Yearly MRI (1-3 y)
EEG/Seiz. PRN -Birth every 6 weeks? – Inf. Spasm education
Behavior Yearly TAND screening
Heart Echo/ECG at birth f/u as needed
Eyes At birth –Yearly?
Kidney Yearly MRI (US), Blood pressure, kidney function
Lungs Women > 18 y.o. PFT’s, Lung CT’s
every 5-10 years

13. Surveillance & Management Recommendations For Newly Diagnosed Or Suspected TSC
ORGAN SYSTEM
RECOMMENDATION
Skin
Perform a detailed clinical dermatologic inspection/exam.
Teeth
Perform a detailed clinical dental inspection/exam.
Dental
F/U
Perform a dental examination twice per year by a dentist experienced with recognition and management of dental issues common in TSC

14. Hypomelanotic macules: Criteria > 3 with size > 5 mm
(1 lesion seen in 5% of gen. popul.)
Often seen at birth
May increase for 1st few years
Shape:
-Oval, polygonal
-Lance like (European mountain ash tree leaf).
-Confetti (minor criteria)
Wood’s lamp (UV light) helps

15. Facial angiofibroma
-“Adenoma sebaceum”
-Red or pink, glistening
papules
- 90% of the pts older
than 4 years.
-Increase in number
over time.
-Respond to topical mTOR inhibitors
-Later onset consider:
-Birt-Hogg-Dube (BHD)
syndrome
-Multiple endocrine
neoplasia type 1

16. -Similar to angiofibroma but larger
Facial Plaques
-Similar to angiofibroma but larger
-Usually on the forehead but also scalp and cheeks
-Surgical removal a/w scarring
-Rapamycin % cream may help
Northup 2013

17. Shagreen patch (Northup 2012) 50% of TSC pts Elevated lesion
“Orange-peel” appearance
Lower back
May be subtle
Consider: -Birt-Hogg-Dube (BHD)
syndrome, Multiple endocr. neopl. type 1
Northrup et al 2013

18. Oral lesions in TSC: -Affects 11% of the TSC patients.
-Appears between age 4 years and puberty.
-Gingival fibroma and papillomas
-Located in the upper jaw and anterior gingiva.
Enamel pits
Present in 76% of TSC < age 11
Present in 100% of TSC > age 11
Gomes 1988

19. Oral lesions in TSC: -Affects 11% of the TSC patients.
-Appears between age 4 years and puberty.
-Gingival fibroma and papillomas
-Located in the upper jaw and anterior gingiva.
Enamel pits
Present in 76% of TSC < age 11
Present in 100% of TSC > age 11
Gomes 1988; Northup 2013

20. Surveillance & Management Recommendations For Newly Diagnosed Or Suspected TSC
ORGAN SYSTEM
RECOMMENDATION
Brain
Perform MRI of the brain to assess for the presence of tubers, subependymal nodules (SEN), migrational defects, and subependymal giant cell astrocytoma (SEGA).
During infancy, educate parents to recognize infantile spasms.
Obtain baseline routine electroencephalogram (EEG). If abnormal, especially if features of TAND are also present, follow-up with a 24-hour video EEG to assess for subclinical seizure activity.
Evaluate for TSC-associated neurocognitive disorders (TAND).

21. Subependymal nodules (SEN) Giant cell astrocytomas (SEGA)
aka Giant cell tumors (SGCT)
SEN are present in 88-95%
SEGA are seen ~ 10% (3-18%)
SEN and SEGA/SGCT histology and imaging
characteristics (including enhancement) are
identical
SEGA/SGCT = SEN enlargement
MRI is NOT better but more convenient & safer but misses 1/3
of SEN’s
MRI/CT difference usually does not affect management.
Gomes 1988; Northrup 1999; Goh 2004; Verdecchia et al 2006;

22. Subependymal Giant cell astrocytomas (SEGA)/tumors (SGCT)
SEN become SEGA/SGCT via:
-Loss of allelic herozygosity
-Protein phosphorilation
Treatment:
Everolimus – Long-term
Surgical resection

23. TSC and Intelligence (MR/CD)
Cognitive impairment (MR/CD/ID)
IQ < 70 in ~ 50 %
30% TSC severely impaired
TSC with IQ > 70 (normal IQ)
Later onset, low frequency or lack of seizures
Presentation with lung LAM
Learning problems in 30-76%
Working memory, dual tasking, cognitive flexibility deficits
Behavior problems in 60%
ADHD/ADD 30-50%
Anxiety, Mood disorders 30-60%
OCD
P.J. de Vries et al. Pediatric Neurology 52 (2015) 25e35

24. TSC and Behavior ASD/autism spectrum disorder in 50% (range 20-60%)
Psychotic behavior – look for TLE (?)
P.J. de Vries et al. Pediatric Neurology 52 (2015) 25e35

25. TSC and Seizures - Seizures are seen in 82-90% TSC cases
Onset of seizures
Before age 6 months 46%
Before age 12 months 63%
Before age 3 years 82%
Commonest presenting symptom
50% have intractable epilepsy
Most common type complex partial aka focal dyscognitive
1/3 have infantile spasms - risk factor for refractory epilepsy
TSC & normal cognition 73% have seizures
TSC & MR/CD 100% have seizures
Sotero 2015

26. TAND (TSC associated neuropsychiatric d/o) TAND Checklist
Question 1 Basic developmental milestones
Question 2 Current level of functioning
Question 3 Behavioral concerns
Question 4 Psychiatric disorders diagnosed
Question 5 Intellectual ability
Question 6 Academic skills
Question 7 Neuropsychological skills
Question 8 Psychosocial functioning
Question 9 Parent, caregiver, or self-rating of the impact of TAND
Question 10 Prioritizing list
Question 11 Additional concerns
Question 12 Health-care professional rating of the impact of TAND
P.J. de Vries et al. Pediatric Neurology 52 (2015) 25e35 26

27. Ongoing Surveillance & Management Recommendations for Those with Definite or Possible TSC – 1
ORGAN SYSTEM
RECOMMENDATION
Brain
MRI of the brain every 1-3 years in asymptomatic TSC patients under age 25 to monitor for new SEGA. Individuals with asymptomatic SEGA in childhood should continue to be imaged periodically as adults to ensure there is no regrowth. Surgical resection should be performed for acutely symptomatic SEGA. Either surgical resection or medical treatment with mTOR inhibitors may be used for growing but otherwise asymptomatic SEGA.
Basic screening for neuropsychiatric symptoms at least annually at each clinical visit. Additional formal assessment by specialists where available upon entering primary school, secondary school, and young adulthood.
Obtain routine EEG in individuals with known or suspected seizure activity. The frequency of routine EEG should be determined by clinical need. Vigabatrin is the recommended first-line therapy for infantile spasms. ACTH can be used if treatment with vigabatrin is unsuccessful. Anticonvulsant therapy of other seizure types in TSC should generally follow that of other epilepsies.
MRI yearly (1-3) until age 25 years. Adults if SEGA present
Cognitive-psychiatric symptoms survey up young adult age
EEG every few months in babies (?) and as needed

28. Surveillance & Management Recommendations For Newly Diagnosed Or Suspected TSC
ORGAN SYSTEM
RECOMMENDATION
Eye
Perform a complete ophthalmologic evaluation, including dilated fundoscopy, to assess for retinal lesions and visual field deficits.
Yearly afterwards (Kruger 2013)

29. -achromic patch 39% (minor) -hamartoma(ta) 40-50% (major)
Retinal lesions in TSC
-achromic patch 39% (minor)
-hamartoma(ta) 40-50% (major)
-Mulberry lesion
-TSC 2>>1**
-More SEGA’s**
-No clear evidence of progression ?*
*Rowley 2001, **Aronow 2012

30. Surveillance & Management Recommendations For Newly Diagnosed Or Suspected TSC – 1
ORGAN SYSTEM
RECOMMENDATION
Kidney
Obtain MRI of the abdomen to assess for the presence of angiomyolipoma and renal cysts.
Screen for hypertension by obtaining an accurate blood pressure and evaluate renal function by determination of glomerular filtration rate.

31. Ongoing Surveillance & Management Recommendations for Those with Definite or Possible TSC – 2
ORGAN SYSTEM
RECOMMENDATION
Kidney
Screen for hypertension by obtaining an accurate blood pressure and evaluate renal function by determination of glomerular filtration rate.
MRI of the abdomen every 1-3 years (angiomyolipoma and renal cysts) throughout the lifetime. Assess renal function and blood pressure at least annually.
Embolization followed by corticosteroids is first-line therapy for angiomyolipoma presenting with acute hemorrhage. Nephrectomy is to be avoided. For asymptomatic, growing angiomyolipoma measuring larger than 3 cm in diameter, treatment with an mTOR inhibitor is the recommended first-line therapy.

32. TSC and Kidneys Five different renal lesions occur in TSC:
“Benign” angiomyolipoma 70%
Consider Rx if > 3-4 cm,
Acute hemorrhage embolization, steroids
Rx mTOR inhib., resection
Epithelial cysts (20%-30%)
Higher grade cysts TSC2>>TSC1
4.3% of TSC2 have overlap with PKD1 a/w
High risk for renal failure
7-25% of brain aneurysm (worse with FMH of aneurysm) and vasospasm
Oncocytoma (benign adenomatous hamartoma) (<1%);
Malignant angiomyolipoma (<1%);
Renal cell carcinoma (<3%)
Sotero 2015 32

33. New Cardiology-Specific Recommendations for TSC
If fetal diagnosis, then serial observation and at least 1 postnatal echocardiogram Surveillance studies until regression demonstrated
Electrocardiogram at the time of diagnosis Surveillance studies every 3 to 5 years Holter monitor as indicated for appropriate signs and symptoms
Cardiology consultation at time of diagnosis Ongoing cardiology surveillance as indicated Medical and surgical intervention as indicated

34. TSC – Cardiac Involvement
Manifests usually in the neonatal period in 43-67% of TSC cases
Due to cardiac rhabdomyoma(ta)
-70-90% due to TSC. Single ventricular lesion only 30% TSC
-Visible on fetal echo by wks GA
Tend to regress before age 1-2 years (AVB may not).
May be the presenting symptoms of TSC.
Clinical picture: Asymptomatic, heart failure, ventricular outflow obstruction, AV block.
Echocardiogram at the time of the diagnosis, if rhabdomyoma present consult pediatric cardiology. Serial echo’s and rarely resection or pacemaker placement may be necessary (prevents MRI’s).
Hinton 2014; Northup et al 2011

35. TSC – Cardiac Involvement
-Cardiac manifestations of TSC
-cardiac rhabdomyoma
-arrhythmias, AV block.
-heart failure,
-ventricular outflow obstruction,
-no unusual to be asymptomatic
-Present in the neonatal period in 43-67% of TSC cases
-May be the presenting symptoms of TSC.
Hinton 2014; Northup et al 2011

36. TSC – Cardiac Involvement
Cardiac rhabdomyoma(ta)
-70-90% due to TSC.
-Single ventricular lesion only 30% TSC
-Visible on fetal echo by wks GA
-Tend to regress before age 1-2 years (AV block may not).
Recommendations
Echocardiogram at the time of the diagnosis
If rhabdomyoma present consult pediatric cardiology.
Serial echo’s
Treatment: MTOR inhibitor rarely resection
Arrhythmias or AV block - pacemaker placement may be necessary (prevents MRI’s).
Hinton 2014; Northup et al 2011

37. Surveillance & Management Recommendations For Newly Diagnosed Or Suspected TSC
ORGAN SYSTEM
RECOMMENDATION
Heart
Obtain an echocardiogram < 3 years of age.
Consider fetal echocardiography after delivery when rhabdomyomas are identified via prenatal ultrasound.
Electrocardiogram (ECG) in all ages to assess for underlying conduction defects. Holter monitor as needed
Consider Pediatric Cardiology consultation at the diagnosis
f/u
Obtain an echocardiogram every 1-3 years (if cardiac rhabdomyomas until regression/stabilization of cardiac rhabdomyomas). 
Obtain an ECG every 3-5 years to check for problems with electrical activity in the heart.

38. TSC – Vascular Involvement
Aortic and cerebral artery aneurysms may be seen in TSC
Abdominal Aorta: Asymptomatic, hypertension, abdominal mass, urinary retention.
Cerebral artery: Focal neurological signs, changes in vision, nausea, vomiting
Gomez 1988; Che et al 2001; Boronat et al 2014

39. TSC – Vascular Involvement
Cerebral aneurysms in TSC are rare (0.7%) but more common that in the general population
Look for TSC2-PKD1 overlap mutations (deletions) family history of the aneurysms
Cerebral Aneurysms in PKD1
Adults 2-7%
+ FMH of aneurysm 12-15%
25% at autopsy
Gomez 1988; Che et al 2001; Boronat et al 2014

40. TSC and other organs Vascular – Aneurysms aortic and cerebral
Gastrointestinal
Hamartomas and polyposis stomach, intestine and colon
Often asymptomatic but GI bleeding possible
Liver angiomyolipomas
typically asymptomatic and nonprogressive,
10-25 % of individuals with TSC,
Female predominance (female-to-male ratio 5:1).
Endocrine
Angiomyolipoma adrenal > pituitary, pancreas, gonads
Thyroid papillary adenoma
Bone
Sclerotic or cystic lesions
Sotero 2015 40

41. TSC and other organs Vascular – Aneurysms aortic and cerebral
Gastrointestinal
Hamartomas and polyposis stomach, intestine and colon
Often asymptomatic but GI bleeding possible
Liver angiomyolipomas
typically asymptomatic and nonprogressive,
10-25 % of individuals with TSC,
Female predominance (female-to-male ratio 5:1).
Endocrine
Angiomyolipoma adrenal > pituitary, pancreas, gonads
Thyroid papillary adenoma
Bone
Sclerotic or cystic lesions
Sotero 2015 41