para>Prenatal diagnosis by mutational analysis is possible when a familial mutation has been identified.
EPIDEMIOLOGY
Incidence
- 6.8 to 12.4/10,000 live births (1)
- 1/5,800 persons (1)
- Predominant age: Clinical expression is variable; usually is diagnosed during the 1st decade of life.
- No gender predominance
ETIOLOGY AND PATHOPHYSIOLOGY
- Mutations in either of two genes " TSC1 and TSC2 " that code for hamartin and tuberin, respectively These form a heterodimer that acts as a tumor suppressor.
- Decreased production of TSC proteins and excessive cell proliferation results in tuber formation.
- Loss of gene function is associated with hyperactivity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling (2).
- In TSC, some hamartomas show loss of heterozygosity on chromosome 9q34.13 or 16p13.3.
- The patient has inherited a mutation or a deletion in one copy of the gene but develops a lesion only when there is a somatic mutation in the other.
- This 2-hit mechanism explains the variable expressivity and seems to apply to cardiac rhabdomyomas, renal angiomyolipomas, and subependymal giant cell tumors (SGCTs), but not to cerebral tubers.
Genetics
- Autosomal dominant with complete penetrance and variable expressivity (OMIM 191100 and 191092)
- 2/3 of cases result from new mutations. Somatic mosaicism occurs in 2 " 10% of de novo TSC.
- 2 chromosomal loci: TSC1 (9q34.13); TSC2 (16p13.3) (TSC2 3x as common as TSC1)
- Genetic testing is recommended when TSC is suspected but not clinically confirmed (3)[A], and for all new patients with TSC (1)[C]
- Clinical phenotype of TSC1 mutations generally is milder than that of TSC2 mutations (4)
- There is a contiguous gene deletion involving large deletions and rearrangements of TSC2 and PKD1 (causing polycystic kidney disease).
RISK FACTORS
- Family history. Expressivity is variable, even within a family.
- If neither parent meets criteria for TSC, the recurrence risk is 1 " 2% per child.
GENERAL PREVENTION
Genetic counseling
COMMONLY ASSOCIATED CONDITIONS
- Mental retardation (60 " 70%): usually associated with history of seizures
- Seizures (80%): 25% of patients with infantile spasms have TSC
- TAND: interrelated functional and clinical manifestations of brain dysfunction common in TSC: aggressive behaviors, autism spectrum disorders, intellectual disabilities, psychiatric disorders, neuropsychological deficits, and school and occupational difficulties (1,3).
- Cardiac rhabdomyomas (47 " 67%)
- Autism (40 " 50%)
- Lymphangiomyomatosis (LAM) of the lung, especially in women (30 " 40%)
- Cardiac arrhythmias
- Renal insufficiency
- Retinal lesions: hamartomas (up to 75%), achromic patches (39%)
DIAGNOSIS
- Most common presenting signs: seizures, infantile spasms, cardiac rhabdomyomas, hypopigmented macules; most patients are diagnosed before age 10, frequently missed at first presentation (5).
- Genetic diagnostic criteria (6): Either TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of TSC. A pathogenic mutation clearly inactivates the function of TSC1 or TSC2 proteins (e.g., out-of-frame indel or nonsense mutation), prevents protein synthesis (e.g., large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment. Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria and are not sufficient to make a definite diagnosis of TSC. 10 " 25% of TSC patients have no mutation identified by conventional genetic testing. Normal result does not exclude TSC or have any effect on the use of clinical diagnostic criteria to diagnose TSC.
- Clinical diagnostic criteria (6):
- Major features
- Hypomelanotic macules ( ≥3, at least 5-mm diameter)
- Angiofibromas ( ≥3) or fibrous cephalic plaque
- Ungual fibromas ( ≥2)
- Shagreen patch
- Multiple retinal hamartomas
- Cortical dysplasias include tubers and cerebral white matter radial migration lines.
- Subependymal nodules
- Subependymal giant cell astrocytoma (SEGA)
- Cardiac rhabdomyoma
- Lymphangioleiomyomatosis (LAM) (lung) Angiomyolipomas ( ≥2) (kidney)
- Minor features
- "Confetti " skin lesions
- Dental enamel pits (>3)
- Intraoral fibromas ( ≥2)
- Retinal achromic patch
- Multiple renal cysts
- Nonrenal hamartomas
- Definite diagnosis: two major features or one major feature with two minor features. Possible diagnosis: one major feature or two minor features
- LAM and/or angiomyolipomas without other features does not meet criteria for a definite diagnosis.
- 80 " 90% of patients may have a seizure disorder.
- Although epilepsy and mental retardation are more common in patients with TSC, they are not included among diagnostic criteria because they are common in the general population.
- When a new diagnosis is made in a child with no family history of TSC, careful evaluation of the parents should include:
- A comprehensive dermatologic exam (in room light and with a Wood lamp)
- Ophthalmologic exam
- Cranial CT scan or MRI
- Renal US
HISTORY
- Family history of TSC stigmata; about 1/3 of patients have a positive family history. Obtain a three-generation family history to identify at-risk family members (3)[A].
- Assess for seizures and developmental delay in children.
- Increased risk for brain tumors: May present with symptoms of obstructive hydrocephalus (headaches, vomiting, and neurologic deficits, including loss of vision). Children with obstructive hydrocephalus may present with nonspecific symptoms, including fatigue, decreased appetite, depression, and increased frequency of seizures.
PHYSICAL EXAM
- Dermatologic: detailed exam at diagnosis (3)[B]
- Almost all patients with TSC have characteristic skin lesions:
- Hypopigmented macules (87 " 100%) (ash-leaf spots, usually elliptical); not usually present before age 5 years, confetti lesions
- Angiofibromas (47 " 90%) (formerly, and incorrectly, adenoma sebaceum); typically involve the malar regions of the face (butterfly distribution); usually appear later than hypopigmented macules
- Shagreen patches (20 " 80%), most common on the lower trunk
- Fibrous cephalic plaques: Brown, fibrous plaque on the forehead may be the first recognized feature of TSC in infants (17 " 87%).
- Periungual and ungual fibromas may appear during adolescence or adulthood.
- Ophthalmologic
- Funduscopic evaluation (3)[A]
- Retinal hamartomas (up to 75%): Hamartoma may be a flat, translucent lesion (most common) or a multilobular mulberry lesion (calcification); may have features of both
- Achromic patches, chorioretinal depigmentation (punched-out appearance)
- Retinal giant cell astrocytoma, secondary retinal detachment
- Papilledema or visual loss: Rule out brain tumors.
- An abnormal red reflex should not be mistaken for retinoblastoma.
- Angiofibromas of the eyelids, nonparalytic strabismus, colobomas, and sector iris depigmentation
- Refractive errors not different from those of the general population
- Dental: multiple, randomly distributed pits in enamel, intraoral fibromas
- Neurologic: Brain tumors may cause focal deficits.
DIFFERENTIAL DIAGNOSIS
- Other causes of seizure disorders, mental retardation, autistic behavior
- LAM of the lung, +/ ’ renal angiomyolipomas in patients not meeting diagnostic criteria for TSC
- Non-TSC polycystic kidney disease. Renal cysts are common in the general population but are uncommon in individuals <30 years old.
- Traumatic ungual fibromata (usually single)
- Other phakomatoses: neurofibromatosis, Sturge-Weber syndrome, von Hippel-Lindau syndrome
- Other skin conditions resembling angiofibromas
DIAGNOSTIC TESTS & INTERPRETATION
- Molecular diagnostics: Identification of a mutation in TSC1 or TSC2 can confirm diagnosis in a child whose clinical evaluation is suggestive but not diagnostic.
- Mutational analysis for prenatal diagnosis and evaluation of relatives of those with a known mutation
- Cranial MRI before age 2 years (or at time of diagnosis), with gadolinium (3)[A]
- Baseline EEG in children even without seizures (3)[B]
- Fetal cardiac rhabdomyomas may be seen on US or MRI in late gestation; fetal echocardiogram (3)[A]
- Baseline EKG (3)[B]
- Abdominal imaging for renal cysts (MRI preferable) may also reveal aortic aneurysms or extrarenal hamartomas of the liver, pancreas, other organs (3)[A]
- Evaluate renal function: GFR or cystatin c (3)[A]
- Baseline pulmonary function testing (PFT), 6-minute walk test, high-resolution chest CT (HRCT), even if asymptomatic, if at risk of LAM (females ≥18 years of age), and symptomatic adult males (3)[B].
Diagnostic Procedures/Other
- Ash-leaf spots more readily seen with a Wood lamp
- Biopsy of questionable lesions
- Panoramic dental radiographs by age 7 (1)[C]
- Comprehensive neuropsychological assessment at diagnosis, early intervention if appropriate (3)[A]
Test Interpretation
- Lesions may be sparse at birth. Facial angiofibromas, ungual fibromas, and renal angiomyolipomas may develop months or years later.
- Brain lesions (leading cause morbidity and mortality):
- Cortical tubers (glioneural hamartomas): disorganized neuronal and glial elements with astrocytosis (possibly epileptogenic)
- White matter heterotopia: dysplastic and dysmyelinated white matter
- Subependymal nodules: hamartomas of atypical glial and neuronal cells may transform to SEGA.
- SGCT of mixed glioneuronal lineage
- Calcification of subependymal lesions may not occur until several months after birth.
- Extensive anatomic abnormalities in gray and white matter, even with normal intelligence.
- Renal lesions (50 " 80%): angiomyolipomas, benign cysts, and lymphangiomas; may adversely affect renal function; typically identifiable by age 10.5 years
- Pulmonary lesions (up to 40% of women with TSC): 1% of patients may present with pulmonary LAM, usually women of reproductive age.
- Cardiac rhabdomyoma (50 " 70% of infants), usually asymptomatic, but may require surgical intervention
TREATMENT
MEDICATION
- Anticonvulsants for seizure control. Vigabatrin controls infantile spasms in 73% of children with TSC (serial visual field testing necessary). Early control of seizures reduces negative behavioral outcomes.
- mTOR inhibitors are FDA-approved to treat enlarging giant cell astrocytomas; everolimus for SEGA and angiomyolipomas and pulmonary LAM (7)[B]
- Baseline CBC, fasting lipid panel, LFTs, metabolic panel, BUN, creatinine prior to starting everolimus
- Monitor for therapeutic level of 5 to 15 ng/mL.
ISSUES FOR REFERRAL
- Multidisciplinary team evaluation: genetics, neurology, dermatology, ophthalmology, nephrology, surgery, neurosurgery, radiology, plastic surgery
- Physical, occupational, and speech therapy; social workers for home care; vocational training support
SURGERY/OTHER PROCEDURES
- Surgery may be necessary for hydrocephalus, increased intracranial pressure, rapidly growing SGCT, malignant tumors, and seizure control.
- Renal arterial embolization or renal-sparing surgery for angiomyolipomas
- Surgical resection of SEGA if resectable
- LAM may require lung transplant.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Pediatric
- Annual physical exam, growth assessment
- Teach parents to recognize infantile spasms.
- Annual ophthalmologic exam (3)[C]
- Annual developmental testing and review of school progress, neuropsychological evaluation (3)[A], and IEP (3)[B], if indicated
- Pediatric cardiologist should follow children with cardiac rhabdomyoma. EKG every 1 to 3 years until regression; cardiac rhabdomyomas typically develop in utero, regress spontaneously in early childhood, and involute completely by adulthood (3)[A]
- 12-lead EKG every 3 to 5 years for conduction defects
- EEG: for seizure management or to evaluate changes in neurologic function (3)[B]
- TAND screening by expert team: 0 to 3 years old, preschool (3 to 6 years old), before middle school (6 to 9 years old), during adolescence (12 to 16 years old), early adulthood (18 to 25 years old) (3)[B]. Thereafter, PRN (1),(3)[A]
- Screening head MRI without contrast: every 1 to 3 years until age 25 years (3)[B], thereafter as clinically appropriate (3)[C]; surgery for resectable SGCT (3)[A]
- Screen for hypertension (3)[A]. Avoid ACE inhibitor in those treated with mTOR inhibitors (3)[A].
- Abdominal MRI every 1 to 3 years; for asympt0omatic, growing renal angiomyolipoma >3 cm, mTOR inhibitor
- Lung: HRCT and PFT every 5 to 10 years; 2 to 3 years if cysts present, up to every 3 to 6 months for treatment decisions (3)[A] mTOR treatment (3)[A]
- Counsel women on smoking risks and estrogen use; ambulatory event monitoring if symptomatic (3)[A]
- Annual ophthalmologic exam, every 3 months if on vigabatrin
- Annual skin survey, ophthalmologic exam (3)[C]
- For oral fibromas, dental evaluation every 3 to 6 months
PATIENT EDUCATION
- Tuberous Sclerosis Alliance: info@tsalliance.org; www.tsalliance.org
- TSC International: http://www.tscinternational.org
- OrphaNet: http://www.orpha.net
- Autism Society: http://www.autism-society.org
- The LAM Foundation: http://www.thelamfoundation.org
PROGNOSIS
Variable; complications may shorten longevity
COMPLICATIONS
- 18 times increase in risk of malignancy: kidney, brain, soft tissues; also benign tumors: angiofibromas, hamartomas, rhabdomyomas, and angiomyolipomas
- Rhabdomyosarcoma is rare, but increased incidence.
- Renal cell carcinoma (often multiple) in 1 " 2% of adults, distinct histology, 25 years earlier than in the general population, indolent clinical course
- CNS complications, including epilepsy, cognitive impairment, behavioral problems, hyperactivity, self-injurious behavior, and autism; occur in 85% of children and adolescents with TSC
- Neuropsychological attention deficit may be greater than intellectual impairment.
- Causes of death: Neurologic disease is most common (SGCT and status epilepticus); renal disease, pulmonary disease
REFERENCES
11 Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14(7):733 " 745.22 DiMario FJJr, Sahin M, Ebrahami-Fakhari D. Tuberous sclerosis complex. Pediatr Clin North Am. 2015:62(3):633 " 648.33 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(4):255 " 265.44 Kothare SV, Singh K, Chalifoux JR, et al. Severity of manifestations in tuberous sclerosis complex in relation to genotype. Epilepsia. 2014;55(7):1025 " 1029.55 Staley BA, Vail EA, Thiele EA. Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatrics. 2011;127(1):e117 " e125.66 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(4):243 " 254.77 Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9869):817 " 824.88 Moavero R, Pinci M, Bombardieri R, et al. The management of subependymal giant cell tumors in tuberous sclerosis: a clinician 's perspective. Childs Nerv Syst. 2011;27(8):1203 " 1210.99 Hinton RB, Prakash A, Romp RL. Cardiovascular Manifestations of Tuberous Sclerosis Complex and Summary of the Revised Diagnostic Criteria and Surveillance and Management Recommendations From the International Tuberous Sclerosis Consensus Group. J Am Heart Assoc. 2014;3(6):e001493.
SEE ALSO
Neurofibromatosis
CODES
ICD10
Q85.1 Tuberous sclerosis
ICD9
759.5 Tuberous sclerosis
SNOMED
- tuberous sclerosis syndrome (disorder)
- Fibrous skin tumor of tuberous sclerosis (disorder)
- Ash leaf spot, tuberous sclerosis (disorder)
- Pulmonary tuberose sclerosis (disorder)
CLINICAL PEARLS
- Hypopigmented areas (ash-leaf spots), on the trunk and extremities, often the first sign. Present at birth or shortly after (50%), best seen with a Wood lamp.
- Cardiac rhabdomyoma may be presenting sign prenatally or in infancy.
- Diagnosis of TSC is frequently missed.
- Molecular-targeted therapy with mTORC1 inhibitors is a treatment option for renal angiolipomas and unresectable subependymal giant cell astrocytomas.