Abstract
Neurofibromatosis (NF) and tuberous sclerosis complex (TSC) are the two most common
neurocutaneous disorders, both transmitted as autosomal dominant or, in the case of
NF, also as a mosaic condition. The causative genetic mutations in these neurocutaneous
disorders can lead to benign skin changes or uninhibited growth and proliferation
in multiple organ systems due to the loss of tumor suppression in mitogen-activated
protein kinase and mammalian target of rapamycin signaling pathways. Common clinical
features in NF include pigmented lesions, known as café au lait patches, neurofibromas,
intertriginous freckles (Crowe's sign), and benign fibrous growths, such as hamartomas
in multiple organ systems. Common clinical features in TSC include hypopigmented macules,
known as ash leaf spots, in addition to neurologic sequelae, such as autism, seizures,
and developmental delays. Advances in genetic sequencing technologies have allowed
an exponential expansion in the understanding of NF and TSC.
Consensus criteria have been established for both diagnoses that can be confirmed
in most cases through gene testing. Once diagnosed, the clinical and diagnostic value
of disease-specific surveillance include early identification of benign and malignant
tumors. Genetic counseling is important for informed reproductive decision-making
for patients and at-risk family members. The improvement in understanding of pathways
of pathogenic disease development and oncogenesis in both conditions have produced
a new series of therapeutic options that can be used to control seizures and tumor
growth. Tremendous advances in life expectancy and quality of life are now a reality
due to early introduction of seizure control and novel medications. While we lack
cures, early institution of interventions, such as seizure control in tuberous sclerosis,
appears to be disease-modifying and holds immense promise to offer patients better
lives.
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References
- Intrafamilial phenotypic variability in tuberous sclerosis complex.J Child Neurol. 2007; 22: 1348-1355
- Embryology of the neural crest: its inductive role in the neurocutaneous syndromes.J Child Neurol. 2005; 20: 637-643
- Epidemiology of tuberous sclerosis.Ann NY Acad Sci. 1991; 615: 125-127
- Von recklinghausen neurofibromatosis: a clinical and population study in south-east Wales.Brain. 1988; 111: 1355-1381
- An estimate of the heritable fraction of childhood cancer.Br J Cancer. 1991; 63: 993-999
- Prevalence of tuberous sclerosis estimated by capture-recapture analysis.Lancet. 1998; 351: 1490
- Neurocutaneous disorders in children.Pediatr Rev. 2017; 38: 119-128
- Neurocutaneous disorders.Contin Lifelong Learn Neurol. 2018; 24: 96-129
- Neurocutaneous disorders for the practicing neurologist: a focused review.Curr Neurol Neurosci Rep. 2016; 16: 1-17
- Phenotypic variation of tuberous sclerosis in a single extended kindred.J Med Genet. 1994; 31: 761-765
- A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.J Med Genet. 1992; 29: 841-846
- A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.J Med Genet. 1989; 26: 704-711
- Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas.Neurology. 2000; 54: 71-76
- Schwannomatosis: a genetic and epidemiological study.J Neurol Neurosurg Psychiatry. 2018; 89: 1215-1219
- Neurofibromatosis type 2: presentation, major complications, and management, with a focus on the pediatric age group.J Child Neurol. 2017; 32: 9-22
- Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22.Nature. 1987; 329: 246-248
- SMARCB1/INI1 maternal germ line mosaicism in schwannomatosis.Clin Genet. 2010; 77: 86-91
- Feedback activation of neurofibromin terminates growth factor-induced Ras activation.Cell Commun Signal. 2016; 14: 5
- Contextual signaling in cancer.Semin Cell Devel Bio. 2016; 58: 118-126
- Merlin, a tumor suppressor, interacts with transactivation-responsive RNA-binding protein and inhibits its oncogenic activity.J Biol Chem. 2004; 279: 30265-30273
- First International Conference on RASopathies and Neurofibromatoses in Asia: identification and advances of new therapeutics.Am J Med Genet A. 2019; 179: 1091-1097
- Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.Nat Genet. 2014; 46: 182-187
- Clinical features of schwannomatosis: a retrospective analysis of 87 patients.oncologist. 2012; 17: 1317-1322
- Further genotype – phenotype correlations in neurofibromatosis 2.Clin Genet. 2010; 77: 163-170
- Suicidal behaviour: an epidemiological and genetic study.Psychol Med. 1998; 28: 839-855
- Therapeutics for childhood neurofibromatosis type 1 and type 2.Curr Treat Options Neurol. 2011; 13: 529-543
Friedman JM. Neurofibromatosis 1. Available at: https://www.ncbi.nlm.nih.gov/sites/books/NBK1109/. Accessed 06/05/2020.
- Reproductive decisions after prenatal diagnosis in neurofibromatosis type 1: importance of genetic counseling.Genet Couns. 2009; 20: 195-202
- Preimplantation genetic diagnosis for neurofibromatosis type 1.Mol Hum Reprod. 2005; 11: 381-387
- Genetic diagnosis of neurofibromatosis type 1: targeted next- generation sequencing with multiple ligation-dependent probe amplification analysis.J Biomed Sci. 2018; 25: 1-10
- A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals.Am J Hum Genet. 1994; 55: 69-73
- Mutation type and position varies between mosaic and inherited NF2 and correlates with disease severity.Clin Genet. 2013; 83: 594-595
- Genetic testing and screening of individuals at risk of NF2.Clin Genet. 2012; 82: 416-424
- Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings.Human Mutation. 2007; 28: 1-12
- Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors.Gene Ther. 2019; 26: 277-286
- Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).Genet Med. 2018; 20: 671-682
- Neurofibromatosis type 1: review and update on emerging therapies.Asia Pac J Ophthalmol (Phila). 2019; 8: 62-72
- Trametinib induces neurofibroma shrinkage and enables surgery.Neuropediatr. 2019; 50: 300-303
- Increased breast cancer risk in women with neurofibromatosis type 1: a meta-analysis and systematic review of the literature.Hered Cancer Clin Pract. 2019; 17: 12
- Neurofibromatosis.Natl Inst Health Consens Dev Conf Consens Statement. 1987; 6: 1-7
- Neurofibromatois type 1 without neurofibromas: genotype-phenotype correlations in NF1.Hum Mutat. 2015; 36: 5
- Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.Nat Genet. 2007; 39: 1120-1126
- High incidence of noonan syndrome features including short stature and pulmonic stenosis in patients carrying nf1 missense mutations affecting p.arg1809: genotype-phenotype correlation.Hum Mutat. 2015; 26: 1052-1063
- Evidence for genetic heterogeneity in tuberous sclerosis: one locus on chromosome 9 and at least one locus elsewhere.Am J Hum Genet. 1992; 51: 709-720
- The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16.Cell. 1993; 75: 1305-1315
- Variability of expression in tuberous sclerosis.J Med Genet. 1993; 30: 41-43
- The molecular genetics of tuberous sclerosis.Hum Mol Genet. 1994; 3: 1477-1480
- Alternative splicing of the tuberous sclerosis 2 (TSC2) gene in human and mouse tissues.Genomics. 1995; 27: 475-480
- Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.Genet Med. 2007; 9: 88-100
- Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.Am J Hum Genet. 2002; 68: 64-80
- Genetic aspects of tuberous sclerosis in the west of Scotland.J Med Genet. 1989; 26: 28-31
- Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.Science. 1997; 80: 805-808
- The tuberous sclerosis complex subunit TBC1D7 is stabilized by Akt phosphorylation-mediated 14-3-3 binding.J Biol Chem. 2018; 293: 16142-16159
- Structural basis of the interaction between tuberous sclerosis complex 1 (TSC1) and tre2-bub2-cdc16 domain family member 7 (TBC1D7).J Biol Chem. 2016; 291: 8591-8601
- Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling.Proc Natl Acad Sci. 2002; 99: 13571-13576
- Mutation and cancer: statistical study of retinoblastoma.Proc Natl Acad Sci USA. 1971; 68: 820-823
- TSC1/TSC2 signaling in the CNS.FEBS Lett. 2011; 585: 973-980
- Genetic etiologies, diagnosis, and treatment of tuberous sclerosis complex.Annu Rev Genom Hum Genet. 2019; 20: 217-240
- Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.Hum Mutat. 1999; 14: 412-422
- Comprehensive mutation analysis of TSC1 and TSC2—and phenotypic correlations in 150 families with tuberous sclerosis.Am J Hum Genet. 2002; 64: 1305-1315
- Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds.Clin Genet. 2012; 81: 453-461
- High rate of mosaicism in tuberous sclerosis complex.Am J Hum Genet. 1999; 64: 1632-1637
- Germ-line mosaicism in tuberous sclerosis: how common?.Am J Hum Genet. 2002; 64: 986-992
- Mosaic and intronic mutations in TSC1/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing.PLoS Genet. 2015; 11e1005637
- Tuberous sclerosis consensus conference: recommendations for diagnostic evaluation.J Child Neurol. 1999; 14: 401-407
- Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis.Hum Mol Genet. 1997; 6: 2265-2269
- Genetics of tuberous sclerosis.Lancet. 1987; 1: 751
- Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis.J Med Genet. 2004; 41: e69
- Tuberous sclerosis complex.Brain Nerve. 2019; 71: 374-379
- Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex.Eur J Hum Genet. 2005; 13: 731-741
- Clinical application of whole-exome sequencing across clinical indications.Genet Med. 2016; 18: 696-704
- Finishing the euchromatic sequence of the human genome.Nature. 2004; 431: 931-945
- Targeted next generation sequencing reveals previously unidentified TSC1 and TSC2 mutations.BMC Med Genet. 2015; 16: 10
- What is next generation sequencing?.Arch Dis Child Educ Pract Ed. 2013; 98: 236-238
- Next-generation AAV vectors for clinical use: an ever-accelerating race.Virus Genes. 2017; 53: 707-713
- Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1.Mol Ther Methods Clin Dev. 2019; 15: 18-26
- 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
- The UK guidelines for management and surveillance of tuberous sclerosis complex.QJM. 2019; 112: 171-182
- Evaluating the risk of tuberous sclerosis in cases with prenatal diagnosis of cardiac rhabdomyoma.Prenat Diagn. 2002; 22: 1044-1047
- Precise prenatal diagnosis of tuberous sclerosis by sequencing the TSC2 gene.Prenat Diagn. 2005; 25: 582-585
- Preimplantation genetic diagnosis at 20 years.Prenat Diagn. 2007; 27: 380-381
- Preimplantation genetic diagnosis: state of the art.Eur J Obstet Gynecol Reprod Biol. 2009; 145: 9-13
- Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis.N Engl J Med. 1999; 340: 703-707
- Genetics of tuberous sclerosis complex: implications for clinical practice.Appl Clin Genet. 2017; 10: 1-8
- Clinical presentation and diagnosis of tuberous sclerosis complex in infancy.J Child Neurol. 2008; 23: 268-273
- Modifying genetic epilepsies – results from studies on tuberous sclerosis complex.Neuropharmacology. 2020; 166107908
- Pharmacological and therapeutic properties of cannabidiol for epilepsy.Drugs. 2019; 79: 1435-1454
- Rapid involution of large cardiac rhabdomyomas with everolimus therapy.World J Pediatr Congenit Heart Surg. 2021; 12: 426-429
- Photodynamic therapy in a patient with facial angiofibromas due to tuberous sclerosis complex.Photodiagnosis Photodyn Ther. 2019; 28: 183-185
- Fibrous cephalic plaque in tuberous sclerosis complex: treatment with 0.2% rapamycin.Actas Dermosifiliogr. 2019; 110: e13
Zureick AH, McFadden KA, Mody R, Koschmann C. Successful treatment of a TSC2-mutant glioblastoma with everolimus. BMJ Case Rep. 20191;12:e227734.
- Effects of sirolimus in lymphangioleiomyomatosis patients on lung cysts and pulmonary function: long-term follow-up observational study.Eur Radiol. 2020; 30: 735-743
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Published online: March 03, 2022
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