• Clinical science

Neurocutaneous syndromes

Summary

Neurocutaneous syndromes (phakomatoses) are a diverse class of congenital disorders that affect organs of ectodermal origin, especially the skin, the central nervous system, and the eyes. The disorders most typically included in this class are neurofibromatosis type 1 (NF type 1, von Recklinghausen syndrome), neurofibromatosis type 2 (NF type 2), tuberous sclerosis, von Hippel-Lindau syndrome, Sturge-Weber syndrome, and ataxia telangiectasia. With the exception of Sturge-Weber syndrome, which is caused by a noninherited developmental anomaly of neural crest derivatives, and ataxia telangiectasia, which follows an autosomal recessive inheritance pattern, neurocutaneous syndromes disorders follow an autosomal dominant inheritance pattern, although spontaneous mutations are also possible. Characteristic features include neurofibromas, café au lait spots, axillary freckling, pheochromocytoma, optic glioma, and Lisch nodules (NF 1); bilateral vestibular schwannomas, meningiomas, ependymomas, and bilateral cataracts (NF 2); adenoma sebaceum, ash-leaf spots, shagreen patch, giant cell astrocytoma, cardiac rhabdomyoma, and renal angiomyolipoma (tuberous sclerosis); hemangioblastoma, angiomatosis, bilateral renal cell carcinoma, pheochromocytoma (von Hippel-Lindau syndrome); Port-wine stain and leptomeningeal angioma (Sturge-Weber syndrome); spider angioma, lymphoma, leukemia, gastric carcinoma, and ocular telangiectasia (ataxia telangiectasia). Diagnosis is based on clinical findings and is confirmed by genetic testing. Since there is no curative treatment, the management of neurocutaneous syndromes is symptom-oriented.

Overview

Neurocutaneous syndromes

Disorder

Cause

Main features

Inheritance Mutation Skin changes Common tumors Other features
Neurofibromatosis type 1
Neurofibromatosis type 2
Tuberous sclerosis
von Hippel-Lindau syndrome
  • Uncommon
Sturge-Weber syndrome
  • Not inherited
Ataxia telangiectasia
  • ATM gene

Neurofibromatosis

Epidemiology

Etiology

Pathophysiology

Clinical features

Neurofibromatosis type 1 (von Recklinghausen syndrome) [3]

Think CAFE SPOTS to remember features of NF type 1: Café au lait spots, Axillary freckling, neuroFibromas, nodules in the Eye, Skeletal abnormalities (e.g., Scoliosis), high blood Pressure, Optic Tumor, Stature (usually Short).

Neurofibromatosis type 2 [6]

In NF Type 2, the mutation is in chromosome Twenty-2 and the clinical findings (schwannoma and cataracts) manifest on 2 sides.

Diagnostics

Differential diagnosis

Treatment

Prognosis

  • Increased mortality due to malignant transformation of tumors
  • Average life expectancy

Tuberous sclerosis

Epidemiology

Etiology

Pathophysiology

Clinical features [13][14]

Infantile spasms occur in children < 3 years of age. They can consist of head bobbing, flexor spasms, extensor spasms, or movements that mimic the startle response. They may be associated with psychomotor regression or behavioral changes.

To remember the features of tuberous sclerosis, think: HAMAARTOMASS Hamartomas, Ash leaf spots, Mind (intellectual disability), Adenoma sebaceum, renal Angiomyolipoma, Rhabdomyoma, Tumor suppressor genes (TSC1 gene and TSC2 gene), autosomal dOminant, Mitral regurgitation, Astrocytomas, Seizures, and Shagreen patches.

Diagnostics [16]

Differential diagnosis

Treatment [16]

Prognosis [17]

  • Renal disease and epilepsy are the most common causes of death.
  • Life expectancy depends on severity of disease but can be normal if symptoms are mild and complications are treated accordingly.

von Hippel-Lindau syndrome

Epidemiology

Etiology

Pathophysiology

Clinical features [19][20]

Characterized by the development of numerous benign and malignant tumors

Von HIPPEL-Lindau syndrome: Hemangioblastoma, Increased risk of renal cell carcinoma, Pheochromocytoma, Pancreatic lesions (cysts, cystadenomas, and neuroendocrine tumors), Eye Lesions (retinal angiomas or hemangioblastomas).

Diagnostics [20]

Differential diagnosis

Treatment [21]

Mainly consists of regular surveillance and, if necessary, surgical treatment of tumors

Prognosis [22]

  • CNS hemangioblastoma is the main cause of death.
  • Average life expectancy: 60 years for women and 67 years for men

Sturge-Weber syndrome

Epidemiology

Etiology

  • Congenital noninherited developmental anomaly of neural crest derivatives

Pathophysiology

Clinical features [24]

Vascular malformations involving the following:

Think of “SSTURGGE-Weber” to remember the symptoms of Sturge-Weber syndrome: Sporadic, port-wine Stain, Tram-Track calcifications, Unilateral, Recurrent strokes or seizures, Glaucoma, GNAQ gene, Epilepsy.

Diagnostics

Differential diagnosis

Treatment

Prognosis [27][28]

  • Severity of the disease depends on:
    • Extent of skin and brain involvement
    • Age of onset of seizures
  • Life expectancy is normal.

Ataxia-telangiectasia

Epidemiology

Etiology

Pathophysiology

Clinical features [30]

The 4 A's of ataxia telangiectasia: ATM gene, Ataxia, spider Angiomas, and IgA deficiency.

Avoid x-ray exposure because of high sensitivity to radiation and increased risk of malignancy.

Diagnostics

Differential diagnosis [30]

Treatment

  • Antibiotic therapy: for acute infection and/or prophylaxis
  • IV immunoglobulin therapy, depending on the severity of Ig deficiency

Prognosis

  • Variable rate of progression
  • Affected individuals typically require a wheelchair by adolescence.
  • Malignancy is the most common cause of death. [33]
  • Average life expectancy: 25 years of age [34]
  • 1. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. The Lancet Neurology. 2014; 13(8): pp. 834–843. doi: 10.1016/s1474-4422(14)70063-8.
  • 2. National Organisation for Rare Disorders. Neurofibromatosis 2. https://rarediseases.org/rare-diseases/neurofibromatosis-2/. Updated January 1, 2018. Accessed June 22, 2020.
  • 3. Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis Type 1 Revisited. Pediatrics. 2009; 123(1): pp. 124–133. doi: 10.1542/peds.2007-3204.
  • 4. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007; 44(2): pp. 81–88. doi: 10.1136/jmg.2006.045906.
  • 5. Stay EJ, Vawter G. The relationship between nephroblastoma and neurofibromatosis (Von Recklinghausen's disease). Cancer. 1977; 39(6): pp. 2550–2555. doi: 10.1002/1097-0142(197706)39:6<2550::aid-cncr2820390636>3.0.co;2-y.
  • 6. Evans DG. Neurofibromatosis type 2 (NF2): A clinical and molecular review. Orphanet J Rare Dis. 2009; 4. doi: 10.1186/1750-1172-4-16.
  • 7. Campian J, Gutmann DH. CNS Tumors in Neurofibromatosis. Journal of Clinical Oncology. 2017; 35(21): pp. 2378–2385. doi: 10.1200/jco.2016.71.7199.
  • 8. Editors of Genetics Home Reference. Bloom syndrome. https://ghr.nlm.nih.gov/condition/bloom-syndrome. Updated August 4, 2020. Accessed August 13, 2020.
  • 9. Rasmussen SA, Yang Q, Friedman JM. Mortality in Neurofibromatosis 1: An Analysis Using U.S. Death Certificates. The American Journal of Human Genetics. 2001; 68(5): pp. 1110–1118. doi: 10.1086/320121.
  • 10. Aboukais R, Zairi F, Bonne N-X, et al. Causes of mortality in neurofibromatosis type 2. Br J Neurosurg. 2015; 29(1): pp. 37–40. doi: 10.3109/02688697.2014.952266.
  • 11. Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Q J Med. 1992; 84(304): pp. 603–18. pmid: 1484939.
  • 12. DiMario FJ. Tuberous sclerosis. https://rarediseases.org/rare-diseases/tuberous-sclerosis/. Updated January 1, 2019. Accessed June 24, 2020.
  • 13. Portocarrero LKL, Quental KN, et al. Tuberous sclerosis complex: review based on new diagnostic criteria. An Bras Dermatol. 2018; 93(3): pp. 323–331. doi: 10.1590/abd1806-4841.20186972.
  • 14. Northrup H, Krueger DA, et al. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013; 49(4): pp. 243–254. doi: 10.1016/j.pediatrneurol.2013.08.001.
  • 15. Henske EP, Jóźwiak S, et al. Tuberous sclerosis complex. Nature Reviews Disease Primers. 2016; 2(1). doi: 10.1038/nrdp.2016.35.
  • 16. Krueger DA, Northrup H, Northrup H, et al. Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013; 49(4): pp. 255–265. doi: 10.1016/j.pediatrneurol.2013.08.002.
  • 17. Amin S, Lux A, Calder N, et al. Causes of mortality in individuals with tuberous sclerosis complex. Developmental Medicine & Child Neurology. 2016; 59(6): pp. 612–617. doi: 10.1111/dmcn.13352.
  • 18. Von Hippel-Lindau Disease. https://rarediseases.org/rare-diseases/von-hippel-lindau-disease/. Updated January 1, 2019. Accessed June 30, 2020.
  • 19. Maher ER, Neumann HP, et al. von Hippel–Lindau disease: A clinical and scientific review. European Journal of Human Genetics. 2011; 19(6): pp. 617–623. doi: 10.1038/ejhg.2010.175.
  • 20. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. The Lancet. 2003; 361(9374): pp. 2059–2067. doi: 10.1016/s0140-6736(03)13643-4.
  • 21. Varshney N, Kebede AA, et al. A Review of Von Hippel-Lindau Syndrome. Journal of Kidney Cancer and VHL. 2017; 4(3): pp. 20–29. doi: 10.15586/jkcvhl.2017.88.
  • 22. Binderup MLM, Jensen AM, et al. Survival and causes of death in patients with von Hippel-Lindau disease. J Med Genet. 2017; 54(1): pp. 11–18. doi: 10.1136/jmedgenet-2016-104058.
  • 23. Comi A. Sturge Weber Syndrome. https://rarediseases.org/rare-diseases/sturge-weber-syndrome/. Updated January 1, 2017. Accessed July 1, 2020.
  • 24. Thomas-Sohl KA, Vaslow DF, et al. Sturge-Weber syndrome: A review. Pediatr Neurol. 2004; 30(5): pp. 303–310. doi: 10.1016/j.pediatrneurol.2003.12.015.
  • 25. Lambiase A, Mantelli F, Bruscolini A, et al. Ocular manifestations of Sturge–Weber syndrome: pathogenesis, diagnosis, and management. Clinical Ophthalmology. 2016: pp. 871–878. doi: 10.2147/opth.s101963.
  • 26. Lance EI, Sreenivasan AK, et al. Aspirin Use in Sturge-Weber Syndrome. J Child Neurol. 2012; 28(2): pp. 213–218. doi: 10.1177/0883073812463607.
  • 27. Sujansky E, Conradi S. Outcome of Sturge-Weber syndrome in 52 adults. Am J Med Genet. 1995; 57(1): pp. 35–45. doi: 10.1002/ajmg.1320570110.
  • 28. Day AM, McCulloch CE, Hammill AM, et al. Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome. Pediatr Neurol. 2019; 96: pp. 30–36. doi: 10.1016/j.pediatrneurol.2018.12.002.
  • 29. Stefans VA. Ataxia Telangiectasia. https://now.aapmr.org/ataxia-telangiectasia/. Updated April 12, 2013. Accessed July 6, 2020.
  • 30. Amirifar P, Ranjouri MR, Yazdani R, et al. Ataxia‐telangiectasia: A review of clinical features and molecular pathology. Pediatric Allergy and Immunology. 2019; 30(3): pp. 277–288. doi: 10.1111/pai.13020.
  • 31. Stray-Pedersen A, Borresen-Dale AL, et al. Alpha fetoprotein is increasing with age in ataxia–telangiectasia. European Journal of Paediatric Neurology. 2007; 11(6): pp. 375–380. doi: 10.1016/j.ejpn.2007.04.001.
  • 32. Ishiguro T, Taketa K, Gatti RA. Tissue of origin of elevated alpha-fetoprotein in ataxia-telangiectasia. Dis Markers. 1986; 4(4): pp. 293–7. pmid: 2454778.
  • 33. Swift M, Morrell D, et al. Incidence of Cancer in 161 Families Affected by Ataxia–Telangiectasia. N Engl J Med. 1991; 325(26): pp. 1831–1836. doi: 10.1056/nejm199112263252602.
  • 34. Crawford TO. Survival probability in ataxia telangiectasia. Arch Dis Child. 2006; 91(7): pp. 610–611. doi: 10.1136/adc.2006.094268.
last updated 09/10/2020
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