What is the Epidemiology and Genetics of the Major Phacomatoses?

Patient Presentation

An 8-year-old female came to the emergency room with a new onset seizure that was witnessed at school, when she suddenly stopped, fell towards her left side and then fell to the floor. She was not able to speak and had movements of her left upper extremities. She was given lorazepam and taken by ambulance to the local emergency room where she had left sided weakness and some abnormal eye movements noted. She was airlifted to a regional children’s center. She had a past medical history of Sturge-Weber Syndrome diagnosed because of a port-wine stain. The review of systems showed she was previously well with no seizures, headaches, auras or other neurological problems. She had no infectious disease symptoms.

The pertinent physical exam showed a child who was tired but arousable. Her vital signs were normal and her growth parameters were 10-50%. She had a port-wine nevus in the distribution of the first and second divisions of the right trigeminal nerve but it also crossed the midline. There were no obvious hemangiomas. Neurologically she had left-sided weakness of both upper and lower extremities and face. Cranial nerves were intact. Deep tendon reflexes were normal. The radiologic evaluation of a head computed tomography examination showed no changes to the previously documented right-sided leptomeningeal angioma. The work-up included normal electrolytes, calcium, phosphorous and magnesium. A video electroencephalogram showed many seizures. Ophthalmological consultation found no glaucoma or other disease. During a later patient interview, the patient said that she could remember people screaming at her during the episode. The diagnosis of Sturge-Weber syndrome and complex-partial seizures was made. She was started on Keppra®. At discharge she had mild left-sided weakness and she had started receiving physical therapy. She had had no obvious seizures for 2 days and was to continue on anti-epileptic medication.

Case Image
Figure 87 – Axial image from a computed tomography scan of the brain performed with intravenous contrast shows marked enhancement of the leptomeninges in the right temporal, parietal and occipital lobes and minimal leptomeningeal enhancement in the right frontal lobe. There was mild atrophy of the right cerebral hemisphere.

Discussion
Neurocutaneous syndromes or phacomatoses are a group of congenital or hereditary diseases that develop hamartomas of various tissues and usually additional cutaneous stigmata. Most phacomatoses have quite variable phenotypical presentations for an affected individual. Those that are listed below are common for that disease process.

Learning Point
Common major phacomatosis include:

  • Sturge-Weber Syndrome
    • Genetics: non-genetic
    • Neurological: seizures (often contralateral to the nevus and focal), hemiparesis (again often contralateral to the nevus), mental retardation, ophthalmological problems including glaucoma
    • Dermatological: port-wine nevus often in the trigeminal nerve’s first division, hemangiomas
    • Other clinical features: may be associated with Klippel-Trenaunay-Weber syndrome (hemangiomas with hypertrophy of the related adjacent tissues)
    • Radiological features: intracranial paired lines of calcifications often called trolley tracks caused by leptomeningeal angiomas

  • Neurofibromatosis Type 1
    • Epidemiology: 1:2500-3000 – most common phacomatosis
    • Genetics: autosomal dominant with variable penetrance, associated with chromosome 17
    • Neurological: various central nervous system tumors especially neurofibromas (often benign but may act malignant because of location or size, tumors may also degenerate into a malignant variant or cause other problems such as hypothalamic problems secondary to an optic chiasm tumor ), optic nerve tumors, pheochromocytomas, mental retardation
    • Dermatological: neurofibromas, cafe-au-lait spots
    • Other clinical features: Lisch nodules of eye, other congenital anomalies may be associated including bone (rib, vertebra) and renal artery stenosis.
    • Radiological features: lesions tend to be more scattered in brain and more peripheral than tuberous sclerosis

  • Neurofibromatosis Type 2
    • Epidemiology: 1-33,000-40,000
    • Genetics: autosomal dominant with variable penetrance, associated with chromosome 22
    • Neurological: bilateral vestibular nerve schwannomas, brain meningiomas and dorsal root schwannomas
    • Dermatological: various skin changes can be seen but are less consistently associated
    • Other clinical features: eye lens opacities

  • Tuberous Sclerosis
    • Epidemiology: 1:5700-10,000
    • Genetics: autosomal dominant with variable penetrance, often is new mutation
    • Neurological: seizures (infantile spasms, grand mal), mental retardation, learning problems, behavior problems, autism
    • Dermatological: ash-leaf spots (depigmented spots), adenoma sebaceum (pink/yellow/brown raised nevi predominantly in butterfly distribution), shagreen patches (flesh-colored leather-like plaque)
    • Other clinical features: fibromas of other tissues include rhabdomyoma of heart
    • Radiological features: calcified periventricular lesions, lesions may also be scattered but are more central than Neurofibromatosis type 1

  • von Hippel-Lindau Syndrome
    • Epidemiology: 1:40,000-50,000
    • Genetics: autosomal dominant
    • Neurological: hemangioblastomas of cerebellum, angioma of retina, presents usually because of increased intracranial pressure
    • Dermatological: relatively uncommon
    • Other clinical features: cystic lesions of other tissues and other central nervous system locations

Other phakomatosis include:

  • Chédiak-Higashi syndrome
  • Cutaneous Spinal Angiomatosis
  • Epidermal Nevus Syndrome (Linear nevus sebaceous)
  • Hereditary Hemorrhagic Telangectasis (Osler-Rendu-Weber Syndrome)
  • Incontinentia Pigmenti
  • Incontinentia Pigmenti Achromaians (Hypomelanosis of Ito)
  • Neurocutaneous Melanosis
  • Polyostotic Fibrosis Dysplasia (McCune-Albright syndrome)
  • Sjögren-Larsson syndrome
  • Wyburn-Mason Syndrome

Questions for Further Discussion
1. What are the size and number criteria for cafe-au-lait spots used for diagnosing neurofibromatosis?
2. What are the primary diagnostic criteria for diagnosing tuberous sclerosis?
3. What is the role of a general pediatrician and a geneticist in counseling a family about a phacomatosis?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Neurological Disease and Skin Pigmentation Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:769-774, 2344-2349.

Online Mendelian Inheritance in Man. NEUROFIBROMATOSIS, TYPE I; NF1. Available from the Internet at http://www.ncbi.nlm.nih.gov/omim/162200 (rev. 3/18/10, cited 5/27/10).
Online Mendelian Inheritance in Man. NEUROFIBROMATOSIS, TYPE II; NF2. Available from the Internet at http://www.ncbi.nlm.nih.gov/omim/101000 (rev. 3/31/10, cited 5/27/10).
Online Mendelian Inheritance in Man. STURGE-WEBER SYNDROME. Available from the Internet at http://www.ncbi.nlm.nih.gov/omim/185300 (rev. 2/26/10, cited 5/27/10).
Online Mendelian Inheritance in Man. TUBEROUS SCLEROSIS 1; TSC1. Available from the Internet at http://www.ncbi.nlm.nih.gov/omim/191100 (rev. 1/27/10, cited 5/27/10).
Online Mendelian Inheritance in Man. VON HIPPEL-LINDAU SYNDROME; VHL. Available from the Internet at http://www.ncbi.nlm.nih.gov/omim/193300 (rev. 8/18/09, cited 5/27/10).

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Systems Based Practice
    26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.

    Author

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital