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2021 NPB-16

This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

Clinical History

The patient is a six-year-old boy with a congenital vascular lesion involving the forehead and upper and lower eyelids and a history of seizures since infancy. Initially, he had focal motor seizures, but over time he developed generalized tonic-clonic seizures. He also experienced sporadic episodes of hemiparesis and transient focal neurological deficits that improved over days to weeks. He underwent resection of an epileptogenic focus in the occipital lobe.

Tissue Site
Occipital lobe

Whole Slide Image

The whole slide image provided is an H&E-stained image from an occipital lobe resection specimen.

Questions

  1. What is the most likely clinical diagnosis?

    1. Lhermitte–Duclos disease

    2. Tuberous sclerosis

    3. Megalencephaly-capillary malformation syndrome

    4. Neurofibromatosis type 1

    5. Sturge-Weber syndrome

  2. Alterations in which gene are associated with this entity?

    1. NF1

    2. NF2

    3. GNAQ

    4. PTEN

    5. TSC1

  3. Which ocular manifestation is frequently associated with this entity?

    1. Retinal dystrophy

    2. Lisch nodules

    3. Pilocytic astrocytoma of the optic nerve

    4. Choroidal angioma

    5. Optic nerve hamartoma

View Answer Key

Discussion and Diagnosis

The patient is a child with a facial vascular malformation consistent with a port-wine stain and a long history of seizures and stroke-like episodes. Based on this information, Sturge-Weber syndrome (SWS) should be clinically suspected. The gross images of the resection specimen show increased leptomeningeal vascularity (Image A) with atrophy of the underlying cortex (Image B). H&E-stained sections (Image C and Image D) show leptomeningeal angiomatosis composed of a dense proliferation of small capillaries and venules that lack elastic fibers. The underlying atrophic cerebral cortex contains numerous intraparenchymal and vascular microcalcifications (Image E). These neuropathologic findings are consistent with SWS.

Image A: Gross image, occipital lobe, external surface.

Image A: Gross image, occipital lobe, external surface.

Image B: Gross image, occipital lobe, cut surface.

Image B: Gross image, occipital lobe, cut surface.

Image C: H&E.

Image C: H&E.

Image D: H&E.

Image D: H&E.

Image E: H&E.

Image E: H&E.

SWS is a sporadic neurocutaneous syndrome characterized by cutaneous, leptomeningeal, and ocular vascular malformations. SWS is caused by an activating somatic alteration in GNAQ. This alteration can be confirmed by detection of a p.Arg183Gln mutation in GNAQ, present only in affected tissues (eg, port-wine stain or leptomeningeal angiomatosis) from patients with SWS. GNAQ plays a role in the development of abnormal blood vessels in the skin, brain, and eyes. The somatic alteration in SWS occurs in the ectoderm during embryogenesis. Alterations in GNAQ that occur earlier in embryogenesis are thought to be associated with more extensive vascular malformations. GNAQ alterations also occur in SWS cases with facial port-wine stains but without brain or ocular involvement. Thus, detection of GNAQ alteration in a facial port-wine stain does not correlate with brain involvement.

The pathologic and clinical manifestations of SWS are dependent on the extent of vascular malformations involving the skin, brain, and eyes. The port-wine stain (nevus flammeus) is a cutaneous capillary malformation. Leptomeningeal angiomatosis is a malformation composed of capillary to venous-sized vessels found in a primarily parieto-occipital distribution. Ocular findings include diffuse choroidal angiomas as well as conjunctival and episcleral telangiectasias. Vascular lesions associated with SWS are not true neoplasms, as they are thought to be localized defects of vascular morphogenesis.

The majority of patients with SWS have a facial port-wine stain at birth. However, most children with a congenital port-wine stain do not have SWS. Isolated port-wine stains occur with an estimated frequency of one per 600 live births, while SWS prevalence range from one in 20,000-50,000 live births. The presence of a port-wine stain is not essential for the diagnosis of SWS, as approximately 10% of patients with SWS have brain involvement with no port-wine stain. In SWS, the port-wine stain typically follows the distribution of the ophthalmic branch of the trigeminal nerve involving the forehead and upper eyelid, the size and distribution of which correlates with the extent and severity of brain and ocular involvement. Leptomeningeal vascular malformations tend to be ipsilateral to the port-wine stain. Bilateral cutaneous lesions are associated with a higher likelihood of involvement of both cerebral hemispheres and increased severity of neurological symptoms. Port-wine stains involving the upper and lower eyelids are more frequently associated with glaucoma than those with isolated upper eyelid involvement.

Cortical and subcortical atrophy, neuronal loss with gliosis, and microcalcifications (Image D and Image E) are likely secondary to ischemia due to impaired blood flow and hemodynamic function related to the leptomeningeal vascular malformation. In some cases, focal cortical dysplasia may also be present. Patients with a port-wine stain can be screened for brain involvement by neuroimaging. MRI with and without contrast is a sensitive technique for visualizing leptomeningeal angiomatosis, cortical atrophy, and cortical dysgenesis. CT scan may show “tram-track” sign of cortical and subcortical calcifications.

Image D: H&E.

Image D: H&E.

Image E: H&E.

Image E: H&E.

Leptomeningeal angiomatosis and underlying brain changes associated with Sturge-Weber syndrome.

Take Home Points

  • SWS is a sporadic neurocutaneous syndrome clinically characterized by vascular malformations that include facial port-wine stain, leptomeningeal angiomatosis, and choroidal angioma of the eye.
  • SWS is caused by a somatic alteration in GNAQ in affected tissues (eg, port-wine stain and leptomeningeal angiomatosis).
  • Neuroimaging is recommended for screening of brain involvement in patients with a facial port-wine stain at birth.
  • Leptomeningeal angiomatosis may result in abnormal blood flow that causes localized cerebral ischemia leading to progressive atrophy, gliosis, and microcalcifications in the underlying cortex.

References

  1. Ellison D, Love S, Chimelli L, Harding BN, Lowe J, Vinters HV. Neuropathology: A Reference Text of CNS Pathology. 3rd ed. Edinburgh, UK: Mosby; 2013:115.
  2. Comi AM. Sturge-Weber syndrome. Handb Clin Neurol. 2015;132:157-168.
  3. Comi AM, Marchuk DA, Pevsner J. Sturge–Weber Syndrome. In: Rosenberg RN, Pascual JM, eds. Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease. 5th ed. London, England: Academic Press; 2015: 945-953.
  4. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971-1979.
  5. Yanoff M. Ophthalmic Diagnosis & Treatment. 3rd ed. New Delhi, India: Jaypee Brothers Medical Pub Ltd; 2014: 180-183.

Answer Key

  1. What is the most likely clinical diagnosis?
    A. Lhermitte–Duclos disease
    B. Tuberous sclerosis
    C. Megalencephaly-capillary malformation syndrome
    D. Neurofibromatosis type 1
    E. Sturge-Weber syndrome
  2. Alterations in which gene are associated with this entity?
    A. NF1
    B. NF2
    C. GNAQ
    D. PTEN
    E. TSC1
  3. Which ocular manifestation is frequently associated with this entity?
    A. Retinal dystrophy
    B. Lisch nodules
    C. Pilocytic astrocytoma of the optic nerve
    D. Choroidal angioma
    E. Optic nerve hamartoma
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