Case of the Week: October 17-October 24, 2002

2 year old with vomiting

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Case Details

Answer

Diagnosis: Tuberous Sclerosis Complex (TSC)

One of the phakomatoses described by Van der Hoeve (1933) or neuroectodermal dysplasia by van Bogaert (1935). Phakomatosis manifests in the form of development of benign tumors/malformations especially in organs of ectodermal origin.

PHAKOMATOSES

  • Neurofibromatosis

  • Tuberous Sclerosis Complex

  • Von Hippel-Lindau disease

  • Sturge-Weber-Dimitri Syndrome

  • Ataxia-Telangiectasia

  • Wyburn-Mason Syndrome

  • Osler-Weber-Rendu disease

  • Klippel-Trenaunay-Weber Syndrome

  • Nevus of Ota Syndrome

  • Hypomelanosis of Ito

TRIAD

  • Adenoma sebaceum

  • Seizures

  • Mental retardation

The classic triad of symptoms described by Volt in 1908 of seizures, mental retardation and adenoma sebaceum is seen in less than one third of the cases. Tuberous sclerosis complex was first described in the 1800s and affects 40,00 Americans and approximately 2 million people worldwide. The gene site designated TSC1 is found on chromosome 9, while the first discovered TSC2 site is on chromosome 16. TSC is an autosomal dominant disorder, although up to 70% of cases occur spontaneously. The diagnostic criteria for TSC complex has been described. 

CARDIAC RHABDOMYOMAS: 

The incidence of cardiac rhabdomyomas in TSC has been reported to vary from 47% to 67%. Any cardiac intracavitary mass in an infant is suggestive for a cardiac rhabdomyoma unless proven otherwise. Spontaneous regression of these tumors has been well established and surgical intervention is indicated only for obstructive cardiac failure. A retrospective study showed that 90% of infants with cardiac rhabdo had associated TSC. There is a secondary peak in the incidence of these tumors in prepubertal females with TSC. Rhabdomyomas are circumscribed, but not encapsulated and vary in size from a few millimeters to several centimeters and may totally obliterate the cardiac chambers. The clinical presentation is dominated by cardiac enlargement, congestive heart failure, arrhythmias and sudden death. Stillbirth and perinatal deaths have been reported. 

RENAL MANIFESTATIONS OF TSC:

Five different lesions occur in the kidneys of patients with TSC: Benign and malignant angiomyolipomas (AML) and cysts, oncocytoma and renal cell carcinoma. Benign angiomyolipomas are the most common occurring in 70% to 80% of adults and older children with TSC. A patient is at increased risk for angiomyolipoma bleeding, the primary complication of this lesion, when the tumors become larger than 4 cms. Intrarenal, perirenal, retroperitoneal and intraperitoneal hemorrhage have all been reported and embolization of AML is a recognized treatment. Renal cysts (multiple and bilateral) are the second most common kidney lesion, and occur in 20% of patients. Recent investigation shows a proximity of the polycystic kidney disease gene and the TSC2 gene. They may play a synergistic role in cyst development.

PULMONARY MANIFESTATIONS OF TSC:

The three main pulmonary lesions found in TSC are lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia, and clear cell tumor of the lung. LAM is by far the most common; the average onset is 32-34 years, and it is essentially a disease of women only.  LAM is characterized by proliferation of smooth muscle cells of the bronchi, alveoli, vessels and lymphatics and is found in about 1% of patients with TSC. Treatment options include hormone therapy and lung transplantation.

CNS MANIFESTATIONS OF TSC:

TSC derives its name from the cortical hamartomas or tubers seen in the gyri (most commonly frontal lobe). These lesions are seen in 95% of cases. Some calcify and the number of calcified cortical lesions increases with age; by age 10, 50% have calcified tubers. Giant cell astrocytomas occur in up to 15% of TSC patients (Figure 16). They occur at the foramen of Monro and present as enlarging partly calcified masses with hydrocephalus. Serpentine flow voids due to dilated vessels are seen in one third. Their appearance varies and neither signal intensity or contrast enhancement can differentiate this tumor from a subependymal nodule - the change in the size is the most important finding.

Diagnostic criteria for tuberous sclerosis are:
Primary features 


  • Facial angiofibromas
  • Multiple ungual fibromas
  • Cortical tuber (histologically confirmed)
  • Subependymal nodule or giant cell astrocytoma (histologically confirmed)
  • Multiple calcified subependymal nodules protruding into the ventricle (radiographic evidence)
  • Multiple retinal astrocytomas
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Secondary features 
  • Affected first-degree relative
  • Cardiac rhabdomyoma (histologic or radiographic confirmation)
  • Other retinal hamartoma or achromic patch
  • Noncalcified subependymal nodules (radiographic confirmation)
  • Shagreen patch
  • Forehead plaque
  • Pulmonary lymphangiomyomatosis (histological confirmation)
  • Renal angiomyolipoma (radiographic or histologic confirmation)
  • Renal cysts (histologic confirmation)

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Tertiary features 
  • Hypomelanotic macules
  • ‘Confetti’ skin lesions
  • Renal cysts (radiographic evidence)
  • Randomly distributed enamel pits in deciduous and/or permanent teeth
  • Bone cysts (radiographic confirmation)
  • Hamartomatous rectal polyps (histologic confirmation)
  • Pulmonary lymphangiomyomatosis (radiographic evidence)
  • Cerebral white matter migration tracts or heterotopias (radiographic evidence)
  • Gingival fibromas
  • Hamartomas of other organs (histologic confirmation)
  • Infantile spasms

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Definite TS 
  • Either one primary and two secondary features, or one secondary and two tertiary features

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Probable TS 
  • Either one secondary and one tertiary feature, or three tertiary features

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Suspect TS 
  • Either one secondary or two tertiary features

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VCU Department of Pediatric Radiology Virginia Commonwealth University VCU Medical Center