DOI: 10.1148/radiol.2292020154
(Radiology 2003;229:385-388.)
Case 64: Tuberous Sclerosis1
Gael J. Lonergan, Col, USAF MC and
James G. Smirniotopoulos, MD
1 From the Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md; and the Department of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC. Received February 25, 2002; revision requested April 25; revision received July 15; accepted August 15. Address correspondence to G.J.L., 6101 W Courtyard Dr, Bldg 4, Austin, TX, 78765.
Index terms: Diagnosis Please • Hamartoma, 50.314, 77.314, 81.3141 • Sclerosis, tuberous, 30.1832, 40.1832 60.1471, 10.1832
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HISTORY
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A term girl had two partial seizures in the 1st day of life. The mother was gravida 1, para 1. The pregnancy and delivery were uncomplicated. The Apgar score was 9 at 1 minute and 10 at 5 minutes. There was no family history of seizure disorder or other congenital anomaly. The findings of a physical examination were normal. The neonate underwent cranial, cardiac, and renal ultrasonography (US) (Figs 1–4).
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Figure 1. Sagittal cranial US image (7.5 MHz, phased array) of the left lateral ventricle obtained through the anterior fontanel reveals small nodules (straight arrows) in the floor of the ventricle, which protrude into the lumen. Rounded areas (curved arrows) of increased echogenicity are seen in the subcortical white matter.
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Figure 2. Transverse echocardiogram of the heart (7.5 MHz, phased array) obtained through the sternum shows echogenic material (*) filling the interventricular septum (arrow) and ventricular wall (arrowheads).
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Figure 3. Longitudinal left parasternal echocardiogram of the heart (7.5 MHz, phased array) shows echogenic material filling much of the right ventricle (white arrow) and left ventricle (black arrow). A = aorta.
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IMAGING FINDINGS
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Figure 1 reveals several small nodules protruding into the ventricular lumen. There are also rounded areas of increased echogenicity in the subcortical white matter. Echocardiograms of the heart show large, confluent areas of increased echogenicity filling much of the cardiac chambers. The interventricular septum and ventricular walls appear as hypoechoic rims of tissue around the echogenic material in Figure 2. In Figure 3, the aorta is seen arising from the left ventricle and appears normal, with anechoic contents (blood). The right and left ventricles contain echogenic material. Figure 4 shows three well-defined, rounded anechoic areas in the renal parenchyma that are consistent with small renal cysts.
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DISCUSSION
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Tuberous sclerosis (TS) is a neurocutaneous disease characterized by hamartomatous changes in the lungs, brain, kidneys, skin, heart, and other organs. TS is also known as Bourneville disease, named after the French physician who described a series of patients with this illness in 1880 (1). It is an autosomal dominant disease associated with at least two separate chromosomes (TSC1, found on chromosome 9, and TSC2, on chromosome 16). TS is thought to result from sporadic mutation in the majority of patients, since most patients have no family history of the disease (2). The rate of familial transmission may be underestimated, however, if the parents are asymptomatic. The triad of symptoms of TS, as described by Vogt (3), consists of seizure, adenoma sebaceum (facial angiofibroma), and mental retardation. Not all patients have this classic triad, however, and half of all patients are of normal intellect and a quarter do not have seizures (4). Although facial angiofibromas are commonly described as the hamartomatous lesions of TS, hamartomas may involve virtually any organ. A variety of lesions may be present in patients with TS; therefore, diagnosis rests on the discovery of one or more lesions with findings typical of TS. Gomez (5) established diagnostic criteria that consist of major features (eg, cortical tuber, cardiac rhabdomyoma, facial angiofibroma, retinal hamartoma, and renal angiomyolipoma) and minor features (eg, gingival fibroma, hamartomatous rectal polyp, and renal or bone cyst). A diagnosis of TS is definite when two major features or one major and two minor features exist, probable if one major and one minor feature are present, and possible when more than two minor features or only one major feature is present.
Hamartomas are the hallmark of TS. They are tumors composed of normal cells but disorganized tissue, and they can develop in any organ. The hamartomas of TS include angiomyolipoma of the kidney, cortical and subependymal tubers of the brain, and rhabdomyomas of the heart, among others. Lymphangioleiomyomatosis of the lung occurs in approximately 1%–4% of patients with TS, although it may also occur in patients without TS (usually women of child-bearing age) (6,7). Patients with TS come to medical attention for a variety of reasons, including seizure, renal failure from cystic disease, and mental retardation.
This patient has typical findings associated with TS, including subependymal nodules, white matter changes, cardiac rhabdomyomas, and renal cysts that occur in a baby with seizure. The cranial US image shows nodules in the wall of the lateral ventricle, most of which are near the caudothalamic groove (also known as the striothalamate groove, which is between the caudate head and the thalamus) (8). In early childhood, these subependymal nodules are small and only some are calcified. Over time, more of these subependymal nodules become calcified, and by the age of 20 years, nearly 100% will be calcified (9,10). Germinal matrix and intraventricular hemorrhage may simulate subependymal tubers, although hemorrhage tends to have a hyperechoic appearance and to resolve in a few weeks. Other nervous system lesions that occur in conjunction with TS include cortical hamartomas (disorganized masses of neurons and other nervous tissue in the cortex), subependymal giant cell astrocytoma (a low-grade, slow-growing glioma that arises adjacent to the caudate head and may cause ventricular obstruction), and white matter hamartomas (8,9,11). The echogenic white matter findings in this patient likely represent hamartomatous changes.
Cardiac rhabdomyomas are discovered in at least 50% of patients with TS (12). They usually appear as intracardiac tumors, either protruding into the chamber or contained in the myocardium (13). The majority of patients are often diagnosed with obstetric US or early in postnatal life, and the rhabdomyomas regress (usually completely) in the first several years of life (14,15). Other tumors of the heart, including fibroma, myxoma, and fibroelastoma, may have similar appearances, but they are usually solitary and distinctly uncommon in infancy (16). Renal findings in patients with TS include angiomyolipoma (the most common lesion, estimated to occur in 40%–80% of patients) and renal cysts (17). This patient had multiple renal cysts in infancy, an unusual finding that suggests underlying renal disease or heritable cystic disease. Illnesses such as obstructive cystic dysplasia, medullary cystic disease (juvenile nephronophthisis), and autosomal dominant polycystic kidney disease could all have a similar appearance.
The combination of subependymal tubers, renal cysts, and multiple cardiac rhabdomyomas in an infant with seizure is diagnostic of TS and fulfills the criteria established by Gomez for definitive diagnosis (5). The diagnosis of TS should be considered in all children with either single or multiple cardiac rhabdomyoma and in those children with multiple renal cysts. Prognosis for patients with TS varies with the severity of disease manifestations.
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FOOTNOTES
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The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Departments of the Air Force or Defense.
Part 1 of this case appeared 4 months previously and may contain larger images.
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REFERENCES
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- Bourneville DM. Sclerose tubereuse des circonvolutions cerebrales: idotie et epilipsie hemiplegique. Arch Neurol 1880; 1:81-91.
- Winship IM, Connor JM, Beighton PH. Genetic heterogeneity in tuberous sclerosis: phenotypic correlations. J Med Genet 1990; 27:418-421.[Abstract/Free Full Text]
- Vogt H. Zur pathologie und pathologischen anatomie der verschiedenen idiotieformer. Monatsschr Psychiatr Neurol 1908; 24:106-150.
- O’Callaghan FJ, Osborne JP. Advances in the understanding of tuberous sclerosis. Arch Dis Child 2000; 83:140-142.[Free Full Text]
- Gomez MR. Diagnostic criteria. In: Gomez MR, eds. Tuberous sclerosis. 2nd ed. New York, NY: Raven, 1985; 9-20.
- Hancock E, Tomkins S, Sampson J, Osborne J. Lymphangioleiomyomatosis and tuberous sclerosis. Respir Med 2002; 96:7-13.[CrossRef][Medline]
- Castro M, Shepherd CW, Gomez MR, Lie JT, Ryu JH. Pulmonary tuberous sclerosis. Chest 1995; 107:189-195.[Abstract/Free Full Text]
- Boesel CP, Paulson GW, Kosnik EJ, Earle KM. Brain hamartomas and tumors associated with tuberous sclerosis. Neurosurgery 1979; 4:410-417.[Medline]
- Fitz CR, Harwood-Nash DC, Thompson JR. Neuroradiology of tuberous sclerosis in children. Radiology 1974; 110:635-642.[Medline]
- Lee BC, Gawler J. Tuberous sclerosis: comparison of computed tomography and conventional neuroradiology. Radiology 1978; 127:403-407.[Abstract]
- Altman NR, Purser RK, Post MJ. Tuberous sclerosis: characteristics at CT and MR imaging. Radiology 1988; 167:527-532.[Abstract/Free Full Text]
- Harding CO, Pagon RA. Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. Am J Med Genet 1990; 37:443-446.[CrossRef][Medline]
- Christophe C, Bartholome J, Blum D, et al. Neonatal tuberous sclerosis: US, CT, and MR diagnosis of brain and cardiac lesions. Pediatr Radiol 1989; 19:446-448.[CrossRef][Medline]
- Smythe JF, Dyck JD, Smallhorn JF, Freedom RM. Natural history of cardiac rhabdomyoma in infancy and childhood. Am J Cardiol 1990; 66:1247-1249.[CrossRef][Medline]
- Pipitone S, Mongiovi M, Grillo R, Gagliano S, Sperandeo V. Cardiac rhabdomyoma in intrauterine life: clinical features and natural history: a case series and review of published reports. Ital Heart J 2002; 3:48-52.[Medline]
- Grebenc ML, Rosado de Christenson ML, Burke AP, Green CE, Galvin JR. Primary cardiac and pericardial neoplasms: radiologic-pathologic correlation. RadioGraphics 2000; 20:1073-1103.[Abstract/Free Full Text]
- Bissada NK, White HJ, Sun CN, Smith PL, Barbour GL, Redman JF. Tuberous sclerosis complex and renal angiomyolipoma: collective review. Urology 1975; 6:105-113.[CrossRef][Medline]
Congratulations to the 213 individuals who submitted the most likely diagnosis (tuberous sclerosis) for Diagnosis Please, Case 64. The names and locations of the individuals, as submitted, are as follows:
- Hisashi Abe, Osaka, Japan
- Chris Abraham, Kingston, Ontario, Canada
- Ira N. Adler, MD, Greenville, NC
- Gholamali Afshang, MD, Tinley Park, Ill
- Dr Jorge Ahualli, Tucumán, Argentina
- Silvio Cavalcanti Albuquerque, Recife, Brazil
- Khalid A. Al-Ismail, MD, Riyadh, Saudi Arabia
- Jeevak Almast, MD, Castel, Mauritius
- Dr Ahmed Al-Sinan, Saudi Arabia
- Sedat Altay, MD, Izmir, Turkey
- Albert J. Alter, Madison, Wis
- Roger Antonelli, MD, Dayton, Ohio
- Andrew E. Auber, San Antonio, Tex
- Angus Baird, Birmingham, Ala
- Ken Baliga, Rockford, Ill
- Joseph J. Baraga, MD, PhD, Shoreview, Minn
- Ana Carolina Barragan Serôa da Motta, São Paulo, Brazil
- Dr Murray J. Bartlett, West Leederville, Australia
- Ufuk Bayraktar, MD, Manavgat, Antalya, Turkey
- Rich Benedikt, San Antonio, Tex
- Debra M. Berger, MD, New York, NY
- Antonio Botero, MD, Bogotá, Colombia
- Eric L. Bressler, MD, Minnetonka, Minn
- Ghislain Brousseau, MD, Quebec, Canada
- Michael P. Buetow, MD, Okemos, Mich
- Peter C. Buetow, Bellingham, Wash
- Brian J. Burke, MD, Manhasset, NY
- Charles H. Bush, MD, Gainesville, Fla
- Marcella Camicia, Putignano, Italy
- Jim Cardoza, MD, Oakland, Calif
- Keenan L. Carroll, MD, Nassau, Bahamas
- Oscar Luis Casado Verdugo, Vitoria, Spain
- Luisa Fernanda Cervantes, Miami, Fla
- Daniel M. Chernoff, MD, PhD, Saratoga Springs, NY
- Michael H. Childress, MD, Silver Spring, Md
- Bharath Chinta, Rochester Hills, Mich
- Pablo Cikman, MD, Cordoba, Argentina
- Timothy Clark, Greenville, NC
- James W. Cole, MD, Cincinnati, Ohio
- David A. Cory, MD, South Bend, Ind
- Thuan Dang, MD, Colton, Calif
- Holt Daniel, MD, Ft Worth, Tex
- Marc de Baets, MD, Lugano, Switzerland
- Wagner Diniz de Paula, MD, Brasilia, Brazil
- Jon De Witte, Phoenix, Ariz
- Mustafa Kemal Demir, MD, Ataköy, Istanbul, Turkey
- María Jesús Díaz Candamio, La Coruña, Spain
- R. Lance Dillon, MD, Newark, Del
- Nam Ky Do, Duluth, Ga
- Juliet Fallah, Oakbrook Terrace, Ill
- Shella Farooki, MD, Dublin, Ohio
- Laura Z. Fenton, MD, Denver, Colo
- Gabriel C. Fernández Pérez, Vigo, Spain
- Sandra K. Fernbach, Chicago, Ill
- Francis Flaherty, MD, Ridgefield, Conn
- Ricardo B. Fonseca, MD, Nashville, Tenn
- Arie Franco, MD, Livingston, NJ
- Mary Frates, MD, Boston, Mass
- Richard Friedland, Pougkeepsie, NY
- Akira Fujikawa, Tokyo, Japan
- Ann S. Fulcher, MD, Richmond, Va
- Angelo K. Galiber, MD, Christiansted, VI
- Douglas Gardner, MD, Windsor, Ontario, Canada
- Dr Roberto E. Perez Gautrin, Sonora, Mexico
- Randy Gehl, MD, Grand Junction, Colo
- Gilles Genin, MD, Annecy, France
- Ted Glass, MD, Jackson, Miss
- Ronald B. J. Glass, MD, New York, NY
- Mark Goldshein, MD, Andover, Mass
- Michael B. Gotway, MD, San Francisco, Calif
- D. Joseph Grunz, MD, Ladue, Mo
- F. Gudinchet, MD, Lausanne, Switzerland
- Flavius Guglielmo, MD, Basking Ridge, NJ
- Ferris M. Hall, MD, Boston, Mass
- Yukihiro Hama, MD, Tokorozawa, Japan
- Ian Hammond, MD, Ottawa, Ontario, Canada
- Bill Hastrup, Fresno, Calif
- Poya Hedayati, MD, Phoenix, Ariz
- Howard T. Heller, MD, Garden City, NY
- Thomas C. Hoffer, MD, El Paso, Tex
- Brian Hu, MD, Nashua, NH
- Alberto Iaia, MD, Wilmington, Del
- Mihai Iancu, MD, Tucson, Ariz
- Rekha Jain, Pontiac, Mich
- Vinay Jain, Pontiac, Mich
- Vladislav Jankulov, MD, Dearborn, Mich
- Sanjay Jeganathan, MB, ChB, MMed, Auckland, New Zealand
- Sanjeeva Prasad Kalva, MD, Boston, Mass
- Atul Kapur, MD, Amritsar, India
- Ercan Karaarslan, MD, Istanbul, Turkey
- Ajit Singh Kashyap, MD, Pune, India
- Nurettin Katranci, MD, Antalya, Turkey
- Pat Kiely, MB, FRCR, FFR (RCSI), Limerick, Ireland
- Eric Kinder, MD, Seattle, Wash
- Russell F. King, MD, Suffolk, Va
- Mitchell A. Klein, MD, Milwaukee, Wis
- Steven A. Klein, MD, Shrewsbury, Mass
- Arlene Klink, MD, Irvine, Calif
- Ercan Kocakoc, MD, Elazig, Turkey
- Masashi Koyama, Aichi, Japan
- Stefanos Lachanis, MD, Athens, Greece
- Mario Laguna, West Allis, Wis
- A. H. Lam, Sydney, Australia
- Margaret H. Lee, MD, Los Angeles, Calif
- Walter Lesley, MD, St. Louis, Mo
- Richard A. Levy, MD, Saginaw, Mich
- Donald R. Lewis, Jr, MD, Huntington, WV
- John T. Lim, MD, Newport Coast, Calif
- David A Lisle, Brisbane, Australia
- Joseph Lock, MD, Sparta, NJ
- Jorge A. López García, MD, Tenerife, Spain
- Julio Loureiro, MD, Buenos Aires, Argentina
- Guilherme Lourenço De Lima Reis, Belo Horizonte, Brazil
- Antonio J. Madureira, MD, Porto, Portugal
- Antonio Maia, São Paulo, Brazil
- N. B. S. Mani, MD, Nassau, Bahamas
- Jose Luiz C. Marins, Campinas, Brazil
- María I. Martínez-León, Málaga, Spain
- Fernando Más-Estellés, Valencia, Spain
- Maximiliano Matteoda, Mar del Plata, Argentina
- John A. Mattingly, MD, Belleville, Ill
- Frank McKowne, MD, Vancouver, Wash
- Dr Ivan Melo Guzman, Santiago, Chile
- Flávia Mendez, MD, Porto Alegre, Brazil
- Luis Mendez-Uriburu, Tucuman, Argentina
- Edward Menges, MD, Aptos, Calif
- Manabu Minami, MD, Tokyo, Japan
- Sankar Ranjan Mondal, MD, Nassau, Bahamas
- Eduardo Mondello, MD, Buenos Aires, Argentina
- Dr Moataz Montasser, Alexandria, Egypt
- Elizabeth Moorehead, Austin, Tex
- Harold Moskowitz, West Hartford, Conn
- Martha M. Munden, MD, Houston, Tex
- Tetsuo Nakayama, MD, Osaka, Japan
- Oscar K. Navarro, MD, Toronto, Ontario, Canada
- Tammam Nehme, Wenatchee, Wash
- Michael Neuman, MD, Portland, Ore
- Vung Duy Nguyen, MD, San Antonio, Tex
- Ralph E. Norton, MD, Houston, Tex
- Mehmet Noyan Zenger, MD, Izmir, Turkey
- Dr Ramón Olagüe de Ros, Valencia, Spain
- Laura Oleaga, Bilbao, Spain
- Mike O’Loughlin, MD, West Hartford, Conn
- Víctor Oporto, São Paulo, Brazil
- Sanford M. Ornstein, MD, Phoenix, Ariz
- Anoop Kumar Pandey, Chandigarh, India
- Chris Payne, MD, Memphis, Tenn
- Ernesto Oscar Pearson, MD, Córdoba, Argentina
- Víctor Pérez-Candela, MD, Las Palmas de Gran Canaria, Spain
- Dennis N. Peters, Philadelphia, Pa
- Alex Petersen, MD, Nowra, Australia
- Krishna R. Pillai, MD, Madison, Wis
- Mario P. Pliego, MD, Bloomington, Minn
- John M. Plotke, Naperville, Ill
- Dr S. P. Prabhu, Bristol, United Kingdom
- Le-Ping Pu, MD, Potomac, Md
- Lisa K. Quane, MD, Orange, Calif
- Shawn P. Quillin, MD, Charlotte, NC
- Nasrollah Rahbar, MD, Houston, Tex
- Karthik Ramakrishnan, Big Stone Gap, Va
- Enrique Remartinez Escobar, MD, Melilla, Spain
- Giuseppe Riboni, MD, Milano, Italy
- Luiz Antonio Rossi, MD, São Paulo, Brazil
- Dr N. Saravanan, Chandigarh, India
- Pierre J. Sauvage, MD, Mâcon, France
- Dr Abdelhafid Sbihi, Rabat, Morocco
- Janet Scheraga, Syracuse, NY
- Mark Schiffer, MD, Woodstock, Ill
- Dr Pierre Schmit, L’Haÿ les Roses, France
- Steven M. Schultz, MD, Ft. Worth, Tex
- Anthony J. Scuderi, MD, Johnstown, Pa
- Sandip R. Shah, Ahmedabad, India
- Matt Shapiro, MD, Staunton, Va
- Dr Kenneth Sheah, Singapore
- Taro Shimono, MD, Osaka, Japan
- Grady Shue, Heidelberg, Germany
- Michael K. Silberman, Durham, NC
- Darrin S. Smith, MD, Fresno, Calif
- Stephen Smith, Peoria, Ill
- Amarnath Sortur, MD, Greenville, Del
- Mleden Sostaric, Brezice, Slovenia
- James D. Sprinkle, Jr, MD, Spotsylvania, Va
- E. P. Stecz, Laguna Beach, Calif
- Dr Anne Stroh Marcy, Arras, France
- K. Venkata Subbaiah, Hyderabad, India
- Kouichi Sugiyama, Hamamatsu, Japan
- Satoru Takahashi, Osaka, Japan
- Robert Tash, MD, Nyack, NY
- Douglas L. Teich, MD, Brookline, Mass
- Will Thompson, Adelaide, South Australia
- Eugene Tong, MD, Austin, Tex
- Meriç Tüzün, Ankara, Turkey
- Herminia Tyminski Al-Saffar, MD, Manama, Bahrain
- Hiroyuki Ueda, Kyoto, Japan
- Piet Vanhoenacker, MD, Moorsel, Belgium
- Joseph Varriano, Leawood, Kan
- Klara A. Vergesslich, MD, Basel, Switzerland
- Kai Vilanova Busquets, MD, Girona, Spain
- Pier Carlo Villani, MD, Bari, Italy
- Christopher Vittore, MD, Rockford, Ill
- Lynne Voutsinas, MD, Staten Island, NY
- Thuan T. Vu, Houston, Tex
- Zhen Jane Wang, MD, San Francisco, Calif
- Thomas Waslen, Saskatoon, Saskatchewan, Canada
- Jeff West, MD, Jacksonville, Fla
- Howard C. Williams, MD, Garden City, NY
- Paul Wilson, Kingston, Ontario, Canada
- Mary Wyers, MD, Chicago, Ill
- Tatsuya Yamamoto, Obama, Japan
- Benjamin M. Yeh, MD, San Francisco, Calif
- Joe Yut, Olathe, Kan
- Jeffrey H. Zapolsky, MD, Oshkosh, Wis
- Sérgio Zoriki, São Paulo, Brazil
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HISTORY
IMAGING FINDINGS
