Causes of Death in Patients With Tuberous Sclerosis

CHARLES W. SHEPHERD, M.D.,* Department ofNeurology; MANUEL R. GOMEZ, M.D.,Section ofPediatric Neurology; J. T. LIE, M.D., Section ofMedical Pathology;CYNTHIA S. CROWSON, BoA., Section ofBiostatistics

Of the 355 patients with tuberous sclerosis complex (TSC) examined at the MayoClinic, 49 had died (9 of causes other than TSC). We attempted to determine whatpattern oforgan involvement occurred most often in the 40 patients who died ofTSC.One baby died ofcardiac failure due to cardiac rhabdomyomas, and one child died ofrupture of an aneurysm of the thoracic aorta. Eleven patients died of renal disease,which was the commonest cause of death. Ten patients died as a result of braintumors, and four patients (who were 40 years of age or older) died of lymphangio­myomatosis of the lung. Thirteen patients with severe mental handicaps died ofeither status epilepticus or bronchopneumonia; in all but one of these patients, theonly source of information was the death certificate. Survival curves show adecreased survival for patients with TSC in comparison with that for the generalpopulation. Patients with TSC need lifelong follow-up for early detection of poten­tially life-threatening complications.

Tuberous sclerosis complex (TSC) is an autoso­mal dominant disease characterized by the pres­ence of hamartias and the growth of hamarto­mas in every organ, except possibly the skeletalmuscles and the peripheral nerves. The TSCgene or genes are expressed with various pheno­types,' even within the same family. The resultdepends on which organ or organs are involvedand the extent of involvement. In some organs­for example, the eye-the hamartomas almostnever cause symptoms," but in other organs-forexample, the brain-the hamartomas may causeintracranial hypertension. In some patients, nosymptoms occur and only signs ofthe disease aredisclosed, whereas in other patients, the in-

*Current address: Craigavan Hospital, Lurgan, Co Ar­magh, Northern Ireland.

Address reprint requests to Dr. M. R. Gomez, Section ofPediatric Neurology, Mayo Clinic, Rochester, MN 55905.

volvement causes severe symptoms, disability,or even death.

As part of a review of the medical records of allMayo Clinic patients with TSC, the cause of andage at death were determined in those patientsknown to have died. We have attempted todocument which organ involvement was mostoften fatal for these patients. We hope that thisinformation will help prevent early deaths fromTSC.

METHODSAll patients with TSC examined at the MayoClinic were identified by a computer search ofthe medical records. TSC was diagnosed on thebasis of published criteria.3 We reviewed themedical records of all patients with TSC todetermine their current clinical signs and symp­toms related to TSC. Further information aboutthe patient's current clinical status was obtainedby using a standard questionnaire. When a

Mayo Clin Proc 66:792-796,1991 792

Mayo Clin Proc, August 1991, Vol 66 DEATH FROM TUBEROUS SCLEROSIS 793

Fig. 1. Distribution of ages of 40 patients (22 female and 18male; mean age, 26 years) who died of tuberous sclerosiscomplex.

DISCUSSIONAlthough 49% of our patients with TSC who arealive and who were examined by echocardiogra­phy (most ofwhom are children) had one or morerhabdomyomas, only 1 death in 40 could beattributed to this tumor (obstruction of the

toma. In the three other patients, no histologicobservations were available; however, the radio­logic and clinical features were consistent withan intraventricular tumor. Deaths due to braintumors were most common in the 10- to 19-year­old group.

Deathfrom lymphangiomyomatosisofthe lungoccurred in patients who were 40 years of age orolder. Of the 10 patients with biopsy-provenlung disease, 4 (3 female and 1 male) had died.

In this series, 13 patients (7 female and 6male) with severe mental handicaps due to TSCdied; the cause of death was listed as statusepilepticus in 9 and bronchopneumonia in 4. In12 patients, the only information on the cause ofdeath was from the death certificate; in 1 pa­tient, additional information was obtained fromthe patient's mother. No autopsies were done onthese patients.

The survival curve for all the Mayo patientswith TSC (regardless of cause of death) is plottedin Figure 3. For comparison, the survival curvefor the white population of the United States in1970 is also shown.

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patient's death was reported, the cause wasascertained by reviewing the autopsy report andpathologic materials if available, outside medi­cal records, and death certificate. A Kaplan­Meier survival curve" was plotted for all patientswho had died, regardless of the cause of death.

RESULTSOf the 355 patients with TSC who had beenassessed at the Mayo Clinic, 49 (26 female and23 male patients) were known to have died, and50 had been lost to follow-up. The other 256patients were directly contacted to establishtheir current health status. In 9 of the 49patients who had died, the cause of death wasconsidered not directly attributable to TSC. Thedistribution of ages of the 40 patients who diedof TSC is shown in Figure 1, and the distribu­tion of deaths by cause of death and by age ofthepatient is depicted in Figure 2.

Cardiovascular deaths occurred in infancy orearly childhood. Only one patient, a 3-day-oldboy, died of cardiac rhabdomyomas that ob­structed the atrial and mitral valves. In ourseries, ofthe 91 patients screened by echocardi­ography, 45 (49%) had cardiac rhabdomyomas.The other cardiovascular death was due to rup­ture of an aneurysm of the thoracic aorta in a 3­year-old girl.

Of the 11 patients (7 female and 4 male) whodied of renal disease, all were 10 years of age orolder, and the frequency of renal deaths in­creased with advancing age. Seven patientsdied of renal failure, two died of bleeding angio­myolipoma, and two died of renal cell carcinoma.Of the 148 patients screened for renal involve­ment in this series, 55 (37%) had angiomyolipo­mas, 10 (7%) had cysts, and 14 (9%) had bothcysts and angiomyolipomas.

Of the 216 patients who were screened in thisstudy, 191 (88%) had evidence of subependymalnodules, and 21 (10%) had subependymal giantcell astrocytoma thought to arise from suchnodules." In 10 patients (5 female and 5 male),death was either a result of the tumor (in 6 cases)or related to treatment (in 4 cases). In seven ofthese patients, the tumor was proved histologi­cally to be a subependymal giant cell astrocy-

794 DEATH FROM TUBEROUS SCLEROSIS

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Mayo Clin Proc, August 1991, Vol 66

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Fig. 2. Distribution of causes of death and ages of patients at time of death from tuberoussclerosis complex.

ventricular outflow tracts by intracavitarytumors in a 3-day-old baby). Rhabdomyomascan be embedded in the myocardium or canprotrude into a cardiac cavity." Echocardio­graphic studies have shown that rhabdomyomasshrink as the patient ages.? Although a pub­lished study reported sudden death in a 10-year­old girl with rhabdomyomas embedded in themyocardium and compensatory hypertrophy ofunaffected myocardium (it did not state that shehad TSC), B rhabdomyoma apparently causessymptoms in only a small proportion of new­borns with this tumor.

Intrinsic disease of the medium-sized andlarge vessels in TSC is rare but often fatal.Larbre and associates" described a 21h -year-oldboy and Freycon and colleagues!" described a 2­year-old girl who both had TSC and an aneu­rysm of the abdominal aorta, and both patientsdied. The other known cause of an aortic aneu­rysm reported in infants is sepsis from catheter­ization of the umbilical artery. 11 Other investi­gators have reported the association of TSC withfibromuscular dysplasia of the aneurysmal ves­sel. 12,13 In our series, only one patient with TSChad an aneurysm of the ascending thoracic aor-

ta, and its rupture and the resultant hemotho­rax caused death.

In our series, the most common cause of deathwas renal disease in the form of angiomyolipo­mas,':' cysts, or both. Angiomyolipomas aremore common than renal cysts." The presenceof numerous renal cysts may cause renal failureeven in children, and this finding may be aninitial clinical feature of TSC.16 Cysts that ledto renal failure occurred in young patients; an­giomyolipomas occurred in two older patients inour study group. Angiomyolipomas also werefatal in two patients because of a massive hem­orrhage within the tumor."? Renal clear cellcarcinoma is a malignant tumor that may beassociated with angiomyolipomas.v" It origi­nates in the same hyperplastic tubular epithe­lium seen only in TSC,20 which lines the renalcysts." In our study, two patients, including a31-year-old man, died of this malignant lesion.Other investigators have found this tumor inyoung patients with TSC.22,23 The potentiallyfatal outcome in patients with TSC who haverenal involvement warrants periodic examina­tion with use of renal imaging and measurementof renal function.

Mayo Clio Proc, August 1991, Vol 66 DEATH FROM TUBEROUS SCLEROSIS 795

REFERENCES1. Gomez MR: Varieties of expression oftuberous scle­

rosis. Neurofibromatosis 1:330-338, 19882. Robertson DM: Ophthalmic findings. In Tuberous

Sclerosis. Secondedition. EditedbyMRGomez. NewYork, Raven Press, 1988, pp 89-109

3. Gomez MR: Criteria for diagnosis. In TuberousSclerosis. Secondedition. Edited by MR Gomez. NewYork, Raven Press, 1988, pp 9-19

4. Kaplan EL, Meier P: Nonparametric estimation fromincomplete observations. J Am Stat Assoc 53:457­481, 1958

5. Fujiwara S, Takaki T, Hikita T, Nishio S: Subependy­mal giant-cell astrocytoma associated with tuberoussclerosis: do subependymal nodules grow? ChildsNerv Syst 5:43-44,1989

6. Fenoglio JJ Jr, McAllister HA Jr, Ferrans VJ: Car­diac rhabdomyoma: a clinicopathologic and elec­tron microscopic study. Am J Cardiol 38:241-251,1976

volvement from TSC, four of whom died. Theprognosis associated with pulmonary TSC is lessfavorable than that associated with other organinvolvement in TSC; a higher percentage ofpatients died ofTSC with lung disease than withheart, kidney, or brain involvement.

Death certificates are often inaccurate fordetermining the cause of death, and they werethe only available source of information for 12of the 13 mentally handicapped patients whodied of bronchopneumonia or status epilepti­cus. Bronchopneumonia is a frequent complica­tion of all types of severe mental handicap.Death from bronchopneumonia was not the di­rect effect of the pathologic lesions of TSC, butseverely mentally handicapped patients have agreater risk for this disease than does the rest ofthe population.

Although status epilepticus or convulsionswere the cause of death listed on the deathcertificates of nine patients, this number maybe questioned and was not definitely establishedfor our study. The survival curve for all patientswith TSC in our study shows that, when ana­lyzed collectively, patients with TSC have adecreased life expectancy in comparison withthe overall population; however, by dividingthe patients into groups according to the organsinvolved and the severity of involvement, pre­diction of survival can be more accurate.

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Subependymalgiant cell astrocytoma, a tumorthat we have found only in patients with othersigns ofTSC, OCcurs in 6% ofthese patients.v' Itarises from the subependymal nodules" andmay grow sufficiently to block one or both foram­ina of Monro, which causes obstructive hydro­cephalus." The histopathologic features of sub­ependymal giant cell astrocytoma are identicalto those of subependymal nodules." It growsslowly and rarely has a malignant appearance.P"In our series, six patients died as a direct resultof this tumor-five because of increased intra­cranial pressure and one because of a hemor­rhage into the tumor, an infrequent occurrence.29In four other patients, complications of treat­ment of the tumor preceded death.

Computed tomography can be used to detectthe tumor before it becomes symptomatic." Therecent trend of using regular computed tomogra­phy of the head in young patients with cerebralTSC facilitates early detection and treatment,which result in decreased mortality.

Pulmonary involvement has been estimatedto occur in less than 1% of all cases ofTSC.31 Thepathologic features are similar to those oflymph­angiomyomatosis of the lung32,33-cystic changesand focallymphangiomyomatosis. 34,35 The con­dition is almost always found in women of child­bearing age; in our series of patients with TSC,only one male patient died of this lung disease.Ten of our patients had biopsy-proven lung in-

Fig. 3. Kaplan-Meier survival curves for patients withtuberous sclerosis complex (solid line) and for the whitepopulation of the United States in 1970 (broken line).

796 DEATH FROM TUBEROUS SCLEROSIS

7. Smith HC, Watson GH, Patel RG, Super M: Cardiacrhabdomyomata, in tuberous sclerosis: their courseand diagnostic value. Arch Dis Child 64:196-200,1989

8. Winstanley DP: Sudden death from multiple rhab­domyomata of the heart. J Pathol Bacteriol 81:249­251, 1961

9. Larbre F, Loire R, Guibaud P, Lauras B, Weill B:Observation clinique et anatomiqued'un anevrysmede l'aorte au cours d'une sclerose tubereuse de Bourne­ville. Arch Fr Pediatr 28:975-984, 1971

10. Freycon F, Mollard P, Hermier M, Guibaud P,Chazalette J-P, Weill B, Flattot M, Jeune M:Anevrysme de 1'aorte abdominale au cours d'unesclerose tubereuse de Bourneville. Pediatrie 26:421­427, 1971

11. Roques X, Choussat A, Bourdeaud'hui A, LabordeN, Baudet E: Aneurysms of the abdominal aorta inthe neonate and infant. Ann Vase Surg 3:335-340,1989

12. Rolfes DB, Towbin R, Bove KE: Vascular dysplasia ina child with tuberous sclerosis. Pediatr Pathol 3:359­373, 1985

13. Hagood CO Jr, Garvin DD, Lachina FM, Polsky WS,Ball TP, BobroffLM: Abdominal aortic aneurysm andrenal hamartoma in an infant with tuberous sclero­sis. Surgery 79:713-715, 1976

14. Van Baal JG, Fleury P, Brummelkamp WH: Tuber­ous sclerosis and the relation with renal angiomyo­lipoma: a genetic study on the clinical aspects. ClinGenet 35:167-173,1989

15. Stillwell TJ, Gomez MR, Kelalis PP: Renal lesions intuberous sclerosis. J Urol 138:477-481, 1987

16. Stapleton FB, Johnson D, Kaplan GW, Griswold W:The cystic renal lesion in tuberous sclerosis. J Pediatr97:574-579, 1980

17. Azmy AF, Stephenson J, Ziervogel M: Angiomyo­lipoma causing life-threatening hematuria in a childwith tuberous sclerosis. J Pediatr Surg 24:1308­1309, 1989

18. Taylor RS, Joseph DB, Kohaut EC, Wilson ER, Bues­chen AJ: Renal angiomyolipoma associated withlymph node involvement and renal cell carcinoma inpatients with tuberous sclerosis. JUrol 141:930-932,1989

19. Kavaney PB, Fielding I: Angiomyolipoma and renalcell carcinoma in same kidney. Urology 6:643-646,1975

20. Robbins TO, Bernstein J: Renal involvement. InTuberous Sclerosis. Second edition. Edited by MRGomez. New York, Raven Press, 1988, pp 133-146

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21. Bernstein J, Robbins TO, Kissane JM: The renallesions of tuberous sclerosis. Semin Diagn Pathol3:97-105, 1986

22. Weinblatt ME, Kahn E, Kochen J: Renal cell carci­noma in patients with tuberous sclerosis. Pediatrics80:898-903, 1987

23. Graves N, Barnes WF: Renal cell carcinoma andangiomyolipoma in tuberous sclerosis: case report. JUrol 135:122-123, 1986

24. Shepherd CW, Scheithauer BW, Gomez MR, Al­termatt HJ, Katzmann JA: Subependymal giantcell astrocytoma: a clinical, pathological, and flowcytometric study. Neurosurgery 28:864-868,1991

25. Morimoto K, Mogami H: Sequential CT study ofsubependymal giant-cell astrocytoma associated withtuberous sclerosis: case report. J Neurosurg 65:874­877, 1986

26. Moran V, O'Keeffe F: Giant cell astrocytoma intuberous sclerosis: computed tomographic findings.Clin Radiol 37:543-545, 1986

27. Boesel CP, Paulson GW, Kosnik EJ, Earle KM: Brainhamartomas and tumors associated with tuberoussclerosis. Neurosurgery 4:410-417,1979

28. Brown JM: Tuberose sclerosis with malignant astro­cytoma. Med J Aust 1:811-814, 1975

29. WagaS,YamamotoY,KojimaT,SakakuraM: Massivehemorrhage in tumor of tuberous sclerosis. SurgNeurol 8:99-101, 1977

30. Konishi Y, Ito M, Okuno T, Hojo H, Okudo R, NakanoY, Handa J: Tuberous sclerosis: early neurologicmanifestations and CT features in 18 patients. BrainDev 1:31-37, 1979

31. DwyerJM,HickieJB, GarvanJ: Pulmonary tuberoussclerosis: report of three patients and a review of theliterature. Q J Med 40:115-125,1971

32. Vejlens G: Specific pulmonary alterations in tuber­ous sclerosis. Acta Pathol Microbiol Scand 18:317­330, 1941

33. Capron F, Ameille J, Leclerc P, Mornet P, Barbagel­lata M, Reynes M, Rochemaure J: Pulmonary lymph­angioleiomyomatosis and Bourneville's tuberous scle­rosis with pulmonary involvement: the same disease?Cancer 52:851-855, 1983

34. Lie JT, Miller RD, Williams DE: Cystic disease ofthe lungs in tuberous sclerosis: clinicopathologiccorrelation, including body plethysmographic lungfunction tests. Mayo Clin Proc 55:547-553,1980

35. Lie JT: Cardiac, pulmonary, and vascular involve­ments in tuberous sclerosis. Ann N Y Acad Sci615:58-70, 1991