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Am J Perinatol 2009; 26(10): 755-760
DOI: 10.1055/s-0029-1223267
© Thieme Medical Publishers

Perinatal (Fetal and Neonatal) Tuberous Sclerosis: A Review

Hart Isaacs1 , 2
  • 1Departments of Pathology, Rady Children's Hospital San Diego, San Diego, California
  • 2University of California San Diego School of Medicine, La Jolla, California
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Publication History

Publication Date:
18 May 2009 (online)

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ABSTRACT

Tuberous sclerosis (TSC) is an autosomal-dominant disorder that presents with highly variable clinical manifestations including seizures, mental retardation, skin lesions, and hamartomas affecting multiple organ systems such as the heart, brain, eye, and kidney. A 42-year retrospective review of 70 patients consisting of 43 fetuses and 27 neonates with TSC were analyzed. There was a 16% positive family history for the disease. Obvious signs are present in the perinatal period. Cardiac rhabdomyoma(s) detected on routine antenatal sonography, arrhythmias, cerebral lesions, hydrops, and stillbirth are the major presenting findings in the fetus, whereas respiratory distress, arrhythmias, murmurs, and cardiomegaly are the main signs initially in the neonate. Cardiac rhabdomyomas comprised 32.8% of the TSC pathological findings; those of central nervous system origin, 47.5%; and renal cystic disease, 13.2%. Skin lesions and retinal hamartomas were noted rarely at birth. Of the 15 survivors, 87% developed a seizure disorder; 33%, residual cardiac rhabdomyomas; and 27%, mental retardation. The survival rates of patients diagnosed antenatally was practically the same as for those after birth, 21% and 22%, respectively. The overall survival was low, 15/70 or 21%. When TSC occurs in the perinatal period, it is associated with a high incidence of morbidity and mortality.

KEYWORDS

Fetal tuberous sclerosis - neonatal tuberous sclerosis - cardiac rhabdomyoma - cortical tuber - subependymal nodule - subependymal giant cell astrocytoma - cystic kidney disease

REFERENCES

  • 1 Webb D W, Osborne J P. Tuberous sclerosis.  Arch Dis Child. 1995;  72 471-474
    CrossrefPubMedGoogle Scholar
  • 2 Ruggieri M, Carbonara C, Magro G et al.. Tuberous sclerosis complex: neonatal deaths in three of four children of consanguineous, non-expressing parents.  J Med Genet. 1997;  34 256-260
    CrossrefPubMedGoogle Scholar
  • 3 Opitz J M, Wilson G N, Gilbert-Barness E. Analysis of developmental pathology. In: Gilbert-Barness E Potter's Pathology of the Fetus, Infant and Child. 2nd ed. Vol. 1. Philadelphia; Mosby-Elsevier 2007: 119-121
    Google Scholar
  • 4 Wei J, Li P, Chiriboga L et al.. Tuberous sclerosis in a 19-week fetus: immunohistochemical and molecular study of hamartin and tuberin.  Pediatr Dev Pathol. 2002;  5 448-464
    CrossrefPubMedGoogle Scholar
  • 5 Vinaitheerthan M, Wei J, Mizuguchi M, Greco A, Barness E G. Tuberous sclerosis: immunohistochemistry expression of tuberin and hamartin in a 31-week gestational fetus.  Fetal Pediatr Pathol. 2004;  23 241-249
    CrossrefPubMedGoogle Scholar
  • 6 Milunsky A, Shim S H, Ito M et al.. Precise prenatal diagnosis of tuberous sclerosis by sequencing the TSC2 gene.  Prenat Diagn. 2005;  25 582-585
    CrossrefPubMedGoogle Scholar
  • 7 Sampson J R, Maheshwar M M, Aspinwall R et al.. Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene.  Am J Hum Genet. 1997;  61 843-851
    CrossrefPubMedGoogle Scholar
  • 8 Weber M A, Risdon R A, Malone M, Duffy P G, Sebire N J. Isolated unilateral tuberous sclerosis-associated renal cystic disease in a neonate.  Fetal Pediatr Pathol. 2005;  24 267-275
    CrossrefPubMedGoogle Scholar
  • 9 Wortmann S B, Reimer A, Creemers J W, Mullaart R A. Prenatal diagnosis of cerebral lesions in Tuberous sclerosis complex (TSC). Case report and review of the literature.  Eur J Paediatr Neurol. 2008;  12 123-126
    CrossrefPubMedGoogle Scholar
  • 10 King J A, Stamilio D M. Maternal and fetal tuberous sclerosis complicating pregnancy: a case report and overview of the literature.  Am J Perinatol. 2005;  22 103-108
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Werner Jr H, Mirlesse V, Jacquemard F et al.. Prenatal diagnosis of tuberous sclerosis. Use of magnetic resonance imaging and its implications for prognosis.  Prenat Diagn. 1994;  14 1151-1154
    CrossrefPubMedGoogle Scholar
  • 12 Kauffmann E, Randrianaivo H, Boumahni B et al.. Post mortem brain MRI: an alternative for pathology examination in Bourneville tuberous sclerosis of the fetus?.  J Gynécol Obstét Biol Reprod (Paris). 2004;  33 245-247
    PubMedGoogle Scholar
  • 13 Khanna P C, Godinho S, Pungavkar S A, Patkar D P. Ultrafast MRI in the prenatal diagnosis of Bourneville's tuberous sclerosis.  Neurol India. 2005;  53 349-350
    PubMedGoogle Scholar
  • 14 Scheithauer B W. The neuropathology of tuberous sclerosis.  J Dermatol. 1992;  19 897-903
    PubMedGoogle Scholar
  • 15 Burger P C, Scheithauer B W. Tumors of the Central Nervous System. Atlas of Tumor Pathology. Third series, Fasicle 10. Armed Forces Institute of Pathology Washington, DC; 1994: 383-385
    Google Scholar
  • 16 Ostör A G, Fortune D W. Tuberous sclerosis initially seen as hydrops fetalis: report of a case and review of the literature.  Arch Pathol Lab Med. 1978;  102 34-39
    PubMedGoogle Scholar
  • 17 Chou T M, Chou S M. Tuberous sclerosis in the premature infant: a report of a case with immunohistochemistry on the CNS.  Clin Neuropathol. 1989;  8 45-52
    PubMedGoogle Scholar
  • 18 Park S H, Pepkowitz S H, Kerfoot C et al.. Tuberous sclerosis in a 20-week gestation fetus: immunohistochemical study.  Acta Neuropathol. 1997;  94 180-186
    CrossrefPubMedGoogle Scholar
  • 19 Bernstein J. Renal cystic disease in the tuberous sclerosis complex.  Pediatr Nephrol. 1993;  7 490-495
    CrossrefPubMedGoogle Scholar
  • 20 Isaacs Jr H. Fetal and neonatal cardiac tumors.  Pediatr Cardiol. 2004;  25 252-273
    PubMedGoogle Scholar
  • 21 Simopoulos A P, Breslow A. Tuberous sclerosis in the newborn.  Am J Dis Child. 1966;  111 313-316
    PubMedGoogle Scholar
  • 22 Thibault J H, Manuelidis E E. Tuberous sclerosis in a premature infant. Report of a case and review of the literature.  Neurology. 1970;  20 139-146
    PubMedGoogle Scholar
  • 23 Batstone G F, Cole A P, Sandry S A. A case of tuberose sclerosis in the newborn.  Acta Paediatr Scand. 1971;  60 349-352
    CrossrefPubMedGoogle Scholar
  • 24 Tsakraklides V, Burke B, Mastri A, Runge W, Roe E, Anderson R. Rhabdomyomas of heart: a report of four cases.  Am J Dis Child. 1974;  128 639-646
    PubMedGoogle Scholar
  • 25 Probst A, Ohnacker H. [Tuberous sclerosis in a premature infant (author's transl)].  Acta Neuropathol. 1977;  40 157-161
    CrossrefPubMedGoogle Scholar
  • 26 Stapleton F B, Johnson D, Kaplan G W, Griswold W. The cystic renal lesion in tuberous sclerosis.  J Pediatr. 1980;  97 574-579
    PubMedGoogle Scholar
  • 27 Milner S, Abramowitz J A, Levin S E. Rhabdomyoma of the heart in a newborn infant. Diagnosis by echocardiography.  Br Heart J. 1980;  44 224-227
    CrossrefPubMedGoogle Scholar
  • 28 Ohri G L, DeVenecia R, Acs H. Tuberous sclerosis presenting as diaphragmatic hernia in a newborn.  Dev Med Child Neurol. 1980;  22 509-512
    PubMedGoogle Scholar
  • 29 Soltan M H, Keohane C. Hydrops fetalis due to congenital cardiac rhabdomyoma. Case report.  Br J Obstet Gynaecol. 1981;  88 771-773
    PubMedGoogle Scholar
  • 30 Grasso S, Manusia M, Sciacca F. Unusual liver lesion in tuberous sclerosis.  Arch Pathol Lab Med. 1982;  106 49
    PubMedGoogle Scholar
  • 31 Sharp D, Robertson D M. Tuberous sclerosis in an infant of 28 weeks gestational age.  Can J Neurol Sci. 1983;  10 59-62
    PubMedGoogle Scholar
  • 32 Foster E D, Spooner E W, Farina M A, Shaher R M, Alley R D. Cardiac rhabdomyoma in the neonate: surgical management.  Ann Thorac Surg. 1984;  37 249-253
    PubMedGoogle Scholar
  • 33 Painter M J, Pang D, Ahdab-Barmada M, Bergman I. Connatal brain tumors in patients with tuberous sclerosis.  Neurosurgery. 1984;  14 570-573
    PubMedGoogle Scholar
  • 34 Nishimura M, Takashima S, Takeshita K, Tanaka J. Immunocytochemical studies on a fetal brain of tuberous sclerosis.  Pediatr Neurol. 1985;  1 245-248
    CrossrefPubMedGoogle Scholar
  • 35 Pesonen E, Leijala M, Järvenpää A L, Teramo K. Cardiac rhabdomyomas in a newborn baby. Early diagnosis and treatment.  Acta Paediatr Scand. 1985;  74 824-827
    CrossrefPubMedGoogle Scholar
  • 36 Guereta L G, Burgueros M, Elorza M D, Alix A G, Benito F, Gamallo C. Cardiac rhabdomyoma presenting as fetal hydrops.  Pediatr Cardiol. 1986;  7 171-174
    CrossrefPubMedGoogle Scholar
  • 37 Hoadley S D, Wallace R L, Miller J F, Murgo J P. Prenatal diagnosis of multiple cardiac tumors presenting as an arrhythmia.  J Clin Ultrasound. 1986;  14 639-643
    CrossrefPubMedGoogle Scholar
  • 38 Yamashita H, Nagaoka H, Matsushima R et al.. Cardiac rhabdomyoma associated with tuberous sclerosis. An autopsy case of newborn infant died of cardiac failure.  Acta Pathol Jpn. 1987;  37 645-653
    PubMedGoogle Scholar
  • 39 Miller I D, Gray E S, Lloyd D L. Unilateral cystic disease of the neonatal kidney: a rare presentation of tuberous sclerosis.  Histopathology. 1989;  14 529-532
    CrossrefPubMedGoogle Scholar
  • 40 Deeg K H, Voigt H J, Hofbeck M, Singer H, Kraus J. Prenatal ultrasound diagnosis of multiple cardiac rhabdomyomas.  Pediatr Radiol. 1990;  20 291-292
    CrossrefPubMedGoogle Scholar
  • 41 Blethyn J, Jones A, Sullivan B. Prenatal diagnosis of unilateral renal disease in tuberous sclerosis.  Br J Radiol. 1991;  64 161-164
    PubMedGoogle Scholar
  • 42 Geva T, Santini F, Pear W, Driscoll S G, Van Praagh R. Cardiac rhabdomyoma. Rare cause of fetal death.  Chest. 1991;  99 139-142
    CrossrefPubMedGoogle Scholar
  • 43 Björkhem G, Lundström N R, Lingman G. Intracardiac rhabdomyomas in neonates: report of three cases.  Acta Paediatr. 1992;  81 712-715
    CrossrefPubMedGoogle Scholar
  • 44 Saguem M H, Laarif M, Remadi S, Bozakoura C, Cox J N. Diffuse bilateral glomerulocystic disease of the kidneys and multiple cardiac rhabdomyomas in a newborn. Relationship with tuberous sclerosis and review of the literature.  Pathol Res Pract. 1992;  188 367-373 discussion 373-374
    PubMedGoogle Scholar
  • 45 Scurry J, Watkins A, Acton C, Drew J. Tachyarrhythmia, cardiac rhabdomyomata and fetal hydrops in a premature infant with tuberous sclerosis.  J Paediatr Child Health. 1992;  28 260-262
    PubMedGoogle Scholar
  • 46 Bordarier C, Lellouch-Tubiana A, Robain O. Cardiac rhabdomyoma and tuberous sclerosis in three fetuses: a neuropathological study.  Brain Dev. 1994;  16 467-471
    CrossrefPubMedGoogle Scholar
  • 47 Lago P, Boniver C, Casara G L et al.. Neonatal tuberous sclerosis presenting with intractable seizures.  Brain Dev. 1994;  16 257-259
    CrossrefPubMedGoogle Scholar
  • 48 Oikawa S, Sakamoto K, Kobayashi N. A neonatal huge subependymal giant cell astrocytoma: case report.  Neurosurgery. 1994;  35 748-750
    PubMedGoogle Scholar
  • 49 Komori S, Bessho T, Fukuda H, Kanazawa R, Koyama K. A report on the perinatal diagnosis of 4 cases of cardiac tumors.  Arch Gynecol Obstet. 1995;  256 213-218
    CrossrefPubMedGoogle Scholar
  • 50 Ramenghi L A, Verrotti A, Domizio S, Di Rocco C, Morgese G, Sabatino G. Neonatal diagnosis of tuberous sclerosis.  Childs Nerv Syst. 1996;  12 121-123
    CrossrefPubMedGoogle Scholar
  • 51 Wagner M, Fitz H, Schindler C. [Early manifestation of polycystic kidney changes in tuberous sclerosis].  Pathologe. 1996;  17 462-466
    CrossrefPubMedGoogle Scholar
  • 52 Wu C T, Chen M R, Hou S H. Neonatal tuberous sclerosis with cardiac rhabdomyomas presenting as fetal supraventricular tachycardia.  Jpn Heart J. 1997;  38 133-137
    PubMedGoogle Scholar
  • 53 Krapp M, Baschat A A, Gembruch U, Gloeckner K, Schwinger E, Reusche E. Tuberous sclerosis with intracardiac rhabdomyoma in a fetus with trisomy 21: case report and review of literature.  Prenat Diagn. 1999;  19 610-613
    CrossrefPubMedGoogle Scholar
  • 54 Mirkin L D, Ey E H, Chaparro M. Congenital subependymal giant-cell astrocytoma: case report with prenatal ultrasonogram.  Pediatr Radiol. 1999;  29 776-780
    CrossrefPubMedGoogle Scholar
  • 55 Mitra A G, Dickerson C. Central nervous system tumor with associated unilateral ventriculomegaly: unusual prenatal presentation of subsequently diagnosed tuberous sclerosis.  J Ultrasound Med. 2000;  19 651-654
    PubMedGoogle Scholar
  • 56 Choi J M, Jaffe R, Maidman J, Baxi L V. Multiple cardiac rhabdomyomas detected in utero.  Fetal Diagn Ther. 2000;  15 174-176
    CrossrefPubMedGoogle Scholar
  • 57 Senger C. Pathologic quiz case: infant girl with unilateral nephromegaly.  Arch Pathol Lab Med. 2000;  124 327-329
    PubMedGoogle Scholar
  • 58 Axt-Fliedner R, Qush H, Hendrik H J et al.. Prenatal diagnosis of cerebral lesions and multiple intracardiac rhabdomyomas in a fetus with tuberous sclerosis.  J Ultrasound Med. 2001;  20 63-67
    PubMedGoogle Scholar
  • 59 Bonnamy L, Perrotin F, Megier P, Haddad G, Body G, Lansac J. Fetal intracardiac tumor(s): prenatal diagnosis and management. Three case reports.  Eur J Obstet Gynecol Reprod Biol. 2001;  99 112-117
    CrossrefPubMedGoogle Scholar
  • 60 Bussani R, Rustico M A, Silvestri F. Fetal cardiac rhabdomyomatosis as a prenatal marker for the detection of latent tuberous sclerosis. An autopsy case report.  Pathol Res Pract. 2001;  197 559-561
    CrossrefPubMedGoogle Scholar
  • 61 Lethor J P, de Moor M. Multiple cardiac tumors in the fetus.  Circulation. 2001;  103 E55
    PubMedGoogle Scholar
  • 62 Breysem L, Nijs E, Proesmans W, Smet M H. Tuberous sclerosis with cystic renal disease and multifocal renal cell carcinoma in a baby girl.  Pediatr Radiol. 2002;  32 677-680
    CrossrefPubMedGoogle Scholar
  • 63 Medhkour A, Traul D, Husain M. Neonatal subependymal giant cell astrocytoma.  Pediatr Neurosurg. 2002;  36 271-274
    CrossrefPubMedGoogle Scholar
  • 64 Kagan K O, Schmidt M, Kuhn U, Kimmig R. Ventricular outflow obstruction, valve aplasia, bradyarrhythmia, pulmonary hypoplasia and non-immune fetal hydrops because of a large rhabdomyoma in a case of unknown tuberous sclerosis: a prenatal diagnosed cardiac rhabdomyoma with multiple symptoms.  BJOG. 2004;  111 1478-1480
    PubMedGoogle Scholar
  • 65 Tunali N, Gümürdülü D, Zorludemir S. Splenic involvement in a stillborn fetus with tuberous sclerosis and multiple cardiac rhabdomyomas.  Turk J Pediatr. 2004;  46 357-361
    PubMedGoogle Scholar
  • 66 Hussain N, Curran A, Pilling D et al.. Congenital subependymal giant cell astrocytoma diagnosed on fetal MRI.  Arch Dis Child. 2006;  91 520
    CrossrefPubMedGoogle Scholar
  • 67 Raju G P, Urion D K, Sahin M. Neonatal subependymal giant cell astrocytoma: new case and review of literature.  Pediatr Neurol. 2007;  36 128-131
    CrossrefPubMedGoogle Scholar
  • 68 Zhang Y X, Meng H, Zhong D R, Jiang Y X, Dai Q, Zhang H. Cardiac rhabdomyoma and renal cyst in a fetus: early onset of tuberous sclerosis with renal cystic disease.  J Ultrasound Med. 2008;  27 979-982
    PubMedGoogle Scholar
  • 69 Shami M J, Benedict W L, Myers M. Early manifestation of retinal hamartomas in tuberous sclerosis.  Am J Ophthalmol. 1993;  115 539-540
    PubMedGoogle Scholar
  • 70 Stillwell T J, Gomez M R, Kelalis P P. Renal lesions in tuberous sclerosis.  J Urol. 1987;  138 477-481
    PubMedGoogle Scholar
  • 71 Bender B L, Yunis E J. Splenic involvement in tuberous sclerosis. Report of three cases.  Virchows Arch A Pathol Anat Histol. 1981;  391 363-369
    CrossrefPubMedGoogle Scholar

Hart IsaacsJr. M.D. 

Department of Pathology, Rady Children's Hospital San Diego

3020 Children's Hospital Way MC 5007, San Diego, CA 92123

Email: hisaacs@ucsd.edu