Skip to main content

Advertisement

Log in

The cerebral cortex malformation in thanatophoric dysplasia: neuropathology and pathogenesis

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Thanatophoric dysplasia (TD) is a relatively common, fatal form of chondrodysplastic dwarfism in which the cerebral cortex displays a unique and complex malformation. The malformation is characterized by a combination of abnormalities, which affect the temporal lobe most severely. Salient features include temporal lobe enlargement, deep transverse sulci across the inferomedial temporal surface, and hippocampal dysplasia. TD is caused by mutations of the fibroblast growth factor (FGF) receptor 3 gene (FGFR3), which result in constitutive activation of the FGFR3 tyrosine kinase. However, the link between constitutive FGFR3 activation and malformation of the cortex has been difficult to elucidate. In this review, I describe the neuropathological features of human TD, especially the cortical malformation, ascertained by examination of 45 published cases and 5 new cases, spanning gestational ages from 18 to 42 weeks. The cortical malformation is interpreted with regard to developmental mechanisms, and observations from a mouse model of TD. The evidence suggests that FGFR3 activation perturbs three key processes in cortical development: areal patterning, progenitor proliferation, and apoptosis. Defective patterning accounts for hippocampal dysplasia, while increased proliferation and decreased apoptosis account for temporal lobe hyperplasia and premature development of aberrant sulci. Disturbances in these processes may also contribute to other cortical malformations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Assimacopoulos S, Grove EA, Ragsdale CW (2003) Identification of a Pax6-dependent epidermal growth factor family signaling source at the lateral edge of the embryonic cerebral cortex. J Neurosci 23:6399–6403

    PubMed  Google Scholar 

  2. Baker KM, Olson DS, Harding CO, Pauli RM (1997) Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet 70:427–436

    Article  PubMed  Google Scholar 

  3. Bansal R, Lakhina V, Remedios R, Tole S (2003) Expression of FGF receptors 1, 2, 3 in the embryonic and postnatal mouse brain compared with Pdgfrα, Olig2 and Plp/dm20: implications for oligodendrocyte development. Dev Neurosci 25:83–95

    Article  PubMed  Google Scholar 

  4. Bishop KM, Garel S, Nakagawa Y, Rubenstein JLR, O’Leary DDM (2003) Emx1 and Emx2 cooperate to regulate cortical size, lamination, neuronal differentiation, development of cortical efferents, and thalamocortical pathfinding. J Comp Neurol 457:345–360

    Article  PubMed  Google Scholar 

  5. Bloomfield JA (1970) Cloverleaf skull and thanatophoric dwarfism. Australas Radiol 14:429–437

    PubMed  Google Scholar 

  6. Chenn A, Walsh CA (2002) Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365–369

    Article  PubMed  Google Scholar 

  7. Cohen MM Jr (2002) Some chondrodysplasias with short limbs: molecular perspectives. Am J Med Genet 112:304–313

    Article  PubMed  Google Scholar 

  8. Cohen MM Jr, Kreiborg S (1990) The central nervous system in the Apert syndrome. Am J Med Genet 35:36–45

    Article  PubMed  Google Scholar 

  9. Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12:390–397

    Article  PubMed  Google Scholar 

  10. Coulter CL, Leech RW, Brumback RA, Schaefer GB (1991) Cerebral abnormalities in thanatophoric dysplasia. Child’s Nerv Syst 7:21–26

  11. Crossley PH, Martin GR (1995) The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121:439–451

    PubMed  Google Scholar 

  12. De Basio P, Prefumo F, Baffico M, Baldi M, Priolo M, Lerone M, Toma P, Venturini PL (2000) Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. Prenat Diagn 20:835–837

    Article  PubMed  Google Scholar 

  13. Dennis JP, Rosenberg HS, Alvord EC Jr (1961) Megalencephaly, internal hydrocephalus and other neurological aspects of achondroplasia. Brain 84:427–445

    PubMed  Google Scholar 

  14. Dono R, Texido G, Dussel R, Ehmke H, Zeller R (1998) Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice. EMBO J 17:4213–4225

    Article  PubMed  Google Scholar 

  15. Faye-Peterson OM, Knisely AS (1991) Neural arch stenosis and spinal cord injury in thanatophoric dysplasia. Am J Dis Child 145:87–89

    PubMed  Google Scholar 

  16. Ford-Perriss M, Abud H, Murphy M (2001) Fibroblast growth factors in the developing central nervous system. Clin Exp Pharmacol Physiol 28:493–503

    Article  PubMed  Google Scholar 

  17. Fukuchi-Shimogori T, Grove EA (2001) Neocortex patterning by the secreted signaling molecule FGF8. Science 294:1071–1074

    Article  PubMed  Google Scholar 

  18. Galatioto S, Gemelli M, Granese D, Longo M (1984) Thanatophoric dwarfism and “cloverleaf skull” syndrome: a neuropathological report. Pathologica 76:255–261

    PubMed  Google Scholar 

  19. Garel S, Huffman KJ, Rubenstein JLR (2003) Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants. Development 130:1903–1914

    Article  PubMed  Google Scholar 

  20. Gemelli M, Galatioto S, Longo M, Granese D (1982) Nanismo tanatoforo con cranio a trifoglio [Thanatophoric dwarfism with cloverleaf skull]. Minerva Pediatr 34:977–982

    PubMed  Google Scholar 

  21. Golden JA (2001) Periventricular heterotopia may result from radial glial fiber disruption. J Neuropathol Exp Neurol 60:856–862

    Google Scholar 

  22. Goutières F, Aicardi J, Farkas-Bargeton E (1971) Une malformation cérébrale particulière associée au nanisme thanatophore. Presse Med 79:960

    Google Scholar 

  23. Goutieres F, Aicardi J, Farkas-Bargeton E (1971) Une malformation cérébrale particuliere associée au nanisme thanatophore. Rev Neurol 125:435–440

    PubMed  Google Scholar 

  24. Grove EA, Fukuchi-Shimogori T (2003) Generating the cerebral cortical area map. Annu Rev Neurosci 26:355–380

    Article  PubMed  Google Scholar 

  25. Gruenwald P, Minh HN (1960) Evaluation of body and organ weights in perinatal pathology. I. Normal standards derived from autopsies. Am J Clin Pathol 34:247–253

    PubMed  Google Scholar 

  26. Hamasaki T, Leingartner A, Ringstedt T, O’Leary D (2004) EMX2 regulates sizes and positioning of the primary sensory and motor areas in neocortex by direct specification of cortical progenitors. Neuron 43:359–372

    Article  PubMed  Google Scholar 

  27. Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R (2004) Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131:5539–5550

    Article  PubMed  Google Scholar 

  28. Haydar TF, Kuan C-Y, Flavell RA, Rakic P (1999) The role of cell death in regulating the size and shape of the mammalian forebrain. Cereb Cortex 9:621–626

    Article  PubMed  Google Scholar 

  29. Hevner RF (2005) From radial glia to pyramidal-projection neuron: transcription factor cascades in cerebral cortex development. Mol Neurobiol, in press

  30. Ho K-L, Chang C-H, Yang SS, Chason JL (1984) Neuropathologic findings in thanatophoric dysplasia. Acta Neuropathol (Berl) 63:218–228

    Google Scholar 

  31. Hodge RD, D’Ercole AJ, O’Kusky JR (2004) Insulin-like growth factor-I accelerates the cell cycle by decreasing G1 phase length and increases cell cycle reentry in the embryonic cerebral cortex. J Neurosci 10:10201–10210

    Article  Google Scholar 

  32. Hodge RD, D’Ercole AJ, O’Kusky JR (2005) Increased expression of insulin-like growth factor-I (IGF-I) during embryonic development produces neocortical overgrowth with differentially greater effects on specific architectonic areas and cortical layers. Brain Res Dev Brain Res 154:227–237

    Article  PubMed  Google Scholar 

  33. Hori A, Friede RL, Fischer G (1983) Ventricular diverticles with localized dysgenesis of the temporal lobe in cloverleaf skull anomaly. Acta Neuropathol (Berl) 60:132–136

    Google Scholar 

  34. Huguenin M, Godard C, Ferrier PE, Bamatter F (1969) Two different mutations within the same sibship: thanatophoric dwarfism and Ullrich-Feichtiger syndrome. Helv Paediatr Acta 24:239–245

    PubMed  Google Scholar 

  35. Inglis-Broadgate SL, Thomson RE, Pellicano F, Tartaglia MA, Pontikis CC, Cooper JD, Iwata T (2005) FGFR3 regulates brain size by controlling progenitor cell proliferation and apoptosis during embryonic development. Dev Biol 279:73–85

    Article  PubMed  Google Scholar 

  36. International nomenclature of constitutional diseases of bone (1978) Revision—May, 1977. J Pediatr 93:614–616

    PubMed  Google Scholar 

  37. Iwata T, Chen L, Li C, Ovchinnikov DA, Behringer RR, Francomano CA, Deng CX (2000) A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. Hum Mol Genet 9:1603–1613

    Article  PubMed  Google Scholar 

  38. Joyner AL, Liu A, Millet S (2000) Otx2, Gbx2 and Fgf8 interact to position and maintain a mid–hindbrain organizer. Curr Opin Cell Biol 12:736–741

    Article  PubMed  Google Scholar 

  39. Kalache KD, Lehmann K, Chaoui R, Kivelitz DE, Mundlos S, Bollmann R (2002) Prenatal diagnosis of partial agenesis of the corpus callosum in a fetus with thanatophoric dysplasia type 2. Prenat Diagn 22:404–407

    Article  PubMed  Google Scholar 

  40. Knisely AS, Ambler MW (1988) Temporal-lobe abnormalities in thanatophoric dysplasia. Pediatr Neurosci 14:169–176

    PubMed  Google Scholar 

  41. Kozlowski K, Warren PS, Fisher CC (1985) Cloverleaf skull with generalized bone dysplasia: report of a case with short review of the literature. Pediatr Radiol 15:412–414

    PubMed  Google Scholar 

  42. Kuida K, Haydar TF, Kuan C-Y, Gu Y, Taya C, Karasuyama H, Su MS-S, Rakic P, Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337

    Article  PubMed  Google Scholar 

  43. Langer LO Jr, Yang SS, Hall JG, Sommer A, Kottamasu SR, Golabi M, Krassikoff N (1987) Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet (Suppl) 3:167–179

    Google Scholar 

  44. Leroy JG, Timmermans J, Elsen AF van (1974) Fatal neonatal dwarfism: examples of thanatophoric dwarfism and of hypophosphatasia. Birth Defects Orig Artic Ser 10:21–30

    PubMed  Google Scholar 

  45. Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA (2003) Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 302:1560–1563

    Article  PubMed  Google Scholar 

  46. Lievens PM-J, Liboi E (2003) The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem 278:17344–17349

    Article  PubMed  Google Scholar 

  47. Lin T, Sandusky SB, Xue H, Fishbein KW, Spencer RG, Rao MS, Francomano CA (2003) A central nervous system specific mouse model for thanatophoric dysplasia type II. Hum Mol Genet 12:2863–2871

    Article  PubMed  Google Scholar 

  48. Maksem JA, Roessmann U (1979) Apert’s syndrome with central nervous system anomalies. Acta Neuropathol (Berl) 48:59–61

    Google Scholar 

  49. Maroteaux P, Lamy M, Robert J-M (1967) Le nanisme thanatophore [Thanatophoric dwarfism]. Presse Med 75:2519–2524

    PubMed  Google Scholar 

  50. Martinelli B, Campailla E, Ferrari G (1975) Malformation cerebrale particuliere et nanisme thanatophore. Arch Fr Pediatr 32:455–459

    PubMed  Google Scholar 

  51. Maruoka Y, Ohbayashi N, Hoshikawa M, Itoh N, Hogan BLM, Furuta Y (1998) Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo. Mech Dev 74:175–177

    Article  PubMed  Google Scholar 

  52. Mueller SM (1980) Enlarged cerebral ventricular system in infant achondroplastic dwarf. Neurology 30:767–769

    Google Scholar 

  53. Muzio L, DiBenedetto B, Stoykova A, Boncinelli E, Gruss P, Mallamaci A (2002) Emx2 and Pax6 control regionalization of the pre-neuronogenic cortical primordium. Cereb Cortex 12:129–139

    Article  PubMed  Google Scholar 

  54. Naski MC, Wang Q, Xu J, Ornitz DM (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet 13:233–237

    Article  PubMed  Google Scholar 

  55. Norman A, Rimmer S, Landy S, Donnai D (1992) Thanatophoric dysplasia of the straight–bone type (type 2). Clin Dysmorphol 1:115–120

    PubMed  Google Scholar 

  56. Noronha L, Prevedello LMS, Maggio EM, Serapião MJ, Torres LFB (2002) Displasia tanatofórica: relato de dois casos com estudo neuropatológico. Arq Neuropsiquiatr 60:133–137

    PubMed  Google Scholar 

  57. Orioli I, Castilla E, Barbosa-Neto J (1986) The birth prevalence rates for the skeletal dysplasias. J Med Genet 23:328–332

    PubMed  Google Scholar 

  58. Partington MW, Gonzales-Crussi F, Khakee SG, Wollin DG (1971) Cloverleaf skull and thanatophoric dwarfism: report of four cases, two in the same sibship. Arch Dis Child 46:656–664

    PubMed  Google Scholar 

  59. Peters K, Ornitz D, Werner S, Williams L (1993) Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol 155:423–430

    Article  PubMed  Google Scholar 

  60. Plomp AS, Hamel BCJ, Cobben JM, Verloes A, Offermans JPM, Lajeunie E, Fryns JP, Die-Smulders CEM de (1998) Pfeiffer syndrome type 2: further delineation and review of the literature. Am J Med Genet 75:245–251

    Article  PubMed  Google Scholar 

  61. Potter EL, Craig J (1972) Pathology of the fetus and infant. Year Book Medical Publishers, Chicago

  62. Raballo R, Rhee J, Lyn-Cook R, Leckman JF, Schwartz ML, Vaccarino FM (2000) Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex. J Neurosci 20:5012–5023

    PubMed  Google Scholar 

  63. Ragsdale CW, Grove EA (2001) Patterning the mammalian cerebral cortex. Curr Opin Neurobiol 11:50–58

    Article  PubMed  Google Scholar 

  64. Rakic P (1988) Specification of cerebral cortical areas. Science 241:170–176

    PubMed  Google Scholar 

  65. Ronconi GF, Pesenti P, Mercurella A, Sassolino S (1986) Descrizione di un caso di displasia tanatofora con cranio a trifoglio [A case of thanatophoric dysplasia with cloverleaf skull]. Pediatr Med Chir 8:423–426

    PubMed  Google Scholar 

  66. Rubenstein JLR, Anderson S, Shi L, Miyashita-Lin E, Bulfone A, Hevner R (1999) Genetic control of cortical regionalization and connectivity. Cereb Cortex 9:524–532

    Article  PubMed  Google Scholar 

  67. Sahinoglu Z, Uludogan M, Gurbuz A, Karateke A (2003) Prenatal diagnosis of thanatophoric dysplasia in the second trimester: ultrasonography and other diagnostic modalities. Arch Gynecol Obstet 269:57–61

    Article  PubMed  Google Scholar 

  68. Shah K, Astley R, Cameron AH (1973) Thanatophoric dwarfism. J Med Genet 10:243–252

    PubMed  Google Scholar 

  69. Shigematsu H, Takashima S, Otani K, Ieshima A (1985) Neuropathological and Golgi study on a case of thanatophoric dysplasia. Brain Dev 7:628–632

    PubMed  Google Scholar 

  70. Shimogori T, Banuchi V, Ng HY, Strauss JB, Grove EA (2004) Embryonic signaling centers expressing BMP, WNT, and FGF proteins interact to pattern the cerebral cortex. Development 131:5639–5647

    Article  PubMed  Google Scholar 

  71. Tavormina PL, Shiang R, Thompson LM, Zhu Y-Z, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321–328.

    Article  PubMed  Google Scholar 

  72. Ueno H, Gunn M, Dell K, Tseng A Jr, Williams L (1992) A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor. J Biol Chem 267:1470–1476

    PubMed  Google Scholar 

  73. Van der Harten HJ, Brons JTJ, Dijkstra PF, Barth PG, Niermeyer MF, Meijer CJLM, van Geijn HP, Arts NFT (1993) Some variants of lethal neonatal short-limbed platyspondylic dysplasia: a radiological ultrasonographic, neuropathological and histopathological study of 22 cases. Clin Dysmorphol 2:1–19

    PubMed  Google Scholar 

  74. Webster MK, D’Avis PY, Robertson SC, Donoghue DJ (1996) Profound ligand–independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol Cell Biol 16:4081–4087

    PubMed  Google Scholar 

  75. Wilcox WR, Tavormina PL, Krakow D, Kitoh H, Lachman RS, Wasmuth JJ, Thompson LM, Rimoin DL (1998) Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet 78:274–281

    Article  PubMed  Google Scholar 

  76. Wongmongkolrit T, Bush M, Roessmann U (1983) Neuropathological findings in thanatophoric dysplasia. Arch Pathol Lab Med 107:132–135

    PubMed  Google Scholar 

  77. Yamaguchi K, Honma K (2001) Autopsy case of thanatophoric dysplasia: observations on the serial sections of the brain. Neuropathology 21:222–228

    Article  PubMed  Google Scholar 

  78. Yun K, Mantani A, Garel S, Rubenstein J, Israel MA (2004) Id4 regulates neural progenitor proliferation and differentiation in vivo. Development 131:5441–5448

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

I gratefully acknowledge Rebecca Folkerth for generously sharing cases, Hannah Kinney and Dara Nachmanoff for discussions of TD pathogenesis, and Nelson Fausto for help translating an article from the original Portuguese. Supported by grants from the National Institutes of Health, the Edward Mallinckrodt Jr. Foundation, and the C.–M. Shaw Professorship in Investigative Neuropathology.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert F. Hevner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hevner, R.F. The cerebral cortex malformation in thanatophoric dysplasia: neuropathology and pathogenesis. Acta Neuropathol 110, 208–221 (2005). https://doi.org/10.1007/s00401-005-1059-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-005-1059-8

Keywords

Navigation