Thanatophoric Dysplasia Clinical Presentation

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 12, 2012
 

History

Most cases of a severe fetal skeletal dysplasia can be diagnosed by prenatal ultrasonography during the second or third trimester of pregnancy. However, making the diagnosis of thanatophoric dysplasia (TD) using only this imaging tool can be difficult. Key ultrasonography findings are the following:

  • Growth deficiency with limb length of less than 5% (by 20 weeks' gestation)
  • Ventriculomegaly
  • Macrocephaly
  • Cloverleaf-shaped skull or kleeblattschãdel (indicates thanatophoric dysplasia type II [TDII], also seen in thanatophoric dysplasia type I [TDI])[3]
  • Well-ossified skull and spine
  • Platyspondyly of the vertebrae
  • Micromelia
  • Bowed femurs (usually indicates TDI)
  • Narrow chest cavity with shortened ribs
  • Polyhydramnios
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Physical

Salient phenotypic features in an affected newborn are cited below:

  • Severe growth deficiency with an average length of 40 cm (about 16 in) at term
  • Generalized hypotonia
  • Macrocephalic head with frontal bossing and large anterior fontanel
  • Flat facies with low nasal bridge and proptotic eyes
  • Cloverleaf-shaped skull due to premature closure of the cranial sutures
  • Narrow, bell-shaped thorax with short ribs
  • Normal trunk length
  • Protuberant abdomen
  • Marked bilateral shortening of the limbs (micromelia) with redundant skin folds
  • Brachydactyly with a trident hand configuration
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Causes

  • Thanatophoric dysplasia is an autosomal dominant disorder that results from sporadic de novo mutations in the FGFR3 gene. Sequence and targeted mutation analysis of FGFR3 is available to assist with diagnosis when clinical concerns are present. Germline mosaicism has been suggested as a possibility but has not been clearly documented.
  • The following mutations that affect distinct domains of FGFR3 cause the thanatophoric dysplasia subtypes:
    • TDI: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TDI. The most common mutation in TDI is p.Arg248Cys (R248C), which is present in approximately 50% of patients.
    • TDII: p.Lys650Glu (K650E) is the only reported gene mutation and is present in more than 99% of patients with TDII.
  • TDI occurs more often than TDII. TDI and TDII do not share common FGFR3 mutations within the gene.
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Contributor Information and Disclosures
Author

Germaine L Defendi, MD, MS, FAAP  Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Ian Krantz, MD  Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia

Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina School of Medicine; Senior Clinical Geneticist, Greenwood Genetic Center

Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors M Carter, MS, and Susan J Gross, MD, FRCS(C), FACOG, FACMG, to the original writing and development of this article.

References

  1. Martínez-Frías ML, Egüés X, Puras A, Hualde J, de Frutos CA, Bermejo E, et al. Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis. Am J Med Genet A. Jan 2011;155A(1):197-202. [Medline].

  2. Naveen NS, Murlimanju BV, Kumar V, Pulakunta T. Thanatophoric dysplasia: a rare entity. Oman Med J. May 2011;26(3):196-7. [Medline]. [Full Text].

  3. Cohen MM Jr. Cloverleaf skulls: etiologic heterogeneity and pathogenetic variability. J Craniofac Surg. Mar 2009;20 Suppl 1:652-6. [Medline].

  4. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94. [Medline].

  5. Blaas HG, Vogt C, Eik-Nes SH. Abnormal gyration of the temporal lobe and megalencephaly are typical features of thanatophoric dysplasia and can be visualized prenatally by ultrasound. Ultrasound Obstet Gynecol. Feb 28 2012;[Medline].

  6. Ulla M, Aiello H, Cobos MP, Orioli I, García-Mónaco R, Etchegaray A, et al. Prenatal diagnosis of skeletal dysplasias: contribution of three-dimensional computed tomography. Fetal Diagn Ther. 2011;29(3):238-47. [Medline].

  7. Baker KM, Olson DS, Harding CO, Pauli RM. Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet. Jun 27 1997;70(4):427-36. [Medline].

  8. Chen CP, Chern SR, Wang W, Wang TY. Second-trimester molecular diagnosis of a heterozygous 742 --> T (R248C) mutation in the FGFR3 gene in a thanatophoric dysplasia variant following suspicious ultrasound findings. Ultrasound Obstet Gynecol. Mar 2001;17(3):272-3. [Medline].

  9. Delezoide AL, Lasselin-Benoist C, Legeai-Mallet L, et al. Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses. Hum Mol Genet. Oct 1997;6(11):1899-906. [Medline].

  10. Garjian KV, Pretorius DH, Budorick NE, et al. Fetal skeletal dysplasia: three-dimensional US--initial experience. Radiology. Mar 2000;214(3):717-23. [Medline].

  11. Ho KL, Chang CH, Yang SS, Chason JL. Neuropathologic findings in thanatophoric dysplasia. Acta Neuropathol (Berl). 1984;63(3):218-28. [Medline].

  12. Karczeski B, Cutting GR. Thanatophoric Dysplasia. GeneReviews. Available at http://www.ncbi.nlm.nih.gov/books/NBK1366/. Accessed September 1, 2009.

  13. Kolble N, Sobetzko D, Ersch J. Diagnosis of skeletal dysplasia by multidisciplinary assessment: a report of two cases of thanatophoric dysplasia. Ultrasound Obstet Gynecol. Jan 2002;19(1):92-8. [Medline].

  14. Lemyre E, Azouz EM, Teebi AS, et al. Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J. Jun 1999;50(3):185-97. [Medline].

  15. Li D, Liao C, Ma X. Prenatal diagnosis and molecular analysis of type 1 thanatophoric dysplasia. Int J Gynaecol Obstet. Dec 2005;91(3):268-70. [Medline].

  16. Liboi E, Lievens P.M-J. Thanatophoric dysplasia. Orphanet encyclopedia. Available at http://www.orpha.net/data/patho/GB/uk-Thanatophoric-dysplasia.pdf. Accessed September 1, 2009.

  17. Machado LE, Bonilla-Musoles F, Osborne NG. Thanatophoric dysplasia. Ultrasound Obstet Gynecol. Jul 2001;18(1):85-6. [Medline].

  18. Rousseau F, el Ghouzzi V, Delezoide AL, et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. Apr 1996;5(4):509-12. [Medline].

  19. Sahinoglu Z, Uludogan M, Gurbuz A. Prenatal diagnosis of thanatophoric dysplasia in the second trimester: ultrasonography and other diagnostic modalities. Arch Gynecol Obstet. Nov 2003;269(1):57-61. [Medline].

  20. Schild RL, Hunt GH, Moore J, et al. Antenatal sonographic diagnosis of thanatophoric dysplasia: a report of three cases and a review of the literature with special emphasis on the differential diagnosis. Ultrasound Obstet Gynecol. Jul 1996;8(1):62-7. [Medline].

  21. Simsek M, Al-Gazali L, Al-Mjeni R. Improved diagnosis of a common mutation (R248C) in the human growth factor receptor 3 (FGFR3) gene that causes type I Thanatophoric dysplasia. Clin Biochem. Mar 2003;36(2):151-3. [Medline].

  22. Tavormina PL, Shiang R, Thompson LM, et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. Mar 1995;9(3):321-8. [Medline].

  23. Thanatophoric dysplasia. Genetics Home Reference. Available at http://ghr.nlm.nih.gov/condition=thanatophoricdysplasia. Accessed September 1, 2009.

  24. Thanatophoric Dysplasia, Type I; TD1. Online Mendelian Inheritance in Man. Available at http://www.ncbi.nlm.nih.gov. Accessed September 1, 2009.

  25. Thanatophoric Dysplasia, Type II; TD2. Online Mendelian Inheritance in Man. Available at http://www.ncbi.nlm.nih.gov. Accessed September 1, 2009.

  26. Tretter AE, Saunders RC, Meyers CM, et al. Antenatal diagnosis of lethal skeletal dysplasias. Am J Med Genet. Feb 17 1998;75(5):518-22. [Medline].

  27. Vidaeff AC, Lucas MJ, Strassberg MB, Spooner KI, Ramin SM. Dichorionic twins discordant for thanatophoric dysplasia managed with selective reduction at 20 weeks' gestation: a case report. J Reprod Med. Aug 2005;50(8):638-42. [Medline].

  28. Weber M, Johannisson T, Thomsen M, et al. Thanatophoric dysplasia type I: new radiologic, morphologic, and histologic aspects toward the exact definition of the disorder. J Pediatr Orthop B. Jan 1998;7(1):1-9. [Medline].

  29. Wilcox WR, Tavormina PL, Krakow D, et al. Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet. Jul 7 1998;78(3):274-81. [Medline].

  30. Yuce MA, Yardim T, Kurtul M, et al. Prenatal diagnosis of thanatophoric dwarfism in second trimester. A case report. Clin Exp Obstet Gynecol. 1998;25(4):149-50. [Medline].

 
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Infant with thanatophoric dysplasia. Note short-limbed dysplasia, large head, short neck, narrow thorax, short and small fingers, and bowed extremities. Radiographs demonstrate thin flattened vertebrae, short ribs, small sacrosciatic notch, extremely short long tubular bones, and markedly short and curved femora (telephone receiver–like appearance).
 
 
 
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