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Thanatophoric Dysplasia Clinical Presentation

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Nov 23, 2015
 

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 conclusive diagnosis of thanatophoric dysplasia (TD) using only this imaging tool can be difficult.

Key ultrasonography findings include the following:

  • Growth deficiency with limb length of less than 5% (by 20 weeks' gestation)
  • Macrocephaly
  • Cloverleaf-shaped skull or kleeblattschädel (indicates TDII, but also seen in TDI)[5]
  • Ventriculomegaly Well-ossified skull and spine
  • Platyspondyly of the vertebrae
  • Narrow chest cavity with shortened ribs
  • Micromelia
  • Bowed femurs (usually indicates TDI)
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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
  • Cloverleaf-shaped skull due to premature closure of the cranial sutures
  • Flat facies with low nasal bridge and proptotic eyes
  • 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

See the list below:

  • Thanatophoric dysplasia is an autosomal dominant disorder that results from sporadic de novopoint mutations in the FGFR3 gene. Sequence and targeted mutation DNA analyses of FGFR3areavailable to assist with diagnosis when clinical concerns are present. Germline mosaicism has been suggested as another possible cause, but has not been clearly documented.
  • The following mutations that affect distinct domains of FGFR3 cause the thanatophoric dysplasia subtypes, TDI and TDII:
    • TDI: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TDI. The more common mutation occurring in TDI is R248C (p.Arg248Cys), which is confirmed in approximately 50% of patients.
    • TDII: K650E (p.Lys650Glu) 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 FGFR3mutations 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

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.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference 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
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  16. 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. 2003 Mar. 36(2):151-3. [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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