Thanatophoric Dysplasia 

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

Background

Thanatophoric dysplasia (TD) is the most common form of skeletal dysplasia that is lethal in the neonatal period. The term, thanatophoric, derives from the Greek word thanatophorus, which means "death bringing" or "death bearing." Some salient phenotypic features of thanatophoric dysplasia include macrocephaly, narrow bell-shaped thorax, normal trunk length, and severe shortening of the limbs. See the image below.

Infant with thanatophoric dysplasia. Note short-liInfant 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).

Thanatophoric dysplasia is divided into 2 clinically defined subtypes: thanatophoric dysplasia type I (TDI or TD1) and thanatophoric dysplasia type II (TDII or TD2). The clinical subtypes of thanatophoric dysplasia are defined by the curved or straight appearance of the long bones. TDI, the more common subtype, is characterized by a normal-shaped skull and curved long bones (shaped like a telephone receiver); the femurs are most affected. TDII is associated with a cloverleaf-shaped skull and straight femurs. However, clinical overlap is observed between these subtypes.

TDI and TDII are caused by an autosomal dominant mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which has been mapped to chromosome band 4p16.3. Penetrance of this mutation is 100%. Currently, all cases of thanatophoric dysplasia are due to de novo mutations in FGFR3. Germline mosaicism has not been clearly documented but remains a theoretical possibility.[1, 2]

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Pathophysiology

FGFR3 is part of the tyrosine kinase receptor family. Normally, FGFR3 is a negative regulator of bone growth. The mutations in thanatophoric dysplasia that code for FGFR3 cause a gain in function, sending negative signals to the cartilage cells (chondrocytes). This occurs when ligand binding within the chondrocytes induces receptor homodimerization and heterodimerization. This, in turn, activates tyrosine kinase function, which potentiates many effects on cell growth and differentiation.

Researchers suggest that mutations in FGFR3 lead to the formation of cysteine residues that create disulfide bonds between extracellular domains of mutant monomers. Activation of the homodimer receptor complex increases its stability and promotes translocation of the complex into the nucleus, where it may interfere with terminal chondrocyte differentiation. Hence, generalized disorganization of endochondral ossification at the bone growth plate occurs.

TDI is caused by several different mutations that affect either the extracellular or intracellular domains of FGFR3. The two missense mutations, R248C and Y373C, account for as much as 80% of TDI cases. The more common of these two TDI mutations, R248C (known as p.Arg248Cys), is a C-to-T nucleotide transition and impacts the extracellular domain of FGFR3.

To date, all patients with TDII have a single point mutation, p.Lys650Glu, with an A → G nucleotide transition in the tyrosine kinase domain of FGFR3, also known as K650E.

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Epidemiology

Frequency

United States

Thanatophoric dysplasia has an incidence of 1 per 20,000-50,000 births.

International

Incidence in Spain is reported as 1 per 37,000 births.

Mortality/Morbidity

Newborns with thanatophoric dysplasia are stillborn or die shortly after birth. Death in the neonatal period is due to severe respiratory insufficiency from reduced thoracic capacity and hypoplastic lungs or respiratory failure due to brainstem compression. Very rare reports of survival into early childhood have been cited.

Sex

Males and females are equally affected.

Age

Thanatophoric dysplasia is lethal in neonates; however, survival beyond the neonatal period has been rarely reported.

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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

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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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