Thanatophoric Dysplasia

Updated: Sep 07, 2016
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
  • Print
Overview

Background

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

Infant with thanatophoric dysplasia. Note short-li 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).

TD is divided into 2 clinically defined subtypes: TD type I (TD-I or TD-1) and TD type II (TD-II or TD-2). The clinical subtypes of TD are defined by either a curved or straight appearance of the long bones. TD-I, the more common subtype, is characterized by a normal-shaped skull and curved long bones (shaped like old-fashioned telephone receivers); the femurs are most affected in TD-I. TD-II is associated with a cloverleaf-shaped skull and straight femurs. However, reported cases have cited clinical overlap between these subtypes.

Both TD-I and TD-II are part of a group of skeletal disorders associated with mutations within the Fibroblast Growth Factor Receptor 3 gene (FGFR3). TD-I and TD-II are due to an autosomal dominant point mutation, with the gene responsible, FGFR3, being mapped to the short arm of chromosome 4 (4p16.3). Penetrance of this mutation is 100%. Currently, all cases of TD are due to de novo mutations in FGFR3. Germline mosaicism has not been clearly documented but remains a theoretical possibility. [1, 2]

Next:

Pathophysiology

FGFR3 is part of the tyrosine kinase receptor family. Normally, FGFR3 is a negative regulator of bone growth. Point mutations within FGFR3 causing thanatophoric dysplasia (TD) initiate a gain in function by sending negative signals to the cartilage cells (chondrocytes). These signals occur when ligand binding within the chondrocytes induces receptor homodimerization and heterodimerization. Subsequently, activation of tyrosine kinase function potentiates many effects on cell growth and differentiation.

Researchers believe 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.

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

To date, all patients with TD-II have a single point mutation, K650E (known as p.Lys650Glu), with an A→G purine nucleotide transition in the tyrosine kinase domain of FGFR3.

Previous
Next:

Epidemiology

Frequency

United States

Thanatophoric dysplasia (TD) has an incidence of 1 per 20,000 to 1 per 50,000 births.

International

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

Mortality/Morbidity

Newborns with TD are stillborn or die shortly after birth. Death occurs usually within 48 hours and is due to severe respiratory insufficiency from a reduced thoracic capacity and hypoplastic lungs and/or respiratory failure due to brainstem compression. Survival into early childhood has been rarely reported. [3, 4]

Sex

Males and females are equally affected.

Age

TD is lethal in neonates. Although extremely rare, survival beyond the neonatal period has been described in the medical literature.

Previous