ALL CASES OF THANATOPHORIC DYSPLASIA ARE CAUSED BY NEW MUTATIONS IN THE FGFR3 GENE due to ADVANCED PATERNAL AGE

1: Am J Med Genet. 1995 Nov 6;59(2):209-17. Links
Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta.Orioli IM, Castilla EE, Scarano G, Mastroiacovo P.
Departamento de Genetica, Universidade Federal do Rio de Janeiro, Brazil.

The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area





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Reviewed June 2006
What is thanatophoric dysplasia?
Thanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and folds of extra (redundant) skin on the arms and legs. Other features of this condition include a narrow chest, short ribs, underdeveloped lungs, and an enlarged head with a large forehead and prominent, wide-spaced eyes.

Researchers have described two major forms of thanatophoric dysplasia, type I and type II. Type I thanatophoric dysplasia is distinguished by the presence of curved thigh bones and flattened bones of the spine (platyspondyly). Type II thanatophoric dysplasia is characterized by straight thigh bones and a moderate to severe skull abnormality called a cloverleaf skull.

The term thanatophoric is Greek for "death bearing." Infants with thanatophoric dysplasia are usually stillborn or die shortly after birth from respiratory failure; however, a few affected individuals have survived into childhood with extensive medical help.

How common is thanatophoric dysplasia?
This condition occurs in 1 in 20,000 to 50,000 newborns. Type I thanatophoric dysplasia is more common than type II.

What genes are related to thanatophoric dysplasia?
Mutations in the FGFR3 gene cause thanatophoric dysplasia.

What genes are related to thanatophoric dysplasia?
Mutations in the FGFR3 gene cause thanatophoric dysplasia.

Both types of thanatophoric dysplasia result from mutations in the FGFR3 gene. This gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. Mutations in this gene cause the FGFR3 protein to be overly active, which leads to the severe disturbances in bone growth that are characteristic of thanatophoric dysplasia. It is not known how FGFR3 mutations cause the brain and skin abnormalities associated with this disorder.

How do people inherit thanatophoric dysplasia?
Thanatophoric dysplasia is considered an autosomal dominant disorder because one mutated copy of the FGFR3 gene in each cell is sufficient to cause the condition. Virtually all cases of thanatophoric dysplasia are caused by new mutations in the FGFR3 gene and occur in people with no history of the disorder in their family. No affected individuals are known to have had children; therefore, the disorder has not been passed to the next generation.

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1: Am J Med Genet. 1988 Dec;31(4):815-20. Links
Thanatophoric dysplasia: an autosomal dominant condition?Martinez-Frias ML, Ramos-Arroyo MA, Salvador J.
Estudio Colaborativo Espanol de Malformaciones Congenitas, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

We present 13 cases of thanatophoric dysplasia collected in the Spanish Collaborative Study of Congenital Malformations from a total population of 517,970 births. The incidence (live and stillbirth) was 2.7 per 100,000 births. All cases were sporadic, and there was no evidence of parental consanguinity. Parental age was significantly higher as compared with control parents. These findings suggest the occurrence of autosomal dominant mutation, with an overall mutation rate of 1.34 X 10(-5) in our population, which is close to that observed in achondroplasia.

PMID: 3239573 [PubMed - indexed for MEDLINE]