Thanatophoric Dysplasia Health Article

Definition

Thanatophoric dysplasia is one of the most common and most severe forms of dwarfism. Affected infants have marked shortening of their arms and legs, a small chest, and a relatively large head. Most die within a few days after birth; longer-term survivors have been reported but are rare.

Description

Thanatophoric dysplasia (TD) was first described in 1967 to refer to infants with a severe form of dwarfism who died within the first hours of life. The word "thanatophoric" is derived from the Greek word, thanatophorus, which means "death-bringing." The term thanatophoric dwarfism is occasionally used. However, over time, the word dysplasia, which refers to any disorder in growth, has become the preferred terminology.

Two distinct types of TD were delineated in 1987. Affected infants are divided based on their particular combination of physical features and skeletal findings. While all individuals with TD have micromelia, or abnormally small or short arms and legs, differences in the length and shape of the femurs, the bones of the thigh, can be used to distinguish between TD types 1 (TD1) and 2 (TD2). Infants with TD1 have curved, "telephone-receiver"-like femurs. In contrast, the femurs of infants with TD2 are longer and straighter.

The presence of skull abnormalities is another important distinction between the two types: infants with TD2 typically have a severe abnormality of the bones of the skull, referred to as cloverleaf skull or kleeblattschadel anomaly. The skull of a normal infant is composed of several segments of bone, some of which are completely joined together, or fused, by the time of delivery. Their lines of fusion are referred to as sutures. Some sutures are only partially fused, leaving soft, skin-covered openings that will gradually close over the first year of life. Premature closure of these sutures leads to a condition called craniosynostosis. Craniosynostosis often leads to an abnormal skull shape and, if not eventually corrected by surgery, prevents normal growth of the brain. The most extreme form of craniosynostosis, as seen in infants with TD2, causes a severely abnormal skull whose shape resembles that of a cloverleaf. Although milder forms of craniosynostosis may be found in infants with TD1, cloverleaf skull is not typically present.

Other bone abnormalities occur in both TD types 1 and 2, including an abnormal shape of and spacing between the bones in the spine (vertebrae), shortened ribs, and small pelvic bones. Most of the other organs of the body, with the exception of the brain, are normal, although occasional abnormalities of the kidneys have been reported. A variety of abnormal changes in the structure of the brain have been described. The small number of children with TD who have survived past infancy have been severely mentally and physically handicapped.

The most common cause of death among individuals with TD is respiratory insufficiency. The small chest and, consequently, limited growth of the lungs, are the primary reasons for the breathing problems. However, associated abnormalities of the central nervous system are most likely also involved since these interfere with the body's ability to regulate normal breathing.

Genetic profile

Both types of thanatophoric dysplasia occur as sporadic, autosomal dominant conditions. Only one copy of the altered gene causing TD needs to be present in order for the condition to occur. Males and females are equally likely to be affected. The parents of an affected child do not have TD and are normal. Thus, it is believed that, in most cases, a new genetic mutation, or change, causing TD occurred in either the egg or sperm cell that gave rise to that particular pregnancy. Such a mutation cannot be made to happen; it occurs simply by chance. A very low risk of recurrence, or chance of another affected child in a future pregnancy, would be expected. Unfortunately, families have been described with more than one child with TD. The most likely explanation in these families is gonadal mosaicism.

Gonadal mosaicism occurs when a normal adult has a mixed population of cells in his or her gonads (testes or ovaries). All of the other cells in that individual's body are presumably normal. Most sperm or egg cells from these gonads would be normal and would not have a TD mutation; however, an unknown percentage would carry the mutation. As a result, even though the parent would be normal, he or she could, with the same or a different partner, have another child with TD. It is virtually impossible to prove whether or not a parent has gonadal mosaicism. Even so, all parents of an affected child are counseled that gonadal mosaicism in one of them is a possibility.

Thanatophoric dysplasia is caused by mutations in the fibroblast growth factor receptor 3 gene (FGFR3), located on the short arm of chromosome 4 at band 16.3 (abbreviated as 4p16.3). The fibroblast growth factors are a family of important proteins in the human body. They are involved in the production of new cells and new blood vessels as well as in the healing of wounds. Mutations in each of the fibroblast growth factor genes (FGFR1, 2, and 3) have been linked to a variety of genetic conditions. The FGFR3 protein is primarily found in cartilage and the central nervous system. Different mutations in the FGFR3 gene have been associated with other skeletal dysplasias, most notably achondroplasia and hypochondroplasia.

As might be expected, different mutations in FGFR3 have been found in patients with TD1 versus those with TD2. A wider variety of mutations have been identified among infants with TD1. One predominant mutation has been present in nearly all cases of TD2 studied so far. Regardless of the specific mutation, the net effect of each of the mutations in both TD1 and TD2 is the same: the linear growth of bone is prevented, resulting in very short, small bones.