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.
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, "telephonereceiver"-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
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.
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. As of 2001, 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.
Signs and symptoms
Infants with TD are typically identified either during pregnancy or at the time of birth. Affected pregnancies are often complicated by polyhydramnios, or excess amniotic fluid around the fetus. As a result, the mother often appears more pregnant than she actually is. It is common for a prenatal ultrasound examination to be performed to rule out a fetal birth defect as the cause. The serious limb abnormalities typical of TD are often identified in this way. Polyhydramnios may also lead to an increased chance of early labor and premature delivery. The pregnant woman may require more intensive monitoring of her pregnancy.
At birth, newborns with TD typically have a very large head with a prominent forehead, a flattened bridge of the nose, and prominent, bulging eyes. Their limbs are extremely short and are often held extended out from the rest of the body. The neck is short, the chest is narrow, and the belly appears unusually large, giving an overall resemblance to a pear. The shape of the skull may be abnormal due to either cloverleaf skull or a milder form of craniosynostosis. Newborns are often rather floppy, or hypotonic, with poor muscle tone and absent primitive neurologic reflexes. Breathing is very difficult due to the small chest and lungs, often leading to the use of a ventilator to prolong survival.
The physical appearance of individuals with TD who survive the neonatal period does not dramatically change over time. Affected children remain very small and have limited potential to walk or move about unaided. Mental retardation due to structural brain malformations has been reported. Seizures and hearing loss frequently develop.
Prenatal diagnosis of TD is possible based on ultrasound examination, usually during the second half of pregnancy. However, it is important to realize that many of the physical abnormalities seen in fetuses with TD, such as an enlarged head and shortened long bones, may also be found in fetuses with other forms of skeletal dysplasia. Consequently, while ultrasound may suggest a diagnosis of a skeletal dysplasia, it may not be possible to confirm a diagnosis of TD until after birth.
Upon delivery, a careful examination of the infant should be performed to look for many of the more obvious external features of TD. Radiologic studies are extremely important, particularly to distinguish between TD1 and TD2. X ray will confirm the marked shortening of the long bones, identify curved or straight femurs, document the shape and appearance of the spinal vertebrae, and reveal the extent of craniosynostosis. An autopsy, including x rays, is highly recommended on any stillborn infant with TD to confirm the diagnosis.
Mutation studies by analysis of the FGFR3 gene are being used more often to confirm a diagnosis of TD and to determine TD type. Perhaps the greatest benefit of direct genetic testing is for those parents who have been told by a prenatal ultrasound examination that their unborn child has a serious bone dysplasia. An amniocentesis for additional genetic studies may be offered. Further clarification of the diagnosis allows for more refined counseling regarding the infant's likely prognosis. Termination of the pregnancy may be an option for some couples. For those couples wishing to continue an affected pregnancy, plans can be made for the remaining prenatal care, especially given the risk for polyhydramnios and/or early labor and delivery. Careful consideration may be given as to the level of intervention and medical care desired for the infant after birth.
Knowledge of the specific TD mutation is also helpful in planning care for any future pregnancy. Despite the sporadic nature of TD, a couple with a history of one affected child has a small risk of having a second affected child due to the possibility of gonadal mosaicism. Prenatal testing in a new pregnancy, such as chorionic villus sampling or amniocentesis, may be offered to look for a TD mutation. However, in order for this to be possible, the TD mutation in the previous child must have been determined.
Studies are ongoing to assess whether or not three-dimensional ultrasound, in contrast to the current, much more widely available, two-dimensional ultrasound, may be used to accurately prenatally diagnosis TD and other skeletal dysplasias. If effective, additional prenatal studies could become less common. However, early results have shown no significant improvement in the detection or diagnosis of TD and related disorders. The present standard of care therefore remains a prenatal ultrasound examination, if available, physical evaluations after delivery, and identification of the underlying genetic mutation, whenever possible.
Treatment and management
The treatment and care of an infant with TD is mainly supportive. The poor prognosis associated with TD should be discussed. Infants who survive the newborn period will require intensive, ongoing medical care.
Nearly all infants with TD, both types 1 and 2, die either at the time of delivery or shortly thereafter due to severe respiratory distress. Aggressive medical treatment after birth has not always helped affected infants live even a short amount of time. Prolonged survival, including one child who, as of 1997, was still alive at the age of nine years, has been reported but is highly unusual. Survival is associated with poor growth and development and with continuing, serious respiratory problems.
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Greenberg Center for Skeletal Dysplasias. 600 North Wolfe Street, Blalock 1012C, Baltimore, MD 21287-4922. (410) 614-0977. <http://www.med.jhu.edu/Greenberg.Center/Greenbrg.htm>.
OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov>.
Terri A. Knutel, MS, CGC