Thanatophoric Dysplasia Health Article

Demographics

Thanatophoric dysplasia is the most common lethal skeletal dysplasia, with an estimated incidence of one in 35,000–50,000 births. It has been described in all races and ethnic groups.

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.

Diagnosis

Prenatal diagnosis of TD is possible based on ultra-sound 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.