Thanatophoric Dysplasia

“Thanatophoric” is a Greek term meaning “death-bringing.” There are two distinct forms of this dysplasia: Type 1 and Type 2. Thanatophoric Dwarfism is one of the most common lethal skeletal dysplasias. Its incidence is approximately 2 to 5 in 100,000 births (2).

How Thanatophoric Dysplasia Is Inherited

Thanatophoric dysplasia follows an autosomal dominant inheritance pattern. All cases are a result of spontaneous gene mutations (1).

Causes of Thanatophoric Dysplasia

A mutation in the fibroblast growth factor receptor-3 (FGFR3) gene is responsible for causing Thanatophoric Dysplasia (1).

Physical Characteristics

Thanatophoric dysplasia is characterized by a severe growth deficiency. At birth, children are, on average 40 cm long. Thanatophoric dysplasia type 1 is more common and is characterized by curved long bones, especially the femur, and flat vertebral bodies. A straight femur, taller vertebral bodies, and a cloverleaf skull are typical of Thanatophoric dysplasia type 2.

Face and Skull
Type I:
  • large cranium and fontanelle
  • disproportionately full and pronounced forehead
  • protruding eyes
  • depressed nasal bridge
Type II:
  • cloverleaf skull
  • secondary skull deformities due to premature closure of cranial sutures
Trunk, Chest and Spine:
  • narrow thorax, owing to the shortened ribs
  • protuberant abdomen
  • short spine with flattened vertebrae
Arms and Legs:
  • disproportionately short extremities compared to a relatively average-sized trunk
  • stunted limbs with small fingers
  • bowed long bones in type I
What Are the X-Ray Characteristics?

The major radiographic feature of infants with Thanatophoric dysplasia is a narrow thorax. Ribs are short with the rib ends appearing wide and cupped. Vertebral bodies are flat with a wide intervertebral disk space. The interpediculate distances narrow in the lumbar spine.

The pelvis has a short and square configuration. A small sciatic notch and medial spurs are typical. The long bones of the extremities are characteristically short and broad. The metaphyses exhibit cupped, spur-like flaring. Marked bowing of the femur is characteristic in Thanatophoric dysplasia, type I. Fibulae are markedly shorter than the tibiae. The phalanges, metacarpals, and metatarsal bones are characteristically short (3).

Making the Diagnosis

Thanatophoric dysplasia can be recognized in utero via ultrasound. Indicators include markedly short limbs and a narrow thorax. After birth, physical and radiographic examination can provide a diagnosis. Molecular testing of the FGFR-3 gene can be done to confirm the diagnosis either prenatally via an amniocentesis sample or postnatally from a blood sample.

Associated Medical Problems

Thanatophoric Dysplasia is a type of lethal short-limb platyspondylic dysplasia in which patients usually die shortly after birth, due mostly to respiratory insufficiency. Patients who survive the perinatal period are ventilator-dependent and have severe developmental delay.

Problems Elsewhere in Body

Long-term survival is rare, albeit three Thanatophoric children, between the ages of 9 and 10, have been reported. All have severe developmental delay, growth deficiency, and are ventilator-dependent (3).

  1. Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006.
  2. Orioli, IM. Castilla EE. Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genetics. 23: 328-332
  3. Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.

Genetic Testing

Genetic tests are done by analyzing small samples of blood or body tissues. They determine whether you, your partner, or your baby carry genes for certain inherited disorders.

Genetic testing has developed enough so that doctors can often pinpoint missing or defective genes. The type of genetic test needed to make a specific diagnosis depends on the particular illness that a doctor suspects.

Many different types of body fluids and tissues can be used in genetic testing. For deoxyribonucleic acid (DNA) screening, only a very tiny bit of blood, skin, bone, or other tissue is needed.

Genetic Testing During Pregnancy

For genetic testing before birth, pregnant women may decide to undergo amniocentesis or chorionic villus sampling. There is also a blood test available to women to screen for some disorders. If this screening test finds a possible problem, amniocentesis or chorionic villus sampling may be recommended.

Amniocentesis is a test usually performed between weeks 15 and 20 of a woman's pregnancy. The doctor inserts a hollow needle into the woman's abdomen to remove a small amount of amniotic fluid from around the developing fetus. This fluid can be tested to check for genetic problems and to determine the sex of the child. When there's risk of premature birth, amniocentesis may be done to see how far the baby's lungs have matured. Amniocentesis carries a slight risk of inducing a miscarriage.

Chorionic villus sampling (CVS) is usually performed between the 10th and 12th weeks of pregnancy. The doctor removes a small piece of the placenta to check for genetic problems in the fetus. Because chorionic villus sampling is an invasive test, there's a small risk that it can induce a miscarriage.

Why Doctors Recommend Genetic Testing

A doctor may recommend genetic counseling or testing for any of the following reasons:

  • A couple plans to start a family and one of them or a close relative has an inherited illness. Some people are carriers of genes for genetic illnesses, even though they don't show, or manifest, the illness themselves. This happens because some genetic illnesses are recessive — meaning that they're only expressed if a person inherits two copies of the problem gene, one from each parent. Offspring who inherit one problem gene from one parent but a normal gene from the other parent won't have symptoms of a recessive illness but will have a 50% chance of passing the problem gene on to their children.
  • A parent already has one child with a severe birth defect. Not all children who have birth defects have genetic problems. Sometimes, birth defects are caused by exposure to a toxin (poison), infection, or physical trauma before birth. Often, the cause of a birth defect isn't known. Even if a child does have a genetic problem, there's always a chance that it wasn't inherited and that it happened because of some spontaneous error in the child's cells, not the parents' cells.
  • A woman has had two or more miscarriages. Severe chromosome problems in the fetus can sometimes lead to a spontaneous miscarriage. Several miscarriages may point to a genetic problem.
  • A woman has delivered a stillborn child with physical signs of a genetic illness. Many serious genetic illnesses cause specific physical abnormalities that give an affected child a very distinctive appearance.
  • The pregnant woman is over age 34. Chances of having a child with a chromosomal problem (such as trisomy) increase when a pregnant woman is older. Older fathers are at risk to have children with new dominant genetic mutations (those caused by a single genetic defect that hasn't run in the family before).
  • A standard prenatal screening test had an abnormal result. If a screening test indicates a possible genetic problem, genetic testing may be recommended.
  • A child has medical problems that might be genetic. When a child has medical problems involving more than one body system, genetic testing may be recommended to identify the cause and make a diagnosis.
  • A child has medical problems that are recognized as a specific genetic syndrome. Genetic testing is performed to confirm the diagnosis. In some cases, it also might aid in identifying the specific type or severity of a genetic illness, which can help identify the most appropriate treatment.

A Word of Caution

Although advances in genetic testing have improved doctors' ability to diagnose and treat certain illnesses, there are still some limits. Genetic tests can identify a particular problem gene, but can't always predict how severely that gene will affect the person who carries it. In cystic fibrosis, for example, finding a problem gene on chromosome number 7 can't necessarily predict whether a child will have serious lung problems or milder respiratory symptoms.

Also, simply having problem genes is only half the story because many illnesses develop from a mix of high-risk genes and environmental factors. Knowing that you carry high-risk genes may actually be an advantage if it gives you the chance to modify your lifestyle to avoid becoming sick.

As research continues, genes are being identified that put people at risk for illnesses like cancer, heart disease, psychiatric disorders, and many other medical problems. The hope is that someday it will be possible to develop specific types of gene therapy to totally prevent some diseases and illnesses.

Gene therapy is already being studied as a possible way to treat conditions like cystic fibrosis, cancer, and ADA deficiency (an immune deficiency), sickle cell disease, hemophilia, and thalassemia. However, severe complications have occurred in some patients receiving gene therapy, so current research with gene therapy is very carefully controlled.

Although genetic treatments for some conditions may be a long way off, there is still great hope that many more genetic cures will be found. The Human Genome Project, which was completed in 2003, identified and mapped out all of the genes (about 25,000) carried in our human chromosomes. The map is just the start, but it's a very hopeful beginning.

Reviewed by: Larissa Hirsch, MD
Date reviewed: September 26, 2016