“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).
A mutation in the fibroblast growth factor receptor-3 (FGFR3) gene is responsible for causing Thanatophoric Dysplasia (1).
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.
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).
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.
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.
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).
- Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006.
- Orioli, IM. Castilla EE. Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genetics. 23: 328-332
- Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.
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All About Genetics
What do you know about your family tree? Have any of your relatives had health problems that tend to run in families? Which of these problems affected your parents or grandparents? Which ones affect you or your brothers or sisters now? Which problems might you pass on to your children?
Thanks to advances in medical research, doctors now have the tools to understand much about how certain illnesses, or increased risks for certain illnesses, pass from generation to generation. Here are some basics about genetics.
Genes and Chromosomes
Each of us has a unique set of chemical blueprints affecting how our body looks and functions. These blueprints are contained in our DNA (deoxyribonucleic acid), long, spiral-shaped molecules found inside every cell. DNA carries the codes for genetic information and is made of linked pieces (or subunits) called nucleotides. Each nucleotide contains a phosphate molecule, a sugar molecule (deoxyribose), and one of four so-called "coding" molecules called bases (adenine, guanine, cytosine, or thymidine). The order (or sequence) of these four bases determines each genetic code.
The segments of DNA that contain the instructions for making specific body proteins are called genes. Scientists believe that human DNA carries about 25,000 protein-coding genes. Each gene may be thought of as a "recipe" you'd find in cookbook. Some are recipes for creating physical features, like brown eyes or curly hair. Others are recipes to tell the body how to produce important chemicals called enzymes (which help control the chemical reactions in the body).
Along the segments of our DNA, genes are neatly packaged within structures called chromosomes. Every human cell contains 46 chromosomes, arranged as 23 pairs (called autosomes), with one member of each pair inherited from each parent at the time of conception. After conception (when a sperm cell and an egg come together to make a baby), the chromosomes duplicate again and again to pass on the same genetic information to each new cell in the developing child. Twenty-two autosomes are the same in males and females. In addition, females have two X chromosomes and males have one X and one Y chromosome. The X and the Y are known as sex chromosomes.
Human chromosomes are large enough to be seen with a high-powered microscope, and the 23 pairs can be identified according to differences in their size, shape, and the way they pick up special laboratory dyes.
Errors in the genetic code or "gene recipe" can happen in a variety of ways. Sometimes information is missing from the code, other times codes have too much information, or have information that's in the wrong order.
These errors can be big (for example, if a recipe is missing many ingredients — or all of them) or small (if just one ingredient is missing). But regardless of whether the error is big or small, the outcome can be significant and cause a person to have a disability or at risk of a shortened life span.
Abnormal Numbers of Chromosomes
When a mistake occurs as a cell is dividing, it can cause an error in the number of chromosomes a person has. The developing embryo then grows from cells that have either too many chromosomes or not enough.
In trisomy, for example, there are three copies of one particular chromosome instead of the normal two (one from each parent). Trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome) are examples of this type of genetic problem.
Trisomy 18 affects 1 out of every 7,500 births. Children with this syndrome have a low birth weight and a small head, mouth, and jaw. Their hands typically form clenched fists with fingers that overlap. They also might have birth defects involving the hips and feet, heart and kidney problems, and intellectual disability (also called mental retardation). Only about 5% of these children are expected to live longer than 1 year.
Trisomy 13 affects 1 out of every 15,000 to 25,000 births. Children with this condition often have cleft lip and palate, extra fingers or toes, foot abnormalities, and many different structural abnormalities of the skull and face. This condition also can cause birth defects of the ribs, heart, abdominal organs, and sex organs. Long-term survival is unlikely but possible.
In monosomy, another form of numerical error, one member of a chromosome pair is missing. So there are too few chromosomes rather than too many. A baby with a missing autosome has little chance of survival. However, a baby with a missing sex chromosome can survive in certain cases. For example, girls with Turner syndrome — who are born with just one X chromosome — can live normal, productive lives as long as they receive medical care for any health problems associated with their condition.
Deletions, Translocations, and Inversions
Sometimes it's not the number of chromosomes that's the problem, but that the chromosomes have something wrong with them, like an extra or missing part. When a part is missing, it's called a deletion (if it's visible under a microscope) and a microdeletion (if it's too tiny to be visible). Microdeletions are so small that they may involve only a few genes on a chromosome.
Some genetic disorders caused by deletions and microdeletions include Wolf-Hirschhorn syndrome (affects chromosome 4), Cri-du-chat syndrome (chromosome 5), DiGeorge syndrome (chromosome 22), and Williams syndrome (chromosome 7).
In translocations (which affect about 1 in every 400 newborns), bits of chromosomes shift from one chromosome to another. Most translocations are "balanced," which means there is no gain or loss of genetic material. But some are "unbalanced," which means there may be too much genetic material in some places and not enough in others. With inversions (which affect about 1 in every 100 newborns), small parts of the DNA code seem to be snipped out, flipped over, and reinserted. Translocations may be either inherited from a parent or happen spontaneously in a child's own chromosomes.
Both balanced translocations and inversions typically cause no malformations or developmental problems in the kids who have them. However, those with either translocations or inversions who wish to become parents may have an increased risk of miscarriage or chromosome abnormalities in their own children. Unbalanced translocations or inversions are associated with developmental and/or physical abnormalities.
Genetic problems also occur when abnormalities affect the sex chromosomes. Normally, a child will be a male if he inherits one X chromosome from his mother and one Y chromosome from his father. A child will be a female if she inherits a double dose of X (one from each parent) and no Y.
Sometimes, however, children are born with only one sex chromosome (usually a single X) or with an extra X or Y. Girls with Turner syndrome are born with only one X chromosome, whereas boys with Klinefelter syndrome are born with 1 or more extra X chromosomes ( XXY or XXXY).
Sometimes, too, a genetic problem is X-linked, meaning that it is associated with an abnormality carried on the X chromosome. Fragile X syndrome, which causes intellectual disability in boys, is one such disorder. Other diseases that are caused by abnormalities on the X chromosome include hemophilia and Duchenne muscular dystrophy.
Females may be carriers of these diseases, but because they also inherit a normal X chromosome, the effects of the gene change are minimized. Males, on the other hand, only have one X chromosome and are almost always the ones who show the full effects of the X-linked disorder.
Some genetic problems are caused by a single gene that is present but altered in some way. Such changes in genes are called mutations. When there is a mutation in a gene, the number and appearance of the chromosomes is usually still normal.
To pinpoint the defective gene, scientists use sophisticated DNA testing techniques. Genetic illnesses caused by a single problem gene include phenylketonuria (PKU), cystic fibrosis, sickle cell disease, Tay-Sachs disease, and achondroplasia (a type of dwarfism).
Although experts used to think that no more than 3% of all human diseases were caused by errors in a single gene, new research shows that this is an underestimate. Within the last few years, scientists have discovered genetic links to many different diseases that weren't originally thought of as genetic, including Parkinson's disease, Alzheimer's disease, heart disease, diabetes, and several different types of cancer. Alterations in these genes are thought to increase one's risk of developing these conditions.
Oncogenes (Cancer-Causing Genes)
Researchers have identified about 50 cancer-causing genes that greatly increase a person's odds of developing cancer. By using sophisticated tests, doctors may be able to identify who has these genetic mutations, and determine who is at risk.
For example, scientists have determined that colorectal cancer is sometimes associated with mutations in a gene called APC. They've also discovered that abnormalities in the BRCA1 and BRCA2 gene give women a 50% chance of developing breast cancer and an increased risk for ovarian tumors.
People who are known to have these gene mutations now can be carefully monitored by their doctors. If problems develop, they're more likely to get treated for cancer earlier than if they hadn't known of their risk, and this can increase their odds of survival.
New Discoveries, Better Care
Scientists have made major strides in the field of genetics over the last two decades. The mapping of the human genome and the discovery of many disease-causing genes has led to a better understanding of the human body. This has enabled doctors to provide better care to their patients and to increase the quality of life for people (and their families) living with genetic conditions.
Reviewed by: Nina Powell-Hamilton, MD
Date reviewed: September 05, 2017