An Overview of Thanatophoric Dysplasia

Thanatophoric dysplasia is a severe genetic skeletal disorder, in which limbs are abnormally short, and arms and legs have excess skin. In addition, those with this condition have a narrow chest, short ribs, under-developed lungs (pulmonary hypoplasia), as well as an enlarged head with a large forehead and widely-spaced eyes. This disorder is divided into two types: people with type I have curved thigh bones and flattened bones in the spine (a condition called platyspondyly), whereas those with type II have straight thigh bones and “cloverleaf skull,” an abnormality in which the front and sides of the skull jut out. The condition is very rare—it’s seen in one in every 20,000 to 50,000 births—but the prognosis is very poor, with extensive medical help needed for those affected to reach childhood.

Symptoms

Since thanatophoric dysplasia is a congenital condition, its effects are easily seen at birth. Symptoms vary in severity and frequency. The most common of these—occurring in 80 to 99 percent of cases—include:

• Depressed Nasal Bridge: The bridge of the nose is flatter than usual.
• Very Short Limbs: Also known as “micromelia,” the disorder causes limbs to be underdeveloped and relatively short.
• Abnormal Metaphysis: The growth plates of longer bones (such as the thigh bone) are located in a portion called the metaphysis. In those with this condition, these are malformed and don’t function normally.
• Flat Face: Facial features of those with the condition are flatter and less pronounced.
• Intellectual Disability: Profound intellectual disability—in which IQ is 20 or less—often accompanies the condition.
• Large Skull Size: This condition, called “macrocephaly,” is a prominent sign of the condition. 
• Flattened Vertebrae: The bones of the spine in these cases are malformed and flattened.
• Low Muscle Tone: Those with this condition have lower than typical muscle tone, a condition known as “muscular hypotonia.”
• Narrow Chest: A lower circumference of the chest, alongside narrow shoulder, is another hallmark of the condition.
• Redundant Skin: Excess skin leading to folds and sagging often accompanies thanatophoric dysplasia.
• Short Neck: Those with the condition often display a relatively shorter neck.
• Underdeveloped Lungs: Also known as “pulmonary hypoplasia,” incomplete formation of the lungs—which leads to breathing difficulties—is another hallmark and a leading cause of death due to the condition.

Anywhere from 30 to 79 percent of the time, doctors observe:

• Short Fingers: Unusually short fingers and toes—a condition called “brachydactyly”—often occurs in those with the condition.
• Deafness: Hearing defects up to and including complete deafness is seen in a significant proportion of cases.
• Prenatal Growth Deficiency: During pregnancy, thanatophoric dysplasia can cause slower growth and development in the fetus.
• Decreased Midface Size: Another sign of this condition is a smaller face size relative to the size of the head.
• Bulging Eye: Eyes that are protruding prominently are another more commonly seen sign of the condition.

Finally, rarer symptoms of thanatophoric dysplasia that occur less than 30 percent of the time include:

• Kidney Abnormalities: Some cases of the condition are characterized by kidney abnormalities, affecting their function.
• Altered Sacroiliac Joint: The sacroiliac joint is an important joint between the sacrum bone (tailbone) and the back of the hip. The skeletal abnormalities due to this condition can affect its stability and function. 
• Cloverleaf Skull: This is a severe deformity caused by the bones in the skull fusing together too early in the course of development. This causes severe bulging in the front and sides of the skull.
• Atrial Septic Defect: A congenital cardiac defect, this is an abnormal opening in the wall dividing the upper chambers of the heart.
• Hydrocephalus: Excess cerebrospinal fluid in cerebellum, known as hydrocephalus, can lead to dangerous increases in pressure on the brain.
• Kyphosis: A rounded, hunchback is another sign that thanatophoric dysplasia.
• Hyperflexible Joints: Joint formation can be affected by this condition, leading to hyperflexibility.
• Respiratory Insufficiency: Related to the pulmonary hypoplasia that often accompanies the condition, this is a persistent problem getting enough oxygen from breathing.
• Hip Dysplasia: A lack of complete formation of the hip is another hallmark.

Notably, this condition is extremely debilitating and the prognosis is very poor. Thanatophoric dysplasia often leads to stillborn birth, and survivability into childhood requires a great deal of medical management.

Causes

Primarily, thanatophoric dysplasia is a genetic disorder caused by mutation to the FGFR3 gene. This gene regulates the activity of a protein that guides the development of brain tissues and bone, making it overactive, leading to malformation and deformity.

While the exact mechanism is still being researched, it is known that this follows what’s called an “autosomal dominant” inheritance pattern. In these cases, only one mutation of the gene in each cell is sufficient to lead to the condition. Notably, nearly all cases of thanatophoric dysplasia occur in those with no family history, and no known people with this condition have had children.

Diagnosis

Most often, this condition is diagnosed prenatally. Genetic testing, in which chromosomes, genes, and proteins of the fetus are screened, can help confirm or rule out impending cases of thanatophoric dysplasia. This kind of work will be able to detect abnormalities of the FGFR3 gene. In addition, ultrasound, CT, or radiographic screening of the pregnancy can be used to isolate the delayed or affected cranial development seen in this condition.     

Treatment

There is no cure for thanatophoric dysplasia, so treatment options typically involve management of existing conditions as well as decisions impacting the delivery of the baby. Vaginal birth, for instance, may not be safely possible.

Prognosis of the condition is very poor; most born with it die due to respiratory insufficiency shortly after birth, though some survive longer with medical assistance. As such, if prenatal screening, especially molecular genetic testing, unearths mutation of the relevant gene, termination of the pregnancy is an option to consider.

After birth, the main task of medical staff is to reduce the impact and harm of the many symptoms of this condition. Infants will require respiratory support—the use of tubes to deliver oxygen to the body—to survive. In addition, antiepileptic drugs may be prescribed to take on seizures, surgery can be used to place shunts to take on hydrocephaly (thereby draining excess cerebrospinal fluid), decompression approaches may be required to relieve pressure on the juncture between cranium and neck, and the use of hearing aids for cases of impairment.

Coping

There’s no doubt that the burden of this disease is very heavy, and, despite some solid progress, prevention or reversal of the condition is not possible. Put simply, the challenges faced by family members of people with thanatophoric dysplasia are myriad and multifaceted.

Counseling may be needed to support the loved ones of those affected as they learn to cope with the difficulty of this rare disease. In addition, support groups and organizations advocating for those in need—such as the UCLA International Skeletal Dysplasia Registry—may provide additional help and information. Furthermore, since this condition is a kind of dwarfism, organizations like Little People of America can also provide necessary advocacy and support.

A Word From Verywell

Congenital disorders like thanatophoric dysplasia are incredibly challenging from both a medical and personal perspective. The fact of the matter is that prognosis is very poor, and people with the condition require a great deal of medical intervention and care. But, as with all genetic diseases, methods for detection and treatment are always advancing. Thanks to the tireless efforts of researchers, doctors, advocacy groups, as well as patients and their families, the picture is improving for those with this disease.