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A mutation in the fibroblast growth factor receptor-3 (FGFR3) gene is responsible for causing thanatophoric dysplasia.² Normally the FGFR3 protein functions as the "brake" for endochondral bone growth, which is the type of bone formation that occurs at the growth plates of the long bone. A change in this gene increases the ability of the FGFR3 protein to slow bone growth. This type of change associated with an increased ability is called a "gain-of-function" mutation. Changes in the FGFR3 gene cause a wide spectrum of conditions, from hypochondroplasia and achondroplasia to thanatophoric dysplasia.

Thanatophoric dysplasia follows anÌýautosomal dominantÌýinheritance pattern. All cases are a result of spontaneousÌýgene mutations.²

Thanatophoric dysplasia (TD) is characterized by extreme short stature. At birth, children are, on average, 40 centimeters long. TD type 1 is more common and is characterized by curved long bones, especially theÌýfemurÌýand flat vertebral bodies. A straightÌýfemur, taller vertebral bodies, and aÌýcloverleaf skullÌýare typical of TD type 2.Ìý

Face and Skull

Type I:

• large cranium andÌýfontanelle
• 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

• ²Ô²¹°ù°ù´Ç·ÉÌýthorax, 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

X-Ray Characteristics

• A ²Ô²¹°ù°ù´Ç·ÉÌýthoraxÌý
  
• Ribs are short with the rib ends appearing wide and cupped.Ìý
• Vertebral bodies are flat with a wide intervertebral disk space. TheÌýinterpediculate distancesÌýnarrow in theÌýlumbar spine.
• The pelvis has a short and square configuration. A small sciatic notch and medial spurs are typical.Ìý
• The long bones of the extremities are characteristically short and broad. TheÌýmetaphysesÌýexhibit cupped, spur-like flaring.Ìý
• Marked bowing of theÌýfemurÌýis characteristic in Thanatophoric dysplasia, type I.Ìý
• Fibulae are markedly shorter than the tibiae.Ìý
• Phalanges,Ìýmetacarpals, andÌýmetatarsalÌýbones are characteristically short.³

Thanatophoric dysplasia can be recognized in utero via ultrasound. Indicators include markedly short limbs and a ²Ô²¹°ù°ù´Ç·ÉÌýthorax. 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 anÌýamniocentesisÌýsample or postnatally from a blood sample.

Classically, thanatophoric dysplasia has been understood to be terminal soon after birth due to difficulty with ventilation and development of respiratory failure. However, with advances in technology, survival can be possible for some. For infants who survive the immediate perinatal period, development of critical foramen magnum stenosis is common and decompression is required for continued survival. Patients who survive the perinatal period are frequently ventilator-dependent and typically have global developmental delays.

Children with thanatophoric dysplasia usually have long-term technology dependence for respiratory support, feeding support and mobility.Ìý

Long-term survival with TD is rare. However, nine children between the ages of 5 months and 10 years have been reported. All have significant developmental delays, extreme short stature, and are ventilator-dependent.⁴

1. Orioli, IM. Castilla EE. Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genetics. 23: 328-332
2. Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006.
3. Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.
4. Carroll RS, Duker AL, Schelhaas AJ, Little ME, Miller EG, Bober MB (2020) Should we stop calling thanatophoric dysplasia a lethal condition? A case report of a long-term survivor, Palliative Medicine Reports 1:1, 32–39, DOI: 10.1089/pmr.2020.0016.