Laboratory Studies
The following studies are indicated in suspected cases of thanatophoric dysplasia (TD):
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Chromosome analysis (karyotype) to determine the presence or absence of chromosomal abnormalities.
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DNA molecular testing for FGFR3 using targeted and sequence mutation analyses.
A study published in 2015 by Chitty et al suggested that next-generation sequencing (NGS) is more sensitive than polymerase chain reaction assay and restriction enzyme digest (PCR-RED) in the prenatal diagnostic screening for monogenic disorders, including thanatophoric dysplasia and achondroplasia. In the study, which used cell-free DNA from maternal blood, NGS and PCR-RED were performed to aid in the prenatal diagnosis of thanatophoric dysplasia and achondroplasia, with NGS being 96.2% accurate, compared with 88.6% for PCR-RED. [11]
Imaging Studies
During the second or third semester of pregnancy, prenatal ultrasonography and CT scan assessments may be diagnostically helpful, as follows [12, 13, 14] :
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Two-dimensional (2D) ultrasonography reveals polyhydramnios, growth deficiency, ventriculomegaly, a narrow thorax, flattened vertebrae and micromelia
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Three-dimensional (3D) ultrasonography may reveal the fetal face, scapular anomalies, and chest hypoplasia better than 2D ultrasonography
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A study published in 2014 by Wang et al indicated that the prenatal identification of temporal lobe dysplasia by ultrasonography may aid in the identification of thanatophoric dysplasia; the study found that out of 24 cases of thanatophoric dysplasia, 16 (67%) demonstrated ultrasonographic evidence of temporal lobe dysplasia [15]
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Prenatal 3D CT scanning may complement ultrasonographic findings in cases in which fetal skeletal dysplasia is suspected, but no specific diagnosis can be made using ultrasonography alone; further studies on clinical performance and risk-benefit analysis are needed before 3D CT scanning is incorporated into standard practice guidelines [16]
Postnatal radiography and other imaging studies (CT scanning, MRI) may reveal the following:
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Enlarged skull and a small foramen magnum, with potential evidence of brain stem compression
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CNS abnormalities such as hydrocephalus, brain stem hypoplasia, temporal lobe malformations, neuronal migration abnormalities
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Flattened vertebral bodies (platyspondyly) with wide intervertebral spacing
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Rhizomelic shortening and irregular metaphyses of the long bones and "telephone receiver–shaped" bowed femurs
Histologic Findings
Histologic evaluation of long bone structure in thanatophoric dysplasia shows disruption of endochondral ossification but not of periosteal ossification.
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Infant with thanatophoric dysplasia. Note short-limbed dysplasia, large head, short neck, narrow thorax, short and small fingers, and bowed extremities. Radiographs demonstrate thin flattened vertebrae, short ribs, small sacrosciatic notch, extremely short long tubular bones, and markedly short and curved femora (telephone receiver–like appearance).
