Clinical Guidance

TD type 1. FGFR3 pathogenic variants reported as causing the TD type 1 phenotype can be divided into three categories:

• Missense variants . The two common variants and probably account for 90% of TD type 1 .

• No-stop codon variants represent fewer than 10% of TD type 1-causing variants .

• An insertion variant has been reported in one individual .

TD type 2. A single FGFR3 pathogenic variant has been identified in all individuals with TD type 2 . Other pathogenic variants at this position give rise to different phenotypes: has been identified in TD type 1, and p.Lys650Gln is seen in SADDAN .

Source: GeneReviews — "Thanatophoric Dysplasia"

Penetrance

The penetrance is 100%.

Source: GeneReviews — "Thanatophoric Dysplasia"

Diagnostic Criteria

Formal diagnostic criteria for thanatophoric dysplasia (TD) have not been established.

Suggestive Findings

TD should be suspected in a fetus with the following prenatal imaging findings, or a neonate with the following clinical and radiographic features. Prenatal ultrasound examination [, , , ] findings by trimester:

Source: GeneReviews — "Thanatophoric Dysplasia"

Differential Diagnosis

Table 5. Other Genes of Interest in the Differential Diagnosis of Thanatophoric Dysplasia

Management Guidelines

Evaluations Following Initial Diagnosis Diagnosis of thanatophoric dysplasia (TD) most often occurs prenatally. When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice . Long-term survivors are rare and require aggressive intervention for complications of the condition. The family should be informed of prognosis on the basis of the reports of complications in long-term survivors. , , and are only relevant to the small number of long-term survivors. To establish the extent of disease and needs in a newborn diagnosed with thanatophoric dysplasia (TD), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 6. Recommended Evaluations Following Initial Diagnosis in Individuals with Thanatophoric Dysplasia

Source: GeneReviews — "Thanatophoric Dysplasia"

Therapies Under Investigation

Over the past five years several new precision therapies have begun to emerge for achondroplasia (an allelic FGFR3 skeletal dysplasia) that are now in Phase II and Phase III human clinical trials. These new therapeutic approaches include: use of C-type natriuretic peptides (CNP) to modulate downstream FGFR3 signaling , blocking of FGFR3 using selective tyrosine kinase inhibitors , and ligand traps to decrease the quantity of growth factors able to bind to mutated FGFR3 receptors . These treatments could also be effective for TD, given a similar underlying molecular mechanism , but how this very severe phenotype would be modified is currently unknown. Search ClinicalTrials.

Source: GeneReviews — "Thanatophoric Dysplasia"

Surveillance Guidelines

Table 8.

Recommended Surveillance for Individuals with Thanatophoric Dysplasia

System/Concern | Evaluation | Frequency

Respiratory

insufficiency | • Assessment of respiratory status

• Neuroimaging in event of respiratory deterioration to evaluate for compression of brain stem at craniocervical junction

| Annual clinical eval in long-term survivors

Neurologic

complications | • Assessment of neurologic status

• EEG in event of seizure activity

• Neuroimaging if signs/symptoms of spinal cord compression

| Annual clinical eval for signs symptoms in long-term survivors

Joint contracture

or joint hypermobility | Orthopedics eval | Annual clinical eval in long-term survivors

Hearing impairment

| Audiology assessment

Vision

| Ophthalmology eval

Development

| Developmental assessment

Source: GeneReviews — "Thanatophoric Dysplasia"