Thanatophoric Dysplasia

FGFR3 is part of the tyrosine kinase receptor family. Normally, FGFR3 is a negative regulator of bone growth. Point mutations within FGFR3 causing thanatophoric dysplasia (TD) initiate a gain in function by sending negative signals to the cartilage cells (chondrocytes). These signals occur when ligand binding within the chondrocytes induces receptor homodimerization and heterodimerization. Subsequently, activation of tyrosine kinase function potentiates many effects on cell growth and differentiation.

Researchers believe that mutations in FGFR3 lead to the formation of cysteine residues that create disulfide bonds between extracellular domains of mutant monomers. Activation of the homodimer receptor complex increases its stability and promotes translocation of the complex into the nucleus, where it may interfere with terminal chondrocyte differentiation. Hence, generalized disorganization of endochondral ossification at the bone growth plate occurs.

A study by Martin et al suggested another mechanism for FGFR3 interference with the growth plate. The investigators found evidence that constitutively active FGFR3 causes function loss in chondrocytic primary cilia by impacting cilia length, as well as by impeding the sorting of intraflagellar transport protein 20 and its trafficking to the cilia.[3]

TD-I is caused by several different mutations that affect either the extracellular or intracellular domains of FGFR3.[4] Two missense mutations, R248C and Y373C, account for about 80% of TD-I cases. The more common of these two TD-I point mutations, R248C (known as p.Arg248Cys), is a C→T pyrimidine nucleotide transition and impacts the extracellular domain of FGFR3.

To date, all patients with TD-II have a single point mutation, K650E (known as p.Lys650Glu), with an A→G purine nucleotide transition in the tyrosine kinase domain of FGFR3.

Frequency

United States

Thanatophoric dysplasia (TD) has an incidence of 1 per 20,000 to 1 per 50,000 births.

International

Incidence in Spain is reported as 1 per 37,000 births.

Mortality/Morbidity

Newborns with TD are frequently stillborn or die shortly after birth. Death can occur within 48 hours and is due to severe respiratory insufficiency from a reduced thoracic capacity and hypoplastic lungs and/or respiratory failure due to brain stem compression.

However, survival beyond the neonatal period is possible in TD.[5, 6] A 2020 report by Carroll et al described a boy aged 9 years with TD-I, while a 2013 article discussed a patient in her late 20s.[7, 8] A study by Ushioda et al found 20 individuals with TD-I in Japan who had survived more than 1 year (age range 1.2-27.8 years).[9]

Sex

Males and females are equally affected.

Most cases of a severe fetal skeletal dysplasia can be diagnosed by prenatal ultrasonography during the second or third trimester of pregnancy. However, making the conclusive diagnosis of thanatophoric dysplasia (TD) using only this imaging tool can be difficult.

Key ultrasonography findings include the following:

• Growth deficiency with limb length of less than 5% (by 20 weeks' gestation)

• Macrocephaly

• Ventriculomegaly 

• Cloverleaf-shaped skull or kleeblattschädel (indicates TD-II, but also seen in TD-I)[10]

• Well-ossified skull and spine

• Platyspondyly of the vertebrae

• Narrow chest cavity with shortened ribs

• Micromelia

• Bowed femurs with metaphyseal flaring, described as having a "telephone receiver' appearance (usually indicates TD-I)

• Polyhydramnios

Salient phenotypic features in an affected newborn are cited below:

• Severe growth deficiency with an average length of 40 cm (about 16 in) at term

• Generalized hypotonia

• Macrocephalic head with frontal bossing and large anterior fontanel

• Cloverleaf-shaped skull due to premature closure of the cranial sutures

• Flat facies with low nasal bridge and proptotic eyes

• Narrow, bell-shaped thorax with short ribs

• Normal trunk length

• Protuberant abdomen

• Micromelia (marked bilateral shortening of the limbs) with redundant skin folds

• Brachydactyly with a trident hand configuration

Thanatophoric dysplasia (TD) is an autosomal dominant disorder that results from sporadic de novo point mutations in the FGFR3 gene. Sequence and targeted mutation DNA analyses of FGFR3 are available to assist with diagnosis when clinical concerns are present. Germline mosaicism has been suggested as another possible cause, but has not been clearly documented.

The following mutations that affect distinct domains of FGFR3 cause the TD subtypes, TD-I and TD-II:

• TD-I: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TD-I. The more common mutation occurring in TD-I is R248C (p.Arg248Cys), which is confirmed in approximately 50% of patients.
• TD-II: K650E (p.Lys650Glu) is the only reported gene mutation and is present in more than 99% of patients with TD-II.

TD-I occurs more often than TD-II. TD-I and TD-II do not share common FGFR3 gene mutations. 

The following studies are indicated in suspected cases of thanatophoric dysplasia (TD):

• Chromosome analysis (karyotype) to determine the presence or absence of chromosomal abnormalities.

• 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]  

During the second or third semester of pregnancy, prenatal ultrasonography and CT scan assessments may be diagnostically helpful, as follows[12, 13, 14] :

• Two-dimensional (2D) ultrasonography reveals polyhydramnios, growth deficiency, ventriculomegaly, a narrow thorax, flattened vertebrae and micromelia
• Three-dimensional (3D) ultrasonography may reveal the fetal face, scapular anomalies, and chest hypoplasia better than 2D ultrasonography
• 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]
• 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:

• Enlarged skull and a small foramen magnum, with potential evidence of brain stem compression
• CNS abnormalities such as hydrocephalus, brain stem hypoplasia, temporal lobe malformations, neuronal migration abnormalities
• Flattened vertebral bodies (platyspondyly) with wide intervertebral spacing
• Rhizomelic shortening and irregular metaphyses of the long bones and "telephone receiver–shaped" bowed femurs

Histologic evaluation of long bone structure in thanatophoric dysplasia shows disruption of endochondral ossification but not of periosteal ossification.

Inpatient care is necessary for newborns diagnosed with thanatophoric dysplasia. If intubation is performed to treat respiratory distress, admission to a neonatal intensive care unit (NICU) is required. If treatment intervention is deferred, palliative care is essential to keep the infant warm, comfortable, and nourished.

See the list below:

• Neonatologist

• Pediatric pulmonologist

• Pediatric neurologist

• Pediatric radiologist

• Geneticist and genetic counselor

• Social work and psychological support services

See the list below:

• Currently, drug therapy is not part of the treatment plan.

• Medications may be indicated to treat concurrent medical conditions associated with thanatophoric dysplasia.

Outpatient care is indicated only in cases of long-term survival.

Admit patients born with thanatophoric dysplasia to the NICU if survival beyond the immediate newborn period seems possible.

Transfer to a long-term care facility or to hospice palliative care may be required for those affected infants in whom survival is prolonged.

Complications can include the following:

• Severe growth and developmental delay

• Severe neurological impairment - Hydrocephalus, seizure disorder

• Marked respiratory insufficiency - Ventilator dependency

• Auditory impairment

• Joint contractures/Joint hypermobility

Thanatophoric dysplasia is often lethal within the first few days of life. Death is due to respiratory failure caused by marked respiratory insufficiency from reduced thoracic capacity and hypoplastic lungs and/or brain stem compression.

However, survival beyond the neonatal period is possible in thanatophoric dysphoria (TD).[5, 6]  A 2020 report by Carroll et al described a boy aged 9 years with TD-I, while a 2013 article discussed a patient in her late 20s.[7, 8] A study by Ushioda et al found 20 individuals with TD-I in Japan who had survived more than 1 year (age range 1.2-27.8 years).[9]

Ushioda and colleagues reported that all of the patients in their study had severely impaired motor and cognitive development, while psychosocial development did not progress beyond 2 years. All of the individuals needed ventilator assistance, and although four patients could take nutrition by oral feeding alone, the rest required tube feeding either exclusively or in combination with oral feeding.[9]

Prenatally, if a fetus is diagnosed with thanatophoric dysplasia, options to discontinue or continue the pregnancy must be discussed with the parents by medical professionals.

If the pregnancy has proceeded beyond the gestational time during which a therapeutic abortion can safely be performed, discuss interventional and palliative medical approaches with the parents to enable planning for when the infant is born.

Genetic counseling can be used to discuss concerns with future family planning.

Resources for patients and caregivers are listed below:

• UCLA International Skeletal Dysplasia Registry

• Little People of America Inc

• The Magic Foundation