Clinical characteristics.

Thanatophoric dysplasia (TD) is a short-limb skeletal dysplasia that is usually lethal in the perinatal period. TD is divided into subtypes:

• TD type 1 is characterized by micromelia with bowed femurs and, uncommonly, the presence of craniosynostosis of varying severity.
• TD type 2 is characterized by micromelia with straight femurs and uniform presence of moderate-to-severe craniosynostosis with cloverleaf skull deformity.

Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported.

Diagnosis/testing.

The diagnosis of TD is established in a proband with characteristic clinical and/or radiologic features and/or a heterozygous pathogenic variant in FGFR3 identified on molecular genetic testing.

Management.

Treatment of manifestations: Most individuals with TD die in the perinatal period because of the multisystem complications of the disorder. Management goals should be established with the family and may focus on provision of comfort care. Newborns require long-term respiratory support (typically with tracheostomy and ventilation) to survive. Anesthetic management guidelines for skeletal dysplasias are applicable to individuals with TD. Other treatment measures may include shunt placement for hydrocephalus, suboccipital decompression for relief of craniocervical junction constriction, anti-seizure medication to control seizures, and hearing aids.

Surveillance: Long-term survivors need neuroimaging to monitor for craniocervical constriction, assessment of neurologic status, and EEG to monitor for seizure activity, as well as developmental, orthopedic, and audiology evaluations.

Pregnancy management: When TD is diagnosed prenatally, treatment goals are to avoid potential pregnancy complications including prematurity, polyhydramnios, malpresentation, and delivery complications from macrocephaly and/or a flexed and rigid neck; cephalocentesis and cesarean section may be considered to avoid maternal complications.

Genetic counseling.

TD is inherited in an autosomal dominant manner; the majority of probands have a de novo FGFR3 pathogenic variant. Risk of sib recurrence for parents who have had one affected child is not significantly increased over that of the general population. Germline mosaicism in healthy parents, although not reported to date, remains a theoretic possibility. Prenatal diagnosis is possible by ultrasound examination and molecular genetic testing.

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 [Tonni et al 2010, Khalil et al 2011, Martínez-Frías et al 2011, Bondioni et al 2017] findings by trimester:

• First trimester
  • Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
  • Increased nuchal translucency
• Second/third trimester
  • Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
  • Well-ossified spine and skull
  • Platyspondyly
  • Ventriculomegaly
  • Narrow chest cavity with short ribs
  • Polyhydramnios
  • Bowed femurs (TD type 1)
  • Brain anomalies
  • Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as Kleeblattschädel (often in TD type 2; occasionally in TD type 1)
  • Relative macrocephaly

Postnatal physical examination

• Relative macrocephaly
• Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
• Large anterior fontanelle
• Frontal bossing, flat facies with a depressed nasal bridge, ocular proptosis
• Marked shortening of the limbs (micromelia)
• Redundant skin folds
• Narrow bell-shaped thorax with short ribs and protuberant abdomen
• Relatively normal trunk length
• Brachydactyly with trident hand
• Bowed femurs (TD type 1)
• Generalized hypotonia

Radiographs / other imaging studies [Wilcox et al 1998, Lemyre et al 1999, Bondioni et al 2017]

• Rhizomelic shortening of the long bones
• Irregular metaphyses of the long bones
• Platyspondyly
• Small foramen magnum with brain stem compression
• Bowed femurs (TD type 1)
• Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
• CNS abnormalities including temporal lobe malformations, hydrocephalus, brain stem hypoplasia, neuronal migration abnormalities [Wang et al 2014]

Other rarely reported findings that are not part of the core phenotype include cardiac defects, renal abnormalities, and abnormalities of lymphatic development (see Clinical Characteristics).

Establishing the Diagnosis

The diagnosis of thanatophoric dysplasia is established in a proband with the above clinical and radiographic features and/or a heterozygous pathogenic (or likely pathogenic) variant in FGFR3 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous FGFR3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (targeted analysis, single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of thanatophoric dysplasia is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other lethal skeletal dysplasias are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The clinical and radiographic features of thanatophoric dysplasia (TD) types 1 and 2 are evident prenatally or in the immediate newborn period. Respiratory insufficiency typically results in early neonatal death, and is due to a small chest cavity and/or foramen magnum narrowing with brain stem compression. However, long-term survivors have been reported, including rare reports of survival to adulthood with aggressive ventilatory support and surgical management of neurologic complications.

To date, more than 200 individuals with TD have been identified with a pathogenic variant in FGFR3 [Xue et al 2014]. The following description of the phenotypic features associated with this condition is based on these reports.

Respiratory insufficiency. Most affected infants die of respiratory insufficiency in the first hours or days of life. Respiratory insufficiency may be secondary to a small chest with lung hypoplasia and/or compression of the brain stem due to a small foramen magnum. Some affected children have survived into childhood, universally requiring tracheostomy and aggressive ventilatory support. Nikkel et al [2013] described a long-term survivor with TD at age 28 years. Her course was exceptional, as she did not require invasive ventilatory support until age four months and required full-time ventilatory support from age 15 years.

Neurologic complications include small foramen magnum with brain stem compression, brain malformations (predominantly involving the temporal lobe), hydrocephalus, seizures, and profound developmental impairment in rare long-term survivors.

One infant reported at age 11 months required suboccipital decompression due to clonus and decreased limb movements secondary to a narrow foramen magnum [Thompson et al 2011]. One individual reported at age 28 years underwent surgical decompression of a small foramen magnum and insertion of a ventriculoperitoneal shunt [Nikkel et al 2013]. Despite this intervention, the individual developed cervical spinal cord compression and quadriplegia.

Temporal lobe malformations and megalencephaly are likely universal [Hevner 2005, Itoh et al 2013]. Temporal lobe abnormalities include enlargement, abnormal gyration and sulcation, polymicrogyria, and hippocampal abnormalities. Hydrocephalus is also common [Hevner 2005].

Brain malformations are the most likely etiology of seizures in individuals with TD; however, additional complications such as hypoxia related to respiratory insufficiency may also play a role.

Severe developmental delay is reported, with a stall in developmental progress at a developmental age of 12-20 months (see Table 3). Motor skills may be more significantly impaired due to the skeletal features and micromelia. Later deterioration in abilities following complications such as cord compression is described [Nikkel et al 2013].

Less common neurologic findings include hypoplasia or agenesis of the corpus callosum. Encephalocele has been reported, likely as a secondary consequence of raised intracranial pressure and abnormal skull formation [Martínez-Frías et al 2011].

Craniofacial. Relative macrocephaly is present at birth. Craniosynostosis with cloverleaf skull in individuals with TD type 2 contributes to hydrocephalus and neurologic complications. Dysmorphic facial features including frontal bossing, flat facies, depressed nasal bridge, and ocular proptosis are present.

Musculoskeletal complications in long-term survivors include kyphosis, osteopenia, and both joint hypermobility and joint contractures.

Growth deficiency. Prenatal short-limb short stature is present in all individuals. Growth deficiency persists with micromelia and redundant skin folds. Global growth deficiency is present in long-term survivors (see Table 3).

Integument. Extensive acanthosis nigricans has been reported with development of seborrheic keratoses in adult survivors [Nakai et al 2010, Nikkel et al 2013].

Hearing impairment is reported in several long-term survivors (see Table 3), but the etiology is not clear. The presence of midface hypoplasia in individuals with TD type 1, and recognition that FGFR3 may be implicated in inner ear development [Colvin et al 1996], suggest that hearing loss in individuals with TD type 1 may be multifactorial.

Vision. Intermittent exotropia has been reported in a long-term survivor [Nikkel et al 2013].

Other rarely reported findings that do not have a proven association with TD include:

• Cardiac defects. Truncus arteriosus, ventricular septal defect, and patent foramen ovale have been reported [McBrien et al 2008]. Bradycardia has been reported in two individuals [Baker et al 1997, Nikkel et al 2013].
• Renal abnormalities [Prontera et al 2006]. In two long-term survivors, renal calculi were reported [Baker et al 1997, Kuno et al 2000].
• Protein losing enteropathy with intestinal lymphangestasia, reported in one individual [Yang & Dehner 2016]. An infant with TD was reported to have chylous ascites [Soo-Kyeong et al 2018].

Mosaicism. A female age 47 years who was mosaic for the common TD type 1-causing pathogenic variant p.Arg248Cys had asymmetric limb length, bilateral congenital hip dislocation, focal areas of bone bowing, an S-shaped humerus, extensive acanthosis nigricans, redundant skin folds along the length of the limbs, and flexion deformities of the knees and elbows [Hyland et al 2003]. She had delayed developmental milestones as a child. Academic achievements were below those of healthy sibs, but she is able to read and write and is employed as a factory worker. Her only pregnancy ended with the stillbirth at 30 weeks' gestation of a male with a short-limb skeletal dysplasia and pulmonary hypoplasia.

Takagi et al [2012] described an individual with somatic mosaicism for the p.Arg248Cys substitution in FGFR3 (a pathogenic variant which typically results in TD type 1) who presented with features labeled as atypical achondroplasia.

Genotype-Phenotype Correlations

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

• Missense variants [Passos-Bueno et al 1999]. The two common variants p.Arg248Cys and p.Tyr373Cys probably account for 90% of TD type 1 [Xue et al 2014].
• No-stop codon variants represent fewer than 10% of TD type 1-causing variants (see Table 9).
• An insertion variant has been reported in one individual [Lindy et al 2016] (see Table 9).

TD type 2. A single FGFR3 pathogenic variant (p.Lys650Glu) has been identified in all individuals with TD type 2 [Bellus et al 2000]. Other pathogenic variants at this position give rise to different phenotypes: p.Lys650Met has been identified in TD type 1, and p.Lys650Gln is seen in SADDAN (see Table 9).

Penetrance

The penetrance is 100%.

Nomenclature

Thanatophoric dysplasia was originally described as thanatophoric dwarfism, a term no longer in use. The descriptor "thanatophoric" is derived from the Greek for "death bearing," and refers to the very high incidence of perinatal death due to the multisystem complications of this condition. However, aggressive management has resulted in rare reports of long-term survivors, contradicting this initial description.

The lethal platyspondylic dysplasia (San Diego type) was previously considered a separate clinical entity, but is now recognized as the same condition as TD [Brodie et al 1999, Hall 2002].

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], TD type 1 is referred to as FGFR3-related thanatophoric dysplasia (type 1), and TD type 2 is referred to as FGFR3-related thanatophoric dysplasia (type 2); both are included in the FGFR3 chondrodysplasias group.

Prevalence

The incidence of TD is reported to be 1:20,000 [Barbosa-Buck et al 2012] or higher (1:12,000 in Northern Ireland) in a population with optimized ascertainment [Donnelly et al 2010].

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 (see Pregnancy Management).

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.

Table 6, Table 7, and Table 8 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 in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Decisions about management should be made following consultation with parents and a discussion of the complications, clinical course, and prognosis of the condition. Considerations may include the parents' desire for extreme life-support measures or provision of comfort care for the newborn.

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice. Potential pregnancy complications include prematurity, polyhydramnios, malpresentation, and cephalopelvic disproportion caused by macrocephaly from hydrocephalus or a flexed and rigid neck. Cephalocentesis and cesarean section may be considered to avoid maternal complications.

Management of an affected pregnancy is determined following discussion between the medical team and family regarding prognosis and the need for aggressive life-saving measures in survivors. This is often center-specific. Indicators of lethality on ultrasound can provide additional information.

Consensus guidelines on perinatal management of skeletal dysplasias have been published [Savarirayan et al 2018]. Management considerations can be addressed on three levels:

• Maternal. Surveillance for cephalopelvic disproportion, polyhydramnios, and/or preterm labor; avoidance of emergency C-section for fetal distress
• Fetal. Surveillance for malpresentation, periodic prenatal ultrasound monitoring of head circumference, MRI for fetal lung volume, and/or fetal stress testing
• Perinatal. Establishment of a plan for assessment, care, and/or withdrawal of care after delivery. Postnatal clinical and radiographic assessment should occur. In terminated pregnancies, postmortem evaluation including radiography and storage of DNA in case of diagnostic uncertainty should be discussed.

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 [Savarirayan et al 2019a, Breinholt et al 2019], blocking of FGFR3 using selective tyrosine kinase inhibitors [Komla-Ebri et al 2016], and ligand traps to decrease the quantity of growth factors able to bind to mutated FGFR3 receptors [Garcia et al 2013]. These treatments could also be effective for TD, given a similar underlying molecular mechanism [Savarirayan et al 2019b], but how this very severe phenotype would be modified is currently unknown.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Thanatophoric dysplasia (TD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Almost all probands reported to date with TD represent simplex cases (i.e., the only affected family member) and have the disorder as a result of a de novo FGFR3 pathogenic variant. The parents of a proband with a de novo FGFR3 pathogenic variant are not affected.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant to confirm the genetic status of the parents and to facilitate reliable recurrence risk assessment.
• If the FGFR3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with somatic and/or germline mosaicism. (Note: Parental somatic mosaicism is difficult to detect in leukocyte DNA using standard molecular genetic techniques.)
  • Somatic and germline mosaicism for the p.Arg248Cys FGFR3 pathogenic variant was reported in a parent with a skeletal dysplasia; this individual's only offspring had a lethal skeletal dysplasia with findings consistent with TD [Hyland et al 2003].
  • Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
• An advanced paternal age effect has been reported [Donnelly et al 2010].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the FGFR3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent and neither parent has signs of a skeletal dysplasia, the recurrence risk to sibs is presumed to be low but slightly greater than that of the general population because of the possibility of parental mosaicism [Hyland et al 2003].

Offspring of a proband. Individuals with TD do not reproduce.

Other family members. Extended family members of the proband are not at increased risk.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies. Once the FGFR3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for TD are possible.

Low-risk pregnancies. Routine prenatal ultrasound examination may identify skeletal findings (e.g., cloverleaf skull, very short extremities, small thorax) that raise the possible diagnosis of TD in a fetus not known to be at risk. Once a lethal skeletal dysplasia is identified prenatally, it is often difficult to pinpoint a specific diagnosis. Consideration of molecular genetic testing for FGFR3 pathogenic variants in these situations is appropriate.

Cell-free DNA testing techniques have been reported for noninvasive prenatal diagnosis of TD [Chitty et al 2015, Zhang et al 2019].

Note: When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice (see Pregnancy Management).

Molecular Pathogenesis

FGFR3 encodes fibroblast growth factor receptor 3 (FGFR3), a negative regulator of bone growth during ossification [Cohen 2002]. Mice with knockout variants of Fgfr3 have expanded growth plates and are overgrown, with elongated vertebrae, femurs, and tails.

Pathogenic variants in FGFR3 are gain-of-function variants that facilitate dimerization and activation of FGFR3 in the absence of ligand binding [Baitner et al 2000, Cohen 2002]. This constitutional activation leads to premature differentiation of proliferative chondrocytes into prehypertrophic chondrocytes, and ultimately to premature maturation of the bone [Cohen 2002, Legeai-Mallet et al 2004].

FGFR3-related skeletal dysplasias display a spectrum of phenotypic severity. The level of increased tyrosine kinase activity conferred by different FGFR3 pathogenic variants correlates with the severity of disorganization of endochondral ossification and, therefore, with the skeletal phenotype [Bellus et al 1999, Bellus et al 2000, Foldynova-Trantirkova et al 2012].

Mechanism of disease causation. Gain of function.

• Of note, no-stop variants resulting in protein extension are associated with thanatophoric dysplasia (TD).
• Missense variants causing TD type 1 introduce a cysteine (Tyr373Cys, Arg428Cys) resulting in dimerization by covalent bonding (see Genotype-Phenotype Correlations).
• Missense variants involving residue 650 (e.g., Lys650Met [TD type 1] or Lys650Glu [TD type 2]) mimic conformational changes in the tyrosine kinase domain, which mimic the conformational changes that occur with ligand binding.
• The p.Lys650Glu pathogenic variant causing TD type 2 has been shown to cause accumulation of intermediate, activated forms of FGFR3 in the endoplasmic reticulum [Lievens & Liboi 2003]. It is unclear how this may contribute to the more severe phenotype in TD type 2.

Author History

Garry R Cutting, MD; Johns Hopkins University (2004–2020)
Tegan French, BMBS (2020–present)
Barbara Karczeski, MS, MA; Johns Hopkins University (2004–2020)
Ravi Savarirayan, MBBS, MD, FRACP, ARCPA (Hon) (2020–present)

Revision History

• 18 May 2023 (sw) Revision: GeneReview Scope table included; Nosology of Genetic Skeletal Disorders: 2023 Revision [Unger et al 2023] added to Nomenclature
• 18 June 2020 (sw) Comprehensive update posted live
• 12 September 2013 (me) Comprehensive update posted live
• 30 September 2008 (cg) Comprehensive update posted live
• 7 July 2006 (me) Comprehensive update posted live
• 21 May 2004 (me) Review posted live
• 27 February 2004 (bk, gc) Original submission

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