NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Thanatophoric Dysplasia

, MS, MA and , MD.

Author Information

Initial Posting: ; Last Update: September 12, 2013.

Estimated reading time: 23 minutes


Clinical characteristics.

Thanatophoric dysplasia (TD) is a short-limb dwarfism syndrome that is usually lethal in the perinatal period. TD is divided into type I, characterized by micromelia with bowed femurs and, uncommonly, the presence of cloverleaf skull deformity (Kleeblattschädel) of varying severity; and type II, characterized by micromelia with straight femurs and uniform presence of moderate-to-severe cloverleaf skull deformity. Other features common to type I and type II include: short ribs, narrow thorax, 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 of TD is based on clinical examination and/or prenatal ultrasound examination and radiologic studies. Characteristic histopathology is also present. FGFR3 is the only gene in which mutation is known to cause TD. Up to 99% of pathogenic variants causing TD type I and more than 99% of pathogenic variants causing TD type II can be identified through molecular genetic testing of FGFR3.


Treatment of manifestations: Management focuses on the parents' wishes for provision of comfort-care for the newborn. Newborns require respiratory support (with tracheostomy and ventilation) to survive. Anesthetic management may include: intubation with a flexible fiberoptic scope with the cervical spine in a neutral position; use of evoked potential monitoring during the procedure; and avoidance of volatile anesthetic agents and muscle relaxants that may interfere with evoked potential recordings. Other treatment measures may include: antiepileptic drugs to control seizures, shunt placement for hydrocephaly, suboccipital decompression for relief of craniocervical junction constriction, and hearing aids.

Surveillance: Long-term survivors need neurologic, orthopedic, and audiologic evaluations, CT to monitor for craniocervical constriction, and EEG to monitor for seizure activity.

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 de novo pathogenic variant of FGFR3. Risk of 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 previously reported, remains a theoretic possibility. Prenatal diagnosis is possible by ultrasound examination and molecular genetic testing.


Clinical Diagnosis

Thanatophoric dysplasia (TD) is one of the short-limb dwarfism conditions suspected when significantly shortened long bones and a narrow thorax are detected prenatally or neonatally, especially when perinatal death occurs.

Prenatal ultrasound examination [De Biasio et al 2000, Chen et al 2001, Ferreira et al 2004, De Biasio et al 2005, Tonni et al 2010, Khalil et al 2011, Martínez-Frías et al 2011] findings by trimester include the following:

  • First trimester
    • Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
    • Increased nuchal translucency
    • Reverse flow in the ductus venosus (one case report), possibly the result of the narrow thorax compressing vascular flow
  • 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 I)
    • Encephalocele (infrequently; other brain abnormalities also described)
    • Cloverleaf skull (Kleeblattschädel) (often in TD type II; occasionally in TD type I) and/or relative macrocephaly

Note: Although identification of a lethal skeletal dysplasia in the second trimester is often straightforward, establishing the specific diagnosis can be difficult [Parilla et al 2003, Krakow et al 2008, Schramm et al 2009]. Ultrasound examination or review of the ultrasound films by an OB/geneticist may be most helpful in making a specific diagnosis prenatally. A three-dimensional ultrasound examination may also aid in visualizing facial features and other soft tissue findings of TD [Chen et al 2001].

Postnatal physical examination [Lemyre et al 1999, Passos-Bueno et al 1999, De Biasio et al 2000]:

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

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

  • Rhizomelic shortening of the long bones
  • Irregular metaphyses of the long bones
  • Platyspondyly
  • Small foramen magnum with brain stem compression
  • CNS abnormalities including temporal lobe malformations, hydrocephaly, brain stem hypoplasia, neuronal migration abnormalities
  • Bowed femurs (TD type I)
  • Cloverleaf skull (always in TD type II; sometimes in TD type I)

Other reported findings include cardiac defects (patent ductus arteriosis and atrial septal defect) and renal abnormalities.

Molecular Genetic Testing

Gene. FGFR3 is the only gene in which mutation is known to cause TD type I and TD type II. The FGFR3 pathogenic variant p.Lys650Glu has been identified in all individuals with TD type II [Bellus et al 2000].

Clinical testing

  • Sequence analysis of the entire FGFR3 coding region is not clinically indicated for TD as there is no increase in test sensitivity, and test specificity may decrease as a result of the finding of novel variants of uncertain clinical significance.

Table 1.

Molecular Genetic Testing Used in Thanatophoric Dysplasia

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method and Phenotype 3
TD Type ITD Type II
FGFR3Targeted analysis for pathogenic variants; sequence analysis of select regionsReported variants 4, 5Up to 99%NA
Sequence analysis of entire coding region 6, 7FGFR3 sequence variants>99%>99%

NA = not applicable


See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Some labs do not test for p.Lys650Met, the pathogenic variant that causes both severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) and thanatophoric dysplasia, type I [Bellus et al 2000].


Variant panels and detection rates may vary among laboratories. Selected exons of FGFR3 previously reported to contain pathogenic variants: for TD type I, FGFR3 exons 7, 10, 15, and 19; for TD type II, FGFR3 exon 15.


Not clinically indicated; see Molecular Genetic Testing, Sequence analysis of the entire FGFR3 coding region.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis when TD is suspected based on findings of pre- or postnatal examination:

Prenatal diagnosis for at-risk pregnancies requires prior identification of the pathogenic variant in the family.

Note: Some families with a previous child with confirmed TD may opt for molecular genetic testing (even though recurrence risk is not significantly elevated and ultrasound examination can detect TD early in pregnancy).

Clinical Characteristics

Clinical Description

Thanatophoric dysplasia (TD) types I and II are diagnosed prenatally or in the immediate newborn period. Both subtypes are considered lethal skeletal dysplasias; most affected infants die of respiratory insufficiency in the first hours or days of life. Respiratory insufficiency may be secondary to a small chest cavity and lung hypoplasia, compression of the brain stem by the small foramen magnum, or a combination of both. Some affected children have survived into childhood with aggressive ventilatory support.

Long-term survivors. The clinical findings of two children (a male aged 4.75 years and a female aged 3.7 years at last follow up) were summarized by MacDonald et al [1989]. Both had birth length and weight below the third centile. Head circumference was at the 97th centile. In both, growth plateaued after age ten months:

  • The male required ventilatory support at birth and tracheostomy at age three months. Other clinical findings included: micromelia, redundant skin folds, hydrocephalus diagnosed at age two months, seizure activity at age three months, a small foramen magnum with compression of the brain stem diagnosed at age 15 months, and little developmental progress after age 20 months. Platyspondyly, bowed tubular bones, and splayed ribs were noted radiographically. Head CT showed abnormal differentiation of the white and grey matter of the brain.
  • The female required ventilatory support beginning at age two months. A small foramen magnum with brain stem compression was diagnosed at age two months, and hydrocephaly was diagnosed at age four months. Bilateral hearing loss and progressive lack of ossification of the caudal spine were noted at age 3.7 years. She had two words and knew some sign language.

A male age nine years with the common TD type I-causing pathogenic variant p.Arg248Cys was reported. Birth weight was at the 50th centile (normal growth charts); birth length was more than four SD below the mean (achondroplasia growth charts). He required tracheostomy and ventilatory support. At age three years, he demonstrated stable ventriculomegaly, craniosynostosis, and little limb growth. By age eight years, he had seizures, bilateral hearing loss, kyphosis, and both joint hypermobility and joint contractures. At age nine years, the limbs had grown little; and radiologic findings were similar to those expected in TD. Extensive acanthosis nigricans was present. He was severely developmentally delayed and had no language. Final height was estimated to be 80-90 cm (32-35 inches).

Thompson et al [2011] described an 11-month (at time of publication) survivor who required suboccipital decompression in infancy due to clonus and decreased limb movements secondary to a narrow foramen magnum.

Mosaicism. A female age 47 years who was mosaic for the common TD type I-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 I) who presented with features of atypical achondroplasia.

Genotype-Phenotype Correlations

TD types I and II do not share common FGFR3 pathogenic variants [Wilcox et al 1998, Brodie et al 1999, Camera et al 2001].

No strong genotype-phenotype correlation for FGFR3 pathogenic variants exists within TD type I and TD type II, respectively. Variability in the TD phenotype has been described and, with the exception of the proposed pathogenic variant-dependent differences in severity of endochondral disturbance in the long bones [Bellus et al 2000], is not variant specific.

Cases of TD caused by two FGFR3 pathogenic variants in cis have been reported [Pannier et al 2009, Marquis-Nicholson et al 2013]. In both cases one pathogenic variant was previously reported to be associated with hypochondroplasia and one was a novel pathogenic missense variant.

Other clinical disorders rarely involve FGFR3 pathogenic variants previously identified in individuals with TD (see Genetically Related Disorders).


The penetrance of FGFR3 pathogenic variants is 100%.


Anticipation is not observed.


TD was originally described as thanatophoric dwarfism, a term no longer in use.

Although considered to be one of the platyspondylic lethal skeletal dysplasias, the term PLSD used with a specific subtype (San Diego, Luton, or Torrance) would be considered a separate clinical entity from TD types I and II. The PLSDs are sometimes referred to as "TD variants" because of their clinical similarity.


The incidence of TD was originally estimated at 1:20,000 to 1:50,000 births [Wilcox et al 1998, Baitner et al 2000, Chen et al 2001]. Recent studies suggest that the incidence is actually closer to 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].

Differential Diagnosis

Disorders to consider in the differential diagnosis of thanatophoric dysplasia (TD) [Passos-Bueno et al 1999, De Biasio et al 2000, Lee et al 2002, Neumann et al 2003]:

  • Homozygous achondroplasia has a similar clinical presentation and should be a part of the differential diagnosis when both parents have achondroplasia.
  • Achondrogenesis, including achondrogenesis type IA, type IB, and type II, Schneckenbecken dysplasia. Clinical features of achondrogenesis type 1B (ACG1B) include extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton. The face is flat, the neck is short, and the soft tissue of the neck may be thickened. The vertebral bodies show no or minimal ossification. The ribs are short. The iliac bones are ossified only in their upper part, giving a crescent-shaped, "paraglider-like" appearance on x-ray. The ischia are usually not ossified. The tubular bones are shortened such that no major axis can be recognized; metaphyseal spurring gives the appearance of a "thorn apple." The phalanges are poorly ossified and therefore only rarely identified in x-rays. Death occurs prenatally or shortly after birth. The final diagnosis should be based on molecular genetic testing of SLC26A2 (DTDST). The presence of rib fractures and the absence of ossification of vertebral pedicles may suggest ACG1A. ACG2 shows more severe underossification of the vertebral bodies than ACG1B, in addition to quite typical configuration of the iliac bones with concave medial and inferior borders, and non-ossification of the ischial and pubic bones. The gene in which pathogenic variants occur to cause ACG1A is TRIP11; ACG2 is caused by COL2A1 pathogenic variants.
  • SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) (see Achondroplasia) is a rare disorder characterized by extremely short stature, severe tibial bowing, profound developmental delay, and acanthosis nigricans. Unlike individuals with TD, those with SADDAN dysplasia survive past infancy. The three unrelated individuals with this phenotype who have been observed to date have had obstructive apnea but have not required prolonged mechanical ventilation. An FGFR3 p.Lys650Met pathogenic variant has been identified in all three individuals.
  • Osteogenesis imperfecta type II (OI type II). Osteogenesis imperfecta (OI) is characterized by fractures with minimal or absent trauma. Clinically, OI was classified into four types; the type most reminiscent of TD is OI type II (the perinatal lethal form). This disorder is characterized by extremely short stature, dark blue sclerae, severe limb deformity, multiple fractures of ribs, minimal calvarial mineralization, platyspondyly, and marked compression of long bones. Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with OI type II. Most individuals with OI type II have pathogenic variants in either COL1A1 or COL1A2, the two genes encoding type I collagen. Osteogenesis imperfecta type II is inherited in an autosomal dominant manner.
  • Short rib-polydactyly syndromes are short-limb dwarfisms with narrow thorax. They are currently classified into four subtypes that may or may not be proven to be distinct clinical entities. Findings distinguishing these disorders from TD include polydactyly and/or syndactyly of the hands or feet. Type I (Saldino-Noonan type) features cardiac defects. Type II (Majewski type) may have cleft lip, cleft palate, ambiguous genitalia, and renal abnormalities. Inheritance is autosomal recessive.
  • Campomelic dysplasia (CD) is a prenatal-onset, usually lethal skeletal dysplasia with narrow thorax. Individuals with CD have bowed tibiae, skin dimples, and hypoplastic scapulae. Many individuals with CD have 11 pairs of ribs. The tubular bones are poorly developed and show immature ossification. Mansour et al [1995] found that up to 75% of individuals with CD with a 46,XY karyotype have either female external genitalia or ambiguous genitalia. Campomelic dysplasia is caused by de novo, autosomal dominant pathogenic variants in SOX9 or chromosomal rearrangements upstream or downstream of SOX9 on chromosome 17.
  • Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome biogenesis. Type 1 (RCDP1), the classic type, is characterized by rhizomelia (shortening of the humerus and to a lesser degree the femur), punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. The diagnosis of RCDP1 is confirmed by the demonstration of deficiency of red blood cell plasmalogens, increased plasma concentration of phytanic acid, and deficiencies in plasmalogen biosynthesis and phytanic acid oxidation in cultured skin fibroblasts. The disorder is caused by pathogenic variants in PEX7, the gene encoding the receptor for a subset of peroxisomal matrix enzymes. A common pathogenic variant is responsible in the majority. Inheritance is autosomal recessive.
  • Asphyxiating thoracic dystrophy (Jeune thoracic dystrophy) is another chondrodysplasia marked by a narrow thorax. Short stature and short limbs are noted in infancy, but survivors may manifest only mild-to-moderate short stature. Survivors commonly develop renal insufficiency and can develop liver disease. Inheritance is autosomal recessive.
  • Platyspondylic lethal skeletal dysplasia (PLSD) – San Diego type, Torrance type, and Luton type. These short-limb dwarfism syndromes are clinically very similar to TD and have often been referred to as "TD variants." The Luton type is considered to be a mild form of the Torrance type [Nishimura et al 2004]. PLSD, Torrance type is characterized by shortened long bones with ragged metaphyses, radial bowing, and wafer-like vertebrae. All subtypes can be distinguished from TD histologically by the consistent presence of dilated loops of endoplasmic reticulum in the chondrocytes. FGFR3 pathogenic variants have been identified in PLSD, San Diego type, but not in Torrance or Luton types [Brodie et al 1999, Neumann et al 2003]. Nishimura et al [2004] and Zankl et al [2005] identified COL2A1 pathogenic variants in several families with PLSD, Torrance type or PLSD, Torrance-Luton type.
  • Dyssegmental dysplasia, Silverman-Handmaker type (DDSH) is a lethal disorder characterized by narrow thorax, short neck, short stature, bowed limbs, and irregular ossification of the vertebral bodies. Encephalocele and cleft palate are common. DDSH is caused by pathogenic variants in the heparan sulfate proteoglycan gene, HSPG2 [Arikawa-Hirasawa et al 2001]. Inheritance is autosomal recessive.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a newborn diagnosed with thanatophoric dysplasia (TD), the following evaluations are recommended if they have not already been completed:

  • Assessment of respiratory status by respiratory rate and skin color; arterial blood gases may be helpful in infants who survive the immediate postnatal period.
  • Assessment of the presence of hydrocephaly or other central nervous system abnormalities by CT or MRI
  • Consultation with a clinical geneticist and genetic counselor

Treatment of Manifestations

Management concerns are limited to the parents' desire for extreme life-support measures and provision-of-comfort care for the newborn.

Newborns require respiratory support (with tracheostomy and ventilation) to survive.

Anesthesia management concerns are described by Thompson et al [2011] and include:

  • Intubation with the cervical spine in a neutral position using a flexible fiber-optic scope
  • Utilization of evoked potential monitoring (somatosensory evoked potentials [SEPs] and motor evoked potentials [MEPs]) during the procedure to evaluate safety during intraoperative manipulations
  • Avoidance of volatile anesthetic agents and muscle relaxants which could affect the evoked potential recordings

Other measures:

  • Medication to control seizures, as in the general population
  • Shunt placement, when hydrocephaly is identified
  • Suboccipital decompression for relief of craniocervical junction constriction
  • Hearing aids, when hearing loss is identified


The following are appropriate:

  • Routine assessment of neurologic status on physical examination
  • Orthopedic evaluation upon the development of joint contractures or joint hypermobility [Wilcox et al 1998]
  • Audiology assessment
  • CT to evaluate for craniocervical constriction in long-term survivors if respiratory insufficiency is potentially the result of compression of the brain stem at the craniocervical junction
  • EEG for seizure activity

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, 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 directed by the level of parental desire for heroic life-saving measures and is often highly center-specific. It 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
  • Familial. Establishment of a perinatal plan for assessment, care, and/or withdrawal of care after delivery

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Thanatophoric dysplasia (TD) is inherited in an autosomal dominant manner; the majority of probands have a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • Because TD generally occurs as the result of a de novo pathogenic variant, the risk to the sibs of a proband is small.
  • Although no instances of germline mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.

Offspring of a proband

Other family members of a proband. 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 testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

High-risk pregnancies. Once the FGFR3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis 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.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Compassionate Friends
    Supporting Family After a Child Dies
    PO Box 3696
    Oak Brook IL 60522
    Phone: 877-969-0010 (toll free); 630-990-0010
    Fax: 630-990-0246
  • Helping After Neonatal Death (HAND)
    PO Box 341
    Los Gatos CA 95031
    Phone: 888-908-HAND (4263)
  • Medline Plus
  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Thanatophoric Dysplasia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FGFR34p16​.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3FGFR3

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Thanatophoric Dysplasia (View All in OMIM)


Gene structure. FGFR3 is 17 exons in length with transcription initiation located in exon 2. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. See Table 2 for known normal variants.

Pathogenic variants

  • TD type I. FGFR3 pathogenic variants responsible for the TD type I phenotype can be divided into two categories:
    • Missense variants [Passos-Bueno et al 1999]. Most of these pathogenic variants create new, unpaired cysteine residues in the protein. The two common variants p.Arg248Cys and p.Tyr373Cys probably account for 60%-80% of TD type I (see Table 2).
    • Stop codon variants. These pathogenic variants cause a read-through of the native stop codon, adding a highly hydrophobic alpha helix-containing domain to the C terminus of the protein. Pathogenic variants that obliterate the stop codon represent 10% or more of TD type I-causing variants (see Table 2).
  • TD type II. A single FGFR3 pathogenic variant (p.Lys650Glu) has been identified in all cases of TD type II [Bellus et al 2000]. The lysine residue at position 650 plays a role in stabilizing the activation loop of the tyrosine kinase domain in an inactive state. Pathogenic variants of this residue destabilize the loop, allowing ligand-independent activation of the tyrosine kinase domain, likely without the need for receptor dimerization at the cell surface [Bellus et al 2000]. Other pathogenic variants at this position give rise to different phenotypes: p.Lys650Met has been identified in TD type I, and p.Lys650Gln is seen in SADDAN (see Table 2).

Table 2.

Selected FGFR3 Variants

PhenotypeVariant ClassificationDNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Not applicableBenignc.882C>Tp.(=) 2
TD type IPathogenicc.742C>Tp.Arg248Cys 3
c.1118A>Gp.Tyr373Cys 3
TD type IIc.1948A>Gp.Lys650Glu

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


p.(=) indicates that the protein has not been analyzed but no change is expected.


Two most common pathogenic variants

Normal gene product. FGFR3 encodes one of four known fibroblast growth factor receptors (FGFRs). All FGFRs share considerable amino acid homology, and the genomic organization is nearly identical to that seen in mice. FGFRs are proteoglycans that function as tyrosine kinases upon binding of a ligand — usually one of more than 20 fibroblast growth factors (FGFs) plus proteoglycans containing heparan sulfate [McIntosh et al 2000, Torley et al 2002, Lievens & Liboi 2003]. Once a ligand binds, the FGFRs form homo- or heterodimers and undergo phosphorylation of the tyrosine residues in the tyrosine kinase domain. This is followed by a conformational change that frees intracellular binding sites. Intracellular proteins bind and initiate a signal cascade that usually influences protein activation or gene expression [Cohen 2002, Torley et al 2002]. Multiple pathways have been implicated, including ras/MAPK/ERK, P13/Akt, PLC-γ, and STAT1 [Cohen 2002, Torley et al 2002]. After activation, the complex is internalized for signal downregulation. This is accomplished via one of two pathways [Lievens et al 2006]: ubiquitination and degradation of the activated FGFR or feedback from the end targets (namely ERK) through the docking protein FRS2α.

FGFR3 consists of an extracellular signal peptide, three immunoglobulin-like domains (IgI, IgII, and IgIII) with an acid box between IgI and IgII, a transmembrane domain, and a split intracellular tyrosine kinase domain [Hyland et al 2003]. Ligand binding occurs between IgII and IgIII [McIntosh et al 2000]. The normal function of FGFR3 is to serve as a negative regulator of bone growth during ossification [Legeai-Mallet et al 1998, Cohen 2002]. Mice with knockout variants of Fgfr3 are overgrown with elongated vertebrae and long femurs and tails. The growth plates of the long bones are expanded [McIntosh et al 2000, Cohen 2002]. Alternative splicing of exons 8 and 9 has been documented, with such diversity conferring the capacity for differential expression and binding of multiple ligands [Cohen 2002]. Three reported isoforms of FGFR3 include: the native protein, an intermediate intracellular membrane-associated glycoprotein, and a mature glycoprotein [Lievens & Liboi 2003].

FGFR3 is expressed in a spatial- and temporal-specific pattern during embryogenesis [McIntosh et al 2000]. The highest levels of expression occur in cartilage and the central nervous system [Cohen 2002]. FGFR3 is also expressed in the dermis and epidermis [McIntosh et al 2000, Torley et al 2002].

The FGFR3 signaling pathway is activated in several cancers, including bladder and cervical cancer and multiple myeloma. Meyer et al [2004] identified FGFR3 in complex with Pyk2, a focal adhesion kinase known to regulate apoptosis in multiple myeloma cells and to activate Stat5B. FGFR3 phosphorylates Pyk2 and activates a signaling pathway without recruitment of proteins from the Src family (which are normally recruited by Pyk2 in the absence of FGFR3). Hyperactivated FGFR3 (i.e., pathogenic variants similar to those causing TD) causes hyperphosphorylation of Pyk2. FGFR3 may also sequester Pyk2 from Shp2, which normally functions to decrease Pyk2 phosphorylation and downregulate Pyk2 signaling. Both FGFR3 and Pyk2 may work in concert to maximally activate Stat5B [Meyer et al 2004].

Abnormal gene product. Pathogenic variants in FGFR3 are gain-of-function variants that produce a constitutively active protein capable of initiating intracellular signal pathways in the absence of ligand binding [Baitner et al 2000, Cohen 2002]. This activation leads to premature differentiation of proliferative chondrocytes into pre-hypertrophic chondrocytes and, ultimately, to premature maturation of the bone [Cohen 2002, Legeai-Mallet et al 2004]. The mechanism for other clinical findings in TD type I and TD type II (CNS and dermal abnormalities) is less clear. All reported pathogenic variants cause constitutive activation through the creation of new, unpaired cysteine residues that induce ligand-independent dimerization [Cohen 2002], activation of the tyrosine kinase loop [Tavormina et al 1999, Cohen 2002], or creation of an elongated protein through destruction of the native stop codon.

Studies have shown that the level of ligand-independent tyrosine kinase activity conferred by different FGFR3 pathogenic variants is correlated with the severity of disorganization of endochondral ossification and, therefore, with the skeletal phenotype [Bellus et al 1999, Bellus et al 2000].

The p.Lys650Glu pathogenic variant causing thanatophoric dysplasia type II has been shown to cause accumulation of intermediate, activated forms of FGFR3 in the endoplasmic reticulum [Lievens & Liboi 2003]. This immature, cellular FGFR3 is able to signal through an FRS2α-independent pathway (via the JAK/STAT pathway) that is then not subject to FRS2α-mediated downregulation [Lievens et al 2006].


Literature Cited

  • Arikawa-Hirasawa E, Wilcox WR, Yamada Y. Dyssegmental dysplasia, Silverman-Handmaker type: unexpected role of perlecan in cartilage development. Am J Med Genet. 2001;106:254–7. [PubMed: 11891676]
  • Baitner AC, Maurer SG, Gruen MB, Di Cesare PE. The genetic basis of the osteochondrodysplasias. J Pediatr Orthop. 2000;20:594–605. [PubMed: 11008738]
  • Barbosa-Buck CO, Orioli IM, Dutra MG, Lopez-Camelo J, Castilla EE, Cavalcanti DP. Clinical epidemiology of skeletal dysplasias in South America. Am J Med Genet Part A. 2012;158A:1038–45. [PubMed: 22407836]
  • Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, Jabs EW, Curry CJ, Wilcox WR, Lachman RS, Rimoin DL, Francomano CA. Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am J Med Genet. 1999;85:53–65. [PubMed: 10377013]
  • Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000;67:1411–21. [PMC free article: PMC1287918] [PubMed: 11055896]
  • Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet. 1999;84:476–80. [PubMed: 10360402]
  • Camera G, Baldi M, Strisciuglio G, Concolino D, Mastroiacovo P, Baffico M. Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype. Am J Med Genet. 2001;104:277–81. [PubMed: 11754059]
  • Chen CP, Chern SR, Shih JC, Wang W, Yeh LF, Chang TY, Tzen CY. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn. 2001;21:89–95. [PubMed: 11241532]
  • Cohen MM Jr. Some chondrodysplasias with short limbs: molecular perspectives. Am J Med Genet. 2002;112:304–13. [PubMed: 12357475]
  • De Biasio P, Ichim IB, Scarso E, Baldi M, Barban A, Venturini PL. Thanatophoric dysplasia type I presenting with increased nuchal translucency in the first trimester. Prenat Diagn. 2005;25:426–8. [PubMed: 15906417]
  • De Biasio P, Prefumo F, Baffico M, Baldi M, Priolo M, Lerone M, Toma P, Venturini PL. Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. Prenat Diagn. 2000;20:835–7. [PubMed: 11038465]
  • Donnelly DE, McConnell V, Paterson A, Morrison PJ. The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study. Ulster Med J. 2010;79:114–8. [PMC free article: PMC3284715] [PubMed: 22375084]
  • Ferreira A, Matias A, Brandao O, Montenegro N. Nuchal translucency and ductus venosus blood flow as early sonographic markers of thanatophoric dysplasia. A case report. Fetal Diagn Ther. 2004;19:241–5. [PubMed: 15067234]
  • Hyland VJ, Robertson SP, Flanagan S, Savarirayan R, Roscioli T, Masel J, Hayes M, Glass IA. Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia. Am J Med Genet A. 2003;120A:157–68. [PubMed: 12833394]
  • Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn. 2011;31:115–24. [PubMed: 21210484]
  • Krakow D, Alanay Y, Rimoin LP, Lin V, Wilcox WR, Lachman RS, Rimoin DL. Evaluation of prenatal-onset osteochondrodysplasias by ultrasonography: a retrospective and prospective analysis. Am J Med Genet A. 2008;146A:1917–24. [PMC free article: PMC2713784] [PubMed: 18627037]
  • Lee SH, Cho JY, Song MJ, Min JY, Han BH, Lee YH, Cho BJ, Kim SH. Fetal musculoskeletal malformations with a poor outcome: ultrasonographic, pathologic, and radiographic findings. Korean J Radiol. 2002;3:113–24. [PMC free article: PMC2713834] [PubMed: 12087201]
  • Legeai-Mallet L, Benoist-Lasselin C, Delezoide AL, Munnich A, Bonaventure J. Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. J Biol Chem. 1998;273:13007–14. [PubMed: 9582336]
  • Legeai-Mallet L, Benoist-Lasselin C, Munnich A, Bonaventure J. Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. Bone. 2004;34:26–36. [PubMed: 14751560]
  • Lemyre E, Azouz EM, Teebi AS, Glanc P, Chen MF. Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J. 1999;50:185–97. [PubMed: 10405653]
  • Lievens PM, Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem. 2003;278:17344–9. [PubMed: 12624096]
  • Lievens PM, Roncador A, Liboi E. K644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC gamma-independent pathways. J Mol Biol. 2006;357:783–92. [PubMed: 16476447]
  • MacDonald IM, Hunter AG, MacLeod PM, MacMurray SB. Growth and development in thanatophoric dysplasia. Am J Med Genet. 1989;33:508–12. [PubMed: 2596513]
  • Mansour S, Hall CM, Pembrey ME, Young ID. A clinical and genetic study of campomelic dysplasia. J Med Genet. 1995;32:415–20. [PMC free article: PMC1050480] [PubMed: 7666392]
  • Marquis-Nicholson R, Aftimos S, Love DR. Molecular analysis of a case of thanatophoric dysplasia reveals two de novo FGFR3 missense mutations located in cis. Sultan Qaboos Univ Med J. 2013 2013 Feb;13:80–7. [PMC free article: PMC3616804] [PubMed: 23573386]
  • Martínez-Frías ML, Egüés X, Puras A, Hualde J, de Frutos CA, Bermejo E, Nieto MA, Martínez S. Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis. Am J Med Genet A. 2011;155A:197–202. [PubMed: 21204232]
  • McIntosh I, Bellus GA, Jab EW. The pleiotropic effects of fibroblast growth factor receptors in mammalian development. Cell Struct Funct. 2000;25:85–96. [PubMed: 10885578]
  • Meyer AN, Gastwirt RF, Schlaepfer DD, Donoghue DJ. The cytoplasmic tyrosine kinase Pyk2 as a novel effector of fibroblast growth factor receptor 3 activation. J Biol Chem. 2004;279:28450–7. [PubMed: 15105428]
  • Neumann L, Kunze J, Uhl M, Stover B, Zabel B, Spranger J. Survival to adulthood and dominant inheritance of platyspondylic skeletal dysplasia, Torrance-Luton type. Pediatr Radiol. 2003;33:786–90. [PubMed: 12961049]
  • Nishimura G, Nakashima E, Mabuchi A, Shimamoto K, Shimamoto T, Shimao Y, Nagai T, Yamaguchi T, Kosaki R, Ohashi H, Makita Y, Ikegawa S. Identification of COL2A1 mutations in platyspondylic skeletal dysplasia, Torrance type. J Med Genet. 2004;41:75–9. [PMC free article: PMC1757240] [PubMed: 14729840]
  • Pannier S, Martinovic J, Heuertz S, Delezoide AL, Munnich A, Schibler L, Serre V, Legeai-Mallet L. Thanatophoric dysplasia caused by double missense FGFR3 mutations. Am J Med Genet A. 2009;149A:1296–301. [PubMed: 19449430]
  • Parilla BV, Leeth EA, Kambich MP, Chillis P, MacGregor SN. Antenatal detection of skeletal dysplasias. J Ultrasound Med. 2003;22:255–8. [PubMed: 12636325]
  • Passos-Bueno MR, Wilcox WR, Jabs EW, Sertie AL, Alonso LG, Kitoh H. Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat. 1999;14:115–25. [PubMed: 10425034]
  • Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CW, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38:414–7. [PubMed: 16501574]
  • Schramm T, Gloning KP, Minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, Tutschek B. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol. 2009;34:160–70. [PubMed: 19548204]
  • Takagi M, Kaneko-Schmitt S, Suzumori N, Nishimura G, Hasegawa T. Atypical achondroplasia due to somatic mosaicism for the common thanatophoric dysplasia mutation R248C. Am J Med Genet Part A. 2012;158A:247–50. [PubMed: 22106050]
  • Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet. 1999;64:722–31. [PMC free article: PMC1377789] [PubMed: 10053006]
  • Thompson DR, Browd SR, Sangaré Y, Rowell JC, Slimp JC, Haberkern CM. Anesthetic management of an infant with thanatophoric dysplasia for suboccipital decompression. Paediatr Anaesth. 2011;21:92–4. [PubMed: 21155935]
  • Tonni G, Azzoni D, Ventura A, Ferrari B, Felice CD, Baldi M. Thanatophoric dysplasia type I associated with increased nuchal translucency in the first trimester: Early prenatal diagnosis using combined ultrasonography and molecular biology. Fetal Pediatr Pathol. 2010;29:314–22. [PubMed: 20704477]
  • Torley D, Bellus GA, Munro CS. Genes, growth factors and acanthosis nigricans. Br J Dermatol. 2002;147:1096–101. [PubMed: 12452857]
  • Wilcox WR, Tavormina PL, Krakow D, Kitoh H, Lachman RS, Wasmuth JJ, Thompson LM, Rimoin DL. Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet. 1998;78:274–81. [PubMed: 9677066]
  • Zankl A, Neumann L, Ignatius J, Nikkels P, Schrander-Stumpel C, Mortier G, Omran H, Wright M, Hilbert K, Bonafé L, Spranger J, Zabel B, Superti-Furga A. Dominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within type 2 collagenopathies. Am J Med Genet A. 2005;133A:61–7. [PubMed: 15643621]

Suggested Reading

  • Bonaventure J, Horne WC, Baron R. The localization of FGFR3 mutations causing thanatophoric dysplasia type I differently affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. 2007;274:3078–93. [PubMed: 17509076]
  • You M, Spangler J, Li E, Han X, Ghosh P, Hristova K. Effect of pathogenic cysteine mutations on FGFR3 transmembrane domain dimerization in detergents and lipid bylayers. Biochemistry. 2007;46:11039–46. [PubMed: 17845056]

Chapter Notes


The authors wish to thank Julie Hoover-Fong MD, Clinical Director of the Greenberg Center for Skeletal Dysplasias at Johns Hopkins University, for her clinical insight.

Revision History

  • 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
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source ( and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1366PMID: 20301540


  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...