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Thanatophoric Dysplasia

Includes: Thanatophoric Dysplasia Type I, Thanatophoric Dysplasia Type II

, MS, MA and , MD.

Author Information
, MS, MA
DNA Diagnostic Laboratory
Johns Hopkins University
Baltimore, Maryland
, MD
DNA Diagnostic Laboratory
Johns Hopkins University
Baltimore, Maryland

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

Summary

Disease 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 (kleeblattschaedel) 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/testing. 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 mutations causing TD type I and more than 99% of mutations causing TD type II can be identified through molecular genetic testing of FGFR3.

Management. 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 a de novo mutation in 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.

Diagnosis

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, Martinez-Frias 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 (Kleeblattschaedel) (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 mutation 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 MethodMutations Detected 2Mutation Detection Frequency by Test Method and Phenotype 3
TD Type ITD Type II
FGFR3Targeted mutation analysis; sequence analysis of select regionsReported mutations 4, 5Up to 99%NA
p.Lys650Glu NA>99%
Sequence analysis of entire coding region 6FGFR3 sequence variants 7>99%>99%

NA = not applicable

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

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

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

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

7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic 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 disease-causing mutation 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 Description

Natural History

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 nine-year-old male with the common TD type I mutation 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 47-year-old female mosaic for the common TD type I mutation 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 siblings, 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 mutation 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 mutations [Wilcox et al 1998, Brodie et al 1999, Camera et al 2001].

No strong genotype-phenotype correlation for FGFR3 mutations 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 mutation-dependent differences in severity of endochondral disturbance in the long bones [Bellus et al 2000], is not mutation specific.

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

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

Penetrance

The penetrance of mutations in FGFR3 is 100%.

Anticipation

Anticipation is not observed.

Nomenclature

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.

Prevalence

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 mutations occur to cause ACG1A is TRIP11; ACG2 is caused by COL2A1 mutations.
  • 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 mutation 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 mutations 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 mutations 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 mutations in PEX7, the gene encoding the receptor for a subset of peroxisomal matrix enzymes. A common mutation 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 mutations 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 mutations 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 mutations in the heparan sulfate proteoglycan gene, HSPG2 [Arikawa-Hirasawa et al 2001]. Inheritance is autosomal recessive.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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:

  • 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
  • Medical genetics consultation and genetic counseling

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

Surveillance

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 ClinicalTrials.gov 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 mutation.

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 mutation, 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies. If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

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 mutations in these situations is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

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
    Email: nationaloffice@compassionatefriends.org
  • Helping After Neonatal Death (HAND) - Support Groups
    PO Box 341
    Los Gatos CA 95031
    Phone: 888-908-4263
    Email: info@handonline.org
  • Medline Plus
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FGFR34p16​.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Thanatophoric Dysplasia (View All in OMIM)

134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3
187600THANATOPHORIC DYSPLASIA, TYPE I; TD1
187601THANATOPHORIC DYSPLASIA, TYPE II; TD2

Normal allelic variants. FGFR3 is 17 exons in length with transcription initiation located in exon 2. See Table 2 for known normal allelic variants.

Pathologic allelic variants

  • TD type I. FGFR3 mutations responsible for the TD type I phenotype can be divided into two categories:
    • Missense mutations [Passos-Bueno et al 1999]. Most of these mutations create new, unpaired cysteine residues in the protein. The two common mutations p.Arg248Cys and p.Tyr373Cys probably account for 60%-80% of TD type I (see Table 2).
    • Stop codon mutations. These mutations cause a read-through of the native stop codon, adding a highly hydrophobic alpha helix-containing domain to the C terminus of the protein. Mutations that obliterate the stop codon represent 10% or more of TD type I mutations (see Table 2).
  • TD type II. A single FGFR3 mutation (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. Mutations 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 mutations 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 Allelic Variants

PhenotypeClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Not applicableNormalc.882C>Tp.(=) 2
(N294N)
NM_000142​.3
NP_000133​.1
c.1953A>Gp.(=)
(T651T)
TD type IPathologicc.742C>Tp.Arg248Cys 3
c.746C>Gp.Ser249Cys
c.1108G>Tp.Gly370Cys
c.1111A>Tp.Ser371Cys
c.1118A>Gp.Tyr373Cys 3
c.1949A>Tp.Lys650Met
c.2420G>Tp.*807Leuext*101
c.2419T>Gp.*807Glyext*101
c.2419T>Cp.*807Argext*101
c.2419T>Ap.*807Argext*101
c.2421A>Tp.*807Cysext*101
c.2421A>Cp.*807Cysext*101
c.2421A>Gp.*807Trpext*101
TD type IIc.1948A>Gp.Lys650Glu

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

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

3. Two most common mutations

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 mutations 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., mutations 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. Mutations in FGFR3 are gain-of-function mutations 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 mutations 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 mutations 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 mutation 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].

References

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Suggested Reading

  1. 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]
  2. 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

Acknowledgments

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 to live Web site
  • 21 May 2004 (me) Review posted to live Web site
  • 27 February 2004 (bk, gc) Original submission
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