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 associated with 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, which is available on a clinical basis.
Management. Treatment of manifestations: 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. Management focuses on the parents' wishes for provision of comfort-care for the newborn. Newborns require respiratory support (with tracheostomy and ventilation) to survive. 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.
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 theoretical possibility. Prenatal diagnosis is possible by ultrasound examination and molecular genetic testing.
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 [Sawai et al 1999, De Biasio et al 2000, Chen et al 2001, Ferreira et al 2004, De Biasio et al 2005, Li et al 2006] 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 (two case reports) and 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 (two cases)
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 [Sawai et al 1999, Parilla et al 2003]. 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, Sawai et al 1999, De Biasio et al 2000]:
Macrocephaly
Large anterior fontanel
Frontal bossing, flat facies with low nasal bridge, proptotic eyes
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.
Histopathology [Wilcox et al 1998, Lemyre et al 1999]:
Disorganized chondrocyte columns
Poor cellular proliferation
Lateral overgrowth of the metaphyseal bone
Mesenchymal cells extending inward forming a fibrous band at the periphery of the physeal bone
Increased vascularity of the resting cartilage
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. FGFR3 is the only gene 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].
Targeted mutation analysis of FGFR3 using a panel of most or all of the reported FGFR3 mutations
Sequence analysis of select regions 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
Sequence analysis of the entire FGFR3 coding region is clinically available; however, it 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 summarizes molecular genetic testing for this disorder.
NA = not applicable
1. 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].
2. Mutation panels and detection rates may vary among laboratories.
3. Not clinically indicated; see Clinical testing, Sequence analysis of the entire FGFR3 coding region.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To establish the diagnosis when TD is suspected based on findings of pre- or postnatal examination:
If TD type II is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the p.Lys650Glu mutation may be an appropriate first step in diagnostic testing.
Otherwise, sequence analysis of select exons, or a hybridization-based test of a mutation panel that includes the reported disease-associated mutations is recommended.
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).
FGFR3 mutations have been identified in several disorders with highly variable phenotypes:
Achondroplasia. The causative FGFR3 mutations p.Gly380Arg and p.Gly375Cys have been identified in nearly 100% of individuals [Camera et al 2001]. Camera et al [2001] reported an individual with the common TD type I mutation p.Arg248Cys and a clinical phenotype of achondroplasia. Although mosaicism remains a possible explanation for the mild phenotype, no mosaicism was identified in either buccal mucosal cells or blood.
Hypochondroplasia. Although FGFR3 mutations are identifiable in about 80% of individuals with hypochondroplasia, several families are not linked to FGFR3; therefore, genetic heterogeneity is likely [Camera et al 2001].
SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) is caused by FGFR3 mutation p.Lys650Met [Bellus et al 1999, Tavormina et al 1999].
Crouzon syndrome with acanthosis nigricans (see FGFR-Related Craniosynostosis Syndromes) is caused by FGFR3 mutation p.Ala391Glu.
Familial acanthosis nigricans. A p.Lys650Thr mutation was identified in several affected family members with autosomal dominant acanthosis nigricans and short stature.
Nonsyndromic coronal synostosis (Muenke syndrome) (see also FGFR-Related Craniosynostosis Syndromes), characterized by a p.Pro250Arg mutation in FGFR3 [Passos-Bueno et al 1999, McIntosh et al 2000]
Platyspondylic lethal skeletal dysplasia, San Diego type (PLSD-SD). Although PLSD-SD has been described as a distinct clinical entity, much phenotypic overlap exists with TD. Both disorders feature short, bowed long bones, platyspondyly, and short ribs. In PLSD-SD, metaphyseal flaring and chondrocyte abnormalities can be less severe [Brodie et al 1999]. An important histologic difference is the consistent presence in the chondrocytes in PLSD-SD of dilated loops/inclusion bodies in the endoplasmic reticulum, which are not typical in TD. All individuals with PLSD-SD studied by Brodie et al [1999] had FGFR3 mutations previously reported in association with TD type I.
LADD syndrome (lacrimo-auriculo-dento-digital syndrome, Levy Hollister syndrome). FGFR3 mutation p.Asp513Asn has been reported in one family with this syndrome [Rohmann et al 2006].
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.
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 to 90 cm (32 to 35 inches). The affected individual is alive at age 17 years; status is unchanged [Pauli, personal communication].
Mosaicism. A 47-year-old female mosaic for the common TD type I mutation p.Arg248Cys had asymmetrical 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.
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 causing TD exists. 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.
Other clinical disorders rarely involve FGFR3 mutations previously identified in individuals with TD (see Allelic Disorders).
The penetrance of mutations in FGFR3 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.
TD occurs in approximately 1:20,000 to 1:50,000 births [Wilcox et al 1998, Sawai et al 1999, Baitner et al 2000, Chen et al 2001].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 ischiua 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 defect in ACG1A is not known; 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. Later, severe mental deficiency and postnatal growth retardation are evident. The majority of affected individuals do not survive the first decade of life. 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 a PEX7 receptor defect. 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. A subset of affected individuals have mutations in IFT80 at chromosome 3q25.33 [Beales et al 2007]. Another locus has been mapped to 15q13. 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, Torrence-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 (HSPG) gene [Arikawa-Hirasawa et al 2001]. Inheritance is autosomal recessive.
To establish the extent of disease 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
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.
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
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.
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
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Thanatophoric dysplasia (TD) is inherited in an autosomal dominant manner; the majority of probands have a de novo mutation.
Parents of a proband
TD is almost always caused by a de novo mutation in FGFR3.
Parents of a proband are not affected.
Somatic mosaicism that included the germline mutation in FGFR3 (p.Arg248Cys) has been reported in an affected individual [Hyland et al 2003]; this individual's only offspring had a lethal skeletal dysplasia. Current diagnostic techniques do not detect mosaicism for FGFR3 mutations causing TD.
An advanced paternal age effect has been reported [Lemyre et al 1999].
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 theoretical possibility.
Offspring of a proband
Individuals with TD do not reproduce.
Somatic and germline mosaicism for a mutation in FGFR3 (p.Arg248Cys) has been reported in an affected individual [Hyland et al 2003]; this individual's only offspring had a lethal skeletal dysplasia.
Other family members of a proband. Extended family members of the proband are not at increased risk.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.
High-risk pregnancies. Prenatal diagnosis for pregnancies at increased risk for TD as a result of parental mosaicism is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele in the family should be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
FGFR3 | 4p16.3 | Fibroblast growth factor receptor 3 |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
134934 | FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3 |
187600 | THANATOPHORIC DYSPLASIA, TYPE I; TD1 |
187601 | THANATOPHORIC DYSPLASIA, TYPE II; TD2 |
Gene Symbol | Entrez Gene | HGMD |
---|---|---|
FGFR3 | 2261 (MIM No. 134934) | FGFR3 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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. FGFR3 Allelic Variants Discussed in This GeneReview
Phenotype | Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change (Alias 1) | Reference Sequence |
---|---|---|---|---|
Not applicable | Normal | c. 882C>T | p.(=) 2 (N294N) | NM_000142.3NP_000133.1 |
c.1953A>G | p.(=) (T651T) | |||
TD type I | Pathologic | c.742C>T | p.Arg248Cys 3 | |
c.746C>G | p.Ser249Cys | |||
c.1108G>T | p.Gly370Cys | |||
c.1111A>T | p.Ser371Cys | |||
c.1118A>G | p.Tyr373Cys 3 | |||
c.1949A>T | p.Lys650Met | |||
c.2420G>T | p.X807LeuextX101 | |||
c.2419T>G | p.X807GlyextX101 | |||
c.2419T>C | p.X807ArgextX101 | |||
c.2419T>A | p.X807ArgextX101 | |||
c.2421A>T | p.X807CysextX101 | |||
c.2421A>C | p.X807CysextX101 | |||
c.2421A>G | p.X807TrpextX101 | |||
TD type II | c.1944A>G | p.Lys650Glu | ||
SADDAN | c.1949A>T | p.Lys650Met | ||
Achondroplasia | c.1123G>T | p.Gly375Cys | ||
c.1138G>C/A | p.Gly380Arg | |||
Crouzon syndrome with acanthosis nigricans | c.1172C>A | p.Ala391Glu | ||
Nonsyndromic coronal synostosis (Muenke syndrome) | c.749C>G | p.Pro250Arg | ||
Familial acanthosis nigricans | c.1949A>C | p.Lys650Thr | ||
LADD syndrome | c.1537G>A | p.Asp513Asn |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
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 & Loboi 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].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Thanatophoric Dysplasia
Compassionate Friends
PO Box 3696
Oak Brook IL 60522-3696
Phone: 877-969-0010; 630-990-0010
Fax: 630-990-0246
Email: nationaloffice@compassionatefriends.org
www.compassionatefriends.org
Helping After Neonatal Death (HAND)
A non-profit California-based group that lists support groups
www.handonline.org/resources/groups/index.html
Medline Plus
Dwarfism
European Skeletal Dysplasia Network
c/o Wellcome Trust Centre for Cell-Matrix Research
Faculty of Life Sciences University of Manchester
Michael Smith Building Oxford Road
Manchester M13 9PT United Kingdom
Email: info@esdn.org
www.esdn.org
International Skeletal Dysplasia Registry
Medical Genetics Institute
8635 West Third Street Suite 665
Los Angeles CA 90048
Phone: 800-CEDARS-1 (800-233-2771)
Fax: 310-423-0462
www.csmc.edu
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
The authors wish to thank Julie Hoover-Fong MD, Clinical Director of the Greenberg Center for Skeletal Dysplasias at Johns Hopkins University, for her review of the manuscript and clinical insight.
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