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Home , Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia

Thanatophoric dysplasia

Authors: Professor Elio Liboi1 and Doctor Patricia M-J. Lievens Creation Date: September 2004

Scientific Editor: Professor Raoul Hennekam

1Division of Biochemistry, Department of Neurological Sciences, University of Verona School of Medicine, Strada LeGrazie 8, 37134 Verona, Italy. [email protected]

Abstract Keywords Disease names and synonyms Definition Diagnosis criteria Frequency Etiology Clinical description Genetic counseling Management References

Abstract (TD) is a severe skeletal disorder that is lethal in the neonatal period. Two clinically defined TD subtypes have been classified: type I (TDI), characterized by micromelia with bowed and, occasionally, by the presence of cloverleaf skull deformity of varying severity and type II (TDII), characterized by micromelia with straight femurs and a moderate to severe cloverleaf skull deformity. TD is caused by specific autosomal dominant in the that codifies for the Fibroblast 3 (FGFR3). The mutations constitutively activate the activity of the receptor. As normally FGFR3 is a negative regulator of bone growth, the gain-of-function mutations associated to TD allow the activated receptor to send negative signals within the cells of the (), thus leading to the generalized disorganization of endochondral ossification at the bone growth plate. The estimated birth incidence is approximately 1/20,000 to 1/50,000 TDI being more frequent than TDII. Most individuals with TD die within the first few hours or days of life by respiratory insufficiency secondary to reduced thoracic capacity or compression of the brainstem. Currently, specific therapeutic regiments other than sustenance of symptoms do not exist. Prenatal diagnosis is available, both by ultrasonography and by molecular studies.

Keywords Thanatophoric dysplasia, , Fibroblast Growth Factor Receptor 3 (FGFR3), Tyrosine Kinase, endochondral ossification

the neonatal period. TD is characterized Disease names and synonyms by severe shortening of the limbs, a Thanatophoric dysplasia, Thanatophoric narrow , , and a dwarfism normal trunk length. TD is divided into 2 clinically defined subtypes: TDI and TDII. Definition TDI is characterized by bowed femurs; Thanatophoric Dysplasia (TD) is the most affected children have sometimes a common skeletal dysplasia to be lethal in cloverleaf skull. TDII always presents with

Liboi E and Lievens P.M-J. Thanatophoric dysplasia. Orphanet encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/uk-Thanatophoric-dysplasia.pdf 1

a cloverleaf skull and the neonates have - bowed femurs (TDI). straight femurs. For references see: Wilcox et al. 1998; Other common features to both TD include Lemyre et al. 1999; Gorlin et al. 2001. prominent platyspondyly of the vertebrae, a small foramen magnum with a severe Histopathology risk for brain stem compression and - disorganized chondrocytes columns redundant skin folds along the limbs. - poor cellular proliferation - lateral overgrowth of the metaphyses Diagnosis criteria - mesenchymal cells extending inward Diagnosis can be performed according to forming a fibrous band at the periphery of the following criteria: the metaphyses - increased vascularity of the resting Prenatal ultrasound examination cartilage - growth deficiency recognizable by 20 For references see: Tavormina et al. 1995; weeks gestation Lemyre et al. 1999; Wilcox et al. 1998. - well-ossified spine and skull - platyspondyly Molecular - ventriculomegaly FGFR3 mutants are the cause of both TDI - narrow chest cavity with short ribs and TDII. - polyhydramnios For TDI a series of missense mutations - bowed femurs (for TDI) have been identified: R248C*, Y373C*, - cloverleaf skull (kleeblattschaedel) for S249C, G370C, S371C (Rousseau et al. TDII; sometimes in TDI. 1996; Passos-Bueno et al. 1999). The For references see: Loong, 1987; Sawai et most common mutants (*) account for 60- al.1999; De Biasio et al. 2000; Chen et al. 80% of TDI (of note all mutations create 2001. The identification of a severe new, unpaired cysteine residues in the skeletal dysplasia in the second trimester FGFR3). Furthermore, stop codon is usually straightforward, but establishing mutations (X807L, X807G, X807R, a specific diagnosis like TD can be rather X807C, X807W) have been identified difficult (Sawai et al. 1999, Parilla et al. (Rousseau et al. 1995; Rousseau et al. 2003). 1996). For TDII a single point in the Postnatal physical examination FGFR3 gene (K650E) has been identified - macrocephaly in all TDII analyzed (Rousseau et al. 1996; - large anterior fontanel Gorlin 1997; Bellus et al. 2000). - frontal bossing, flat facies with low nasal bridge, proptosis Differential diagnosis - marked shortening of the limbs The differential diagnosis includes a (micromelia) number of well-delineated skeletal - trident hand with dysplasias (Passos Buenos et al. 1999, - redundant skin folds De Biasio et al. 2000, Gorlin et al. 2001, - narrow, bell-shaped thorax with short ribs Lee et al. 2002, Neumann et al. 2003): and protuberant abdomen Asphyxiating thoracic dysplasia (Jeune - relatively normal trunk length syndrome), a rare autosomal recessive - generalized . chondrodysplasia that often leads to death For references see: Tavormina et al. 1995; in infancy because of a severely Lemyre et al. 1999; Passos-Bueno et al. constricted thoracic cage and respiratory 1999; Sawai et al. 1999; De Biasio et al. insufficiency. 2000. Homozygous has a similar clinical presentation and should be a part Radiographs of the differential diagnosis when both - rhizomelic shortening of the long bones parents have achondroplasia. - irregular metaphyses of the long bones , type IA, type IB and - platyspondyly type II, Schneckenbecken dysplasia. - small foramen magnum with brain stem SADDAN (Severe Achondroplasia with compression Developmental Delay and Acanthosis - cental nervous system (CNS) Nigricans). abnormalities including temporal lobe Short-rib polydactyly syndromes malformations, hydrocephaly, brainstem (especially the Saldino-Noonan type). hypoplasia, neuronal migration Metatropic dysplasia. abnormalities

Liboi E and Lievens P.M-J. Thanatophoric dysplasia. Orphanet encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/uk-Thanatophoric-dysplasia.pdf 2

Osteogenesis Imperfecta (OI) type II that Moscatelli 1992; Plotnikov et al. 1999). is the perinatal lethal form. OI type II has The TD mutations in FGFR3 are gain-of- mutations in either COL1A1 or COL1A2 function mutations that produce a and is inherited in an autosomal constitutively active receptor capable of dominant manner. initiating intracellular signal pathways in Campomelic syndrome. This is an entity the absence of ligand binding. characterized by congenital bowing and TDI - All reported mutations cause angulations of long bones, together with constitutive FGFR3 activation through the other skeletal and extra skeletal defects. It creation of new, unpaired cysteine is caused by mutation in the SOX9 gene. residues that induce ligand-independent Rhizomelic chondrodysplasia punctata dimerization (Rousseau et al. 1996; Cohen also shows micromelia but this is almost 2002) or the creation of an elongated exclusively rhizomelic. Radiologically the through destruction of the native stippling is characteristic; it is caused by stop codon (Rousseau et al. 1995; mutations in the PEX7 gene, which Rousseau et al. 1996). It has been encodes the peroxisomal type 2 targeting recently proposed that mutated FGFR3 signal (PTS2) receptor (Marzioch 1994). induces premature exit of proliferative cells . from the cell cycle and their differentiation The group of platyspondylic lethal skeletal into pre-hypertrophic chondrocytes thus dysplasia, such as Torrance-Luton type ascribing to the defective differentiation of (Gorlin et al. 2001). The latter was chondrociytes the main cause of long originally grouped with TD however, it is bone growth defects in TDI (Legai-Mallet not caused by mutations in the FGFR3 et al. 2004). (Neumann et al. 2003). TDII - A single FGFR3 mutation (K650E) Dyssegmental dysplasia, Silverman- has been identified in all cases of TDII Handmaker type (DDSH). DDSH is (Rousseau et al. 1996; Bellus et al. 2000). caused by mutations in the heparan The K650E mutation is located within a sulfate proteoglycan (HSPG) gene. critical region of the tyrosine kinase domain activation loop. Indeed, amino acid Frequency substitution at this codon results in strong TD has an incidence of approximately autophosphorylation of multiple tyrosine 1/20,000 to 1/50,000 live births (Orioli et residues within the intracellular domain al. 1986; Wilcox et al. 1998; Sawai et al. (Webster et al. 1997). In in vitro studies 1999, Bartner et al 2000; Chen et al. and in mice carrying the TDII mutation it 2001). was shown that the signal transduction and activator of transcription STAT1 is Etiology activated and translocated into the nucleus The long bones elongation is governed by (Iwata et al. 2000). This, together with a process known as endochondral activation of the cell cycle inhibitor p21waf1 ossification, a tightly regulated was proposed as the molecular developmental process that occurs in the mechanism responsible for the TDII epiphyseal growth plate (Caplan and pathology (Su et al. 1997). Furthermore, Pechak 1987). Chondrocytes of the growth ligand-independent activation of the STAT plate are arranged in columns that signalling pathway was demonstrated in sequentially and synchronously progress cultured TD cells and confirmed by through proliferative, pre-hypertrophic and immunodetection of activated STAT1 hypertrophic stages. FGFR3 has been associated to apoptosis of chondrocytes in identified as a negative regulator of TD fetus (Li et al. 1999; Legai-Mallet et al. endochondral growth since the targeted 1998). More recently, in vitro studies with disruption of the mouse fgfr3 gene causes chondrocytic cells (RCS) and human a skeletal overgrowth (Colvin et al. 1996; epithelial cells (HEK293) show that the Deng et al. 1996). FGFR3 belongs to the TDII mutation hampers the complete family (RTKs). maturation of FGFR3 leading the FGFR3 is a glycosylated transmembrane immature phosphorylated FGFR3 forms to protein (Keegan et al. 1991, Lievens and signal from the Endoplasmic Reticulum, Liboi 2003) that upon binding with FGF which fails to be degraded (Lievens and ligands and heparin dimerizes and Liboi 2003). Consequently, it was undergoes interchain autophosphorylation proposed that the defect in down of key tyrosine residues, thus transmitting regulation of the highly activated receptor signals into the cells (Basilico and results in the increased signalling capacity

Liboi E and Lievens P.M-J. Thanatophoric dysplasia. Orphanet encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/uk-Thanatophoric-dysplasia.pdf 3

from intracellular compartments that may weeks gestation or chorionic villus determine the severity of the disease. This sampling at about 10-12 weeks gestation. has been associated to the high level of Routine prenatal ultrasound examination FGFR3 tyrosine kinase activity caused by may identify skeletal alterations associated the K650E substitution (Lievens et al. to TD such as cloverleaf skull, very short 2004). extremities, and a small thorax.

Clinical description Management Prenatal diagnosis allows determining Most individuals with TD die within the first both TDI and TDII. Most affected few hours or days of life by respiratory individuals die of respiratory insufficiency insufficiency secondary to reduced within the first hours of life. Some die after thoracic capacity or compression of the a few days of life. Respiratory insufficiency brainstem. Management concerns are may be secondary to a small chest cavity limited to extreme life support measures and hypoplasia, compression of the for the newborn. brain stem by the small foramen magnum In the rare cases of long-term survival, the or a combination of these (Baker et al. management consists in treatment of 1997). Rare long-term survival (a 4.7 year manifestations: male and a 3.7 year female) has been - respiratory support (tracheostomy, reported (MacDonald et al. 1989). Both ventilation) had birth length and weight below the third - medication to control seizures percentile. In both, growth plateaued after - shunt placement when hydrocephaly is 10 months of age. Clinical profile includes identified micromelia, redundant skin folds, - suboccipital decompression for relief of and a small foramen craniocervical junction constriction magnum. Furthermore, a 9 year-old male - hearing aids when hearing loss is with TDI (R248 mutation) with extensive identified acanthosis nigricans and a severe - orthopedic evaluation upon the developmental delay with no language has development of joint contractures or joint been reported (Baker et al. 1997). . A 47-year-old female with TDI (R248C mutation) presents asymmetrical limb References length, bilateral congenital hip dislocation, Baker K.M., Olson D.M., Harding C.O., focal areas of bone bowing and an S- Pauli R.M. Long term survival in typical shaped humerus, extensive acanthosis thanatophoryc dysplasia type I. Am. J. nigricans, redundant skin folds along the Med. Genet. (1997) 70:427-436. length of the limbs and a flexion Bartner A.C., Maurer S.G., Gruen M.B., deformities of the knees and elbows DiCesare P.E. The genetic basis of (Hyland et al. 2003). . J. Ped. No strong genotype-phenotype correlation Orthoped. (2000) 594-605. for FGFR3 mutations causing TD exists. Basilico C. and Moscatelli D. The FGF family of growth factors and oncogenes. Genetic counseling Adv. Cancer Res. (1992) 59:115-165. Thanatophoric dysplasia type I and Bellus G.A., Spector E.B., Speiser P.W., thanatophoric dysplasia type II are caused Weaver C.A., Garber A.T., Bryke C.R., by de novo autosomal dominant mutations Israel J., Rosengren S.S., Webster M.K., in FGFR3. Recurrence risk is not Donoghue D.J., Francomano C.A. Distinct significantly increased over that of the missense mutations of the FGFR3 Lys650 general population. Germline mosaicism in codon modulate receptor kinase activation healthy parents, although not previously and severity of the skeletal dysplasia reported, remains a theoretical possibility. phenotype. Am. J. Hum. Genet. (2000) Prenatal diagnosis is clinically available, 67:1411-1421. and is reliable both through sonography Caplan A.I. and Pechak D.G. The cellular and through molecular studies. and molecular embryology of bone formation. In: Bone and Mineral research Diagnostic methods (1987) pp.117-183. Prenatal diagnosis is performed by Chen C.P., Chern S.R., Shih J.C., Wang analysis of DNA (FGFR3 sequences) W., Yeh L.F., Chang T.Y., Tzen C.Y. extracted from fetal cells obtained by Prenatal diagnosis and genetic analysis of amniocentesis usually performed at 15-18

Liboi E and Lievens P.M-J. Thanatophoric dysplasia. Orphanet encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/uk-Thanatophoric-dysplasia.pdf 4

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Liboi E and Lievens P.M-J. Thanatophoric dysplasia. Orphanet encyclopedia. September 2004. http://www.orpha.net/data/patho/GB/uk-Thanatophoric-dysplasia.pdf 6