Severe achondroplasia - developmental delay - acanthosis nigricans
General Information (adopted from Orphanet):
Synonyms, Signs:
THANATOPHORIC DYSPLASIA
LETHAL SHORT-LIMBED PLATYSPONDYLIC DWARFISM, SAN DIEGO TYPE ACHONDROPLASIA, SEVERE, WITH DEVELOPMENTAL DELAY AND ACANTHOSIS NIGRICANS, INCLUDED
PLATYSPONDYLIC LETHAL SKELETAL DYSPLASIA, SAN DIEGO TYPE
SADDAN, INCLUDED
SADDAN
THANATOPHORIC DWARFISM
TD
TD1
Thanatophoric dysplasia is a severe short-limb dwarfism syndrome that is usually lethal in the perinatal period. Norman et al. (1992) classified cases of TD into subtypes based on the presence of curved as opposed to straight femurs; patients ... Thanatophoric dysplasia is a severe short-limb dwarfism syndrome that is usually lethal in the perinatal period. Norman et al. (1992) classified cases of TD into subtypes based on the presence of curved as opposed to straight femurs; patients with straight, relatively long femurs always had associated severe cloverleaf skull and were designated TD type II (TD2), while TD cases with curved, short femurs with or without cloverleaf skull were designated TD type I (TD1) (Langer et al., 1987).
In utero diagnosis was demonstrated by Keats et al. (1970).
Although prenatal diagnosis of TD had been accomplished by ultrasonography in the second trimester (Schild et al., 1996), it was not ... - Prenatal Diagnosis In utero diagnosis was demonstrated by Keats et al. (1970). Although prenatal diagnosis of TD had been accomplished by ultrasonography in the second trimester (Schild et al., 1996), it was not always possible to distinguish between TD and other osteochondrodysplasias in utero. Using restriction enzyme analysis, Sawai et al. (1999) identified a mutation in the FGFR3 gene in a fetus at 27 weeks' gestation.
Maroteaux et al. (1967) referred to patients with micromelic dwarfism who died in the first hours of life as having 'thanatophoric dwarfism.' The ribs and bones of the extremities were very short and the vertebral bodies were greatly ... Maroteaux et al. (1967) referred to patients with micromelic dwarfism who died in the first hours of life as having 'thanatophoric dwarfism.' The ribs and bones of the extremities were very short and the vertebral bodies were greatly reduced in height with wide intervertebral spaces; caudad narrowing of the spinal canal was not present. Radiologically, the vertebral bodies were H-shaped in frontal projection, and the femurs were shaped like telephone receivers. Maroteaux et al. (1967) found cases in the literature that matched this description, the earliest reported by Maygrier (1898). Giedion (1968) described a Swiss patient with TD1 who had radioulnar synostosis and survived for 96 hours. Stensvold et al. (1986) reported survival for 169 days. The child had increasing hydrocephalus and the femurs were shaped like telephone receivers. Tonoki (1987) described a patient who survived for 212 days. MacDonald et al. (1989) reported unusually long survival; an unrelated boy and girl were still alive at the ages of 4.75 and 3.7 years, respectively. Both seemed to have disease of the usual severity. Surprisingly, the girl survived unsupported until age 2 months. Knisely (1989) pointed out that megalencephaly and highly characteristic temporal lobe malformations are invariably present in thanatophoric dysplasia and that other abnormalities in central nervous system topography are frequently apparent by microscopy (Wongmongkolrit et al., 1983; Ho et al., 1984). Baker et al. (1997) reported a patient with TD1 who survived beyond age 9 years. This patient also had acanthosis nigricans. The authors referred to another TD long-term survivor with acanthosis nigricans. This skin disorder also occurs in Crouzon syndrome (123500) when caused by a FGFR3 mutation (134934.0011). Genetic analysis in the patient of Baker et al. (1997) identified a common FGFR3 mutation (R248C; 134934.0005). Pannier et al. (2009) reported a fetus with lethal TD1 ascertained at 24 weeks' gestation when the fetus was noted to have severe dwarfism. The pregnancy was terminated. Radiographic studies showed severe rhizomelic shortness of the long bones and mild bowing of the femora, radii, and ulnae. The spine showed severe platyspondyly with H-shaped vertebrae and narrowing of the interpediculate distance. The thorax was small with short ribs, and the iliac bones were short and wide. Macrocrania and frontal bossing were observed; there was no evidence of a cloverleaf skull. Postmortem examination showed cerebral cortical malformations with temporal lobe polymicrogyria and severe disorganization of growth plates in the long bones. Genetic analysis identified heterozygosity for 2 de novo missense mutations in the FGFR3 gene on the same allele (N540K and Q485R; 134934.0034). The authors noted that the N540K mutation in isolation (134934.0010) usually results in the less severe phenotype of hypochondroplasia (HCH; 146000). - Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans Tavormina et al. (1999) reported 4 unrelated individuals with a distinctive syndrome comprising severe achondroplasia with developmental delay and acanthosis nigricans, which they referred to as SADDAN dysplasia. The severity approached that observed in TD1. Differences included the development of extensive areas of acanthosis nigricans beginning in early childhood in 3 of 4 patients, severe neurologic impairments, and survival past infancy without prolonged life-support measures. All had a heterozygous K650M mutation (134934.0015) in the FGFR3 gene resulting in a dramatic increase in constitutive receptor kinase activity. Zankl et al. (2008) reported a patient with the SADDAN phenotype and a heterozygous K650M mutation in the FGFR3 gene. He had severe micromelia, frontal bossing, large anterior fontanel, depressed nasal bridge, reverse tibial bowing, small thorax, and hypotonia. Acanthosis nigricans was not present. He died at age 21 days due to respiratory failure. Zankl et al. (2008) noted that about half of patients reported with the K650M mutation died before 21 days of age, whereas others have shown longer survival. The authors also noted that acanthosis nigricans has been reported in patients with other skeletal dysplasias due to FGFR3 mutations, and thus should be considered a long-term complication rather than a specific feature of SADDAN. In addition, mental retardation only becomes apparent in long-term survivors and thus cannot be used as a diagnostic criterion for SADDAN in the neonatal period. - Reviews Sillence et al. (1978) provided a review of neonatal dwarfism, including thanatophoric dysplasia.
Wilcox et al. (1998) examined the clinical, radiographic, and histologic findings in 91 cases with FGFR3 mutations from the International Skeletal Dysplasia Registry. The most common mutation was R248C (134934.0005), occurring in 45 (50%) cases, and the second ... Wilcox et al. (1998) examined the clinical, radiographic, and histologic findings in 91 cases with FGFR3 mutations from the International Skeletal Dysplasia Registry. The most common mutation was R248C (134934.0005), occurring in 45 (50%) cases, and the second most common mutation was Y373C (134934.0016), occurring in 18 cases (20%). All of these patients had TD1 characterized by curved femora and infrequent cloverleaf skull. All 17 (19%) patients with the K650E mutation (134934.0004) had TD2, characterized by straight femora with craniosynostosis and frequent cloverleaf skull. TD1 patients with the Y373C mutation tended to have more severe radiographic manifestations than TD1 patients with the R248C mutation, but there was phenotypic overlap between them. Histopathologically, all cases shared similar abnormalities, but those with the K650E mutation had better preservation of the growth plate.
Reardon et al. (1994) noted that fibroblast growth factor receptor-3 (FGFR3; 134934), which is mutant in achondroplasia, is structurally very similar to FGFR2. Their observation that FGFR2 mutations cause craniosynostosis suggested to them that the lethal skeletal disorder ... Reardon et al. (1994) noted that fibroblast growth factor receptor-3 (FGFR3; 134934), which is mutant in achondroplasia, is structurally very similar to FGFR2. Their observation that FGFR2 mutations cause craniosynostosis suggested to them that the lethal skeletal disorder TD2 with cloverleaf skull (187601) may be a good candidate for further mutation searches in FGFR3. Furthermore, because of the phenotypic similarities between TD and homozygous achondroplasia, Arthur Beaudet independently suggested to Wasmuth (1995) that FGFR3 be studied in cases of TD. Indeed, Tavormina et al. (1995) found that 23 of 39 TD1 patients harbored amino acid substitutions in the extracellular domain of FGFR3. Of these, 22 patients were found to be heterozygous for the R248C substitution (134934.0005). One patient had a S371C substitution (134934.0006). Phenotypic heterogeneity was observed in TD1, in that 6 of 11 TD1 patients with cloverleaf skull and 16 of 28 patients without cloverleaf skull had the R248C mutation. In addition, Tavormina et al. (1995) found that all 16 patients with TD2 had a heterozygous K650E substitution (134934.0004). All 16 patients with TD2 had severe cloverleaf skull deformity with straight femurs. In a subsequent paper, Tavormina et al. (1995) identified a S249C mutation (134934.0013) in 4 cases of TD1. The authors proposed that the severe lethal phenotype in TD1 was more directly related to the introduction of a new cysteine residue than to the specific site of the amino acid substitution. They speculated that an unpaired cysteine residue in the cytoplasmic region of the protein may result in formation of intermolecular disulfide hybrids between two FGFR3 monomers, resulting in a constitutively active mutant receptor homodimer complex. Rousseau et al. (1996) performed FGFR3 mutation analysis in 26 cases of TD1. Three missense mutations (Y373C, 134934.0016; R248C, 134934.0005; S249C, 134934.0013) accounted for 73% of the cases. Two stop codon mutations (X807R, 134934.0008; X807C, 134934.0009) and 1 rare G370C mutation were also found. Rousseau et al. (1996) noted that all reported missense mutations created cysteine residues and were located in the extracellular domain of the receptor. The findings provided support for the hypothesis that the newly created cysteine residues may allow disulfide bonds to form between the extracellular domains of mutant monomers, thus inducing constitutive activation of the homodimer receptor complex. Brodie et al. (1999) examined 22 cases of thanatophoric dysplasia variants for the presence of missense mutations in FGFR3. All 17 cases of the San Diego variant (originally called the San Diego form of lethal short-limbed platyspondylic dysplasia) were heterozygous for the same FGFR3 mutations found in TD1; the R248C mutation was present in 7 of the 17 cases. Large inclusion bodies were found in all 14 cases of the San Diego type in which they were sought. Similar inclusion bodies were present in 2 of 72 thanatophoric dysplasia type I cases, but not in 39 controls. The material retained within the rough endoplasmic reticulum stained only with antibody to the FGFR3 protein. No mutations were identified in patients with the Torrance and Luton types of TD (151210). Brodie et al. (1999) suggested that the radiographic and cellular differences between thanatophoric dysplasia and the San Diego variant may be a consequence of other genetic factors, perhaps in the processing of mutant FGFR3 molecules within the rough endoplasmic reticulum. Hall (2002) noted that the San Diego form of platyspondylic lethal skeletal dysplasia (PLSD) described by Horton et al. (1979) had been classified as the same as thanatophoric dysplasia type I.
Camera and Mastroiacovo (1982) identified 13 cases of thanatophoric dysplasia among 217,061 Italian births. All were sporadic. In the same series, there were 8 cases of achondroplasia (100800) and 1 case each of camptomelic dysplasia (114290), Ellis-van Creveld ... Camera and Mastroiacovo (1982) identified 13 cases of thanatophoric dysplasia among 217,061 Italian births. All were sporadic. In the same series, there were 8 cases of achondroplasia (100800) and 1 case each of camptomelic dysplasia (114290), Ellis-van Creveld syndrome (225500), Larsen syndrome (150250), and Langer mesomelic dysplasia (249700). Thanatophoric dysplasia was the most frequent skeletal dysplasia. Connor et al. (1985) identified 43 cases of lethal neonatal short-limb chondrodysplasias in the West of Scotland for the period 1970 to 1983, representing a minimum incidence of 1 in 8,900. TD had an incidence of 1 in 42,221 births. The differential diagnosis included a number of well-delineated skeletal dysplasias: asphyxiating thoracic dysplasia (208500), achondrogenesis type II (200700), short-rib polydactyly I (263530), metatropic dysplasia (156530), OI congenita (166210), campomelic dysplasia (114290), rhizomelic chondrodysplasia punctata (215100), hypophosphatasia (241500), SED congenita (183900), one case of Warfarin embryopathy, and one apparently 'new' condition with presumed autosomal recessive inheritance (see 273680). Orioli et al. (1986) estimated the frequency of TD to be approximately 1 in 20,000 births, making it the most common neonatal lethal skeletal dysplasia. In a collaborative study in Spain, Martinez-Frias et al. (1988) identified 13 cases among 517,970 births, an incidence of 2.7 per 100,000 births. Between 1970 and 1983 in Denmark, Andersen (1989) found 2 cases of thanatophoric dysplasia among 77,977 births, including stillbirths. In addition, there was 1 case of thanatophoric dysplasia with cloverleaf skull. Using data from 7 population-based birth defects monitoring programs in the United States, Waller et al. (2008) estimated the prevalence of achondroplasia and thanatophoric dysplasia and presented data on the association between older paternal age and these conditions. The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 live births (1/33,330-1/47,620 live births). The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 live births (1/27,780-1/16,670 live births). These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences on the prevalence of these conditions across monitoring programs were consistent with random fluctuation. In Texas, fathers that were 25-29, 30-34, 35-39, and over 40 years of age had significantly increased rates of de novo achondroplasia and thanatophoric dysplasia among their offspring compared with younger fathers.
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....
Diagnosis
Clinical DiagnosisThanatophoric 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 trimesterShortening of the long bones, possibly visible as early as 12 to 14 weeks' gestationIncreased nuchal translucency (two case reports) and reverse flow in the ductus venosus (one case report), possibly the result of the narrow thorax compressing vascular flowSecond/third trimesterGrowth deficiency with limb length below fifth centile recognizable by 20 weeks' gestationWell-ossified spine and skullPlatyspondylyVentriculomegalyNarrow chest cavity with short ribsPolyhydramniosBowed femurs (TD type I)Encephalocele (two cases)Cloverleaf skull (kleeblattschaedel) (often in TD type II; occasionally in TD type I) and/or relative macrocephalyNote: 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]:MacrocephalyLarge anterior fontanelFrontal bossing, flat facies with low nasal bridge, proptotic eyesMarked shortening of the limbs (micromelia)Trident hand with brachydactylyRedundant skin foldsNarrow bell-shaped thorax with short ribs and protuberant abdomenRelatively normal trunk lengthGeneralized hypotoniaBowed 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 bonesIrregular metaphyses of the long bonesPlatyspondylySmall foramen magnum with brain stem compressionCNS abnormalities including temporal lobe malformations, hydrocephaly, brain stem hypoplasia, neuronal migration abnormalitiesBowed 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.TestingHistopathology [Wilcox et al 1998, Lemyre et al 1999]:Disorganized chondrocyte columnsPoor cellular proliferationLateral overgrowth of the metaphyseal boneMesenchymal cells extending inward forming a fibrous band at the periphery of the physeal boneIncreased vascularity of the resting cartilageMolecular Genetic TestingGene. 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 testingTargeted mutation analysis of FGFR3 using a panel of most or all of the reported FGFR3 mutationsSequence 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 15Sequence 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 DysplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method and Phenotype 1Test AvailabilityTD Type ITD Type IIFGFR3Targeted mutation analysis; sequence analysis of select regions
Reported mutations 2, 3Up to 99%NAClinical p.Lys650Glu NA>99%Sequence analysis of entire coding region 4FGFR3 sequence variants 5>99%>99%NA = not applicable1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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].3. Mutation panels and detection rates may vary among laboratories. 4. Not clinically indicated; see Molecular Genetic Testing, Sequence analysis of the entire FGFR3 coding region.5. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo 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). Genetically Related (Allelic) DisordersFGFR3 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....
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 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]. ...
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 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).
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]:...
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 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 caused by TRIP11 mutations; 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 gene, HSPG2 [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:...
Management
Evaluations Following Initial DiagnosisTo 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 MRITreatment of ManifestationsManagement 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 populationShunt placement, when hydrocephaly is identifiedSuboccipital decompression for relief of craniocervical junction constrictionHearing aids, when hearing loss is identifiedPrevention of Secondary ComplicationsWhen 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.SurveillanceThe following are appropriate:Routine assessment of neurologic status on physical examinationOrthopedic evaluation upon the development of joint contractures or joint hypermobility [Wilcox et al 1998] Audiology assessmentCT 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 activityEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFGFR34p16.3
Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3Data 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) View in own window 134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3 187600THANATOPHORIC DYSPLASIA, TYPE I; TD1 187601THANATOPHORIC DYSPLASIA, TYPE II; TD2Normal 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 variantsTD 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 VariantsView in own windowPhenotypeClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference SequencesNot applicableNormalc. 882C>Tp.(=) 2 (N294N)NM_000142.3 NP_000133.1c.1953A>Gp.(=) (T651T)TD type IPathologicc.742C>Tp.Arg248Cys 3 c.746C>Gp.Ser249Cysc.1108G>Tp.Gly370Cys c.1111A>Tp.Ser371Cys c.1118A>Gp.Tyr373Cys 3 c.1949A>Tp.Lys650Met c.2420G>Tp.X807LeuextX101 c.2419T>Gp.X807GlyextX101 c.2419T>Cp.X807ArgextX101 c.2419T>Ap.X807ArgextX101 c.2421A>Tp.X807CysextX101 c.2421A>Cp.X807CysextX101 c.2421A>Gp.X807TrpextX101 TD type IIc.1948A>Gp.Lys650Glu SADDAN c.1949A>Tp.Lys650Met Achondroplasiac.1123G>Tp.Gly375Cysc.1138G>C/Ap.Gly380ArgCrouzon syndrome with acanthosis nigricansc.1172C>Ap.Ala391GluNonsyndromic coronal synostosis(Muenke syndrome)c.749C>Gp.Pro250ArgFamilial acanthosis nigricans c.1949A>C p.Lys650ThrLADD syndromec.1537G>Ap.Asp513AsnSee 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 mutationsNormal 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].