TD2
MCID: THN010
MIFTS: 45

Thanatophoric Dysplasia, Type Ii (TD2)

Categories: Bone diseases, Fetal diseases, Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Thanatophoric Dysplasia, Type Ii

MalaCards integrated aliases for Thanatophoric Dysplasia, Type Ii:

Name: Thanatophoric Dysplasia, Type Ii 57 13
Td2 57 20 58 72
Thanatophoric Dysplasia with Kleeblattschaedel 57 20 72
Cloverleaf Skull with Thanatophoric Dwarfism 57 20 72
Thanatophoric Dysplasia with Straight Femurs and Cloverleaf Skull 57 72
Cloverleaf Skull-Micromelic Bone Dysplasia Syndrome 20 58
Thanatophoric Dwarfism-Cloverleaf Skull Syndrome 20 58
Thanatophoric Dysplasia Type Ii 20 72
Thanatophoric Dysplasia, Type 2 29 6
Thanatophoric Dysplasia Type 2 20 58
Thanatophoric Dwarfism Type 2 20 58
Thanatophoric Dwarfism - Cloverleaf Skull 20
Dysplasia, Thanatophoric, Type Ii 39
Thanatophoric Dysplasia 2 72

Characteristics:

Orphanet epidemiological data:

58
thanatophoric dysplasia type 2
Inheritance: Autosomal dominant,Not applicable; Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal dominant

Miscellaneous:
death in majority of infants soon after birth


HPO:

31
thanatophoric dysplasia, type ii:
Onset and clinical course neonatal death
Inheritance autosomal dominant inheritance


Classifications:

Orphanet: 58  
Rare bone diseases
Developmental anomalies during embryogenesis


Summaries for Thanatophoric Dysplasia, Type Ii

GARD : 20 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 93274 Definition Thanatophoric dysplasia, type 2 (TD2) is a form of TD (see this term) characterized by micromelia, straight long-bones, macrocephaly, brachydactyly, shortened ribs and a clover-leaf skull ( kleeblattschaedel ). Epidemiology The prevalence is unknown but it is less common than TD1 (see this term). Clinical description TD2 presents in the prenatal period (in the first to second trimester) with micromelia, long-bones (femurs) that are straight and not as short as those seen in TD type 1, platyspondyly of the vertebrae, narrow thorax, and a cloverleaf (trilobed) skull. Distinctive facial features include macrocephaly, frontal bossing, low nasal bridge, large anterior fontanel and proptosis. Polyhydramnios is common. Neonates usually die shortly after birth due to respiratory insufficiency and/or spinal cord/brain stem compression. Etiology TD2 is caused by a single missense mutation (K650E) in the fibroblast growth factor receptor 3 ( FGFR3 ) gene, located to chromosome 4p16.3. Genetic counseling TD2 is inherited autosomal dominantly but the majority of cases are due to a de novo mutation in the proband. Genetic counseling allows families who have already had one child with TD2 to know that recurrence rate is about 2%, so their chance of having a healthy child is high. Expert reviewers: Dr. Michael Bober and Ms. Angie Duker

MalaCards based summary : Thanatophoric Dysplasia, Type Ii, also known as td2, is related to thanatophoric dysplasia, type i and odontochondrodysplasia. An important gene associated with Thanatophoric Dysplasia, Type Ii is FGFR3 (Fibroblast Growth Factor Receptor 3), and among its related pathways/superpathways are ErbB signaling pathway and Negative regulation of FGFR3 signaling. Affiliated tissues include bone, spinal cord and kidney, and related phenotypes are macrocephaly and respiratory insufficiency

OMIM® : 57 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), whereas TD cases with curved, short femurs with or without cloverleaf skull were designated TD type I (TD1; 187600) (Langer et al., 1987). (187601) (Updated 05-Apr-2021)

UniProtKB/Swiss-Prot : 72 Thanatophoric dysplasia 2: A neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull.

Related Diseases for Thanatophoric Dysplasia, Type Ii

Graphical network of the top 20 diseases related to Thanatophoric Dysplasia, Type Ii:



Diseases related to Thanatophoric Dysplasia, Type Ii

Symptoms & Phenotypes for Thanatophoric Dysplasia, Type Ii

Human phenotypes related to Thanatophoric Dysplasia, Type Ii:

58 31 (show all 48)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 macrocephaly 58 31 hallmark (90%) Very frequent (99-80%) HP:0000256
2 respiratory insufficiency 58 31 hallmark (90%) Very frequent (99-80%) HP:0002093
3 skeletal dysplasia 58 31 hallmark (90%) Very frequent (99-80%) HP:0002652
4 depressed nasal bridge 58 31 hallmark (90%) Very frequent (99-80%) HP:0005280
5 short stature 58 31 hallmark (90%) Very frequent (99-80%) HP:0004322
6 cognitive impairment 58 31 hallmark (90%) Very frequent (99-80%) HP:0100543
7 abnormality of the metaphysis 58 31 hallmark (90%) Very frequent (99-80%) HP:0000944
8 short thorax 58 31 hallmark (90%) Very frequent (99-80%) HP:0010306
9 flat face 58 31 hallmark (90%) Very frequent (99-80%) HP:0012368
10 brachydactyly 58 31 hallmark (90%) Very frequent (99-80%) HP:0001156
11 platyspondyly 58 31 hallmark (90%) Very frequent (99-80%) HP:0000926
12 joint hyperflexibility 58 31 hallmark (90%) Very frequent (99-80%) HP:0005692
13 redundant skin 58 31 hallmark (90%) Very frequent (99-80%) HP:0001582
14 aplasia/hypoplasia of the lungs 58 31 hallmark (90%) Very frequent (99-80%) HP:0006703
15 narrow chest 58 31 hallmark (90%) Very frequent (99-80%) HP:0000774
16 micromelia 58 31 hallmark (90%) Very frequent (99-80%) HP:0002983
17 cloverleaf skull 58 31 hallmark (90%) Very frequent (99-80%) HP:0002676
18 hypotonia 31 hallmark (90%) HP:0001252
19 frontal bossing 58 31 frequent (33%) Frequent (79-30%) HP:0002007
20 kyphosis 58 31 frequent (33%) Frequent (79-30%) HP:0002808
21 hearing impairment 58 31 frequent (33%) Frequent (79-30%) HP:0000365
22 polyhydramnios 58 31 frequent (33%) Frequent (79-30%) HP:0001561
23 ventriculomegaly 58 31 frequent (33%) Frequent (79-30%) HP:0002119
24 proptosis 58 31 frequent (33%) Frequent (79-30%) HP:0000520
25 increased nuchal translucency 58 31 frequent (33%) Frequent (79-30%) HP:0010880
26 seizure 31 frequent (33%) HP:0001250
27 hydrocephalus 58 31 occasional (7.5%) Occasional (29-5%) HP:0000238
28 atrial septal defect 58 31 occasional (7.5%) Occasional (29-5%) HP:0001631
29 patent ductus arteriosus 58 31 occasional (7.5%) Occasional (29-5%) HP:0001643
30 holoprosencephaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0001360
31 abnormality of the kidney 58 31 occasional (7.5%) Occasional (29-5%) HP:0000077
32 limitation of joint mobility 58 31 occasional (7.5%) Occasional (29-5%) HP:0001376
33 acanthosis nigricans 58 31 occasional (7.5%) Occasional (29-5%) HP:0000956
34 abnormality of neuronal migration 58 31 occasional (7.5%) Occasional (29-5%) HP:0002269
35 encephalocele 58 31 occasional (7.5%) Occasional (29-5%) HP:0002084
36 seizures 58 Frequent (79-30%)
37 muscular hypotonia 58 Very frequent (99-80%)
38 decreased fetal movement 31 HP:0001558
39 small abnormally formed scapulae 31 HP:0006584
40 short ribs 31 HP:0000773
41 hypoplastic ilia 31 HP:0000946
42 lethal short-limbed short stature 31 HP:0008909
43 flared metaphysis 31 HP:0003015
44 metaphyseal irregularity 31 HP:0003025
45 small face 31 HP:0000274
46 small foramen magnum 31 HP:0002677
47 short greater sciatic notch 31 HP:0003185
48 wide-cupped costochondral junctions 31 HP:0000910

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Respiratory Lung:
respiratory insufficiency

Prenatal Manifestations Amniotic Fluid:
polyhydramnios

Chest Ribs Sternum Clavicles And Scapulae:
short ribs
wide-cupped costochondral junctions
small abnormally formed scapula

Skeletal Skull:
small foramen magnum
severe cloverleaf skull (kleeblattschaedel)

Prenatal Manifestations Movement:
decreased fetal activity

Skeletal Pelvis:
short and small iliac bones
small sacroiliac notches

Prenatal Manifestations:
prenatal diagnosis by ultrasound

Skeletal Hands:
brachydactyly

Skeletal Spine:
platyspondyly

Head And Neck Face:
small face

Chest External Features:
narrow thorax

Growth Height:
dwarfism, lethal micromelic

Skeletal Limbs:
flared and irregular metaphyses
straight femurs

Head And Neck Head:
clover leaf head

Clinical features from OMIM®:

187601 (Updated 05-Apr-2021)

MGI Mouse Phenotypes related to Thanatophoric Dysplasia, Type Ii:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 digestive/alimentary MP:0005381 9.43 FGFR3 SPRY2 STAT1
2 limbs/digits/tail MP:0005371 9.33 FGFR3 SPRY2 STAT1
3 neoplasm MP:0002006 9.13 FGFR3 SPRY2 STAT1
4 respiratory system MP:0005388 8.8 FGFR3 SPRY2 STAT1

Drugs & Therapeutics for Thanatophoric Dysplasia, Type Ii

Search Clinical Trials , NIH Clinical Center for Thanatophoric Dysplasia, Type Ii

Genetic Tests for Thanatophoric Dysplasia, Type Ii

Genetic tests related to Thanatophoric Dysplasia, Type Ii:

# Genetic test Affiliating Genes
1 Thanatophoric Dysplasia, Type 2 29 FGFR3

Anatomical Context for Thanatophoric Dysplasia, Type Ii

MalaCards organs/tissues related to Thanatophoric Dysplasia, Type Ii:

40
Bone, Spinal Cord, Kidney, Brain, Cerebellum

Publications for Thanatophoric Dysplasia, Type Ii

Articles related to Thanatophoric Dysplasia, Type Ii:

(show all 39)
# Title Authors PMID Year
1
Thanatophoric dysplasia type 2 with encephalocele during the second trimester. 6 57
16752380 2006
2
Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. 6 57
9677066 1998
3
Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. 6 57
7773297 1995
4
A central nervous system specific mouse model for thanatophoric dysplasia type II. 61 57
12966031 2003
5
The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. 6 61
12624096 2003
6
Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. 6
19855393 2009
7
Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia. 6
16912704 2006
8
Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. 6
9207791 1997
9
Thanatophoric dysplasia of the straight-bone type (type 2). 57
1345514 1992
10
Prevalence of lethal osteochondrodysplasias in Denmark. 57
2789000 1989
11
Thanatophoric dysplasia with cloverleaf skull. 57
6351595 1983
12
Discordance for the Kleeblattschädel anomaly in monozygotic twins with thanatophoric dysplasia. 57
6683076 1983
13
Cloverleaf skull and thanatophoric dwarfism. Report of four cases, two in the same sibship. 57
5315768 1971
14
Mutant FGFR3 associated with SADDAN disease causes cytoskeleton disorganization through PLCγ1/Src-mediated paxillin hyperphosphorylation. 61
29242050 2018
15
Prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II and a review of prenatal diagnosis of brain anomalies associated with thanatophoric dysplasia. 61
29458880 2018
16
HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia. 61
27506979 2016
17
Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes. 61
25432534 2015
18
Dysmorphic choroid plexuses and hydrocephalus associated with increased nuchal translucency: early ultrasound markers of de novo thanatophoric dysplasia type II with cloverleaf skull (Kleeblattschaedel). 61
24517215 2014
19
FGFR3 induces degradation of BMP type I receptor to regulate skeletal development. 61
24657641 2014
20
Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation. 61
23972473 2013
21
Rapid detection of K650E mutation in FGFR3 using uncultured amniocytes in a pregnancy affected with fetal cloverleaf skull, occipital pseudoencephalocele, ventriculomegaly, straight short femurs, and thanatophoric dysplasia type II. 61
24075385 2013
22
A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. 61
23014564 2012
23
Disruption of a Sox9-β-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II. 61
22843502 2012
24
Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis. 61
21204232 2011
25
Cell adaptation to activated FGFR3 includes Sprouty4 up regulation to inhibit the receptor-mediated ERKs activation from the endoplasmic reticulum. 61
19761767 2009
26
Sprouty 2 disturbs FGFR3 degradation in thanatophoric dysplasia type II: a severe form of human achondroplasia. 61
18485666 2008
27
Transient dimerization and interaction with ERGIC-53 occur in the fibroblast growth factor receptor 3 early secretory pathway. 61
18577465 2008
28
FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. 61
16091734 2005
29
Dichorionic twins discordant for thanatophoric dysplasia managed with selective reduction at 20 weeks' gestation: a case report. 61
16220775 2005
30
Constitutively activated FGFR3 mutants signal through PLCgamma-dependent and -independent pathways for hematopoietic transformation. 61
15784730 2005
31
Thanatophoric dysplasia type II with encephalocele and aortic hypoplasia diagnosed in an anatomical specimen. 61
12605444 2003
32
Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. 61
11406607 2001
33
Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. 61
11055896 2000
34
Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. 61
10918587 2000
35
A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. 61
10861287 2000
36
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. 61
10377013 1999
37
Thanatophoric dysplasia type II: new entity? 61
9481651 1998
38
Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. 61
9069288 1997
39
Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. 61
8754806 1996

Variations for Thanatophoric Dysplasia, Type Ii

ClinVar genetic disease variations for Thanatophoric Dysplasia, Type Ii:

6 (show all 12)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 FGFR3 NM_000142.5(FGFR3):c.1948A>G (p.Lys650Glu) SNV Pathogenic 16331 rs78311289 GRCh37: 4:1807889-1807889
GRCh38: 4:1806162-1806162
2 FGFR3 NM_001163213.1(FGFR3):c.746C>G (p.Ser249Cys) SNV Pathogenic 16339 rs121913483 GRCh37: 4:1803568-1803568
GRCh38: 4:1801841-1801841
3 FGFR3 NM_000142.5(FGFR3):c.1949A>C (p.Lys650Thr) SNV Pathogenic 65855 rs121913105 GRCh37: 4:1807890-1807890
GRCh38: 4:1806163-1806163
4 FGFR3 NM_000142.5(FGFR3):c.742C>T (p.Arg248Cys) SNV Pathogenic 16332 rs121913482 GRCh37: 4:1803564-1803564
GRCh38: 4:1801837-1801837
5 FGFR3 NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg) SNV Pathogenic 16340 rs4647924 GRCh37: 4:1803571-1803571
GRCh38: 4:1801844-1801844
6 FGFR3 NM_000142.5(FGFR3):c.1138G>A SNV Pathogenic 16327 rs28931614 GRCh37: 4:1806119-1806119
GRCh38: 4:1804392-1804392
7 FGFR3 NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys) SNV Pathogenic 16338 rs28933068 GRCh37: 4:1807371-1807371
GRCh38: 4:1805644-1805644
8 FGFR3 NM_000142.5(FGFR3):c.251C>T (p.Ser84Leu) SNV Pathogenic 16358 rs121913116 GRCh37: 4:1801122-1801122
GRCh38: 4:1799395-1799395
9 FGFR3 NM_000142.5(FGFR3):c.200G>A (p.Gly67Asp) SNV Uncertain significance 546226 rs369232922 GRCh37: 4:1801071-1801071
GRCh38: 4:1799344-1799344
10 FGFR3 NM_000142.5(FGFR3):c.1993G>T (p.Ala665Ser) SNV Uncertain significance 465350 rs764892330 GRCh37: 4:1808017-1808017
GRCh38: 4:1806290-1806290
11 FGFR3 NM_000142.5(FGFR3):c.2153A>G (p.Asn718Ser) SNV Uncertain significance 521225 rs139773438 GRCh37: 4:1808395-1808395
GRCh38: 4:1806668-1806668
12 FGFR3 NM_000142.5(FGFR3):c.200G>C (p.Gly67Ala) SNV Uncertain significance 978772 GRCh37: 4:1801071-1801071
GRCh38: 4:1799344-1799344

UniProtKB/Swiss-Prot genetic disease variations for Thanatophoric Dysplasia, Type Ii:

72
# Symbol AA change Variation ID SNP ID
1 FGFR3 p.Lys650Glu VAR_004160 rs78311289

Expression for Thanatophoric Dysplasia, Type Ii

Search GEO for disease gene expression data for Thanatophoric Dysplasia, Type Ii.

Pathways for Thanatophoric Dysplasia, Type Ii

Pathways related to Thanatophoric Dysplasia, Type Ii according to GeneCards Suite gene sharing:

(show all 11)
# Super pathways Score Top Affiliating Genes
1
Show member pathways
12.05 STAT1 FGFR3
2
Show member pathways
11.97 SPRY2 FGFR3
3 11.92 SPRY2 FGFR3
4
Show member pathways
11.87 STAT1 FGFR3
5
Show member pathways
11.69 STAT1 FGFR3
6
Show member pathways
11.66 SPRY2 FGFR3
7 11.54 STAT1 SPRY2
8
Show member pathways
11.46 STAT1 FGFR3
9 11.33 SPRY2 FGFR3
10 10.77 STAT1 FGFR3
11 10.3 STAT1 SPRY2

GO Terms for Thanatophoric Dysplasia, Type Ii

Biological processes related to Thanatophoric Dysplasia, Type Ii according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 positive regulation of ERK1 and ERK2 cascade GO:0070374 9.26 SPRY2 FGFR3
2 regulation of cell proliferation GO:0042127 9.16 STAT1 SPRY2
3 positive regulation of protein kinase B signaling GO:0051897 8.96 SPRY2 FGFR3
4 negative regulation of angiogenesis GO:0016525 8.62 STAT1 SPRY2

Sources for Thanatophoric Dysplasia, Type Ii

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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