TD2
MCID: THN010
MIFTS: 51

Thanatophoric Dysplasia, Type Ii (TD2)

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

Aliases & Classifications for Thanatophoric Dysplasia, Type Ii

MalaCards integrated aliases for Thanatophoric Dysplasia, Type Ii:

Name: Thanatophoric Dysplasia, Type Ii 58 13
Td2 58 54 60 76
Thanatophoric Dysplasia with Kleeblattschaedel 58 54 76
Cloverleaf Skull with Thanatophoric Dwarfism 58 54 76
Thanatophoric Dysplasia with Straight Femurs and Cloverleaf Skull 58 76
Cloverleaf Skull-Micromelic Bone Dysplasia Syndrome 54 60
Thanatophoric Dwarfism-Cloverleaf Skull Syndrome 54 60
Thanatophoric Dysplasia Type Ii 54 76
Thanatophoric Dysplasia, Type 2 30 6
Thanatophoric Dysplasia Type 2 54 60
Thanatophoric Dwarfism Type 2 54 60
Thanatophoric Dwarfism - Cloverleaf Skull 54
Dysplasia, Thanatophoric, Type Ii 41
Thanatophoric Dysplasia 2 76

Characteristics:

Orphanet epidemiological data:

60
thanatophoric dysplasia type 2
Inheritance: Autosomal dominant,Not applicable; Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM:

58
Inheritance:
autosomal dominant

Miscellaneous:
death in majority of infants soon after birth


HPO:

33
thanatophoric dysplasia, type ii:
Mortality/Aging neonatal death
Inheritance autosomal dominant inheritance


Classifications:



Summaries for Thanatophoric Dysplasia, Type Ii

NIH Rare Diseases : 54 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 93274Disease definitionThanatophoric 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).EpidemiologyThe prevalence is unknown but it is less common than TD1 (see this term).Clinical descriptionTD2 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.EtiologyTD2 is caused by a single missense mutation (K650E) in the fibroblast growth factor receptor 3 (FGFR3) gene, located to chromosome 4p16.3.Genetic counselingTD2 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 DukerVisit the Orphanet disease page for more resources.

MalaCards based summary : Thanatophoric Dysplasia, Type Ii, also known as td2, is related to thanatophoric dysplasia, type i and kleeblattschaedel. An important gene associated with Thanatophoric Dysplasia, Type Ii is FGFR3 (Fibroblast Growth Factor Receptor 3), and among its related pathways/superpathways are MicroRNAs in cancer and Signaling by FGFR2. The drugs Linagliptin and tannic acid have been mentioned in the context of this disorder. Affiliated tissues include bone, brain and spinal cord, and related phenotypes are macrocephaly and muscular hypotonia

OMIM : 58 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)

UniProtKB/Swiss-Prot : 76 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

Diseases in the Thanatophoric Dysplasia, Type I family:

Thanatophoric Dysplasia, Type Ii

Diseases related to Thanatophoric Dysplasia, Type Ii via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 thanatophoric dysplasia, type i 30.5 STAT1 FGFR3
2 kleeblattschaedel 10.2
3 encephalocele 10.2
4 corpus callosum, partial agenesis of, x-linked 10.1
5 achondroplasia 10.1
6 holoprosencephaly 10.1
7 hydrocephalus 10.1
8 dwarfism 10.1
9 semilobar holoprosencephaly 10.1
10 achondroplasia, severe, with developmental delay and acanthosis nigricans 9.6 STAT1 FGFR3

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:

60 33 (show all 46)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 macrocephaly 60 33 hallmark (90%) Very frequent (99-80%) HP:0000256
2 muscular hypotonia 60 33 hallmark (90%) Very frequent (99-80%) HP:0001252
3 respiratory insufficiency 60 33 hallmark (90%) Very frequent (99-80%) HP:0002093
4 skeletal dysplasia 60 33 hallmark (90%) Very frequent (99-80%) HP:0002652
5 depressed nasal bridge 60 33 hallmark (90%) Very frequent (99-80%) HP:0005280
6 short stature 60 33 hallmark (90%) Very frequent (99-80%) HP:0004322
7 cognitive impairment 60 33 hallmark (90%) Very frequent (99-80%) HP:0100543
8 cloverleaf skull 60 33 hallmark (90%) Very frequent (99-80%) HP:0002676
9 abnormality of the metaphysis 60 33 hallmark (90%) Very frequent (99-80%) HP:0000944
10 narrow chest 60 33 hallmark (90%) Very frequent (99-80%) HP:0000774
11 platyspondyly 60 33 hallmark (90%) Very frequent (99-80%) HP:0000926
12 micromelia 60 33 hallmark (90%) Very frequent (99-80%) HP:0002983
13 joint hyperflexibility 60 33 hallmark (90%) Very frequent (99-80%) HP:0005692
14 short thorax 60 33 hallmark (90%) Very frequent (99-80%) HP:0010306
15 flat face 60 33 hallmark (90%) Very frequent (99-80%) HP:0012368
16 brachydactyly 60 33 hallmark (90%) Very frequent (99-80%) HP:0001156
17 redundant skin 60 33 hallmark (90%) Very frequent (99-80%) HP:0001582
18 aplasia/hypoplasia of the lungs 60 33 hallmark (90%) Very frequent (99-80%) HP:0006703
19 frontal bossing 60 33 frequent (33%) Frequent (79-30%) HP:0002007
20 seizures 60 33 frequent (33%) Frequent (79-30%) HP:0001250
21 kyphosis 60 33 frequent (33%) Frequent (79-30%) HP:0002808
22 hearing impairment 60 33 frequent (33%) Frequent (79-30%) HP:0000365
23 ventriculomegaly 60 33 frequent (33%) Frequent (79-30%) HP:0002119
24 polyhydramnios 60 33 frequent (33%) Frequent (79-30%) HP:0001561
25 increased nuchal translucency 60 33 frequent (33%) Frequent (79-30%) HP:0010880
26 proptosis 60 33 frequent (33%) Frequent (79-30%) HP:0000520
27 hydrocephalus 60 33 occasional (7.5%) Occasional (29-5%) HP:0000238
28 acanthosis nigricans 60 33 occasional (7.5%) Occasional (29-5%) HP:0000956
29 patent ductus arteriosus 60 33 occasional (7.5%) Occasional (29-5%) HP:0001643
30 limitation of joint mobility 60 33 occasional (7.5%) Occasional (29-5%) HP:0001376
31 atrial septal defect 60 33 occasional (7.5%) Occasional (29-5%) HP:0001631
32 abnormality of neuronal migration 60 33 occasional (7.5%) Occasional (29-5%) HP:0002269
33 abnormality of the kidney 60 33 occasional (7.5%) Occasional (29-5%) HP:0000077
34 holoprosencephaly 60 33 occasional (7.5%) Occasional (29-5%) HP:0001360
35 encephalocele 60 33 occasional (7.5%) Occasional (29-5%) HP:0002084
36 decreased fetal movement 33 HP:0001558
37 small abnormally formed scapulae 33 HP:0006584
38 small face 33 HP:0000274
39 hypoplastic ilia 33 HP:0000946
40 short sacroiliac notch 33 HP:0003185
41 lethal short-limbed short stature 33 HP:0008909
42 short ribs 33 HP:0000773
43 flared metaphysis 33 HP:0003015
44 metaphyseal irregularity 33 HP:0003025
45 wide-cupped costochondral junctions 33 HP:0000910
46 small foramen magnum 33 HP:0002677

Symptoms via clinical synopsis from OMIM:

58
Respiratory Lung:
respiratory insufficiency

Skeletal Hands:
brachydactyly

Head And Neck Face:
small face

Chest External Features:
narrow thorax

Growth Height:
dwarfism, lethal micromelic

Skeletal Pelvis:
short and small iliac bones
small sacroiliac notches

Prenatal Manifestations:
prenatal diagnosis by ultrasound

Skeletal Spine:
platyspondyly

Prenatal Manifestations Amniotic Fluid:
polyhydramnios

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

Prenatal Manifestations Movement:
decreased fetal activity

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

Skeletal Limbs:
flared and irregular metaphyses
straight femurs

Head And Neck Head:
clover leaf head

Clinical features from OMIM:

187601

MGI Mouse Phenotypes related to Thanatophoric Dysplasia, Type Ii:

47
# Description MGI Source Accession Score Top Affiliating Genes
1 digestive/alimentary MP:0005381 9.5 FGFR3 SPRY2 STAT1
2 limbs/digits/tail MP:0005371 9.43 FGFR3 SPRY2 STAT1
3 neoplasm MP:0002006 9.33 FGFR3 SPRY2 STAT1
4 skeleton MP:0005390 9.13 FGFR3 SPRY2 STAT1
5 vision/eye MP:0005391 8.8 FGFR3 SPRY2 STAT1

Drugs & Therapeutics for Thanatophoric Dysplasia, Type Ii

Drugs for Thanatophoric Dysplasia, Type Ii (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 49)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Linagliptin Approved Phase 4 668270-12-0 10096344
2
tannic acid Approved Phase 4 1401-55-4
3
Amisulpride Approved, Investigational Phase 4 71675-85-9, 53583-79-2 2159
4
Benzocaine Approved, Investigational Phase 4 94-09-7, 1994-09-7 2337
5
Olanzapine Approved, Investigational Phase 4 132539-06-1 4585
6
Dopamine Approved Phase 4 62-31-7, 51-61-6 681
7 Hypoglycemic Agents Phase 4,Phase 2
8 HIV Protease Inhibitors Phase 4
9 Hormones Phase 4
10
protease inhibitors Phase 4
11 Glucagon-Like Peptide 1 Phase 4
12 Incretins Phase 4
13 Hormone Antagonists Phase 4
14 Dipeptidyl-Peptidase IV Inhibitors Phase 4
15 Hormones, Hormone Substitutes, and Hormone Antagonists Phase 4
16 Tranquilizing Agents Phase 4
17 Dopamine Antagonists Phase 4
18 Gastrointestinal Agents Phase 4
19 Antipsychotic Agents Phase 4
20 Antiemetics Phase 4
21 Serotonin Agents Phase 4
22 Serotonin Uptake Inhibitors Phase 4
23 Neurotransmitter Agents Phase 4,Phase 2
24 Psychotropic Drugs Phase 4
25 Antidepressive Agents, Second-Generation Phase 4
26 Autonomic Agents Phase 4,Phase 2
27 Antidepressive Agents Phase 4
28 Central Nervous System Depressants Phase 4
29 Neurotransmitter Uptake Inhibitors Phase 4
30 Peripheral Nervous System Agents Phase 4,Phase 2
31 Dopamine Agents Phase 4
32
Serotonin Investigational, Nutraceutical Phase 4 50-67-9 5202
33
Metformin Approved Phase 2 657-24-9 14219 4091
34
Glipizide Approved, Investigational Phase 2 29094-61-9 3478
35
Nevirapine Approved Phase 2 129618-40-2 4463
36
Emtricitabine Approved, Investigational Phase 2 143491-57-0 60877
37
Zidovudine Approved Phase 2 30516-87-1 35370
38
Nicotine Approved Phase 2 54-11-5 942 89594
39
Tenofovir Experimental, Investigational Phase 2 147127-20-6 464205
40 Anti-HIV Agents Phase 2
41 Nucleic Acid Synthesis Inhibitors Phase 2
42 Cytochrome P-450 CYP3A Inducers Phase 2
43 Anti-Retroviral Agents Phase 2
44 Reverse Transcriptase Inhibitors Phase 2
45 Antiviral Agents Phase 2
46 Anti-Infective Agents Phase 2
47 Cholinergic Agents Phase 2
48 Central Nervous System Stimulants Phase 2
49 Nicotinic Agonists Phase 2

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Effects of Linagliptin on Active GLP-1 Concentrations in Subjects With Renal Impairment Completed NCT01903070 Phase 4 Linagliptin
2 Tardive Dyskinesia and Cognitive Function Completed NCT00926965 Phase 4 amisulpride;Olanzapine;Conventional antipsychotics
3 Study to Improve Quality of Care and Patient Health in the Field of Cardiovascular Risk Factors in General Practice Completed NCT00348855 Phase 4
4 Evaluate Efficacy, Safety and Tolerability of AZD1656 as Add-on Treatment to Metformin in Type 2 Diabetes Mellitus (TD2M) Patients Completed NCT01020123 Phase 2 AZD1656;Placebo;Glipizide
5 Maternal TDF and FTC to Reduce NNRTI Resistance Mutations After Intrapartum NVP Completed NCT00204308 Phase 2 Combination tenofovir-emtricitabine
6 Nicotine Patch Safety Study Completed NCT01655082 Phase 2 V0116 transdermal patch;Nicotine transdermal patch
7 Study of Minnelide™ in Patients With Advanced GI Tumors Completed NCT01927965 Phase 1 Minnelide™ 001
8 HIIE and Abdominal Fat Mass in DT2 Postmenopausal Women Unknown status NCT02352246 Not Applicable
9 Genetic Markers and Proliferative Diabetic Retinopathy Recruiting NCT02879422 Not Applicable

Search 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 30 FGFR3

Anatomical Context for Thanatophoric Dysplasia, Type Ii

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

42
Bone, Brain, Spinal Cord, Skin, Kidney, Cerebellum

Publications for Thanatophoric Dysplasia, Type Ii

Articles related to Thanatophoric Dysplasia, Type Ii:

(show all 13)
# Title Authors Year
1
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. ( 29458880 )
2018
2
Dysmorphic choroid plexuses and hydrocephalus associated with increased nuchal translucency: Early ultrasound markers of de novo thanatophoric dysplasia type II with cloverleaf skull (Kleeblattschaedel). ( 24517215 )
2014
3
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. ( 24075385 )
2013
4
Disruption of a Sox9-I^-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II. ( 22843502 )
2012
5
Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis. ( 21204232 )
2011
6
Sprouty 2 disturbs FGFR3 degradation in thanatophoric dysplasia type II: a severe form of human achondroplasia. ( 18485666 )
2008
7
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. ( 12624096 )
2003
8
Thanatophoric dysplasia type II with encephalocele and aortic hypoplasia diagnosed in an anatomical specimen. ( 12605444 )
2003
9
A central nervous system specific mouse model for thanatophoric dysplasia type II. ( 12966031 )
2003
10
Murine pancreatic tumor cell line TD2 bears the characteristic pattern of genetic changes with two independently amplified gene loci. ( 14555993 )
2003
11
Thanatophoric dysplasia type II: new entity? ( 9481651 )
1998
12
Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. ( 9069288 )
1997
13
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. ( 8754806 )
1996

Variations for Thanatophoric Dysplasia, Type Ii

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

76
# Symbol AA change Variation ID SNP ID
1 FGFR3 p.Lys650Glu VAR_004160 rs78311289

ClinVar genetic disease variations for Thanatophoric Dysplasia, Type Ii:

6
# Gene Variation Type Significance SNP ID Assembly Location
1 FGFR3 NM_000142.4(FGFR3): c.1948A> G (p.Lys650Glu) single nucleotide variant Pathogenic rs78311289 GRCh37 Chromosome 4, 1807889: 1807889
2 FGFR3 NM_000142.4(FGFR3): c.1948A> G (p.Lys650Glu) single nucleotide variant Pathogenic rs78311289 GRCh38 Chromosome 4, 1806162: 1806162

Expression for Thanatophoric Dysplasia, Type Ii

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

Pathways for Thanatophoric Dysplasia, Type Ii

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 9.16 FGFR3 SPRY2
2 positive regulation of protein kinase B signaling GO:0051897 8.96 FGFR3 SPRY2
3 negative regulation of angiogenesis GO:0016525 8.62 SPRY2 STAT1

Sources for Thanatophoric Dysplasia, Type Ii

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
20 FMA
29 GO
30 GTR
31 HGMD
32 HMDB
33 HPO
34 ICD10
35 ICD10 via Orphanet
36 ICD9CM
37 IUPHAR
38 KEGG
39 LifeMap
41 LOVD
43 MedGen
45 MeSH
46 MESH via Orphanet
47 MGI
50 NCI
51 NCIt
52 NDF-RT
55 NINDS
56 Novoseek
58 OMIM
59 OMIM via Orphanet
63 PubMed
65 QIAGEN
70 SNOMED-CT via HPO
71 SNOMED-CT via Orphanet
72 TGDB
73 Tocris
74 UMLS
75 UMLS via Orphanet
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