MCID: THN010
MIFTS: 50

Thanatophoric Dysplasia, Type Ii

Categories: Genetic diseases, Rare diseases, Bone diseases, Fetal 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 53 59 75
Thanatophoric Dysplasia with Kleeblattschaedel 57 53 75
Cloverleaf Skull with Thanatophoric Dwarfism 57 53 75
Thanatophoric Dysplasia with Straight Femurs and Cloverleaf Skull 57 75
Cloverleaf Skull-Micromelic Bone Dysplasia Syndrome 53 59
Thanatophoric Dwarfism-Cloverleaf Skull Syndrome 53 59
Thanatophoric Dysplasia Type Ii 53 75
Thanatophoric Dysplasia, Type 2 29 6
Thanatophoric Dysplasia Type 2 53 59
Thanatophoric Dwarfism Type 2 53 59
Thanatophoric Dwarfism - Cloverleaf Skull 53
Dysplasia, Thanatophoric, Type Ii 40
Thanatophoric Dysplasia 2 75

Characteristics:

Orphanet epidemiological data:

59
thanatophoric dysplasia type 2
Inheritance: Autosomal dominant,Not applicable; Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM:

57
Inheritance:
autosomal dominant

Miscellaneous:
death in majority of infants soon after birth


HPO:

32
thanatophoric dysplasia, type ii:
Mortality/Aging neonatal death
Inheritance autosomal dominant inheritance


Classifications:



Summaries for Thanatophoric Dysplasia, Type Ii

NIH Rare Diseases : 53 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 Negative regulation of FGFR3 signaling and MicroRNAs in cancer. The drugs Dopamine and Olanzapine have been mentioned in the context of this disorder. Affiliated tissues include bone, spinal cord and brain, and related phenotypes are abnormality of the kidney and hydrocephalus

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)

UniProtKB/Swiss-Prot : 75 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 29.5 FGFR3 STAT1
2 kleeblattschaedel 10.1
3 encephalocele 10.1
4 achondroplasia 9.9
5 holoprosencephaly 9.9
6 hydrocephalus 9.9
7 choroiditis 9.9
8 dwarfism 9.9
9 skeletal dysplasias 9.9
10 semilobar holoprosencephaly 9.9

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

Symptoms via clinical synopsis from OMIM:

57
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

Human phenotypes related to Thanatophoric Dysplasia, Type Ii:

59 32 (show all 46)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 abnormality of the kidney 59 32 occasional (7.5%) Occasional (29-5%) HP:0000077
2 hydrocephalus 59 32 occasional (7.5%) Occasional (29-5%) HP:0000238
3 macrocephaly 59 32 hallmark (90%) Very frequent (99-80%) HP:0000256
4 hearing impairment 59 32 frequent (33%) Frequent (79-30%) HP:0000365
5 proptosis 59 32 frequent (33%) Frequent (79-30%) HP:0000520
6 narrow chest 59 32 hallmark (90%) Very frequent (99-80%) HP:0000774
7 platyspondyly 59 32 hallmark (90%) Very frequent (99-80%) HP:0000926
8 abnormality of the metaphysis 59 32 hallmark (90%) Very frequent (99-80%) HP:0000944
9 acanthosis nigricans 59 32 occasional (7.5%) Occasional (29-5%) HP:0000956
10 brachydactyly 59 32 hallmark (90%) Very frequent (99-80%) HP:0001156
11 seizures 59 32 frequent (33%) Frequent (79-30%) HP:0001250
12 muscular hypotonia 59 32 hallmark (90%) Very frequent (99-80%) HP:0001252
13 holoprosencephaly 59 32 occasional (7.5%) Occasional (29-5%) HP:0001360
14 limitation of joint mobility 59 32 occasional (7.5%) Occasional (29-5%) HP:0001376
15 polyhydramnios 59 32 frequent (33%) Frequent (79-30%) HP:0001561
16 redundant skin 59 32 hallmark (90%) Very frequent (99-80%) HP:0001582
17 atrial septal defect 59 32 occasional (7.5%) Occasional (29-5%) HP:0001631
18 patent ductus arteriosus 59 32 occasional (7.5%) Occasional (29-5%) HP:0001643
19 frontal bossing 59 32 frequent (33%) Frequent (79-30%) HP:0002007
20 encephalocele 59 32 occasional (7.5%) Occasional (29-5%) HP:0002084
21 respiratory insufficiency 59 32 hallmark (90%) Very frequent (99-80%) HP:0002093
22 ventriculomegaly 59 32 frequent (33%) Frequent (79-30%) HP:0002119
23 abnormality of neuronal migration 59 32 occasional (7.5%) Occasional (29-5%) HP:0002269
24 skeletal dysplasia 59 32 hallmark (90%) Very frequent (99-80%) HP:0002652
25 cloverleaf skull 59 32 hallmark (90%) Very frequent (99-80%) HP:0002676
26 kyphosis 59 32 frequent (33%) Frequent (79-30%) HP:0002808
27 micromelia 59 32 hallmark (90%) Very frequent (99-80%) HP:0002983
28 short stature 59 32 hallmark (90%) Very frequent (99-80%) HP:0004322
29 depressed nasal bridge 59 32 hallmark (90%) Very frequent (99-80%) HP:0005280
30 joint hyperflexibility 59 32 hallmark (90%) Very frequent (99-80%) HP:0005692
31 aplasia/hypoplasia of the lungs 59 32 hallmark (90%) Very frequent (99-80%) HP:0006703
32 short thorax 59 32 hallmark (90%) Very frequent (99-80%) HP:0010306
33 increased nuchal translucency 59 32 frequent (33%) Frequent (79-30%) HP:0010880
34 flat face 59 32 hallmark (90%) Very frequent (99-80%) HP:0012368
35 cognitive impairment 59 32 hallmark (90%) Very frequent (99-80%) HP:0100543
36 small face 32 HP:0000274
37 short ribs 32 HP:0000773
38 wide-cupped costochondral junctions 32 HP:0000910
39 hypoplastic ilia 32 HP:0000946
40 decreased fetal movement 32 HP:0001558
41 small foramen magnum 32 HP:0002677
42 flared metaphysis 32 HP:0003015
43 metaphyseal irregularity 32 HP:0003025
44 short sacroiliac notch 32 HP:0003185
45 small abnormally formed scapulae 32 HP:0006584
46 lethal short-limbed short stature 32 HP:0008909

MGI Mouse Phenotypes related to Thanatophoric Dysplasia, Type Ii:

46
# 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 SPRY2 STAT1 FGFR3

Drugs & Therapeutics for Thanatophoric Dysplasia, Type Ii

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

(show top 50) (show all 59)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Dopamine Approved Phase 4 51-61-6, 62-31-7 681
2
Olanzapine Approved, Investigational Phase 4 132539-06-1 4585
3
Benzocaine Approved, Investigational Phase 4 1994-09-7, 94-09-7 2337
4
Linagliptin Approved Phase 4 668270-12-0 10096344
5 tannic acid Approved, Nutraceutical Phase 4
6 sultopride Phase 4
7
protease inhibitors Phase 4
8 Central Nervous System Depressants Phase 4
9 Serotonin Agents Phase 4
10 Serotonin Uptake Inhibitors Phase 4
11 Gastrointestinal Agents Phase 4
12 Glucagon-Like Peptide 1 Phase 4
13 Neurotransmitter Agents Phase 4,Phase 2
14 Neurotransmitter Uptake Inhibitors Phase 4
15 HIV Protease Inhibitors Phase 4
16 Hormone Antagonists Phase 4
17 Tranquilizing Agents Phase 4
18 Dipeptidyl-Peptidase IV Inhibitors Phase 4
19 Hormones Phase 4
20 Dopamine Agents Phase 4
21 Hormones, Hormone Substitutes, and Hormone Antagonists Phase 4
22 Dopamine Antagonists Phase 4
23 Peripheral Nervous System Agents Phase 4,Phase 2
24 Hypoglycemic Agents Phase 4,Phase 2
25 Incretins Phase 4
26 Antiemetics Phase 4
27 Antipsychotic Agents Phase 4
28 Psychotropic Drugs Phase 4
29 Autonomic Agents Phase 4,Phase 2
30
Serotonin Investigational, Nutraceutical Phase 4 50-67-9 5202
31
Gemcitabine Approved Phase 1, Phase 2 95058-81-4 60750
32
Cisplatin Approved Phase 1, Phase 2 15663-27-1 84093 441203 2767
33
Paclitaxel Approved, Vet_approved Phase 1, Phase 2 33069-62-4 36314
34
Pancrelipase Approved, Investigational Phase 1, Phase 2 53608-75-6
35
Nicotine Approved Phase 2 54-11-5 942 89594
36
Metformin Approved Phase 2 657-24-9 14219 4091
37
Nevirapine Approved Phase 2 129618-40-2 4463
38
Zidovudine Approved Phase 2 30516-87-1 35370
39
Glipizide Approved, Investigational Phase 2 29094-61-9 3478
40
Emtricitabine Approved, Investigational Phase 2 143491-57-0 60877
41 pancreatin Phase 1, Phase 2
42 Albumin-Bound Paclitaxel Phase 1, Phase 2
43 Immunosuppressive Agents Phase 1, Phase 2
44 Anti-Infective Agents Phase 1, Phase 2,Phase 2
45 Antimetabolites Phase 1, Phase 2
46 Antiviral Agents Phase 1, Phase 2,Phase 2
47 Antimetabolites, Antineoplastic Phase 1, Phase 2
48 Antimitotic Agents Phase 1, Phase 2
49 Antineoplastic Agents, Phytogenic Phase 1, Phase 2
50
Tenofovir Phase 2 147127-20-6 464205

Interventional clinical trials:

(show all 15)
# 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 Nab-Paclitaxel+Cisplatin+Gemcitabine in Patients With Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma (PDA) Unknown status NCT01893801 Phase 1, Phase 2 nab-paclitaxel;Cisplatin;gemcitabine
5 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
6 Maternal TDF and FTC to Reduce NNRTI Resistance Mutations After Intrapartum NVP Completed NCT00204308 Phase 2 Combination tenofovir-emtricitabine
7 Nicotine Patch Safety Study Completed NCT01655082 Phase 2 V0116 transdermal patch;Nicotine transdermal patch
8 Study of Minnelide™ in Patients With Advanced GI Tumors Completed NCT01927965 Phase 1 Minnelide™ 001
9 Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis Recruiting NCT03373877 Phase 1 PU-H71;Ruxolitinib
10 Phase 1 Clinical Trial of Metastasis Inhibitor NP-G2-044 in Patients With Advanced or Metastatic Solid Tumors (Including Lymphoma) Recruiting NCT03199586 Phase 1 NP-G2-044
11 A Phase 1, Multi-Center, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Minnelide™ Capsules Given Alone or in Combination With Protein-Bound Paclitaxel in Patients With Advanced Solid Tumors Recruiting NCT03129139 Phase 1 Minnelide™Capsules
12 A Study of TRK-950 in Patients With Advanced Solid Tumors Recruiting NCT02990481 Phase 1
13 Oral TrkA Inhibitor VMD-928 for Treatment of Advanced Adult Solid Tumors or Lymphoma Recruiting NCT03556228 Phase 1 VMD-928 300-mg Capsules
14 HIIE and Abdominal Fat Mass in DT2 Postmenopausal Women Unknown status NCT02352246 Not Applicable
15 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 29 FGFR3

Anatomical Context for Thanatophoric Dysplasia, Type Ii

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

41
Bone, Spinal Cord, Brain, Skin, Kidney, Lung

Publications for Thanatophoric Dysplasia, Type Ii

Articles related to Thanatophoric Dysplasia, Type Ii:

(show all 11)
# Title Authors Year
1
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
2
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
3
Disruption of a Sox9-I^-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II. ( 22843502 )
2012
4
Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis. ( 21204232 )
2011
5
Sprouty 2 disturbs FGFR3 degradation in thanatophoric dysplasia type II: a severe form of human achondroplasia. ( 18485666 )
2008
6
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
7
Thanatophoric dysplasia type II with encephalocele and aortic hypoplasia diagnosed in an anatomical specimen. ( 12605444 )
2003
8
A central nervous system specific mouse model for thanatophoric dysplasia type II. ( 12966031 )
2003
9
Thanatophoric dysplasia type II: new entity? ( 9481651 )
1998
10
Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. ( 9069288 )
1997
11
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:

75
# 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 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
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