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Thanatophoric dysplasia type 1(TD1)

MedGen UID:
358383
Concept ID:
C1868678
Disease or Syndrome
Synonyms: LETHAL SHORT-LIMBED PLATYSPONDYLIC DWARFISM, SAN DIEGO TYPE; PLATYSPONDYLIC LETHAL SKELETAL DYSPLASIA, SAN DIEGO TYPE; TD1; Thanatophoric Dysplasia Type I
SNOMED CT: Thanatophoric dysplasia, type 1 (389157002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): FGFR3 (4p16.3)
 
Monarch Initiative: MONDO:0008546
OMIM®: 187600
Orphanet: ORPHA1860

Disease characteristics

Excerpted from the GeneReview: Thanatophoric Dysplasia
Thanatophoric dysplasia (TD) is a short-limb skeletal dysplasia that is usually lethal in the perinatal period. TD is divided into subtypes: TD type 1 is characterized by micromelia with bowed femurs and, uncommonly, the presence of craniosynostosis of varying severity. TD type 2 is characterized by micromelia with straight femurs and uniform presence of moderate-to-severe craniosynostosis with cloverleaf skull deformity. Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported. [from GeneReviews]
Authors:
Tegan French  |  Ravi Savarirayan   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/187600
From MedlinePlus Genetics
The term thanatophoric is Greek for "death bearing." Infants with thanatophoric dysplasia are usually stillborn or die shortly after birth from respiratory failure; however, a few affected individuals have survived into childhood with extensive medical help.

Researchers have described two major forms of thanatophoric dysplasia, type I and type II. Type I thanatophoric dysplasia is distinguished by the presence of curved thigh bones and flattened bones of the spine (platyspondyly). Type II thanatophoric dysplasia is characterized by straight thigh bones and a moderate to severe skull abnormality called a cloverleaf skull.

Thanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and folds of extra (redundant) skin on the arms and legs. Other features of this condition include a narrow chest, short ribs, underdeveloped lungs, and an enlarged head with a large forehead and prominent, wide-spaced eyes.  https://medlineplus.gov/genetics/condition/thanatophoric-dysplasia

Clinical features

From HPO
Disproportionate short-limb short stature
MedGen UID:
342370
Concept ID:
C1849937
Finding
A type of disproportionate short stature characterized by a short limbs but an average-sized trunk.
Lethal short-limbed short stature
MedGen UID:
388831
Concept ID:
C2674171
Finding
Protuberant abdomen
MedGen UID:
340750
Concept ID:
C1854928
Finding
A thrusting or bulging out of the abdomen.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Gray matter heterotopia
MedGen UID:
452349
Concept ID:
C0266491
Finding
Heterotopia or neuronal heterotopia are macroscopic clusters of misplaced neurons (gray matter), most often situated along the ventricular walls or within the subcortical white matter.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability, profound
MedGen UID:
892508
Concept ID:
C3161330
Mental or Behavioral Dysfunction
Profound mental retardation is defined as an intelligence quotient (IQ) below 20.
Temporal lobe dysplasia
MedGen UID:
1814372
Concept ID:
C5676808
Congenital Abnormality
A developmental defect of the temporal lobe of the cerebral cortex that is characterized by prominent sulcations and radially directed gyrations.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Narrow chest
MedGen UID:
96528
Concept ID:
C0426790
Finding
Reduced width of the chest from side to side, associated with a reduced distance from the sternal notch to the tip of the shoulder.
Short ribs
MedGen UID:
98094
Concept ID:
C0426817
Finding
Reduced rib length.
Thoracic hypoplasia
MedGen UID:
373339
Concept ID:
C1837482
Congenital Abnormality
Metaphyseal irregularity
MedGen UID:
325478
Concept ID:
C1838662
Finding
Irregularity of the normally smooth surface of the metaphyses.
Platyspondyly
MedGen UID:
335010
Concept ID:
C1844704
Finding
A flattened vertebral body shape with reduced distance between the vertebral endplates.
Flared metaphysis
MedGen UID:
337976
Concept ID:
C1850135
Finding
The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.
Severe platyspondyly
MedGen UID:
338014
Concept ID:
C1850293
Finding
Short long bone
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
Bowing of the long bones
MedGen UID:
340849
Concept ID:
C1855340
Congenital Abnormality
A bending or abnormal curvature of a long bone.
Femoral bowing
MedGen UID:
347888
Concept ID:
C1859461
Finding
Bowing (abnormal curvature) of the femur.
Cloverleaf skull
MedGen UID:
348010
Concept ID:
C1860050
Congenital Abnormality
Trilobar skull configuration when viewed from the front or behind.
Wide-cupped costochondral junctions
MedGen UID:
349985
Concept ID:
C1861213
Finding
Small foramen magnum
MedGen UID:
348813
Concept ID:
C1861217
Finding
An abnormal narrowing of the foramen magnum.
Hypoplastic ilia
MedGen UID:
348814
Concept ID:
C1861218
Finding
Underdevelopment of the ilium.
Small abnormally formed scapulae
MedGen UID:
396084
Concept ID:
C1861226
Finding
Short greater sciatic notch
MedGen UID:
401058
Concept ID:
C1866689
Finding
The sacroiliac joint in the bony pelvis connects the sacrum and the ilium of the pelvis, which are joined by strong ligaments. The notch is located directly superior to the joint. This term refers to a reduction in the height of the notch.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Hypoplastic pelvis
MedGen UID:
760700
Concept ID:
C3536734
Anatomical Abnormality
Underdevelopment of the bony pelvis.
Pulmonary hypoplasia
MedGen UID:
78574
Concept ID:
C0265783
Congenital Abnormality
A congenital abnormality in which the lung parenchyma is not fully developed. It may be associated with other congenital abnormalities.
Neonatal respiratory distress
MedGen UID:
924182
Concept ID:
C4281993
Finding
Respiratory difficulty as newborn.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Small face
MedGen UID:
343376
Concept ID:
C1855538
Finding
A face that is short and narrow.
Breech presentation
MedGen UID:
654
Concept ID:
C0006157
Pathologic Function
A position of the fetus at delivery in which the fetus enters the birth canal with the buttocks or feet first.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.
5-minute APGAR score of 1
MedGen UID:
1369112
Concept ID:
C4476851
Finding
1-minute APGAR score of 1
MedGen UID:
1375563
Concept ID:
C4476858
Finding
Champagne cork sign
MedGen UID:
1814376
Concept ID:
C5676812
Sign or Symptom
Characteristic appearance of the chest and abdomen in the sagittal view on prenatal ultrasound when the chest is small and the abdomen protruding.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Bondioni MP, Pazzaglia UE, Izzi C, Di Gaetano G, Laffranchi F, Baldi M, Prefumo F
Radiol Med 2017 Nov;122(11):880-891. Epub 2017 Jul 3 doi: 10.1007/s11547-017-0784-0. PMID: 28674909
Chitty LS, Khalil A, Barrett AN, Pajkrt E, Griffin DR, Cole TJ
Prenat Diagn 2013 May;33(5):416-23. Epub 2013 Feb 14 doi: 10.1002/pd.4066. PMID: 23408600Free PMC Article
Schramm T, Gloning KP, Minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, Tutschek B
Ultrasound Obstet Gynecol 2009 Aug;34(2):160-70. doi: 10.1002/uog.6359. PMID: 19548204

Recent clinical studies

Etiology

Darouich S, Masmoudi A
Fetal Pediatr Pathol 2022 Apr;41(2):179-197. Epub 2020 Jun 18 doi: 10.1080/15513815.2020.1775735. PMID: 32552261
Tan AP, Priego G
Childs Nerv Syst 2019 Jun;35(6):1059-1061. Epub 2019 Jan 4 doi: 10.1007/s00381-018-04035-6. PMID: 30610483
Stoehr CG, Stoehr R, Hartmann A, Hofstaedter F, Junker K, Blaszyk H, Wieland WF, Otto W, Denzinger S, Walter B
J Cancer Res Clin Oncol 2012 Feb;138(2):359-61. Epub 2011 Dec 28 doi: 10.1007/s00432-011-1130-x. PMID: 22203473

Diagnosis

Darouich S, Masmoudi A
Fetal Pediatr Pathol 2022 Apr;41(2):179-197. Epub 2020 Jun 18 doi: 10.1080/15513815.2020.1775735. PMID: 32552261
Mondal A, Mandal B, Das RN, Chatterjee U, Mukherjee S
Indian J Pathol Microbiol 2021 Oct-Dec;64(4):776-779. doi: 10.4103/IJPM.IJPM_917_20. PMID: 34673602
Tan AP, Priego G
Childs Nerv Syst 2019 Jun;35(6):1059-1061. Epub 2019 Jan 4 doi: 10.1007/s00381-018-04035-6. PMID: 30610483
Lindy AS, Basehore MJ, Munisha M, Williams AL, Friez MJ, Writzl K, Willems P, Dougan ST
Am J Med Genet A 2016 Jun;170(6):1573-9. Epub 2016 Mar 30 doi: 10.1002/ajmg.a.37609. PMID: 27028100
Zhen L, Pan M, Han J, Yang X, Liao C, Li DZ
J Obstet Gynaecol 2015;35(7):685-7. Epub 2015 Feb 11 doi: 10.3109/01443615.2015.1006593. PMID: 25671245

Prognosis

Lindy AS, Basehore MJ, Munisha M, Williams AL, Friez MJ, Writzl K, Willems P, Dougan ST
Am J Med Genet A 2016 Jun;170(6):1573-9. Epub 2016 Mar 30 doi: 10.1002/ajmg.a.37609. PMID: 27028100
Salinas-Torres VM
Genet Couns 2015;26(1):61-5. PMID: 26043509
Prontera P, Sensi A, Pilu G, Baldi M, Baffico M, Bonasoni R, Calzolari E
Genet Couns 2006;17(4):407-12. PMID: 17375526

Clinical prediction guides

Lindy AS, Basehore MJ, Munisha M, Williams AL, Friez MJ, Writzl K, Willems P, Dougan ST
Am J Med Genet A 2016 Jun;170(6):1573-9. Epub 2016 Mar 30 doi: 10.1002/ajmg.a.37609. PMID: 27028100
Salinas-Torres VM
Genet Couns 2015;26(1):61-5. PMID: 26043509

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