Thanatophoric Dysplasia

Thanatophoric dysplasia (TD) is the most common lethal skeletal dysplasia in the perinatal period. It is characterized by severe micromelia (generalized short limbs) with rhizomelic predominance (proximal segment). 
It may be divided into two subtypes based both on molecular diagnosis and clinical features, but there is considerable overlap between the two groups:
-    TD type I: severe micromelia with bowed femurs (“telephone receiver” shape). Craniosynostosis is infrequent.
-    TD type II: severe micromelia with straight femurs and moderate-to-severe craniosynostosis with cloverleaf skull (1).
TD is almost uniformly lethal in the neonatal period without aggressive treatment, and there are only a few cases of long-term survivors in the literature (2).

Q77.1 Thanatophoric short stature

TD estimated incidence is about 1/20,000 to 1/50,000 births (3).

TD is a single gene disease caused by pathogenic variants (mutations) in the fibroblast growth factor receptor 3 (FGFR3) gene located on 4p16.3. FGFR3 normally functions as a negative regulator of bone growth during ossification. Pathogenic variants causing TD lead to overactivity of the FGFR3 kinase, resulting in disturbances in bone growth (4).
Three of these are responsible for the majority of cases: the c.742C>T (p.Arg248Cys) and c.1118A>G (p.Tyr373Cys) variants are found in 90 % of TD type I, and the c.1948A>AG (p.Lys650Glu) is the only variant found in TD type II.
TD penetrance is 100% (1).

TD is inherited autosomal dominantly but the majority of cases are sporadic due to a de novo mutation in the proband.

TD is characterized by: generalized short limbs, bowed femurs (only in TD type I), cloverleaf skull (craniosynostoses, almost only in TD type II), relative macrocephaly, frontal bossing, severe midface hypoplasia, depressed nasal bridge, proptosis, brachydactyly (trident-like appearance of fingers), redundant skin folds, small chest causing lung hypoplasia and respiratory insufficiency (the leading cause of death). (1, 5) Anomalies of the temporal lobe are almost always present, and narrowing of the foramen magnum can lead to death by compression of the brainstem. 
At birth, generalized hypotonia and severe developmental delay occur in the few survivors.
Radiographic findings include macrocephaly with a narrow skull base, long narrow trunk, flat vertebral bodies, small flared iliac bones with very narrow sacrosciatic notches, and generalized micromelia. (6)

TD is associated with brain abnormalities in more than 80 % of cases: megalencephaly, hippocampal dysplasia, underdevelopment of the dentate gyrus, polymicrogyria, temporal lobe enlargement, abnormal gyration, subependymal neuronal heterotopia, and subarachnoid neuroglial heterotopia.  In 30 % of cases, there are other findings such as hydrocephalus, abnormalities of the cerebellar cortex, and hypoplasia or partial agenesis of the corpus callosum (7). 
Rarely, cardiac and renal abnormalities have been reported (1).

The recurrence risk of TD for parents who have already had an affected child is not significantly increased compared with the general population (< 1%) because almost all cases reported to date are sporadic (de novo pathogenic variant). Although germline mosaicism in healthy parents has not been reported in the literature, this remains a theoretical possibility (1)

Although formal diagnostic criteria for TD have not yet been established, the diagnosis results from a combination of certain sonographic findings that are later confirmed by molecular genetic testing.
Prenatal sonographic detection usually occurs in the second trimester, but with the increasing use of first-trimester ultrasound, TD may be detected earlier in pregnancy.
At the time of routine anomaly scan, TD is associated with fetal growth restriction with short long bones (at or below the fifth percentile), a narrow chest with short ribs and normal trunk length, macrocephaly, frontal bossing, short fingers (trident-shaped appearance of the hands), cloverleaf skull, and telephone receiver-shaped femur. There are no fractures and mineralization is normal. 
The soft tissues are redundant (compared to micromelia) and have many folds, resembling skin edema (6).
Other revealing findings during the second/third-trimester scan include platyspondyly, relative sparseness of foot length, ventriculomegaly, polyhydramnios, and temporal lobe abnormalities. (1, 5, 8).
In the first trimester, TD may be associated with increased nuchal translucency (NT) and short limbs (8, 9).
If ultrasound or postnatal findings are suggestive of TD, a definitive diagnosis can be made by molecular genetic analysis. This may include targeted analysis of the three most common variants or single-gene testing of the FGRF3 gene. If the phenotype is indistinguishable from other lethal skeletal dysplasias, the use of a multigene panel or more comprehensive genomic testing such as whole-exome sequencing are the best options (1).
Prenatal molecular diagnosis can be made by molecular analysis in amniocytes and chorionic villus or, more recently, by cell-free DNA in maternal plasma of de novo common pathogenic variants (8, 10).

The differential diagnosis includes homozygous achondroplasia, achondrogenesis (types 1A, 1B, and 2), short rib-polydactyly syndromes, perinatal lethal osteogenesis imperfecta (previous type 2), SADDAN (severe achondroplasia w/developmental delay & acanthosis nigricans), dyssegmental dysplasia Silverman-Handmaker type, platyspondylic lethal skeletal dysplasias, and campomelic dysplasia.

The accuracy of prenatal diagnosis of TD based on ultrasound findings has been reported to vary from 40% to 88%. (8)
Prediction of lethality is based on specific sonographic features, namely, the presence of a bell-shaped thorax, short ribs, severe femoral shortening (>4 standard deviations), lung volume <5th percentile of that expected for gestational age, femur length to abdominal circumference ratio <0.16 (especially in polyhydramnios), thoracic circumference to abdominal circumference ratio <0.6, bone bowing (although also present in viable dysplasias such as achondroplasia). (11)

Prenatal diagnosis is commonly accomplished in the second-trimester scan, but occasionally TD is found to be associated with increased nuchal translucency (NT) at the time of the first-trimester screening for aneuploidies. (12)

TD has a poor prognosis and is almost always a lethal condition in the prenatal period or shortly after birth. (8) Death occurs due to respiratory insufficiency and/or compression of the brainstem, and there are few cases of long-term survival after aggressive perinatal management.

Once TD is suspected, the patient should be managed by a multidisciplinary team. A geneticist should counsel the family regarding the best molecular genetic testing for each individual case. 
Elective termination of pregnancy is an option. If the pregnancy is managed expectantly, delivery should occur without monitoring for fetal distress and no futile heroic resuscitation efforts should be performed. A maternal-fetal medicine specialist should provide assessment and advice on the management of potential complications such as polyhydramnios, malpresentation, and cephalopelvic disproportion due to hydrocephalus.
Considerations may include the parent’s desire for extreme life support or provision of comfort care for the newborn. (1, 5)
In terminated pregnancies, postmortem evaluation including radiography and storage of DNA in case of diagnostic uncertainty should be discussed (13).

1.     French T, Savarirayan R. Thanatophoric Dysplasia. 2004 May 21 [Updated 2020 Jun 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.
2.    Carroll, R. S., Duker, A. L., Schelhaas, A. J., Little, M. E., Miller, E. G., & Bober, M. B. (2020). Should we stop calling thanatophoric dysplasia a lethal condition? a case report of a long-term survivor. Palliative Medicine Reports, 1(1), 32-39.
3. Pereira, E. Thanatophoric dysplasia. Orphanet enciclopedia, September, 2019. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=547&Disease(s)/group%20of%20diseases=Thanatophoric-dysplasia&title=Thanatophoric%20dysplasia&search=Disease_Search_Simple&ChdId=0
4.    Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A., & Leder, P. (1996). Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell, 84(6), 911-921.
5.    Wang, D. C., Shannon, P., Toi, A., Chitayat, D., Mohan, U., Barkova, E., ... & Glanc, P. (2014). Temporal lobe dysplasia: a characteristic sonographic finding in thanatophoric dysplasia. Ultrasound in Obstetrics & Gynecology, 44(5), 588-594.
6.    Barkova, E., Mohan, U., Chitayat, D., Keating, S., Toi, A., Frank, J., ... & Glanc, P. (2015). Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases. Clinical Genetics, 87(4), 330-337.
7.    Hevner, R. F. (2005). The cerebral cortex malformation in thanatophoric dysplasia: neuropathology and pathogenesis. Acta neuropathologica, 110(3), 208-221.
8.    Chitty, L. S., Khalil, A., Barrett, A. N., Pajkrt, E., Griffin, D. R., & Cole, T. J. (2013). Safe, accurate, prenatal diagnosis of thanatophoric dysplasia using ultrasound and free fetal DNA. Prenatal diagnosis, 33(5), 416-423.
9.    Giancotti, A., Castori, M., Spagnuolo, A., Binni, F., D'Ambrosio, V., Pasquali, G., ... & Grammatico, P. (2011). Early ultrasound suspect of thanatophoric dysplasia followed by first trimester molecular diagnosis. American Journal of Medical Genetics Part A, 155(7), 1756-1758.
10.    Zhang, J., Li, J., Saucier, J. B., Feng, Y., Jiang, Y., Sinson, J., ... & Eng, C. M. (2019). Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA. Nature medicine, 25(3), 439-447.
11.    Stembalska, A., Dudarewicz, L., & Śmigiel, R. (2021). Lethal and life-limiting skeletal dysplasias: Selected prenatal issues. Advances in Clinical and Experimental Medicine, 30(6), 641-647.
12.    Zhen, L., Pan, M., Han, J., Yang, X., Liao, C., & Li, D. Z. (2015). Increased first-trimester nuchal translucency associated with thanatophoric dysplasia type 1. Journal of Obstetrics and Gynaecology, 35(7), 685-687.
13.    Savarirayan, R., Rossiter, J. P., Hoover-Fong, J. E., Irving, M., Bompadre, V., Goldberg, M. J., ... & Skeletal Dysplasia Management Consortium. (2018). Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia. American journal of obstetrics and gynecology, 219(6), 545-562.    

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