Prenatal diagnosis of thanatophoric dysplasia
Lagutina O.V., Sumina M.V., Kudryavtseva E.V., Mostova N.V., Deryabina S.S.
Thanatophoric dysplasia is an autosomal dominant congenital disorder associated with primary bone dysplasia. Thanatophoric dysplasia is caused by mutation of the gene that encodes fibroblast growth factor 3 (FGFR3).
Case report: The paper presents two clinical observations of thanatophoric dysplasia. In both cases, pregnant women were referred for invasive prenatal diagnosis which identified the normal male karyotype of the fetus.
In the first case, a number of markers of chromosomal abnormalities were detected in the first trimester using ultrasound. There were no markers allowing to suspect skeletal dysplasia. The ultrasound examination performed at 19–20 weeks’ gestation revealed multiple congenital malformations including shortening and bowing of the limbs. The boy who was born at 36–37 weeks’ gestation after surgical delivery had the following congenital malformations: shortening of limb bones, hypoplasia of the chest, anomalies of the ribs and spine, secondary hypoplasia of the lungs. The child died in the neonatal period.
In the second case, there were the following abnormalities of the musculoskeletal system in the fetus at 14–15 weeks’ gestation: shortening and deformation of the tubular bones of the arms and legs, hypoplasia of the chest, clover-shaped skull. The patient provided the consent for termination of pregnancy.
Pathogenic variants in the FGFR3 gene were identified during a subsequent study of DNA which was isolated from chorionic villi. In the first case, the c.1948 A>G variant was identified, while the c.742 C>T was revealed in the second one; both variants were previously described as pathogenic.
Conclusion: It is necessary to confirm the diagnosis of thanatophoric dysplasia using molecular genetic research methods and ultrasound assessment showing the signs of fetal skeletal pathology in order to clarify the medical indications for termination of pregnancy and to determine the prognosis for future offspring in the family.
Authors’ contributions: Lagutina O.V. – developing the concept and design of the study, writing the text of the manuscript; Sumina M.G. – analysis of the medical records, writing the text of the manuscript; Kudryavtseva E.V. – search and analysis of scientific literature, summarizing the data, writing the text of the manuscript; Mostova N.V. – doing ultrasound examination and describing echograms, writing the text of the manuscript; Deryabina S.S. – writing and editing the text of the manuscript.
Conflicts of interest: The authors declare no conflict of interest.
Funding: The study was conducted without sponsorship.
Ethical Approval: The study was approved by the Ethical Review Board of the Yekaterinburg Clinical Perinatal Centre (Protocol No.2 – 26/05/2023).
Patient Consent for Publication: All patients signed an informed consent for the publication of their data and associated images.
For citation: Lagutina O.V., Sumina M.V., Kudryavtseva E.V., Mostova N.V., Deryabina S.S. Prenatal diagnosis of thanatophoric dysplasia. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2023; (11): 193-199 (in Russian)
https://dx.doi.org/10.18565/aig.2023.112
Keywords
thanatophoric dysplasia
FGFR3
prenatal diagnosis
sequence
skeletal deformations
References
- French T., Savarirayan R. Thanatophoric Dysplasia. 2004 May 21 [updated 2023 May 18]. In: Adam M.P., Feldman J., Mirzaa G.M., Pagon R.A., Wallace S.E., Bean L.J.H., Gripp K.W., Amemiya A., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.
- Wainwright H. Thanatophoric dysplasia: A review. S. Afr. Med. J. 2016; 106(6 Suppl 1): S50-3. https://dx.doi.org/10.7196/SAMJ.2016.v106i6.10993.
- Ushioda M., Sawai H., Numabe H., Nishimura G., Shibahara H. Development of individuals with thanatophoric dysplasia surviving beyond infancy. Pediatr. Int. 2022; 64(1): e15007. https://dx.doi.org/10.1111/ped.15007.
- Carroll R.S., Duker A.L., Schelhaas A.J., Little M.E., Miller E.G., Bober M.B. Should we stop calling thanatophoric dysplasia a lethal condition? A case report of a long-term survivor. Palliat. Med. Rep. 2020; 1(1): 32-9. https://dx.doi.org/10.1089/pmr.2020.0016.
- Hall C.M., Liu B., Haworth A., Reed L., Pryce J., Mansour S. Early prenatal presentation of the cartilage-hair hypoplasia/anauxetic dysplasia spectrum of disorders mimicking recurrent thanatophoric dysplasia. Eur. J. Med. Genet. 2021; 64(3): 104162. https://dx.doi.org/10.1016/j.ejmg.2021.104162.
- Jimah B.B., Mensah T.A., Ulzen-Appiah K., Sarkodie B.D., Anim D.A., Amoako E. et al. Prenatal diagnosis of skeletal dysplasia and review of the literature. Case Rep. Obstet. Gynecol. 2021; 2021: 9940063. https://dx.doi.org/10.1155/2021/9940063.
- Kim H.Y., Ko J.M. Clinical management and emerging therapies of FGFR3-related skeletal dysplasia in childhood. Ann. Pediatr. Endocrinol. Metab. 2022; 27(2): 90-7. https://dx.doi.org/10.6065/apem.2244114.057.
- Xue Y., Sun A., Mekikian P.B., Martin J., Rimoin D.L., Lachman R.S., Wilcox W.R. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol. Genet. Genomic Med. 2014; 2(6): 497-503. https://dx.doi.org/10.1002/mgg3.96.
- Foldynova-Trantirkova S., Wilcox W.R., Krejci P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum. Mutat. 2012; 33(1): 29-41. https://dx.doi.org/10.1002/humu.21636.
- Chen C.-P., Chang T.-Y., Lin M.-H., Chern S.-R., Su J.-W., Wang W. 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. Taiwan. J. Obstet. Gynecol. 2013; 52(3): 420-5. https://dx.doi.org/10.1016/j.tjog.2013.05.003.
- Lievens P.M.-J., Liboi E. 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. J. Biol. Chem. 2003; 278(19): 17344-9. https://dx.doi.org/10.1074/jbc.M212710200.
- Gülaşı S., Atıcı A., Çelik Y. A case of thanatophoric dysplasia type 2: a novel mutation. J. Clin. Res. Pediatr. Endocrinol. 2015; 7(1): 73-6. https://dx.doi.org/10.4274/jcrpe.1703.
- Stembalska A., Dudarewicz L., Śmigiel R. Lethal and life-limiting skeletal dysplasias: Selected prenatal issues. Adv. Clin. Exp. Med. 2021; 30(6): 641-7. https://dx.doi.org/10.17219/acem/134166.
- Пашук С.Н., Новикова И.В., Лазаревич А.А., Гусина А.А., Венчикова Н.А. Определение частых мутаций гена FGFR3 для дифференциальной диагностики танатофорной дисплазии: анализ 8 случаев. Пренатальная диагностика. 2022; 21(2): 137-44. [Pashuk S.N., Novikova I.V., Lazarevich A.A., Gusina A.A., Venchikova N.A. Determination of frequent FGFR3 mutations for the differential diagnosis of thanatophoric dysplasia: report of 8 cases. Prenatal Diagnosis. 2022; 21(2): 137-44. (in Russian)]. https://dx.doi.org/10.21516/2413-1458-2022-21-2-137-144.
- Jung M., Park S.-H. Genetically confirmed thanatophoric dysplasia with fibroblast growth factor receptor 3 mutation. Exp. Mol. Pathol. 2017; 102(2): 290-5. https://dx.doi.org/10.1016/j.yexmp.2017.02.019.
- Audu L., Gambo A., Baduku T.S., Farouk B., Yahaya A., Jacob K. Thanatophoric dysplasia: a report of 2 cases with antenatal misdiagnosis. Case Rep. Pediatr. 2022; 2022: 3056324. https://dx.doi.org/10.1155/2022/3056324.
- Hyland V.J., Robertson S.P., Flanagan S., Savarirayan R., Roscioli T., Masel J. et al. Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia. Am. J. Med. Genet. A. 2003; 120A(2): 157-68. https://dx.doi.org/10.1002/ajmg.a.20012.
- Mettler G., Fraser F.C. Recurrence risk for sibs of children with “sporadic” achondroplasia. Am. J. Med. Genet. 2000; 90(3): 250-1.
- Leal G.F., Nishimura G., Voss U., Bertola D.R., Åström E., Svensson J. et al. Expanding the clinical spectrum of phenotypes caused by pathogenic variants in PLOD2. J. Bone Miner. Res. 2018; 33(4): 753-60. https://dx.doi.org/10.1002/jbmr.3348.
- Wang L., Li R., Zhai J., Zhang B., Wu J., Pang L., Liu Y. Whole exome sequencing combined with dynamic ultrasound assessments for fetal skeletal dysplasias: 4 case reports. Medicine (Baltimore). 2022; 101(43): e31321. https://dx.doi.org/10.1097/MD.0000000000031321.
Received 10.05.2023
Accepted 08.06.2023
About the Authors
Olga V. Lagutina, Biologist at the Molecular Diagnostic Laboratory, Medical Center «Health Care of Mother and Child», +7(343)287-57-13,620067, Russia, Yekaterinburg, Flotskaya str., 52; Researcher at the Laboratory of Molecular Genetic Research, Institute of Medical Cell Technologies, +7(343)355-62-40,
620026, Russia, Yekaterinburg, Karla Marksa str., 22A, ovlagutina@bk.ru, https://orcid.org/0009-0003-3888-4294
Maria G. Sumina, Head of the Department of Medical Genetic Counseling, Clinical and Diagnostic Center «Maternal and Child Health Care»,
+7(343)287-57-13, m.sumina@mail.ru, 620067, Russia, Yekaterinburg, Flotskaya str., 52, https://orcid.org/0000-0002-2883-4029
Elena V. Kudryavtseva, Dr. Med. Sci., Head of the Central Research Laboratory, Ural State Medical University, Ministry of Health of Russia, +7(343)214-85-56, elenavladpopova@yandex.ru, 620028, Russia, Yekaterinburg, Repina str., 3; Researcher at the Laboratory of Molecular Genetic Research, Institute of Medical Cell Technologies, +7(343)355-62-40, 620026, Russia, Yekaterinburg, Karla Marksa str., 22A, https://orcid.org/0000-0003-2797-1926
Natal'ja V. Mostova, prenatal diagnostics doctor, Medical Center «Health Care of Mother and Child», +7(343)365-78-50, mostova-n24@yandex.ru,
620067, Russia, Yekaterinburg, Flotskaya str., 52, https://orcid.org/0009-0005-0286-9628
Svetlana S. Deryabina, PhD (Bio), Head of the Laboratory of Molecular Diagnostics, Medical Center «Health Care of Mother and Child», 620067, Russia, Yekaterinburg, Flotskaya str., 52, Institute of Medical Cell Technologies, 620026, Russia, Yekaterinburg, Karla Marksa str., 22A, deryabina.sst@gmail.com,
https://orcid.org/0000-0001-5614-5944
Corresponding author: Elena V. Kudryavtseva, elenavladpopova@yandex.ru
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