Thanatophoric dysplasia

Summary

Thanatophoric dysplasia (TD) is a severe short-limb skeletal dysplasia that is usually lethal in the perinatal period. It is divided into two different subtypes, depending on specific anomalies of the femora and skull. Other common features of TD include short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, redundant skin folds along the limbs, and brain anomalies. Most affected infants die of respiratory insufficiency shortly after birth. TD is caused by heterozygous mutation in the FGFR3 gene and it is inherited in an autosomal dominant manner with complete penetrance. Mutations are usually de novo.

Detailed clinical description

Skeletal dysplasias (SD) are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of SD distinguishes 461 diseases in 42 groups. The incidence of all SD is more than 1 in every 5000 newborns. A particular group of SD is lethal or life-limiting and it is estimated that approximately 75–80% of prenatally detected forms of SD are lethal.
Thanatophoric dysplasia (TD) is one of the most common lethal SD in fetuses and neonates, and it is traditionally divided into two forms, according to specific radiographic findings:

  • thanatophoric dysplasia type 1 (TD1) is characterized by curved femora and usually a normal skull;
  • thanatophoric dysplasia type 2 (TD2) is characterized by straight femora and frequently a trilobal cloverleaf skull.

In both forms, a symmetrical shortening of the limbs with redundant skin folds is observed, along with shortening of hands and feet. Other important features of TD are macrocephaly with frontal bossing, a depressed nasal bridge, small chest, and a large protuberant abdomen, while the length of the trunk is usually normal. Generalized hypotonia is present. Radiographic findings of TD also include irregular metaphyses of the long bones, platyspondyly, small foramen magnum with brain stem compression, and CNS abnormalities as temporal lobe malformations, hydrocephalus, brainstem hypoplasia, and neuronal migration abnormalities.
In the prenatal period, suggestive findings include shortening of the long bones, growth deficiency below fifth centile recognizable by 20 weeks’ gestation, well-ossified spine and skull, platyspondyly, ventriculomegaly, narrow chest cavity with short ribs, polyhydramnios, brain anomalies, relative macrocephaly, bowed femurs in TD1 and cloverleaf skull in TD2.
The clinical and radiographic features of TD are often evident in the prenatal period so that the diagnosis can be established clinically before birth.
Respiratory insufficiency typically results in early neonatal death, due to a small chest cavity or to a foramen magnum narrowing with brain stem compression. However, long-term survivors have been reported, including rare reports of survival to adulthood with aggressive ventilatory support and surgical management of neurologic complications.

Prevalence

Prevalence rate of TD is estimated around in 1:20,000-1:12,000 in prenatal cases and around 1:47,000-1:33,000 in live births. The penetrance of TD is 100%./p>

Molecular genetics

Heterozygous mutations in the FGFR3 gene cause TD, which is inherited in an autosomal dominant manner. The gene encode the fibroblast growth factor receptor, which is a transmembrane protein predominantly expressed in bone-producing cells. It interacts with fibroblast growth factors (FGFs), which are polypeptide growth factors involved in a variety of activities, including mitogenesis and angiogenesis. Interaction between FGFs and the outer end of the receptor causes an activation of the protein, resulting in negative regulation of skeletal developmental by degradation of the bone morphogenetic protein type 1 receptor and a negative effect on chondrogenesis and endochondral bone growth.
The central nervous system abnormality is not secondary to the bone changes in the skull, such as synostosis (which occurs late in gestation), because the FGFR3 protein is also expressed in developing brain. Several studies carried out on mouse models showed that FGFR3 is involved in area patterning, progenitor proliferation, and a reduction in apoptosis within the brain.

Pathogenic variants in the FGFR3 gene are gain-of-function variants that facilitate dimerization and activation of FGFR3 in the absence of ligand binding. This constitutional activation leads to premature differentiation of proliferative chondrocytes into prehypertrophic chondrocytes. The level of increased tyrosine kinase activity conferred by different FGFR3 pathogenic variants correlates with the severity of disorganization of endochondral ossification and, therefore, with the skeletal phenotype maturation of the bone.

The mutations are de novo, however, a case of somatic and germline mosaicism for a mutation in the FGFR3 gene has been reported in one family. Recurrent mutations have been observed as well as hot-spot regions such as exons 7, 10, 15 and 19.
Missense mutations represent the majority of FGFR3 mutations. The most common mutation is c.742C>T (p.Arg248Cys), occurring in 50% of TD1 cases, followed by c.1118A>G (p.Tyr373Cys), occurring in 20% of TD1 cases.
At the same amino acid position, the mutation c.1949A>T (p.Lys650Met) causes TD1, whereas the mutation c.1948A>G (p.Lys650Glu) causes TD2. It is unclear why these two missense mutations at the same amino acid position cause different forms of TD. However, it was observed that the TD2 mutation c.1948A>G (p.Lys650Glu) is associated with an accumulation of an intermediate and activated form of FGFR3 in the endoplasmatic reticulum. The wrong cellular location of an “aberrant” and active form of receptor seems to be related to a more severe phenotype.
Non-stop codon mutations account for less than 10% of mutations causing TD1. They results in extension of the protein, and some of them are not infrequent.
So far, only one pathogenic insertion has been reported to cause TD1. The mutation c.742_743insTGT has been identified in one fetus and it replaces the amino acid arginine in position Arg241 with leucine and cysteine amino acids.

Differential diagnosis

Mutations in the FGFR3 gene have been also identified in other diseases with highly variable phenotypes. Some of them display phenotype features which overlap with TD and they should be taken into account in the differential diagnosis, such as:

  • FGFR3-related form of achondroplasia. It's very similar to TD and usually lethal in the perinatal period;
  • SADDAN. It is a skeletal dysplasia with tibial and clavicular bowing, developmental delay, and acanthosis nigricans. Patients with SADDAN often survive beyond infancy without ventilatory support.

Here below, we report a list of diseases of interest in the differential diagnosis of TD:

  • Skeletal ciliopathies caused by mutations in the following genes: CFAP410, CEP120, DYNC2H1, DYNC2I1, DYNC2I2, DYNC2LI1, IFT52, IFT80, IFT81, IFT122, IFT140, IFT172, KIAA0586, KIAA0753, NEK1, TRAF3IP1, TCTEX1D2, TTC21B, WDR19, WDR35. However, ciliopathies show characteristic features that can distinguish them from TD, as polydactyly and a wide variety of multisystem features.
  • Perinatally lethal osteogenesis imperfecta caused by mutations in the COL1A1 and COL1A2 genes.
  • Achondrogenesis caused by mutations in the COL2A1, SLC26A2, and TRIP11 genes.
  • Spondylometaphyseal dysplasia caused by mutations in the GPX4 gene.
  • Dyssegmental dysplasia, Silverman-Handmaker type, caused by mutations in the HSPG2 gene.
  • Opsismodysplasia caused by mutations in the INPPL1 gene.
  • Classic rhizomelic chondrodysplasia punctata type 1 caused by mutations in the PEX7 gene.
  • Schneckenbecken dysplasia caused by mutations in the SLC35D1 gene.
  • Campomelic dysplasia caused by mutations in the SOX9 gene.

Genetic testing strategy

An accurate diagnosis of a specific skeletal dysplasia is challenging due to its rarity, the variety of the causative genes, and the spectrum of pathogenesis. If a clear diagnosis of TD is clinically established, sequencing analysis of the hot-spot exons 7, 10, 15 and 19 can be the first tier of genetic testing. In case of negative results, complete sequencing of the FGFR3 coding exons can be recommended to search for rare mutations.
More often, when a general diagnosis of pure skeletal dysplasia can be established, an NGS panel for skeletal dysplasia may take into account. Otherwise, if the clinical picture is vague or unclear, and the patient shows symptoms and/or clinical signs which are not typical of a pure skeletal dysplasia, Whole Exome Sequencing may be considered as the first tier of genetic testing.

Panel testing recommended at Breda Genetics for this condition:

Skeletal dysplasias, extended (ACP5, AGPS, ALPL, ARSE, B3GAT3, BGN, BMPR1B, BMP2, C21orf2, CANT1, CHST3, COL10A1, COL11A1, COL11A2, COL2A1, COL9A1, COL9A2, COL9A3, COMP, CRTAP, CSGALNACT1, DDR2, DYM, EBP, EIF2AK3, FGFR3, FLNB, FZD2, GALNS, GDF5, GLB1, GPX4, HSPG2, IHH, IMPAD1, INPPL1, KIF22, LBR, P3H1, LIFR, LONP1, MATN3, MMP13, MMP9, NANS, NEK1, NKX3-2, NOG, NSDHL, PAM16, PAPSS2, PCYT1A, PITX1, PTH1R, RNU4ATAC, ROR2, RSPRY1, RUNX2, SBDS, SLC26A2, SMARCAL1, SOX9, TRAPPC2, TRIP11, TRPV4, WISP3, XYLT1)

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References

Zhao et al. Ultrasound diagnosis of fetal thanatophoric skeletal dysplasia: Three cases report and a brief review. J Huazhong Univ Sci Technolog Med Sci 2017 Feb;37(1):148-152. PMID: 28224438

Chen et al. 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. Taiwan J Obstet Gynecol 2018 Feb;57(1):119-122. PMID: 29458880

Stembalska et al. Lethal and life-limiting skeletal dysplasias: Selected prenatal issues. Adv Clin Exp Med 2021 Jun;30(6):641-647. PMID: 34019743

Wainwright. Thanatophoric dysplasia: A review. S Afr Med J 2016 May; 106(6 Suppl 1):S50-3. PMID: 27245526

Lindy et al. Identification of a novel insertion mutation in FGFR3 that causes thanatophoric dysplasia type 1. Am J Med Genet A 2016 Jun; 170(6):1573-9. PMID: 27028100

French et Savarirayan. Thanatophoric Dysplasia. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. 2004 May 21 [updated 2020 Jun 18]. PMID: 20301540

Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: https://omim.org/

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