Thanatophoric dysplasia

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>

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.

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.

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)