Thanatophoric Dysplasia, Type Ii

A number sign (#) is used with this entry because thanatophoric dysplasia type II (TD2) is caused by heterozygous mutation in the fibroblast growth factor receptor-3 (FGFR3; 134934) gene on chromosome 4p16.

Description

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), whereas TD cases with curved, short femurs with or without cloverleaf skull were designated TD type I (TD1; 187600) (Langer et al., 1987).

Clinical Features

Partington et al. (1971) described cloverleaf skull in association with generalized skeletal dysplasia consistent with thanatophoric dwarfism. Two of their 4 cases were in sibs. Horton et al. (1983) reported monozygotic twins with thanatophoric dysplasia who were discordant for the Kleeblattschaedel anomaly.

In a survey of lethal osteochondrodysplasias in the county of Fyn (Funen), Denmark, Andersen (1989) found 2 cases of thanatophoric dysplasia and 1 case of thanatophoric dysplasia with cloverleaf skull.

Langer et al. (1987) reported 9 infants with this combination and reviewed 22 previously published cases. In general they concluded that there are 2 types of thanatophoric dysplasia: type I, with curved femora and very flat vertebral bodies; and type II, with straight femora and taller vertebral bodies. Consistent though subtle histopathologic characteristics were thought to differentiate the 2 types. Very few type I cases had cloverleaf skull, and the cloverleaf skull was mild. Almost all type II cases had severe cloverleaf skull.

Li et al. (2006) reported a female fetus with TD2 and occipital encephalocele, in whom they identified the K650E mutation in the FGFR3 gene. The authors stated that this was only the second reported case of TD2 with encephalocele.

Inheritance

Isaacson et al. (1983) found no familial cases other than those of Partington et al. (1971). They concluded that the disorder is probably autosomal dominant with germinal mosaicism possibly accounting for the affected sibs reported by Partington et al. (1971).

Molecular Genetics

In 16 individuals with type II thanatophoric dysplasia, Tavormina et al. (1995) identified a heterozygous 1948A-G mutation in the FGFR3 gene, causing a lys650-to-glu (K650E; 134934.0004) substitution in the tyrosine kinase domain.

In a review of 91 cases of TD by Wilcox et al. (1998), the K650E mutation was the only cause of TD type II, and occurred in 17 cases (19%).

Animal Model

To investigate the effect of the Fgfr3 K644E mutation, which corresponds to human K650E mutation, on CNS development, Lin et al. (2003) generated tissue-specific TDII mice by crossing K644E transgenic mice with CNS-specific Nestin-cre (NES; 600915) or cartilage-specific Col2a1-cre (COL2A1; 120140) mice. CNS-specific neonates did not demonstrate a profound skeletal phenotype; however, many pups exhibited round heads. MRI and histochemical analysis illustrated asymmetric changes in cortical thickness and cerebellar abnormalities in these mice, which correlated with brain abnormalities observed in human TDII patients and which were not seen in cartilage-specific mice. Upon examination of the spinal cords of adult CNS-specific mice, premature differentiation of oligodendrocyte progenitors was observed.