Lethal Congenital Contracture Syndrome 3

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-3 (LCCS3) can be caused by homozygous mutation in the PIP5K1C gene (606102) on chromosome 19p13.

For a general phenotypic description and a discussion of genetic heterogeneity of LCCS, see LCCS1 (253310).

Clinical Features

Narkis et al. (2007) described a novel type of autosomal recessive lethal congenital contracture syndrome (LCCS) that, like LCCS2 (607598), was identified in an Israeli Bedouin kindred. The phenotype was similar to that of LCCS2 but lacked the distended bladder (neurogenic bladder defect). Affected individuals were born with severe multiple joint contractures with severe muscle wasting and atrophy, mainly in the legs. Death occurred minutes to hours after birth due to respiratory insufficiency. The phenotype can be distinguished from that of LCCS1 (253310) by the absence of hydrops, fractures, and multiple pterygia.

Mapping

Using homozygosity mapping, Narkis et al. (2007) mapped the LCCS3 phenotype to a 3.4-Mb region on chromosome 19p13.

Molecular Genetics

In affected members of a large 5-generation Israeli Bedouin kindred with LCCS, and in an affected individual from an unrelated family, Narkis et al. (2007) found homozygosity for the same missense mutation in the PIP5K1C gene (D253N; 606102.0001). The mutation affects a conserved residue and abolishes PIP5K1C kinase activity.