Lethal Congenital Contracture Syndrome 10

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-10 (LCCS10) is caused by homozygous mutation in the NEK9 gene (609798) on chromosome 14q24.

For a general phenotypic description and a discussion of genetic heterogeneity of lethal congenital contracture syndrome, see LCCS1 (253310).

Clinical Features

Casey et al. (2016) studied 2 Irish Traveller families with a recessive lethal skeletal dysplasia. In the first family, there were 2 offspring with fetal akinesia, multiple contractures, shortening of upper and lower limbs, short broad ribs, narrow chest and thorax, pulmonary hypoplasia, and protruding abdomen. In the second family, 3 offspring had the same features, and 2 of the 3 also exhibited bowed femurs. None of the affected infants survived past birth: 1 died 1 hour after birth, resuscitation failed in 2, 1 died in utero, and in 1 case the pregnancy was terminated.

Molecular Genetics

In an Irish Traveller family in which 2 offspring had lethal skeletal dysplasia, Casey et al. (2016) performed exome sequencing and identified a homozygous nonsense mutation in the NEK9 gene (R497X; 609798.0001) that segregated with disease. Analysis of a second Irish Traveller family with 3 similarly affected offspring showed that the R497X mutation segregated with disease in that family as well. The 2 families were likely distantly related. Casey et al. (2016) noted 'considerable overlap' between the features of these patients and those with short-rib thoracic dysplasia (SRTD6; 263520) due to mutations in the NEK1 gene (604588); however, the patients with the NEK9 mutation did not exhibit certain SRTD features such as polysyndactyly and renal cysts, but rather presented with fetal akinesia, multiple contractures, and short bowed femurs, which are not seen in the NEK1-associated disorder.