Lethal Congenital Contracture Syndrome 11

A number sign (#) is used with this entry because of evidence that lethal congenital contracture arthrogryposis-11 (LCCS11) is caused by homozygous or compound heterozygous mutation in the GLDN gene (608603) on chromosome 15q21.

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

Clinical Features

Maluenda et al. (2016) studied 4 families with lethal congenital arthrogryposis in 6 affected individuals. The pregnancies were characterized by marked polyhydramnios and fetal akinesia on prenatal ultrasound at about 27 to 32 weeks' gestation (earlier ultrasounds appeared normal). Other features included flexion and extension contractures of the upper and lower limbs, respectively, as well as flexion of the wrists and fingers. Two of the affected individuals died at day 1 of life, 1 died in utero, and 3 pregnancies were terminated after diagnosis. Postmortem examination, which was performed in 4 of the affected individuals, revealed pulmonary hypoplasia in all; 2 exhibited retrognathia, 1 showed camptodactyly, and 1 had bilateral clubfoot. Transmission electron microscopy of the sciatic nerve from 1 of the affected fetuses showed a reduced number of myelinated fibers compared to 2 age-matched controls, and nodal length was significantly increased in the affected individual compared to a control.

Molecular Genetics

In a male fetus from a family with lethal congenital arthrogryposis, Maluenda et al. (2016) performed whole-exome sequencing and identified compound heterozygosity for a 1-bp deletion (608603.0001) and a missense mutation (A475P; 608603.0002) in the GLDN gene. Sanger sequencing confirmed that an affected female sib was also compound heterozygous for the mutations, and that the parents were each heterozygous for 1 of the mutations. Targeted exome sequencing on DNA samples from 106 individuals with arthrogryposis and/or reduced fetal mobility revealed 3 more families with biallelic mutations in GLDN (see 608603.0003-608603.0006).