Lethal Congenital Contracture Syndrome 6

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-6 (LCCS6) is caused by homozygous mutation in the ZBTB42 gene (613915) on chromosome 14q32. One such family has been reported.

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

Clinical Features

Patel et al. (2014) studied a consanguineous Saudi Arabian family in which 3 of 8 children were stillborn with arthrogryposis. The prenatal course of the proposita was complicated by reduced fetal movements, and antenatal ultrasound showed severe polyhydramnios, absent stomach, and multiple contracture deformities, without major renal or central nervous system malformations. Multiple sessions of reductive amniocentesis were required due to the severity of the polyhydramnios. The infant had no respiratory effort at birth, and the parents requested that no resuscitation be undertaken. There was no major craniofacial dysmorphism apart from macrocephaly. The hips were fixed in flexion and associated with severely adducted lower limbs, symmetric fixed extension deformity of the knees, fixed flexion of both hands, and dorsiflexion of the feet. No apparent digital defects were noted, and full-body x-ray showed no gross bony abnormality. Muscle biopsy and autopsy were denied by the parents.

Molecular Genetics

In a consanguineous Saudi Arabian family in which 3 sibs had lethal congenital contracture syndrome, Patel et al. (2014) excluded linkage to known LCCS loci. By combined autozygome analysis and whole-exome sequencing, they identified a homozygous missense mutation in the ZBTB42 gene (R397H; 613915.0001) that segregated with the disease in the family. The mutation was not found in the 1000 Genomes Project or Exome Variant Server databases, in 300 Saudi controls, or in 485 Saudi exomes.