Lethal Congenital Contracture Syndrome 8

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-8 (LCCS8) is caused by homozygous mutation in the ADCY6 gene (600294) on chromosome 12q13. One such family has been reported.

Description

Lethal congenital contracture syndrome-8, an axoglial form of arthrogryposis multiplex congenita, is characterized by congenital distal joint contractures, reduced fetal movements, and severe motor paralysis leading to death early in the neonatal period (Laquerriere et al., 2014).

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

Clinical Features

Laquerriere et al. (2014) reported 2 sibs from a consanguineous family (A649) who were diagnosed with distal arthrogryposis multiplex congenita at 32 weeks' gestation by fetal ultrasound. Both sibs had fetal hypo- or akinesia. At birth, they were noted to have hypotonia, respiratory distress, facial diplegia, areflexia, and swallowing defect. Neither sib had polyhydramnios, pterygium, cleft palate, or hygroma. Severe motor paralysis at birth led to death within the first 3 months of life. No response was found on motor nerve conduction velocity testing. Nerve immunohistochemistry using an S100 protein antibody revealed Schwann cells, but all nerve fascicles were negative for myelin basic protein antibodies. Transmission electron microscopic analysis of nerve showed no myelinated axons and some redundant basal lamina of Schwann cells.

Inheritance

The transmission pattern of lethal arthrogryposis multiplex congenita in the consanguineous family reported by Laquerriere et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous parents, with an axoglial form of lethal arthrogryposis multiplex congenita, Laquerriere et al. (2014) identified a homozygous missense mutation in the ADCY6 gene (R1116C; 600294.0001). The parents were heterozygous for the mutation, which was not found in the Exome Variant Server or the dbSNP (build 138) databases.

Animal Model

Laquerriere et al. (2014) knocked down ADCY6 orthologs in zebrafish and found loss of myelin basic protein expression in the peripheral nervous system but normal expression in the central nervous system when compared with wildtype. No defects in Schwann cell migration and axonal growth were found in the morphants.