Lethal Congenital Contracture Syndrome 7

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-7 (LCCS7) is caused by homozygous mutation in the CNTNAP1 gene (602346) on chromosome 17q21.

Biallelic mutation in the CNTNAP1 gene can also cause congenital hypomyelinating neuropathy-3 (CHN3; 618186), a similar disorder with less prominent contractures. LCCS7 and CHN3 represent a phenotypic spectrum resulting from mutations in the CNTNAP1 gene.

Description

Lethal congenital contracture syndrome-7, an axoglial form of arthrogryposis multiplex congenita (AMC), is characterized by congenital distal joint contractures, polyhydramnios, 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 7 newborns from 4 unrelated consanguineous families (A641, K182, K199, B207) who were diagnosed with distal arthrogryposis multiplex congenita by fetal ultrasound between 28 and 32 weeks of gestation. All 7 had polyhydramnios, distal joint contractures, and severe motor paralysis at birth, leading to death within the first 2 months of life. At least 5 of the patients were known to have fetal hypo- or akinesia. One patient had micrognathia and facial diplegia. None of the patients had pterygium, cleft palate, or hygroma. Laquerriere et al. (2014) noted a dramatic reduction of motor nerve conduction velocities. Transmission electron microscopic analysis of sciatic nerve showed marked widening of the nodes of Ranvier and thin myelin sheaths as compared to control tissue of matched gestational age.

Lakhani et al. (2017) reported a large consanguineous Arab family from Qatar in which 3 sisters had LCCS7. The pregnancies were complicated by polyhydramnios, and prenatal ultrasound showed mild contractures or abnormal positioning of the limbs. Two of the patients lacked spontaneous movements and had poor breathing leading to death in the minutes after birth, whereas the third was immediately intubated and survived. She had microphthalmia, facial weakness, and a stiff jaw. At 13 years of age, this patient was still alive, but she was severely hypotonic, in a vegetative state, and intubated, with severe contractures and muscle wasting. Muscle biopsy suggested neurogenic muscular atrophy. Motor nerve conduction velocities were markedly reduced (about 10 m/s) in the upper limbs with no responses in the lower limbs; sensory responses were absent. Brain imaging in this patient showed profound cerebral and cerebellar atrophy with almost no white matter, thin corpus callosum, and small basal ganglia and hippocampi. Family history revealed 6 first cousins who reportedly died early with a muscle disorder, but no further information was available.

Inheritance

The transmission pattern of LCCS7 in the consanguineous families reported by Laquerriere et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

By genetic mapping and whole-exome sequencing, Laquerriere et al. (2014) identified homozygous frameshift mutations in the CNTNAP1 gene (602346.0001-602346.0003) in 7 newborns from 4 unrelated consanguineous families with lethal arthrogryposis multiplex congenita.

In 3 sibs, born of consanguineous parents from Qatar, with LCCS7, Lakhani et al. (2017) identified a homozygous frameshift mutation in the CNTNAP1 gene (602346.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay and a complete loss of function. Loss of the CASPR protein, which is encoded by the CNTNAP1 gene, results in improper organization of axoglial junctions in nerves. The loss of these axoglial junctions results in swelling of neuronal axons, decreased nerve conduction, reduced motor function, and death. In addition, the loss of myelination also affects the central nervous system.