Lethal Congenital Contracture Syndrome 9

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-9 (LCCS9) is caused by homozygous mutation in the GPR126 gene (ADGRG6; 612243) on chromosome 6q24.

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

Clinical Features

Ravenscroft et al. (2015) reported 4 affected individuals from 3 unrelated consanguineous families with severe arthrogryposis multiplex congenita. In the first family, prenatal ultrasound at 20 weeks of gestation showed distal joint contractures, diaphragmatic defect, and reduced fetal mobility. The pregnancy was terminated, and fetopathologic examination revealed joint retractions associated with pterygium at the right elbow and axilla, as well as thin and elevated diaphragmatic cupolae. In the second family, which was of Portuguese ancestry, prenatal ultrasound at 16 weeks of gestation showed upper limb arthrogryposis, and 8 weeks later, micrognathia and polyhydramnios were also observed. MRI at 25 weeks of gestation revealed micrognathia, fixed extension of the arms, and flexion of the elbows, wrists, and hands; at 28 weeks, intrauterine growth retardation (IUGR) became evident. The female infant was born at 31 weeks by cesarean section after premature amniorrhexis; examination revealed ocular hypertelorism, upper limb arthrogryposis with ulnar deviation of hands, camptodactyly, sparse dermal ridges, ankylosis of the knee joint, and talipes equinovarus. She underwent cardiopulmonary resuscitation and orotracheal intubation, but developed severe pulmonary hypertension and died from cardiorespiratory arrest 1 hour after birth. In the third family, of Iraqi descent, the first pregnancy was complicated by polyhydramnios requiring drainage. Antenatal ultrasound at 30 weeks of gestation showed IUGR, possible talipes equinovarus, and no upper limb movements for over 1 hour. The female infant was delivered by emergency cesarean section at 36 weeks because of severe preeclampsia, and died of respiratory failure at 1 hour of life. Severe arthrogryposis of large and small joints was noted, with adducted thumbs, ulnar deviation, fixed flexion contractures of the hands and wrists, reduced digital creases, severe talipes equinovarus, and generally reduced muscle bulk in the limbs. Dysmorphic facial features included triangular face, low-set ears, depressed nasal bridge, anteverted nares, thin upper lip, and micrognathia. Autopsy confirmed short umbilical cord and pulmonary hypoplasia. A second affected pregnancy in this family was terminated at 19 weeks of gestation after ultrasound at 18 weeks showed bilateral talipes equinovarus, contractures of upper limbs, and no movement of the arms for over 1 hour. Examination revealed a male fetus with arthrogryposis and poorly developed musculature of the limbs, as well as subtle dysmorphic features, including low-set ears and micrognathia. 'Babygram' x-ray in the female infant showed thoracic kyphoscoliosis but no structural abnormalities, whereas multiple segmentation abnormalities of the thoracic spine were seen in the male fetus. Histologic examination of muscle biopsies from the 2 sibs was consistent with diffuse nonspecific myopathy, showing significant variability in muscle-fiber diameter within each muscle sampled, with predominantly normal and atrophic small fibers, but occasional large hypertrophic fibers. Both type 1 and type 2 fibers appeared atrophic on skeletal muscle myosin staining, and the most severely affected muscle was the diaphragm. Analysis of peripheral nerves demonstrated absence of myelin basic protein (MBP; 159430), suggesting that the disease is due to defective myelination of the peripheral axons during fetal development.

Molecular Genetics

By targeted exome sequencing on a DNA sample from a fetus with lethal arthrogryposis, Ravenscroft et al. (2015) identified a homozygous nonsense mutation in the GPR126 gene (R7X; 612243.0001) for which the unaffected first-cousin parents were heterozygous. Exome sequencing of a similarly affected proband from a consanguineous family of Portuguese ancestry revealed homozygosity for a duplication in GPR126 (612243.0002), which was present in heterozygosity in the unaffected first-cousin parents. In a consanguineous family of Iraqi descent, the proband and an affected sib were both homozygous for a GPR126 Ravenscroft et al. (2015) identified homozygosity for a missense mutation (V741E; 612243.0003) that was found in heterozygosity in their unaffected second-cousin parents.