Lethal Congenital Contracture Syndrome 2

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-2 (LCCS2) can be caused by homozygous mutation in the ERBB3 gene (190151) on chromosome 12q13. One such family has been reported.

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

Clinical Features

LCCS is a well-defined autosomal recessive disorder originally described in Finnish families (see 253310). The diagnostic criteria of LCCS are early fetal hydrops and akinesia, the Pena-Shokeir phenotype (208150), specific neuropathology with degeneration of anterior horn neurons, and extreme skeletal muscle atrophy. Landau et al. (2003) described an extended inbred Israeli-Bedouin pedigree with congenital contractures and additional unique phenotypic abnormalities, suggesting it represents a novel variant of autosomal recessive LCCS. Features distinguishing the novel disorder, LCCS2, from the Finnish type of LCCS included additional craniofacial/ocular findings, lack of hydrops, multiple pterygia, and fractures, as well as a normal duration of pregnancy. The major unique and previously undescribed clinical feature in the Israeli Bedouin disorder was markedly distended urinary bladder; other urinary abnormalities were also noted. Most of the infants with LCCS2 died shortly after birth. Sonographic prenatal diagnosis was possible as early as 15 weeks gestation by demonstration of fetal akinesia, limb contractures, hydramnios, and distended urinary bladder. Two girls, aged 12 and 13 years, were still alive at the time of the report. In addition to arthrogryposis and muscle atrophy, they both had left facial palsy, severe ophthalmologic problems with high myopia, and degenerative vitreoretinopathy. One had left hydronephrosis without urinary bladder abnormality, and the other presented no urinary problem. Both had normal cognitive development.

Mapping

By genomewide homozygosity mapping in the Israeli Bedouin kindred with LCCS2, Narkis et al. (2004) mapped the disease locus to a 6.4-Mb region on chromosome 12q13 between markers D12S325 and D12S1072. Maximum lod scores of 10.56 and 9.23 were obtained at D12S1604 and D12S1700, respectively.

Exclusion Studies

In the Israeli Bedouin kindred with LCCS2, Landau et al. (2003) excluded linkage to chromosomes 5q and 9q34, where spinal muscular atrophy I (SMA1; 253300) and the Finnish form of LCCS map, respectively.

Molecular Genetics

In an attempt to identify the specific molecular defect leading to the LCCS2 phenotype, Narkis et al. (2007) sequenced 61 of the 162 genes in the linkage interval on 12q, but found no mutations. Because a similar form of autosomal recessive lethal congenital contractural syndrome (LCCS3; 611369) is caused by a mutation in the PIP5K1C gene (606102), which encodes phosphatidylinositol-4-phosphate 5-kinase, type I, gamma (PIKI-gamma), Narkis et al. (2007) sequenced 2 genes within the LCCS2 locus on the basis of their association with the phosphatidylinositol pathway. They found a homozygous mutation in the ERBB3 gene (190151.0001) in affected members of a large kindred and in an isolated case.