Alternative titles; symbols
SNOMEDCT: 715419004; ORPHA: 137776; DO: 0060560;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.2 | ?Lethal congenital contractural syndrome 2 | 607598 | Autosomal recessive | 3 | ERBB3 | 190151 |
A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-2 (LCCS2) is caused by homozygous mutation in the ERBB3 gene (190151) on chromosome 12q13. One such family has been reported.
Lethal congenital contracture syndrome-2 (LCCS2) is an autosomal recessive disorder characterized by severe multiple congenital contractures with muscle wasting and atrophy. Micrognathia and other craniofacial anomalies, including cleft palate, as well as cardiac defects and enlarged urinary bladder at birth have also been reported. Hydrops fetalis and multiple pterygia are absent. Most patients have died in the neonatal period, although 2 survived to early adolescence (Landau et al., 2003).
For a general phenotypic description and a discussion of genetic heterogeneity of LCCS, see LCCS1 (253310).
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, or fractures, and 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.
The transmission pattern of LCCS2 in the family reported by Landau et al. (2003) was consistent with autosomal recessive inheritance.
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.
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.
Landau, D., Mishori-Dery, A., Hershkovitz, R., Narkis, G., Elbedour, K., Carmi, R. A new autosomal recessive congenital contractural syndrome in an Israeli Bedouin kindred. Am. J. Med. Genet. 117A: 37-40, 2003. [PubMed: 12548738] [Full Text: https://doi.org/10.1002/ajmg.a.10894]
Narkis, G., Landau, D., Manor, E., Elbedour, K., Tzemach, A., Fishelson, M., Geiger, D., Ofir, R., Carmi, R., Birk, O. S. Homozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13. Am. J. Med. Genet. 130A: 272-276, 2004. [PubMed: 15378541] [Full Text: https://doi.org/10.1002/ajmg.a.30266]
Narkis, G., Ofir, R., Manor, E., Landau, D., Elbedour, K., Birk, O. S. Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am. J. Hum. Genet. 81: 589-595, 2007. [PubMed: 17701904] [Full Text: https://doi.org/10.1086/520770]