Lethal Congenital Contracture Syndrome 1

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-1 (LCCS1) is caused by homozygous or compound heterozygous mutation in the mRNA export mediator GLE1 (603371) on chromosome 9q34.

Biallelic mutation in the GLE1 gene can also cause congenital arthrogryposis with anterior horn cell disease (CAAHD; 611890), a disorder with overlapping features but with survival beyond the perinatal period.

Description

Autosomal recessive lethal congenital contracture syndrome (LCCS) is the most severe, neonatally lethal, form of arthrogryposis (see 108120), a disorder characterized by congenital nonprogressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth (summary by Markus et al., 2012).

Genetic Heterogeneity of Lethal Congenital Contracture Syndrome

See also lethal congenital contracture syndrome-2 (LCCS2; 607598), caused by mutation in the ERBB3 gene (190151); LCCS3 (611369), caused by mutation in the PIP5K1C gene (606102); LCCS4 (614915), caused by mutation in the MYBPC1 gene (160794); LCCS5 (615368), caused by mutation in the DNM2 gene (602378); LCCS6 (616248), caused by mutation in the ZBTB42 gene (613915); LCCS7 (616286), caused by mutation in the CNTNAP1 gene (602346); LCCS8 (616287), caused by mutation in the ADCY6 gene (600294); LCCS9 (616503), caused by mutation in the ADGRG6 gene (612243); LCCS10 (617022), caused by mutation in the NEK9 gene (609798); and LCCS11 (617194), caused by mutation in the GLDN gene (608603).

Clinical Features

In Finland, Herva et al. (1985) observed 16 cases of a lethal syndrome with multiple congenital contractures resembling in many ways the Pena-Shokeir I syndrome (208150) but differing from it in failure of survival postnatally and by the presence of marked fetal hydrops. Facial abnormalities, especially micrognathia, were found and autopsies demonstrated pulmonary hypoplasia, muscular atrophy, and paucity of anterior horn motor neurons. (Moerman et al. (1983) found degeneration and paucity of anterior horn cells in Pena-Shokeir I syndrome.) Another characteristic that perhaps differentiates the Finnish multiple contracture syndrome from Pena-Shokeir I syndrome is the generalized thinning of tubular bones in many of the Finnish cases; the ribs were exceedingly thin and fishbone-like. The 16 cases belonged to 10 sibships. The grandparents of 8 sibships originated from neighboring rural communities of the northeastern part of Finland.

Herva et al. (1988) presented the neuropathologic findings on 5 fetuses in whom the diagnosis had been made by the finding of fetal hydrops on ultrasonography. The fetuses showed a typical pattern of malpositioning of hips and knees with occasional pterygia of the neck and elbows. The muscles were hypoplastic and the spinal cords showed severe thinning, most markedly affecting the ventral half. The loss of axons and anterior horn motor neurons, including changes in the brainstem, suggested a degenerative rather than a dysmorphogenetic process.

Vuopala and Herva (1994) reported on 40 fetuses and infants with LCCS identified in Finland through a national morphology-based study of lethal arthrogryposis between 1979 and 1992. The incidence was estimated to be 1 in 19,000 births. There were 20 affected males and 20 affected females in 26 families. In 16 cases, the pregnancy was terminated after the prenatal diagnosis of total akinesia and fetal hydrops on ultrasound. There were 19 stillborn infants and 5 were born showing signs of life, but died within 1 hour. The segregation analyses yielded 0.45 affected by the 'singles' method and 0.34 by the 'sib' method. The birthplaces of grandparents were located in the sparsely populated northeast section of Finland. Vuopala and Herva (1994) illustrated a cross-section of the spinal cord showing marked reduction in the ventral part, a paucity of anterior motor neurons, and hydropic degeneration of descending tracks. Above the decussation of the pyramids, the CNS is normal. Vuopala and Herva (1994) noted that the London Dysmorphology Database listed LCCS as part of the Pena-Shokeir-multiple ankyloses-pulmonary hypoplasia syndrome. The Database noted that this designation covers a number of separate entities. Vuopala and Herva (1994) were of the opinion that LCCS is a distinct autosomal recessive disorder with a recurrence risk of 25%, which is higher than the 10 to 15% risk stated in the London Dysmorphology Database for the Pena-Shokeir syndrome.

Makela-Bengs et al. (1997) noted that LCCS leads to prenatal death of the fetus before the thirty-second week of gestation. The highly specific hallmark of LCCS is early-onset degeneration of the anterior horn motor neurons in the spinal cord.

Population Genetics

In a study of all cases of lethal arthrogryposis diagnosed in Finland between 1987 and 2002, Pakkasjarvi et al. (2006) classified 39 of the total 115 cases as LCCS, characterized by total immobility of the fetus at all ultrasound examinations, multiple joint contractures in upper and lower limbs, hydrops and fetal death before 32 weeks of pregnancy. Pakkasjarvi et al. (2006) concluded that LCCS is a unique Finnish disorder with a prevalence of 1 in 25,250 births and is a major cause of lethal arthrogryposis in Finland.

Mapping

Using DNA samples of 5 affected fetuses from 2 families, Makela-Bengs et al. (1997) performed a genomewide screen and found that affected sibs shared the same chromosome segments on a 20-cM region of 9q. Further linkage analyses in 10 LCCS families with 19 affected individuals confirmed the linkage to this region; they obtained a maximum pairwise lod score of 4.6 and a multipoint lod score of 6.1.

Makela-Bengs et al. (1998) narrowed the assignment of the LCCS locus to a defined region of 9q34, between markers D9S1825 and D9S1830. Linkage disequilibrium analysis restricted the critical chromosomal region to a segment of less than 100 kb in the vicinity of marker D9S61. Two genes, NGAL (600181) and NOTCH1 (190198), were excluded as sites of the mutation causing LCCS.

Exclusion Studies

Since the neuropathologic findings in LCCS closely resemble those of spinal muscular atrophy (SMA; 253300), Vuopala et al. (1995) sought linkage with microsatellite markers assigned to the SMA region on 5q. Linkage was excluded.

Molecular Genetics

Nousiainen et al. (2008) further restricted the critical chromosome region on 9q34 for the LCCS1 locus in Finnish families. Through systematic sequence analyses of candidate genes in the region, they found potential mutations in the GLE1 gene (603371), which encodes a protein required for export of mRNAs from the nucleus to the cytoplasm in both lower and higher eukaryotic cells. Sequence analyses of genomic DNA from LCCS1 cases identified a homozygous A-to-G substitution located within intron 3 of GLE1, 10 nucleotides upstream of exon 4 (603371.0001). This mutation, referred to by the authors as Fin(Major), was homozygous in 51 of 52 LCCS1 cases in 29 unrelated families. One patient was compound heterozygous for the Fin(Major) mutation and a point mutation predicted to result in an arginine-to-histidine substitution in exon 12 (603371.0002). LCCS is enriched in northeastern Finland, where the carrier frequency of the Fin(Major) mutation was found to be 2%; in the general Finnish population it was 1%.

Nousiainen et al. (2008) also studied congenital arthrogryposis with anterior horn cell disease (CAAHD; 611890) to determine whether it is a disorder allelic to LCCS1. They screened 9 unrelated families with LAAHD, for a total of 12 affected individuals with mutation in the GLE1. All 12 cases were compound heterozygotes: 6 were heterozygous for the LCCS1 Fin(Major) and a missense point mutation in exon 13 (603371.0003), and the remaining 6 carried the Fin(Major) mutation and a missense mutation in exon 16 (603371.0004).