lethal congenital contracture syndrome

LCCS1 is characterized by total lack of the movements of the fetus, and is detectable at 13th week of pregnancy. It is accompanied by oedema, small chin, small lungs, crooked joints and occasional skin webs of the neck and elbows. The fetus has characteristic pattern of malpositions recognizable even in severely macerated fetuses with club feet and hyperextension of the knees but the elbows and wrists showing flexion contractures.{{cite journal| vauthors = Herva R, Leisti J, Kirkinen P, Seppänen U| title = A lethal autosomal recessive syndrome of multiple congenital contractures| journal = Am. J. Med. Genet.| volume = 20| pages = 431–439| year = 1985| pmid = 3993672|doi=10.1002/ajmg.1320200303| issue = 3}}

Neuropathological analysis shows lack of anterior horn motoneurons and severe atrophy of the ventral spinal cord. The skeletal muscles are severely hypoplastic.{{cite journal| vauthors = Herva R, Conradi N, Kalimo H, Leisti J, Sourander P| title = A lethal autosomal recessive syndrome of multiple congenital contractures. Neuropathological analysis of five fetal cases| journal = Am. J. Med. Genet.| volume = 29| pages = 67–76| year = 1988| doi = 10.1002/ajmg.1320290109| pmid = 3344776| issue = 1}}

The defective gene associated with LCCS1 is the mRNA export mediator GLE1 at chromosome 9q34. In more than 40 families the fetus has been homozygous for A->G substitution (c.432-10A>G) located in intron 3 of GLE1 creating an illegitimate splice acceptor site resulting in nine extra nucleotides in the GLE1 cDNA (GLE1 FinMajor mutation). In one family the fetus has been compound heterozygous for GLE1 FinMajor and R→H substitution in exon 12.{{cite journal| vauthors = Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J, Vuopala K, Ignatius J, Herva R, Peltonen L| title = Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease| journal = Nature Genetics| volume = 40| issue = 2| pages = 155–157| year = 2008| pmid = 18204449| doi = 10.1038/ng.2007.65| pmc = 2684619}}

A slightly milder phenotype with survival beyond 32nd gestational week also characterized by foetal akinesia, arthrogryposis and anterior horn cell loss (Lethal arthrogryposis with anterior horn cell disease, LAAHD) was also shown to result from mutations in GLE1.{{cite journal|vauthors=Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J, Vuopala K, Ignatius J, Herva R, Peltonen L | title = Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease| journal = Nature Genetics| volume = 40| issue = 2| pages = 155–157|date=February 2008| pmid = 18204449| pmc = 2684619| doi = 10.1038/ng.2007.65}}

LCCS1 is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder (GLE1) is located on an autosome (chromosome 9), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.{{cn|date=October 2021}}

LCCS1 belongs to Finnish heritage of diseases and cases have been confirmed until now (2009) only in Finland. The prevalence is 1 in 25000 births.{{cite journal| vauthors = Pakkasjärvi N, Ritvanen A, Herva R, Peltonen L, Kestilä M, Ignatius J| title = Lethal congenital contracture syndrome (LCC) and other lethal arthrogryposes in Finland – an epidemiological study| journal = Am. J. Med. Genet.| volume = 140A| pages = 1834–1839| year = 2006| doi = 10.1002/ajmg.a.31381| pmid = 16892327| issue = 17| s2cid = 23457002}} The carrier frequency is 1% in whole Finland and 2% in North-Eastern part of Finland where the birthplaces of ancestors of affected individual show clustering.{{cn|date=October 2021}}

Update in regard to "Only in Finland" - In 1990 around my 28th week gestation my waters broke and ended up in Mercy Hospital, East Melbourne, Victoria, Australia. At 31.5 gestation the baby's heartbeat was 185 with no movement and an emergency Caesarean was performed. At my 13-week ultrasound his condition was missed but looking back at the images you can clearly see the condition in his hand. He was kept on life support for 12 hours and as this had never been seen before by the hospital they reached out for a known condition and come back with Lethal Multiple Congenital Contraction Syndrome. He has seized knees, elbows, ankles an abnormally small chin and underdeveloped lungs. At the time of his birth the faulty gene was unknown. He deterioration was in line with report that they normally decease around 32 weeks' gestation. We were lucky to meet him and after 12 hours his life support was turned off. He was our second child, our first was born normally however he has not been tested to know if he has the faulty gene.

Mäkelä-Bengs et al. (1997,1998) performed a genome-wide screening and linkage analysis and assigned the LCCS locus to a defined region of 9q34.{{cite journal| vauthors = Mäkelä-Bengs P, Järvinen N, Vuopala K, Suomalainen A, Palotie A, Peltonen L| title = The assignment the lethal congenital contracture syndrome (LCCS) locus to chromosome 9q33-34 | journal = Am. J. Hum. Genet.| volume = 61| issue = suppl| pages = A30| year = 1997}}

• Lethal arthrogryposis with anterior horn cell disease

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Category:Rare diseases

Category:Autosomal recessive disorders

Category:Syndromes