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Lethal congenital contracture syndrome 3(LCCS3)

MedGen UID:
369555
•Concept ID:
C1969655
•
Disease or Syndrome
Synonyms: Lethal congenital contractural syndrome 3; MULTIPLE CONTRACTURE SYNDROME, ISRAELI BEDOUIN TYPE B
SNOMED CT: Lethal congenital contracture syndrome type 3 (715420005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Gene (location): PIP5K1C (19p13.3)
 
Monarch Initiative: MONDO:0012656
OMIM®: 611369
Orphanet: ORPHA137783

Definition

Lethal congenital contracture syndrome-3 (LCCS3) is a severe autosomal recessive form of arthrogryposis characterized by multiple joint contractures with muscle wasting and atrophy (Narkis et al., 2007). For a general phenotypic description and a discussion of genetic heterogeneity of LCCS, see LCCS1 (253310). [from OMIM]

Clinical features

From HPO
Multiple joint contractures
MedGen UID:
57633
•Concept ID:
C0158118
•
Acquired Abnormality
See: Search on this feature
Muscular atrophy
MedGen UID:
892680
•Concept ID:
C0541794
•
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
See: Feature record | Search on this feature
Arthrogryposis multiplex congenita
MedGen UID:
1830310
•Concept ID:
C5779613
•
Disease or Syndrome
Multiple congenital contractures in different body areas.
See: Feature record | Search on this feature
Respiratory insufficiency
MedGen UID:
11197
•Concept ID:
C0035229
•
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLethal congenital contracture syndrome 3

Professional guidelines

PubMed

Early prenatal diagnosis of a lethal syndrome of multiple congenital contractures.
Kirkinen P, Herva R, Leisti J
Prenat Diagn 1987 Mar;7(3):189-96. doi: 10.1002/pd.1970070306. PMID: 3295844

Recent clinical studies

Etiology

Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care.
Dieterich K, Kimber E, Hall JG
Am J Med Genet C Semin Med Genet 2019 Sep;181(3):345-353. Epub 2019 Aug 13 doi: 10.1002/ajmg.c.31732. PMID: 31410997
Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ.
Zeng X, Uyar A, Sui D, Donyapour N, Wu D, Dickson A, Hu J
Biochem J 2018 Jul 26;475(14):2257-2269. doi: 10.1042/BCJ20180326. PMID: 29959184Free PMC Article
Disorders of nucleotide excision repair.
Rapin I
Handb Clin Neurol 2013;113:1637-50. doi: 10.1016/B978-0-444-59565-2.00032-0. PMID: 23622385
Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway.
Narkis G, Ofir R, Landau D, Manor E, Volokita M, Hershkowitz R, Elbedour K, Birk OS
Am J Hum Genet 2007 Sep;81(3):530-9. Epub 2007 Jul 24 doi: 10.1086/520771. PMID: 17701898Free PMC Article
Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in Finland--an epidemiological study.
Pakkasjärvi N, Ritvanen A, Herva R, Peltonen L, Kestilä M, Ignatius J
Am J Med Genet A 2006 Sep 1;140A(17):1834-9. doi: 10.1002/ajmg.a.31381. PMID: 16892327

Diagnosis

Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital contractural syndrome 3.
Zhang F, Guo H, Zhou X, Deng Z, Xu Q, Wang Q, Yuan H, Luo J
BMC Pediatr 2024 Mar 15;24(1):182. doi: 10.1186/s12887-024-04674-6. PMID: 38491417Free PMC Article
Lethal Restrictive Dermopathy with ZMPSTE24 Mutation.
Pradeep I, Gowrishankar K, Shanmugasundaram L
Pediatr Dev Pathol 2022 May-Jun;25(3):327-329. Epub 2021 Dec 27 doi: 10.1177/10935266211065316. PMID: 34961372
Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care.
Dieterich K, Kimber E, Hall JG
Am J Med Genet C Semin Med Genet 2019 Sep;181(3):345-353. Epub 2019 Aug 13 doi: 10.1002/ajmg.c.31732. PMID: 31410997
Expansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrum.
Smith C, Parboosingh JS, Boycott KM, Bönnemann CG, Mah JK; Care4Rare Canada Consortium, Lamont RE, Micheil Innes A, Bernier FP
Clin Genet 2017 Mar;91(3):426-430. Epub 2017 Jan 30 doi: 10.1111/cge.12876. PMID: 27684565
Disorders of nucleotide excision repair.
Rapin I
Handb Clin Neurol 2013;113:1637-50. doi: 10.1016/B978-0-444-59565-2.00032-0. PMID: 23622385

Prognosis

Lethal respiratory course and additional features expand the phenotypic spectrum of PIEZO2-related distal arthrogryposis type 5.
Oliwa A, Hendson G, Longman C, Synnes A, Seath K, Barnicoat A, Hall JG, Patel MS
Am J Med Genet A 2023 Feb;191(2):546-553. Epub 2022 Nov 1 doi: 10.1002/ajmg.a.63019. PMID: 36317804
Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG.
Schorling DC, Rost S, Lefeber DJ, Brady L, Müller CR, Korinthenberg R, Tarnopolsky M, Bönnemann CG, Rodenburg RJ, Bugiani M, Beytia M, Krüger M, van der Knaap M, Kirschner J
Neurology 2017 Aug 15;89(7):657-664. Epub 2017 Jul 21 doi: 10.1212/WNL.0000000000004234. PMID: 28733338Free PMC Article
Continuous fetal head flexion as a marker for prenatal diagnosis of lethal multiple pterygium syndrome: a case report.
Hasegawa A, Hanaoka M, Murakoshi T
J Med Ultrason (2001) 2017 Jul;44(3):271-273. Epub 2016 Dec 16 doi: 10.1007/s10396-016-0766-1. PMID: 27987045
Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway.
Narkis G, Ofir R, Manor E, Landau D, Elbedour K, Birk OS
Am J Hum Genet 2007 Sep;81(3):589-95. Epub 2007 Jul 24 doi: 10.1086/520770. PMID: 17701904Free PMC Article
Severe spinal muscular atrophy variant associated with congenital bone fractures.
Felderhoff-Mueser U, Grohmann K, Harder A, Stadelmann C, Zerres K, Bührer C, Obladen M
J Child Neurol 2002 Sep;17(9):718-21. doi: 10.1177/088307380201700915. PMID: 12503654

Clinical prediction guides

Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ.
Zeng X, Uyar A, Sui D, Donyapour N, Wu D, Dickson A, Hu J
Biochem J 2018 Jul 26;475(14):2257-2269. doi: 10.1042/BCJ20180326. PMID: 29959184Free PMC Article
Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway.
Narkis G, Ofir R, Manor E, Landau D, Elbedour K, Birk OS
Am J Hum Genet 2007 Sep;81(3):589-95. Epub 2007 Jul 24 doi: 10.1086/520770. PMID: 17701904Free PMC Article
Assignment of the disease locus for lethal congenital contracture syndrome to a restricted region of chromosome 9q34, by genome scan using five affected individuals.
Mäkelä-Bengs P, Järvinen N, Vuopala K, Suomalainen A, Ignatius J, Sipilä M, Herva R, Palotie A, Peltonen L
Am J Hum Genet 1998 Aug;63(2):506-16. doi: 10.1086/301968. PMID: 9683599Free PMC Article

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