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Lethal congenital contracture syndrome 4(LCCS4)

MedGen UID:: 766960
•Concept ID:: C3554046
•: Disease or Syndrome

Synonym:	LCCS4

Gene (location): Gene(s) directly associated with this condition or phenotype.	MYBPC1 (12q23.2)

Monarch Initiative:	MONDO:0013965
OMIM®:	614915

Definition

Lethal congenital contracture syndrome-4 (LCCS4) is a severe form of neuromuscular arthrogryposis characterized by contractures leading to various degrees of flexion or extension limitations evident at birth (Markus et al., 2012). For a general phenotypic description and 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

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Distal arthrogryposis

MedGen UID:: 120512
•Concept ID:: C0265213
•: Disease or Syndrome

An inherited primary limb malformation disorder characterized by congenital contractures of two or more different body areas and without primary neurologic and/or muscle disease that affects limb function.

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Flexion contracture

MedGen UID:: 83069
•Concept ID:: C0333068
•: Anatomical Abnormality

A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.

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Muscular atrophy

MedGen UID:: 892680
•Concept ID:: C0541794
•: Pathologic Function

The presence of skeletal muscular atrophy (which is also known as amyotrophy).

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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.

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Abnormality of the musculoskeletal system
Abnormality of the respiratory system
- Respiratory insufficiency

Recent clinical studies

Etiology

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: 29959184 Free PMC Article

Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis.

Conant A, Curiel J, Pizzino A, Sabetrasekh P, Murphy J, Bloom M, Evans SH, Helman G, Taft RJ, Simons C, Whitehead MT, Moore SA, Vanderver A
J Child Neurol 2018 Sep;33(10):642-650. Epub 2018 Jun 8 doi: 10.1177/0883073818776157. PMID: 29882456 Free PMC Article

Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2.

Leal GF, Nishimura G, Voss U, Bertola DR, Åström E, Svensson J, Yamamoto GL, Hammarsjö A, Horemuzova E, Papadiogannakis N, Iwarsson E, Grigelioniene G, Tham E
J Bone Miner Res 2018 Apr;33(4):753-760. Epub 2018 Jan 4 doi: 10.1002/jbmr.3348. PMID: 29178448

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: 17701904 Free PMC Article

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: 17701898 Free PMC Article

See all (5)

Diagnosis

A homozygous TTN gene variant associated with lethal congenital contracture syndrome.

Chervinsky E, Khayat M, Soltsman S, Habiballa H, Elpeleg O, Shalev S
Am J Med Genet A 2018 Apr;176(4):1001-1005. doi: 10.1002/ajmg.a.38639. PMID: 29575618

Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2.

Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita.

Ekhilevitch N, Kurolap A, Oz-Levi D, Mory A, Hershkovitz T, Ast G, Mandel H, Baris HN
Clin Genet 2016 Jul;90(1):84-9. Epub 2016 Jan 20 doi: 10.1111/cge.12707. PMID: 26661508

Rare cases of congenital arthrogryposis multiplex caused by novel recurrent CHRNG mutations.

Seo J, Choi IH, Lee JS, Yoo Y, Kim NK, Choi M, Ko JM, Shin YB
J Hum Genet 2015 Apr;60(4):213-5. Epub 2015 Jan 22 doi: 10.1038/jhg.2015.2. PMID: 25608830

Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome.

Chen H, Immken L, Lachman R, Yang S, Rimoin DL, Rightmire D, Eteson D, Stewart F, Beemer FA, Opitz JM
Am J Med Genet 1984 Apr;17(4):809-26. doi: 10.1002/ajmg.1320170411. PMID: 6720746

See all (6)

Prognosis

Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6.

Agolini E, Cherchi C, Bellacchio E, Martinelli D, Cocciadiferro D, Cutrera R, Chiarini Testa MB, Barone C, Bianca S, Novelli A
Clin Genet 2020 Apr;97(4):649-654. Epub 2020 Feb 20 doi: 10.1111/cge.13691. PMID: 31846058

A homozygous TTN gene variant associated with lethal congenital contracture syndrome.

Chervinsky E, Khayat M, Soltsman S, Habiballa H, Elpeleg O, Shalev S
Am J Med Genet A 2018 Apr;176(4):1001-1005. doi: 10.1002/ajmg.a.38639. PMID: 29575618

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: 17701904 Free PMC Article

Inverted duplication of 15q with terminal deletion in a multiple malformed newborn with intrauterine growth failure and lethal phenotype.

Genesio R, De Brasi D, Conti A, Borghese A, Di Micco P, Di Costanzo P, Paladini D, Ungaro P, Nitsch L
Am J Med Genet A 2004 Aug 1;128A(4):422-8. doi: 10.1002/ajmg.a.30112. PMID: 15264291

See all (4)

Clinical prediction guides

Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6.

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: 29959184 Free PMC Article

Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita.

Ekhilevitch N, Kurolap A, Oz-Levi D, Mory A, Hershkovitz T, Ast G, Mandel H, Baris HN
Clin Genet 2016 Jul;90(1):84-9. Epub 2016 Jan 20 doi: 10.1111/cge.12707. PMID: 26661508

Rare cases of congenital arthrogryposis multiplex caused by novel recurrent CHRNG mutations.

Seo J, Choi IH, Lee JS, Yoo Y, Kim NK, Choi M, Ko JM, Shin YB
J Hum Genet 2015 Apr;60(4):213-5. Epub 2015 Jan 22 doi: 10.1038/jhg.2015.2. PMID: 25608830

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: 17701904 Free PMC Article

See all (5)

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Lethal congenital contracture syndrome 4(LCCS4)

Definition

Clinical features

Recent clinical studies

Etiology

Diagnosis

Prognosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Molecular resources

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