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Arthrogryposis multiplex congenita 6(AMC6)

MedGen UID:
1786758
Concept ID:
C5543431
Disease or Syndrome
Synonyms: AMC6; ARTHROGRYPOSIS MULTIPLEX CONGENITA 6
 
Gene (location): NEB (2q23.3)
 
Monarch Initiative: MONDO:0030281
OMIM®: 619334

Definition

Arthrogryposis multiplex congenita-6 (AMC6) is a severe autosomal recessive disorder of skeletal muscle with onset of symptoms in utero. The pregnancies are usually complicated by polyhydramnios and reduced fetal movements. Affected individuals have congenital joint contractures, dysmorphic facial features, distal skeletal anomalies with clenched hands and clubfeet, and edema with fetal hydrops. Fetal demise or termination of pregnancy often occurs after ultrasound detection of abnormalities. Those that survive to birth have significant hypotonia with absent spontaneous movements, respiratory insufficiency, arthrogryposis, and multiple pterygia. Skeletal muscle is hypoplastic, immature, and underdeveloped, with nemaline rods, poorly developed sarcomeres, and poor cross-striation. Death in infancy usually occurs (summary by Ahmed et al., 2018, Rocha et al., 2021). For a discussion of genetic heterogeneity of AMC, see AMC1 (617468). [from OMIM]

Clinical features

From HPO
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Thumbs, congenital Clasped
MedGen UID:
98140
Concept ID:
C0431886
Congenital Abnormality
In the resting position, the tip of the thumb is on, or near, the palm, close to the base of the fourth or fifth finger.
Akinesia
MedGen UID:
43218
Concept ID:
C0085623
Finding
Inability to initiate changes in activity or movement and to perform ordinary volitional movements rapidly and easily.
Large fontanelles
MedGen UID:
105329
Concept ID:
C0456132
Finding
In newborns, the two frontal bones, two parietal bones, and one occipital bone are joined by fibrous sutures, which form a small posterior fontanelle, and a larger, diamond-shaped anterior fontanelle. These regions allow for the skull to pass the birth canal and for later growth. The fontanelles gradually ossify, whereby the posterior fontanelle usually closes by eight weeks and the anterior fontanelle by the 9th to 16th month of age. Large fontanelles are diagnosed if the fontanelles are larger than age-dependent norms.
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
Nemaline bodies
MedGen UID:
814369
Concept ID:
C3808039
Finding
Nemaline rods are abnormal bodies that can occur in skeletal muscle fibers. The rods can be observed on histological analysis of muscle biopsy tissue or upon electron microscopy, where they appear either as extensions of sarcomeric Z-lines, in random array without obvious attachment to Z-lines (often in areas devoid of sarcomeres) or in large clusters localized at the sarcolemma or intermyofibrillar spaces.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.

Professional guidelines

PubMed

Hellmund A, Berg C, Geipel A, Müller A, Gembruch U
Arch Gynecol Obstet 2016 Oct;294(4):697-707. Epub 2016 Jan 29 doi: 10.1007/s00404-016-4017-x. PMID: 26825730
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Ogino S, Wilson RB
Hum Genet 2002 Dec;111(6):477-500. Epub 2002 Oct 3 doi: 10.1007/s00439-002-0828-x. PMID: 12436240

Recent clinical studies

Etiology

Taqi D, Nematollahi S, Lemin S, Rauch F, Hamdy R, Dahan-Oliel N
Bone 2024 Feb;179:116955. Epub 2023 Nov 10 doi: 10.1016/j.bone.2023.116955. PMID: 37951521
Filges I, Jünemann S, Viehweger E, Tercanli S
Prenat Diagn 2023 Jun;43(6):798-805. Epub 2023 Jan 12 doi: 10.1002/pd.6299. PMID: 36588183
Hall JG, Aldinger KA, Tanaka KI
Am J Med Genet A 2014 Mar;164A(3):700-30. Epub 2014 Jan 23 doi: 10.1002/ajmg.a.36395. PMID: 24459070
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Preus M, Fraser FC
Am J Dis Child 1972 Dec;124(6):933-43. doi: 10.1001/archpedi.1972.02110180135022. PMID: 4265019

Diagnosis

Filges I, Jünemann S, Viehweger E, Tercanli S
Prenat Diagn 2023 Jun;43(6):798-805. Epub 2023 Jan 12 doi: 10.1002/pd.6299. PMID: 36588183
Laquerriere A, Jaber D, Abiusi E, Maluenda J, Mejlachowicz D, Vivanti A, Dieterich K, Stoeva R, Quevarec L, Nolent F, Biancalana V, Latour P, Sternberg D, Capri Y, Verloes A, Bessieres B, Loeuillet L, Attie-Bitach T, Martinovic J, Blesson S, Petit F, Beneteau C, Whalen S, Marguet F, Bouligand J, Héron D, Viot G, Amiel J, Amram D, Bellesme C, Bucourt M, Faivre L, Jouk PS, Khung S, Sigaudy S, Delezoide AL, Goldenberg A, Jacquemont ML, Lambert L, Layet V, Lyonnet S, Munnich A, Van Maldergem L, Piard J, Guimiot F, Landrieu P, Letard P, Pelluard F, Perrin L, Saint-Frison MH, Topaloglu H, Trestard L, Vincent-Delorme C, Amthor H, Barnerias C, Benachi A, Bieth E, Boucher E, Cormier-Daire V, Delahaye-Duriez A, Desguerre I, Eymard B, Francannet C, Grotto S, Lacombe D, Laffargue F, Legendre M, Martin-Coignard D, Mégarbané A, Mercier S, Nizon M, Rigonnot L, Prieur F, Quélin C, Ranjatoelina-Randrianaivo H, Resta N, Toutain A, Verhelst H, Vincent M, Colin E, Fallet-Bianco C, Granier M, Grigorescu R, Saada J, Gonzales M, Guiochon-Mantel A, Bessereau JL, Tawk M, Gut I, Gitiaux C, Melki J
J Med Genet 2022 Jun;59(6):559-567. Epub 2021 Apr 5 doi: 10.1136/jmedgenet-2020-107595. PMID: 33820833Free PMC Article
Society for Maternal-Fetal Medicine, Rac MWF, McKinney J, Gandhi M
Am J Obstet Gynecol 2019 Dec;221(6):B7-B9. doi: 10.1016/j.ajog.2019.09.021. PMID: 31787162
Hall JG, Aldinger KA, Tanaka KI
Am J Med Genet A 2014 Mar;164A(3):700-30. Epub 2014 Jan 23 doi: 10.1002/ajmg.a.36395. PMID: 24459070
Bernstein RM
J Am Acad Orthop Surg 2002 Nov-Dec;10(6):417-24. doi: 10.5435/00124635-200211000-00006. PMID: 12470044

Therapy

Kindler HL, Novello S, Bearz A, Ceresoli GL, Aerts JGJV, Spicer J, Taylor P, Nackaerts K, Greystoke A, Jennens R, Calabrò L, Burgers JA, Santoro A, Cedrés S, Serwatowski P, Ponce S, Van Meerbeeck JP, Nowak AK, Blumenschein G Jr, Siegel JM, Kasten L, Köchert K, Walter AO, Childs BH, Elbi C, Hassan R, Fennell DA
Lancet Oncol 2022 Apr;23(4):540-552. doi: 10.1016/S1470-2045(22)00061-4. PMID: 35358455Free PMC Article
Thakker A, Sharma SC, Hussain NM, Devani P, Lahiri A
J Plast Reconstr Aesthet Surg 2021 Mar;74(3):549-559. Epub 2020 Nov 8 doi: 10.1016/j.bjps.2020.10.085. PMID: 33268044
Xu L, Chen Z, Qiu Y, Chen X, Li S, Du C, Zhou Q, Sun X
J Neurosurg Pediatr 2019 Jan 1;23(1):22-29. Epub 2018 Oct 12 doi: 10.3171/2018.7.PEDS18347. PMID: 30485184
K McClure P, Kilinc E, Oishi S, I Riccio A, A Karol L
J Pediatr Orthop 2017 Oct/Nov;37(7):e446-e449. doi: 10.1097/BPO.0000000000001009. PMID: 28538051
Bayram Y, Karaca E, Coban Akdemir Z, Yilmaz EO, Tayfun GA, Aydin H, Torun D, Bozdogan ST, Gezdirici A, Isikay S, Atik MM, Gambin T, Harel T, El-Hattab AW, Charng WL, Pehlivan D, Jhangiani SN, Muzny DM, Karaman A, Celik T, Yuregir OO, Yildirim T, Bayhan IA, Boerwinkle E, Gibbs RA, Elcioglu N, Tuysuz B, Lupski JR
J Clin Invest 2016 Feb;126(2):762-78. Epub 2016 Jan 11 doi: 10.1172/JCI84457. PMID: 26752647Free PMC Article

Prognosis

Frizzell K, Kozin SH, Zlotolow DA
J Hand Surg Am 2020 Nov;45(11):1084.e1-1084.e7. Epub 2020 Jun 29 doi: 10.1016/j.jhsa.2020.04.025. PMID: 32616410
Society for Maternal-Fetal Medicine, Rac MWF, McKinney J, Gandhi M
Am J Obstet Gynecol 2019 Dec;221(6):B7-B9. doi: 10.1016/j.ajog.2019.09.021. PMID: 31787162
Bernstein RM
J Am Acad Orthop Surg 2002 Nov-Dec;10(6):417-24. doi: 10.5435/00124635-200211000-00006. PMID: 12470044
Vanpaemel L, Schoenmakers M, van Nesselrooij B, Pruijs H, Helders P
J Pediatr Orthop B 1997 Jul;6(3):172-8. doi: 10.1097/01202412-199707000-00004. PMID: 9260645
Hageman G, Willemse J
Neuropediatrics 1983 Feb;14(1):6-11. doi: 10.1055/s-2008-1059546. PMID: 6339980

Clinical prediction guides

Turgut GT, Altunoglu U, Gulec C, Sarac Sivrikoz T, Kalaycı T, Toksoy G, Avcı Ş, Yıldırım BT, Sayın GY, Kalelioglu IH, Karaman B, Has R, Başaran S, Yuksel A, Kayserili H, Uyguner ZO
Clin Genet 2024 Jun;105(6):596-610. Epub 2024 Jan 26 doi: 10.1111/cge.14490. PMID: 38278647
Taqi D, Nematollahi S, Lemin S, Rauch F, Hamdy R, Dahan-Oliel N
Bone 2024 Feb;179:116955. Epub 2023 Nov 10 doi: 10.1016/j.bone.2023.116955. PMID: 37951521
Sarveswaran S, Mortenson WB, Sawatzky B
Am J Med Genet C Semin Med Genet 2023 Jun;193(2):139-146. Epub 2023 Apr 27 doi: 10.1002/ajmg.c.32042. PMID: 37102433
Laquerriere A, Jaber D, Abiusi E, Maluenda J, Mejlachowicz D, Vivanti A, Dieterich K, Stoeva R, Quevarec L, Nolent F, Biancalana V, Latour P, Sternberg D, Capri Y, Verloes A, Bessieres B, Loeuillet L, Attie-Bitach T, Martinovic J, Blesson S, Petit F, Beneteau C, Whalen S, Marguet F, Bouligand J, Héron D, Viot G, Amiel J, Amram D, Bellesme C, Bucourt M, Faivre L, Jouk PS, Khung S, Sigaudy S, Delezoide AL, Goldenberg A, Jacquemont ML, Lambert L, Layet V, Lyonnet S, Munnich A, Van Maldergem L, Piard J, Guimiot F, Landrieu P, Letard P, Pelluard F, Perrin L, Saint-Frison MH, Topaloglu H, Trestard L, Vincent-Delorme C, Amthor H, Barnerias C, Benachi A, Bieth E, Boucher E, Cormier-Daire V, Delahaye-Duriez A, Desguerre I, Eymard B, Francannet C, Grotto S, Lacombe D, Laffargue F, Legendre M, Martin-Coignard D, Mégarbané A, Mercier S, Nizon M, Rigonnot L, Prieur F, Quélin C, Ranjatoelina-Randrianaivo H, Resta N, Toutain A, Verhelst H, Vincent M, Colin E, Fallet-Bianco C, Granier M, Grigorescu R, Saada J, Gonzales M, Guiochon-Mantel A, Bessereau JL, Tawk M, Gut I, Gitiaux C, Melki J
J Med Genet 2022 Jun;59(6):559-567. Epub 2021 Apr 5 doi: 10.1136/jmedgenet-2020-107595. PMID: 33820833Free PMC Article
Bernstein RM
J Am Acad Orthop Surg 2002 Nov-Dec;10(6):417-24. doi: 10.5435/00124635-200211000-00006. PMID: 12470044

Recent systematic reviews

Erden M, Uyanik E, Demeestere I, Oktay KH
Am J Obstet Gynecol 2024 Nov;231(5):480-489. Epub 2024 Apr 15 doi: 10.1016/j.ajog.2024.04.012. PMID: 38621483Free PMC Article
Taqi D, Nematollahi S, Lemin S, Rauch F, Hamdy R, Dahan-Oliel N
Bone 2024 Feb;179:116955. Epub 2023 Nov 10 doi: 10.1016/j.bone.2023.116955. PMID: 37951521
Thakker A, Sharma SC, Hussain NM, Devani P, Lahiri A
J Plast Reconstr Aesthet Surg 2021 Mar;74(3):549-559. Epub 2020 Nov 8 doi: 10.1016/j.bjps.2020.10.085. PMID: 33268044

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