ARC syndrome
Arthrogryposis, Renal Tubular Dysfunction and Intrahepatic Cholestasis (ARC syndrome) is a variant of arthrogryposis. It is a rare autosomal recessive disease, characterized by arthrogryposis, renal tubular dysfunction and cholestasis. Clinical features include dysmorphic features like small anterior fontanel, low set ears, beaked nose and high arched palate; unilateral choanal atresia, club foot, and bilateral developmental dislocation of hip, renal tubular acidosis, cholestasis and hearing impairment.
Causes
Pathogenic mutations can be found either in the “classic” arthrogryposis congenital multipla genes (ADCY6, TPM2, MYBPC1, MYH3, TNNT3, TNNI2, MYH8, FBN2, PIEZO2, ECEL1) and in genes associated with conditions which also include arthrogryposis as part of the clinical spectrum (the so-called neuromuscular genes): CHRND, CHNRG, ECEL1, GBE1, MTM1, MYH3, NEB and RYR1. Whole exome sequencing has recently identified likely pathogenic mutations also in the FBN3, MYO9A, and PSD3 genes as well as a second locus with either homozygous or compound heterozygous variants in a candidate genes like MYBPC2 and VPS8.
In patients with arthrogryposis and neurodevelopmental impairment, de novo heterozygous mutations have been identified also in the NALCN gene and in the MYOD1 gene. Additional pathogenic mutations have been detected in the GPR126, KLHL40, KLHL41 and SPEG genes.
Fetal Akinesia Deformation Sequence (FADS) can be typically caused by mutations in the DOK7, MUSK or RAPSN genes. However FADS can also be seen in the perinatal form of the neuromuscular presentation of GSD IV (glicogen storage disease IV), caused by mutations in the GBE1 gene. FADS is also seen in proliferative vasculopathy and hydraencephaly-hydrocephaly syndrome (hydranencephaly, Fowler type), caused by mutation in the FLVCR2 gene, and in lethal arthrogryposis with anterior horn cell disease (GLE1 mutation).
Homozyogous mutations in the VIPAS39 gene have been detected as the cause of ARC syndrome.
Overall, autosomal dominant, autosomal recessive, X-linked. Especially in autosomal dominant forms, de novo mutations are very frequent. Parental germline mosaicism in autosomal dominant forms remains a possibility.
In any case, it is important to highlight that although numerous causative genes have been identified for each of these disease groups, in many cases a specific genetic diagnosis remains elusive, even after whole exome sequencing.
Prenatal diagnosis
Arthrogryposis can be suspected in utero from absent fetal movements. Fetal akinesia deformation sequence presents with heterogeneous sonographic findings, mostly affecting the profile, elbow-, knee-, ankle joint, wrists and fingers; in most of cases of sporadic nature. Whereas hydrops fetalis and nuchal edema were earlier signs, thorax hypoplasia, polyhydramnios and IUGR can be found later in pregnancy. Several cases of arthrogryposis congenita are due to a de novo mutation, with an empirical recurrence risk of 5% based on the possibility of parental germline mosaicism. In autosomal recessive and X-linked forms the recurrence risk can be up to 50%. If the disease-causing mutation in the family is know, early prenatal diagnosis through molecular genetic testing is possible.
Treatment
The clinical approach to the treatment of arthrogryposis multipla congenta is multidisciplinary. In general attention should be directed at the development of muscle strength with early stimulation of active movements. Immobilization should be minimized. The Ponseti method is an effective first-line treatment for arthrogrypotic clubfeet to achieve functional plantigrade feet. Children will often require more casts and have a higher risk of relapse. Older patients with arthrogryposis multipla congenital may also benefit from total hip replacement surgery, particularly to treat osteoarthritic hip pain. A congenital anomaly of the thumb, where the metacarpophalangeal joint undergoes radial deviation to compensate for a narrow first web space, is frequent in arthrogryposis patients. Usually the bilateral cases tended to show better rehabilitative improvement compared with the unilateral ones, probably because the latter patients could use their unaffected hand.
Overall patients show less hip extension than the control population. However, with adequate orthotic support, children with AMC and even with severe weakness and contractures can achieve walking. Greater movements in the trunk and pelvis during walking have been observed in children with AMC using orthoses compared to those wearing only shoes.
Recommended testing workflow
To test for arthrogryposis multiplex congenita Breda Genetics recommends the following panel based on exome or full genome sequencing:
Arthrogryposis (ADCY6, ECEL1, FBN1, FBN2, MYBPC1, MYH3, MYH8, PIEZO2, TNNI2, TNNT3, TPM2)
If negative: UPGRADE TO FULL: analysis of variants of all other genes as obtained from exome or full genome sequencing.
Alternatively: EXOME TRIO: clinical exome sequencing in the patient, the mother and the father to boost the identification of novel mutations, which are typical in several forms of arthrogryposis.
References:
Prenatal diagnosis of fetal akinesia deformation sequence (FADS): a study of 79 consecutive cases. Hellmund A, Berg C, Geipel A, Müller A, Gembruch U.Arch Gynecol Obstet. 2016 Oct;294(4):697-707. PMID 26825730
The effectiveness of the Ponseti method for treating clubfoot associated with arthrogryposis: up to 8 years follow-up. Matar HE, Beirne P, Garg N. J Child Orthop. 2016 Feb;10(1):15-8. PMID 26833334
Gait dynamics in the wide spectrum of children with arthrogryposis: a descriptive study. Eriksson M, Bartonek Å, Pontén E, Gutierrez-Farewik EM. BMC Musculoskelet Disord. 2015 Dec 9;16:384. PMID 26821804
Novel VIPAS39 mutation in a syndromic patient with arthrogryposis, renal tubular dysfunction and intrahepatic cholestasis. Aflatounian M, Smith H, Farahani F, Tofighi Naeem A, Straatman-Iwanowska A, Zoghi S, Khatri U, Tajdini P, Fallahi GH, Gissen P, Rezaei N. Eur J Med Genet. 2016 Apr;59(4):237-9. PMID 26808426
De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia. Fukai R, Saitsu H, Okamoto N, Sakai Y, Fattal-Valevski A, Masaaki S, Kitai Y, Torio M, Kojima-Ishii K, Ihara K, Chernuha V, Nakashima M, Miyatake S, Tanaka F, Miyake N, Matsumoto N. J Hum Genet. 2016 May;61(5):451-5. PMID 26763878
Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin. 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. PMID 26752647
Deficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesia. Watson CM, Crinnion LA, Murphy H, Newbould M, Harrison SM, Lascelles C, Antanaviciute A, Carr IM, Sheridan E, Bonthron DT, Smith A. J Med Genet. 2016 Apr;53(4):264-9. PMID 26733463
Evaluation of the first web-space narrowing in congenital anomalies with Z-deformity. Takagi T, Seki A, Takayama S, Mochida J. J Plast Reconstr Aesthet Surg. 2016 Mar;69(3):341-5. PMID 26646401
Bilateral total hip replacement in arthrogryposis multiplex congenita. Dalton DM1, Magill P1, Mulhall KJ2. BMJ Case Rep. 2015 Nov 25;2015. PMID 26607193
Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth. Todd EJ, Yau KS, Ong R, Slee J, McGillivray G, Barnett CP, Haliloglu G, Talim B, Akcoren Z, Kariminejad A, Cairns A, Clarke NF, Freckmann ML, Romero NB, Williams D, Sewry CA, Colley A, Ryan MM, Kiraly-Borri C, Sivadorai P, Allcock RJ, Beeson D, Maxwell S, Davis MR, Laing NG, Ravenscroft G. Orphanet J Rare Dis. 2015 Nov 17;10:148. PMID 26578207
AMC: amyoplasia and distal arthrogryposis. Kimber E. J Child Orthop. 2015 Dec;9(6):427-32. PMID 26537820
Arthrogryposis: a review and update. Bamshad M, Van Heest AE, Pleasure D. J Bone Joint Surg Am. 2009 Jul;91 Suppl 4:40-6. PMID: 19571066
Arthrogryposis Multiplex Congenita (AMC) is a clinically and genetically heterogeneous condition characterized by multiple joint contractures at birth. The condition is generally defined by the presence of congenital joint contractures in two or more body areas, usually associated with hypoplastic muscles. Sometimes the term arthrogryposis multiplex is used to identify a clinical sign rather than a specific disease. When referring to arthrogryposis multiplex as disease, a commonly used name is distal arthrogryposis (DA). Amyoplasia (A = no; myo = muscle; plasia = growth) is a distinct form of arthrogryposis which shows characteristic clinical features. Amyoplasia is sporadic, whether distal arthrogryposes are autosomal dominant. Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies (affected babies die as a result of pulmonary hypoplasia).