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Arthrogryposis, renal dysfunction, and cholestasis 2(ARCS2)

MedGen UID:
462022
Concept ID:
C3150672
Disease or Syndrome
Synonyms: ARCS2; VIPAS39-Related Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome
 
Gene (location): VIPAS39 (14q24.3)
 
Monarch Initiative: MONDO:0013255
OMIM®: 613404

Definition

Arthrogryposis, renal dysfunction, and cholestasis-2 (ARCS2) is a multisystem disorder associated with abnormalities in polarized liver and kidney cells (Qiu et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of ARCS, see ARCS1 (208085). [from OMIM]

Clinical features

From HPO
Glycosuria
MedGen UID:
42267
Concept ID:
C0017979
Finding
An increased concentration of glucose in the urine.
Kidney disorder
MedGen UID:
9635
Concept ID:
C0022658
Disease or Syndrome
A nonspecific term referring to disease or damage of the kidneys.
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Talipes calcaneovalgus
MedGen UID:
56270
Concept ID:
C0152237
Anatomical Abnormality
Talipes calcaneovalgus is a flexible foot deformity (as opposed to a rigid congenital vertical talus foot deformity) that can either present as a positional or structural foot deformity depending on severity and/or causality. The axis of calcaneovalgus deformity is in the tibiotalar joint, where the foot is positioned in extreme hyperextension. On inspection, the foot has an "up and out" appearance, with the dorsal forefoot practically touching the anterior aspect of the ankle and lower leg.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Right ventricular hypertrophy
MedGen UID:
57981
Concept ID:
C0162770
Disease or Syndrome
In this case the right ventricle is more muscular than normal, causing a characteristic boot-shaped (coeur-en-sabot) appearance as seen on anterior- posterior chest x-rays. Right ventricular hypertrophy is commonly associated with any form of right ventricular outflow obstruction or pulmonary hypertension, which may in turn owe its origin to left-sided disease. The echocardiographic signs are thickening of the anterior right ventricular wall and the septum. Cavity size is usually normal, or slightly enlarged. In many cases there is associated volume overload present due to tricuspid regurgitation, in the absence of this, septal motion is normal.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Giant cell hepatitis
MedGen UID:
45030
Concept ID:
C0027613
Disease or Syndrome
Chronic hepatitis characterized by parenchymal inflammation with formation of large multinucleated hepatocytes in response to a variety of insults to the liver.
Cholestatic liver disease
MedGen UID:
163651
Concept ID:
C0860204
Disease or Syndrome
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Lissencephaly
MedGen UID:
78604
Concept ID:
C0266463
Finding
A spectrum of malformations of cortical development caused by insufficient neuronal migration that subsumes the terms agyria, pachygyria and subcortical band heterotopia. See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Hip dysplasia
MedGen UID:
1640560
Concept ID:
C4551649
Congenital Abnormality
Congenital dysplasia of the hip (CDH) is an abnormality of the seating of the femoral head in the acetabulum. Its severity ranges from mild instability of the femoral head with slight capsular laxity, through moderate lateral displacement of the femoral head, without loss of contact of the head with the acetabulum, up to complete dislocation of the femoral head from the acetabulum. It is one of the most common skeletal congenital anomalies (summary by Sollazzo et al., 2000). Acetabular dysplasia is an idiopathic, localized developmental dysplasia of the hip that is characterized by a shallow hip socket and decreased coverage of the femoral head. Its radiologic criteria include the center-edge angle of Wiberg, the Sharp angle, and the acetabular roof obliquity. Most patients with acetabular dysplasia develop osteoarthritis (165720) after midlife, and even mild acetabular dysplasia can cause hip osteoarthritis (summary by Mabuchi et al., 2006). CDH occurs as an isolated anomaly or with more general disorders represented by several syndromes and with chromosomal abnormalities such as trisomy 18 (Wynne-Davies, 1970). Genetic Heterogeneity of Developmental Dysplasia of the Hip Developmental dysplasia of the hip-1 (DDH1) maps to chromosome 13q22; DDH2 (615612) maps to chromosome 3p21. DDH3 (620690) is caused by mutation in the LRP1 gene (107770) on chromosome 12q13.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Renal tubular acidosis
MedGen UID:
90
Concept ID:
C0001126
Disease or Syndrome
Acidosis owing to malfunction of the kidney tubules with accumulation of metabolic acids and hyperchloremia, potentially leading to complications including hypokalemia, hypercalcinuria, nephrolithiasis and nephrocalcinosis.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Conjugated hyperbilirubinemia
MedGen UID:
82787
Concept ID:
C0268307
Disease or Syndrome
Abnormally high level of conjugated bilirubin in the blood.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Sloping forehead
MedGen UID:
346640
Concept ID:
C1857679
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
Ichthyosis
MedGen UID:
7002
Concept ID:
C0020757
Disease or Syndrome
An abnormality of the skin characterized the presence of excessive amounts of dry surface scales on the skin resulting from an abnormality of keratinization.
Pruritus
MedGen UID:
19534
Concept ID:
C0033774
Sign or Symptom
Pruritus is an itch or a sensation that makes a person want to scratch. This term refers to an abnormally increased disposition to experience pruritus.
Nephrogenic diabetes insipidus
MedGen UID:
57876
Concept ID:
C0162283
Disease or Syndrome
Hereditary nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals.

Recent clinical studies

Etiology

Banushi B, Simpson F
Cells 2022 Nov 21;11(22) doi: 10.3390/cells11223702. PMID: 36429129Free PMC Article
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. Epub 2016 Jan 23 doi: 10.1016/j.ejmg.2016.01.005. PMID: 26808426
Jang WY, Cho TJ, Bae JY, Jung HW, Ko JS, Park MS, Yoo WJ, Chung CY, Seo JK, Choi IH
J Pediatr Orthop 2011 Jan-Feb;31(1):107-12. doi: 10.1097/BPO.0b013e3182032c83. PMID: 21150740
Cullinane AR, Straatman-Iwanowska A, Seo JK, Ko JS, Song KS, Gizewska M, Gruszfeld D, Gliwicz D, Tuysuz B, Erdemir G, Sougrat R, Wakabayashi Y, Hinds R, Barnicoat A, Mandel H, Chitayat D, Fischler B, Garcia-Cazorla A, Knisely AS, Kelly DA, Maher ER, Gissen P
Hum Mutat 2009 Feb;30(2):E330-7. doi: 10.1002/humu.20900. PMID: 18853461Free PMC Article
Abdullah MA, Al-Hasnan Z, Okamoto E, Abomelha AM
Saudi Med J 2000 Mar;21(3):297-9. PMID: 11533803

Diagnosis

Saad A, Chauhan A, Tripathi S, Kumar M
BMJ Case Rep 2023 May 18;16(5) doi: 10.1136/bcr-2023-254822. PMID: 37202112Free PMC Article
Liu RJY, Al-Molieh Y, Chen SZ, Drobac M, Urban D, Chen CH, Yao HHY, Geng RSQ, Li L, Pluthero FG, Benlekbir S, Rubinstein JL, Kahr WHA
J Biol Chem 2023 Jun;299(6):104718. Epub 2023 Apr 14 doi: 10.1016/j.jbc.2023.104718. PMID: 37062417Free PMC Article
Chen CH, Lo RW, Urban D, Pluthero FG, Kahr WH
Platelets 2017 Mar;28(2):147-154. Epub 2017 Feb 22 doi: 10.1080/09537104.2017.1280599. PMID: 28277061
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. Epub 2016 Jan 23 doi: 10.1016/j.ejmg.2016.01.005. PMID: 26808426
Jang WY, Cho TJ, Bae JY, Jung HW, Ko JS, Park MS, Yoo WJ, Chung CY, Seo JK, Choi IH
J Pediatr Orthop 2011 Jan-Feb;31(1):107-12. doi: 10.1097/BPO.0b013e3182032c83. PMID: 21150740

Therapy

Abdullah MA, Al-Hasnan Z, Okamoto E, Abomelha AM
Saudi Med J 2000 Mar;21(3):297-9. PMID: 11533803

Prognosis

Wang JS, Zhao J, Li LT
World J Gastroenterol 2014 Apr 28;20(16):4830-4. doi: 10.3748/wjg.v20.i16.4830. PMID: 24782640Free PMC Article
Jang JY, Kim KM, Kim GH, Yu E, Lee JJ, Park YS, Yoo HW
J Pediatr Gastroenterol Nutr 2009 Mar;48(3):348-54. doi: 10.1097/mpg.0b013e31817fcb3f. PMID: 19274792
Cullinane AR, Straatman-Iwanowska A, Seo JK, Ko JS, Song KS, Gizewska M, Gruszfeld D, Gliwicz D, Tuysuz B, Erdemir G, Sougrat R, Wakabayashi Y, Hinds R, Barnicoat A, Mandel H, Chitayat D, Fischler B, Garcia-Cazorla A, Knisely AS, Kelly DA, Maher ER, Gissen P
Hum Mutat 2009 Feb;30(2):E330-7. doi: 10.1002/humu.20900. PMID: 18853461Free PMC Article

Clinical prediction guides

Liu RJY, Al-Molieh Y, Chen SZ, Drobac M, Urban D, Chen CH, Yao HHY, Geng RSQ, Li L, Pluthero FG, Benlekbir S, Rubinstein JL, Kahr WHA
J Biol Chem 2023 Jun;299(6):104718. Epub 2023 Apr 14 doi: 10.1016/j.jbc.2023.104718. PMID: 37062417Free PMC Article
Bem D, Smith H, Banushi B, Burden JJ, White IJ, Hanley J, Jeremiah N, Rieux-Laucat F, Bettels R, Ariceta G, Mumford AD, Thomas SG, Watson SP, Gissen P
Blood 2015 Jul 9;126(2):133-43. Epub 2015 May 6 doi: 10.1182/blood-2014-12-614677. PMID: 25947942Free PMC Article
Wang JS, Zhao J, Li LT
World J Gastroenterol 2014 Apr 28;20(16):4830-4. doi: 10.3748/wjg.v20.i16.4830. PMID: 24782640Free PMC Article
Kim SM, Chang HK, Song JW, Koh H, Han SJ; Severance Pediatric Liver Disease Research Group
J Pediatr Hematol Oncol 2010 May;32(4):253-8. doi: 10.1097/MPH.0b013e3181c3a8d0. PMID: 20224444
Hershkovitz D, Mandel H, Ishida-Yamamoto A, Chefetz I, Hino B, Luder A, Indelman M, Bergman R, Sprecher E
Arch Dermatol 2008 Mar;144(3):334-40. doi: 10.1001/archderm.144.3.334. PMID: 18347289