Abstract：Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations in the VPS33B or VIPAS39 gene. The aim of this study was to investigate the clinical features and VPS33B gene mutations of an infant with ARC syndrome. A 47-day-old female infant was referred to the hospital with the complaint of jaundiced skin and sclera for 45 days and abnormal liver function for 39 days. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined diagnosis. Physical examination showed jaundice of the skin and sclera. Systemic skin was dry with desquamation in the limbs and trunk. There were no positive signs on cardiopulmonary examination. The liver was palpable 2.0 cm under the right subcostal margin. The hips and knees were flexed, and the extension was limited, with low muscular tone in the four limbs. Biochemical analysis demonstrated raised serum total bile acids, bilirubin (predominantly conjugated bilirubin) and transaminases, but the γ-glutamyl transpeptidase level was normal. Routine urine test revealed increased glucose as well as red and white blood cells. On genetic analysis, the infant was proved to be homologous for a VPS33B mutation c.1594C > T (p.R532X). She was definitely diagnosed to have ARC syndrome. Symptomatic and supportive therapy was given, but no improvement was observed, and the infant finally died at 3 months and 29 days of life.
HUANG Da-Gui,LIU Jia-Jia,GUO Li et al. Clinical features and VPS33B mutations in a family affected by arthrogryposis, renal dysfunction, and cholestasis syndrome[J]. CJCP, 2017, 19(10): 1077-1082.
Zhou Y, Zhang J. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome:from molecular genetics to clinical features[J]. Ital J Pediatr, 2014, 40:77.
[2]
Abdullah MA, Al-Hasnan Z, Okamoto E, et al. Arthrogryposis, renal dysfunctionand cholestasis syndrome[J]. Saudi Med J, 2000, 21(3):297-299.
[3]
Bretscher-Dutoit C. Familial bile duct malformations associated with tubular renal insufficiency:A.R. Lutz-Richner and R. F. Landolt. Helv. Paediatr. Acta 28:1-12 (March), 1973[J]. J Pediatr Surg, 1974, 9(4):577.
[4]
Li LT, Zhao J, Chen R, et al. Two novel VPS33B mutations in a patient with arthrogryposis, renal dysfunction and cholestasis syndrome in mainland China[J]. World J Gastroenterol, 2014, 20(1):326-329.
[5]
Wang JS, Zhao J, Li LT. et al. ARC syndrome with high GGT cholestasis caused by VPS33B mutations[J]. World J Gastroenterol, 2014, 20(16):4830-4834.
Song YZ, Zhang ZH, Lin WX, et al. SLC25A13 gene analysis in citrin deficiency:sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China[J]. PLoS One, 2013, 8(9):e74544.
[9]
Rehm HL. Disease-targeted sequencing:a cornerstone in the clinic[J]. Nat Rev Genet, 2013, 14(4):295-300.
[10]
Gissen P, Johnson CA, Morgan NV, et al. Mutations in VPS33B gene, encoding a regulator of SNARE-dependant membrane fusion, cause ARC syndrome[J]. Nat Genet, 2004, 36(4):400-404.
[11]
Smith H, Galmes R, Gogolina E, et al. Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome[J]. Hum Mutat, 2012, 33(12):1656-1664.
Gissen P, Tee L, Johnson CA, et al. Clinical and molecular genetic features of ARC syndrome[J]. Hum Genet, 2006, 120(3):396-409.
[16]
Choi HJ, Lee MW, Ghoi JH, et al. Ichthyosis associated with ARC syndrome:ARC syndrome is one of the differential diagnoses of ichthyosis[J].Pediatr Dermatol, 2005, 22(6):539-542.
[17]
Gissen P, Johnson CA, Gentle D, et al. Comparative evolutionary analysis of VPS33 homologues:genetic and functional insights[J]. Hum Mol Genet, 2005, 14(10):1261-1270.
[18]
Rizo J, Südhof TC. The membrane fusion enigma:SNAREs, Sec1/Munc18 proteins, and their accomplices——guilty as charged?[J]. Annu Rev Cell Dev Biol, 2012, 28(28):279-308.
[19]
van Mil SW, Houwen RH, Klomp LW. Genetics of familial intrahepatic cholestasis syndromes.[J]. J Med Genet, 2005, 42(6):449-463.
[20]
Eastham KM, McKiernan PJ, Milford DV, et al. ARC syndrome:an expanding range of phenotypes[J]. Arch Dis Child, 2001, 85(5):415-420.
[21]
Bull LN, Mahmoodi V, Baker AJ, et al. VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis:Incomplete ARC syndrome phenotype[J]. J Pediatr, 2006, 148(2):269-271.
[22]
Xiang B, Zhang G, Ye S, et al. Characterization of a novel integrin binding protein, VPS33B, which is important for platelet activation and in vivo thrombosis and hemostasis[J]. Circulation, 2015, 132(24):2334-2344.
[23]
Saadah OI, Bokhari BE, Alshaeri TM, et al. Haematological manifestations of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome:A case report[J]. Arab J Gastroenterol, 2013, 14(1):26-28.
[24]
Jang WY, Cho TJ, Bae JY, et al. Orthopaedic manifestations of arthrogryposis-renal dysfunction-cholestasis syndrome[J]. J Pediatr Orthop, 2011, 31(1):107-112.
[25]
Seo SH, Hwang SM, Ko JM, et al. Identification of novel mutations in the VPS33B gene involved in arthrogryposis, renal dysfunction, and cholestasis syndrome[J]. Clin Genet, 2015, 88(1):80-84.
[26]
Dehghani SM, Bahador A, Nikeghbalian S, et al. Liver transplant in a case of arthrogryposis-renal tubular dysfunction-cholestasis syndrome with severe intractable pruritus[J]. Exp Clin Transplant, 2013, 11(3):290-292.
