Arthrogryposis - renal dysfunction - cholestasis

General Information (adopted from Orphanet):

Synonyms, Signs: ARC syndrome
Number of Symptoms 92
OrphanetNr: 2697
OMIM Id: 208085
613404
ICD-10: Q89.7
UMLs: C1859722
MeSH: C535382
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: < 0.1 of 100 000
Inheritance: Autosomal recessive
25239142 [IBIS]
Age of onset: Neonatal
26019847 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Arthrogryposis multiplex congenita
 -Rare developmental defect during embryogenesis
Autosomal ichthyosis syndrome with fatal disease course
 -Rare genetic disease
 -Rare skin disease
Disorder of bilirubin metabolism and excretion
 -Rare genetic disease
Syndromic renal or urinary tract malformation
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare renal disease

Comment:

"Fanconi syndrome - ichthyosis - dysmorphism" has been included (Orphanet, June 2016). Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare but fatal autosomal recessive multisystem disorder caused by mutations in the VPS33B or VIPAS39 (VIPAR) gene. The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Diagnosis of ARC syndrome relies on clinical features, organ biopsy, and mutational analysis. The prognosis of ARC syndrome is so poor that the majority of patients fail to survive beyond the first year of life. However, no specific treatment currently exists for this syndrome. The locus of this disorder has been mapped to chromosome 5q26.1, and germline mutations have been identified in vacuolar protein sorting 33 homolog B (VPS33B ;MIM 608552) and VPS33B-interacting protein, apical-basolateral polarity regulator (VIPAR; MIM 613401). VPS33B mutations are detectable in approximately 75% of patients with a clinical diagnosis of ARC syndrome (PMID:25239142). Involved genes: VPS33B (PMID:25239142); VIPAS39 / VIPAR (PMID:25239142);

Symptom Information: Sort by abundance 

1
 (HPO:0002014) Diarrhea 26019847 IBIS 225 / 7739
2
 (HPO:0008872) Feeding difficulties in infancy 26019847 IBIS 153 / 7739
3
 (HPO:0001892) Abnormal bleeding Frequent [IBIS] rare [HPO:skoehler] 25239142 IBIS 85 / 7739
4
 (HPO:0003010) Prolonged bleeding time Frequent [IBIS] Frequent [Orphanet] 25239142 IBIS 88 / 7739
5
 (HPO:0001942) Metabolic acidosis 10812557 IBIS 81 / 7739
6
 (HPO:0001947) Renal tubular acidosis 25239142 IBIS 21 / 7739
7
 (HPO:0004325) Decreased body weight Very frequent [Orphanet] 26019847 IBIS 492 / 7739
8
 (HPO:0001508) Failure to thrive Frequent [IBIS] 25239142 IBIS 454 / 7739
9
 (HPO:0003076) Glycosuria 26019847 IBIS 32 / 7739
10
 (HPO:0002909) Generalized aminoaciduria 26019847 IBIS 13 / 7739
11
 (HPO:0001631) Atria septal defect 8151641 IBIS 274 / 7739
12
 (HPO:0003073) Hypoalbuminemia 26019847 IBIS 40 / 7739
13
 (HPO:0001928) Abnormality of coagulation Frequent [IBIS] 25239142 IBIS 44 / 7739
14
 (HPO:0001903) Anemia Occasional [Orphanet] 26019847 IBIS 289 / 7739
15
 (HPO:0001944) Dehydration 26019847 IBIS 59 / 7739
16
 (HPO:0004906) Hypernatremic dehydration 26019847 IBIS 2 / 7739
17
 (HPO:0002719) Recurrent infections 25239142 IBIS 107 / 7739
18
 (HPO:0100806) Sepsis 25239142 IBIS 48 / 7739
19
 (HPO:0003228) Hypernatremia 26019847 IBIS 12 / 7739
20
 (HPO:0011423) Hyperchloremia 26019847 IBIS 5 / 7739
21
 (HPO:0003202) Skeletal muscle atrophy Frequent [Orphanet] 25239142 IBIS 281 / 7739
22
 (HPO:0001252) Muscular hypotonia Frequent [Orphanet] 18972129 IBIS 990 / 7739
23
 (HPO:0001290) Generalized hypotonia 18972129 IBIS 51 / 7739
24
 (HPO:0002011) Morphological abnormality of the central nervous system Frequent [IBIS] 25239142 IBIS 5 / 7739
25
 (HPO:0002450) Abnormal motor neuron morphology 25239142 IBIS 2 / 7739
26
 (HPO:0001263) Global developmental delay 18972129 IBIS 853 / 7739
27
 (HPO:0010864) Intellectual disability, severe 9332665 IBIS 120 / 7739
28
 (HPO:0001884) Talipes calcaneovalgus Occasional [IBIS] 30% (n=10) 21150740 IBIS 14 / 7739
29
 (HPO:0001838) Rocker bottom foot Frequent[IBIS] Frequent [Orphanet] 40% (n=10) 21150740 IBIS 85 / 7739
30
 (HPO:0002827) Hip dislocation Occasional [IBIS] 30% (n=10) 21150740 IBIS 94 / 7739
31
 (HPO:0008780) Congenital bilateral hip dislocation 25239142 IBIS 4 / 7739
32
 (HPO:0006380) Knee flexion contracture 25239142 IBIS 56 / 7739
33
 (HPO:0009486) Radial deviation of the hand 25239142 IBIS 13 / 7739
34
 (HPO:0002804) Arthrogryposis multiplex congenita Very frequent [IBIS] 25239142 IBIS 93 / 7739
35
 (HPO:0000768) Pectus carinatum Occasional [Orphanet] 8151641 IBIS 136 / 7739
36
 (HPO:0002808) Kyphosis Occasional [IBIS] Occasional [Orphanet] 20% (n=10) 21150740 IBIS 289 / 7739
37
 (HPO:0001274) Agenesis of corpus callosum Occasional [IBIS] 20% 25239142 IBIS 142 / 7739
38
 (HPO:0000938) Osteopenia 25239142 IBIS 138 / 7739
39
 (HPO:0002659) Increased susceptibility to fractures Frequent [Orphanet] 25239142 IBIS 110 / 7739
40
 (HPO:0002756) Pathologic fracture Frequent [IBIS] 50% (n=10) 21150740 IBIS 30 / 7739
41
 (HPO:0001945) Fever Frequent [Orphanet] 26019847 IBIS 218 / 7739
42
 (HPO:0002630) Fat malabsorption 8151641 IBIS 11 / 7739
43
 (HPO:0002024) Malabsorption Frequent [Orphanet] 26019847 IBIS 142 / 7739
44
 (HPO:0001392) Abnormality of the liver 8151641 IBIS 28 / 7739
45
 (HPO:0001080) Biliary tract abnormality Frequent [Orphanet] 25239142 IBIS 26 / 7739
46
 (HPO:0006571) Reduced number of intrahepatic bile ducts 9332665 IBIS 4 / 7739
47
 (HPO:0002611) Cholestatic liver disease 15500499 IBIS 19 / 7739
48
 (HPO:0001396) Cholestasis Very frequent [IBIS] Very frequent [Orphanet] 25239142 IBIS 136 / 7739
49
 (HPO:0000952) Jaundice Very frequent [IBIS] 25239142 IBIS 105 / 7739
50
 (HPO:0001394) Cirrhosis Occasional [Orphanet] 9332665 IBIS 102 / 7739
51
 (HPO:0001410) Decreased liver function Frequent [Orphanet] 10812557 IBIS 59 / 7739
52
 (HPO:0200084) Giant cell hepatitis 10812557 IBIS 8 / 7739
53
 (HPO:0002240) Hepatomegaly Frequent [Orphanet] 25239142 IBIS 467 / 7739
54
 (HPO:0001626) Abnormality of the cardiovascular system Occasional [IBIS] 10% 25239142 IBIS 73 / 7739
55
 (HPO:0001999) Abnormal facial shape 26019847 IBIS 169 / 7739
56
 (HPO:0002705) High, narrow palate Occasional [Orphanet] 8151641 IBIS 308 / 7739
57
 (HPO:0000407) Sensorineural hearing impairment Occasional [Orphanet] 26019847 IBIS 524 / 7739
58
 (HPO:0000357) Abnormal location of ears Very frequent [Orphanet] 8151641 IBIS 328 / 7739
59
 (HPO:0000369) Low-set ears 8151641 IBIS 372 / 7739
60
 (HPO:0008064) Ichthyosis Frequent [IBIS] Frequent [Orphanet] 50% 25239142 IBIS 108 / 7739
61
 (HPO:0001582) Redundant skin Occasional [Orphanet] 8151641 IBIS 51 / 7739
62
 (HPO:0000821) Hypothyroidism Occasional [Orphanet] 25239142 IBIS 141 / 7739
63
 (HPO:0000114) Proximal tubulopathy 26019847 IBIS 18 / 7739
64
 (HPO:0012573) Global proximal tubulopathy 8151641 IBIS 4 / 7739
65
 (HPO:0000121) Nephrocalcinosis 25239142 IBIS 57 / 7739
66
 (HPO:0000110) Renal dysplasia 25239142 IBIS 44 / 7739
67
 (HPO:0000103) Polyuria 26019847 IBIS 60 / 7739
68
 (HPO:0001994) Renal Fanconi syndrome 8151641 IBIS 12 / 7739
69
 (HPO:0000112) Nephropathy 25239142 IBIS 92 / 7739
70
 (HPO:0009806) Nephrogenic diabetes insipidus rare [HPO:skoehler] 25239142 IBIS 8 / 7739
71
 (HPO:0000124) Renal tubular dysfunction Very frequent [IBIS] Very frequent [Orphanet] 25239142 IBIS 46 / 7739
72
 (HPO:0000093) Proteinuria 26019847 IBIS 169 / 7739
73
 (HPO:0012592) Albuminuria 26019847 IBIS 6 / 7739
74
 (HPO:0001872) Abnormality of thrombocytes 26019847 IBIS 20 / 7739
75
 (HPO:0011869) Abnormal platelet function Occasional [IBIS] Very frequent [Orphanet] 25% 25239142 IBIS 12 / 7739
76
 (HPO:0003110) Abnormality of urine homeostasis 25239142 IBIS 9 / 7739
77
 (HPO:0003109) Hyperphosphaturia 26019847 IBIS 18 / 7739
78
 (HPO:0000873) Diabetes insipidus Frequent [Orphanet] 25239142 IBIS 34 / 7739
79
 (HPO:0001371) Flexion contracture 25239142 IBIS 220 / 7739
80
 (HPO:0002803) Congenital contracture Very frequent [IBIS] Very frequent [Orphanet] 25239142 IBIS 45 / 7739
81
 (HPO:0001510) Growth delay 9332665 IBIS 295 / 7739
82
 (HPO:0000365) Hearing impairment 25239142 IBIS 539 / 7739
83
 (HPO:0002908) Conjugated hyperbilirubinemia 18972129 IBIS 21 / 7739
84
 (HPO:0001273) Abnormality of the corpus callosum 26019847 IBIS 20 / 7739
85
 (HPO:0001522) Death in infancy Very frequent [Orphanet] 25239142 IBIS 275 / 7739
86
 (HPO:0001339) Lissencephaly rare [HPO:skoehler] 16155421 IBIS 30 / 7739
87
 (MedDRA:10001551) Alanine aminotransferase increased 25239142 IBIS 4 / 7739
88
 (MedDRA:10003481) Aspartate aminotransferase increased 25239142 IBIS 4 / 7739
89
 (MedDRA:10061054) Congenital cardiovascular anomaly Occasional [IBIS] 10% 25239142 IBIS 1 / 7739
90
 (MedDRA:10048592) Musculoskeletal disorder 25239142 IBIS 1 / 7739
91
 (MedDRA:10048709) Urosepsis 26019847 IBIS 3 / 7739
92
 (OMIM) Giant cell hepatocytes (1 patient) 8151641 IBIS 2 / 7739

Associated genes:

VPS33B; VIPAS39;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Clinical Description OMIM In 4 male sibs from a sibship of 7 of North African descent, Nezelof et al. (1979) observed arthrogryposis multiplex congenita with jaundice and renal dysfunction. Death occurred at 2 months, 12 days, 22 days and 42 weeks ...
Molecular genetics OMIM To elucidate the molecular basis of ARCS, Gissen et al. (2004) mapped the disorder to a 7-cM interval on 15q26.1 and identified germline mutations in the gene VPS33B (see, e.g., 608552.0001-608552.0003) in 14 kindreds with ARC. VPS33B encodes ...