Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder involving the liver, kidney, skin, and central nervous and musculoskeletal systems. The characteristic features of ARC syndrome include arthrogryposis, renal tubular acidosis, and neonatal cholestatic jaundice. Additional symptoms may present, including ichthyosis, platelet anomalies, agenesis of the corpus callosum, congenital cardiovascular anomalies, deafness, recurrent infection, and internal bleeding owing to coagulation dysfunction. So far, less than 100 cases with ARC syndrome have been reported in the literature. The diagnosis of ARC syndrome is based on laboratory investigations and biopsy findings of liver or kidney. The prognosis of ARC syndrome is very poor, most patients die within the first year of life despite supportive care for metabolic acidosis and cholestasis.
The locus of the ARC syndrome was mapped to chromosome 5q26.1, and the syndrome is attributed to homozygous or compound heterozygous mutations in the VPS33B gene. On the other hand, another form of the syndrome exists; namely, ARCS2, and it is caused by mutations in the VIPAR gene that maps to 14q24.3.
VPS33B gene encodes a 617-amino-acid protein, a member of the Sec1/Munc18 family proteins, which interact with soluble NSF attachment protein receptors (SNAREs). SNAREs proteins are involved in a variety of processes including vesicular exocytosis, synaptic transmission, and general secretion by facilitating vesicle targeting and fusion. A number of different mutations affecting the VPS33B gene were observed in different ethnicities, from nonsense mutations to missense and deletion ones.
Two Lebanese male siblings with (ARC) syndrome were reported by Mikati et al. (1984). A number of characteristic features of the syndrome were observed such as proximal renal tubular insufficiency, cholestatic jaundice, and multiple congenital anomalies. They presented with micrognathia, low set ears, high arched palate, barrel shaped chest, bilateral simian creases, club feet, congenital hip dislocation, hypotonia, conjugated hyperbilirubinemia and severe failure to thrive. Mikati emphasized in a letter he wrote in 2007 that the patients had severe right ventricular hypertrophy as evidenced by electrocardiography in addition to immune deficiency and ichthyosis. The infants died at the ages of 2 and of 4 months.
Gissen et al. (2006) provided a comprehensive account of the clinical and molecular features of 62 ARC syndrome patients from different countries around the world. Among studied pedigrees were two Palestinian families, one with two affecteds (Pedigree23) and the other with three affecteds (Pedigree24). Consanguinity was a common factor between the two pedigrees, and so were the following features; renal fanconi sundrome, nephrogenic diabetes insipidus, neonatal cholestasis, arthrogryposis multiplex congenital, failure to thrive and none of the patients survived beyond the forth month. The homozygous mutation (c.403+1G>A) in exon 6 + 1 of VPS33B was noted in the family with three affecteds (Pedigree24).
Abu-Sa'da et al. (2005) described two unrelated Saudi patients with arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. The first patient was an infant boy who was born to first degree cousins. Shortly after birth, he suffered from jaundice, diarrhea and failure to thrive. He had mild ichthyosis, high arched palate, hepatomegaly, generalized hypotonia and arthrogryposis. He developed Fanconi syndrome when he was two months. His kidneys ultrasounds showed nephrocalcinosis. His liver biopsy showed canalicular and hepatocellular cholestasis, portal fibrosis, minimal hepatocytes giant cell transformation, focal minimum steatosis, and absence of bile duct proliferation. He was also hypotonic with marked development delay. He was admitted several times with febrile illness, dehydration and metabolic acidosis. At the age of seven months he died due to severe dehydration and metabolic acidosis. The second patient was an infant female who was also born to a first cousin parents. Shortly after birth, she presented with fracture of her right femur, developmental dysplasia of hips, and severely ichthyotic skin. She also had metabolic acidosis and Fanconi syndrome, jaundice, and recurrent sepsis. At the age of three months she was hospitalized, she was febrile, hypotensive, severely dehydrated. She died on the second day with sepsis and irreversible shock.
Taha et al. (2007) reported a Saudi patient with ARC syndrome presenting with severe osteopenia and fractures at birth. The male infant was born to a consanguineous family and he suffered ichthyosis, lax skin, prominent occiput, jaundice, hepatomegaly and generalized hypotonia. The gene VPS33B was affected by two mutations; a novel heterozygous splice site mutation (c.700+1G>A, exon 9+1), and a heterozygous nonsense mutation in exon 18 (c.1312C>T, p.Arg438X). The patient died at the age of six months with dehydration and sepsis.
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