Arthrogryposis, Renal Dysfunction, And Cholestasis 1

A number sign (#) is used with this entry because arthrogryposis, renal dysfunction, and cholestasis-1 (ARCS1) is caused by homozygous or compound heterozygous mutation in the VPS33B gene (608552) on chromosome 15q26.

Another form of arthrogryposis, renal dysfunction, and cholestasis, ARCS2 (613404), is caused by mutation in the VIPAR gene on chromosome 14q24 (613401).

Clinical Features

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 of age. Autopsy showed rarefaction of the anterior horn of the spinal cord, renal tubular cell degeneration with nephrocalcinosis, and abundant pigmentary deposits in the liver which gave it a grossly black color similar to that of the Dubin-Johnson syndrome (237500). In the mother's family, 8 other males had died at birth or shortly thereafter, suggesting X-linked recessive inheritance to the authors.

Mikati et al. (1984) and Mikati (2007) described 2 Lebanese brothers with proximal renal tubular insufficiency, cholestatic jaundice, predisposition to infection, and multiple congenital anomalies. Dysmorphic features included micrognathia, low-set ears, high-arched palate, barrel-shaped chest, bilateral simian creases, clubfeet, and congenital hip dislocation. They both had conjugated hyperbilirubinemia, repeated infections, severe failure to thrive, and right ventricular hypertrophy. Liver biopsy revealed paucity of bile ducts, bile stasis, and some inflammatory cell infiltration. Immunologic investigation suggested a defect in polymorphonuclear cell migration and intracellular killing. Both died before 4 months of age.

Di Rocco et al. (1990) reported another family in which the second-born child of first-cousin parents had arthrogryposis, cholestatic liver disease, and renal dysfunction. The child died at age 2 months, and autopsy showed pigmentary storage disease in liver cells, nephrocalcinosis, and rarefaction of the motor neuron cells in the anterior horns of the spinal cord. The family of Di Rocco et al. (1990) is, of course, consistent with either autosomal recessive or X-linked recessive inheritance.

Horslen et al. (1994) described 3 cases from 2 unrelated families and reviewed 10 other cases from the literature. The association of arthrogryposis multiplex congenita, cholestatic jaundice, and renal Fanconi syndrome was first reported by Lutz-Richner and Landolt (1973). Of the 13 cases, including their own, Horslen et al. (1994) found that all of the parents were consanguineous and that all of the patients were male except for a single patient reported by Saraiva et al. (1990). All patients died in the first months of life. Although it had been claimed that there were 2 separate forms of this disorder, one with a paucity of intrahepatic bile ducts and giant cell transformation of hepatocytes and the other with pigment deposition in liver cells and marked cholestasis, Horslen et al. (1994) proposed, based on the histologic findings in one of their cases, that all cases represent variation within a single disorder.

The disorder reported in entry 210550 (biliary malformation with renal tubular insufficiency) may represent the ARC syndrome. Di Rocco et al. (1995) described 2 new families and compared clinical and pathologic findings of 5 patients from 3 Italian families with other reported cases. They proposed that all the patients reported to that time represented a single syndrome.

Abu-Sa'da et al. (2005) reported 2 infants from different consanguineous Saudi families with lethal ARC syndrome. Common clinical features included failure to thrive, jaundice, ichthyosis, generalized arthrogryposis, and hypotonia. Laboratory studies showed conjugated bilirubinemia, metabolic acidosis, and renal tubular dysfunction with Fanconi syndrome. One of the patients had nephrocalcinosis, nephrogenic diabetes insipidus, and lissencephaly. They died at ages 7 and 3 months, respectively. Abu-Sa'da et al. (2005) provided a review of the literature on ARC syndrome and noted the variability of symptoms.

Gissen et al. (2006) characterized clinical features of 62 individuals with ARCS from 35 families (11 of which had previously been reported). In addition to classic features previously described, all patients had severe failure to thrive that was not adequately explained by the degree of liver disease, and 10% had structural cardiac defects. Almost half of patients who underwent diagnostic organ biopsy (7 of 16 patients) developed life-threatening hemorrhage, and most patients (9 of 11) who suffered severe hemorrhage (7 post-biopsy and 4 spontaneous) had normal platelet count and morphology.

Smith et al. (2012) studied an unrelated boy and girl who both had relatively mild ARCS. The boy, who was of nonconsanguineous Peruvian and Puerto Rican descent, exhibited failure to thrive, developmental delay with sensorineural hearing loss, renal loss of protein and amino acids, bilateral talipes with osteopenia, and mild cholestasis. MRI showed dysmorphic ventricles with coaptation of the occipital horns and irregular lateral-ventricular marginal contours. Refractory pruritus and ichthyosis were associated with increased serum concentrations of bile acids; the pruritus responded to cutaneous biliary diversion at 3 years of age. At 5.5 years of age, the boy had severe hyperkeratosis and lichenification of hand skin that interfered with fine motor tasks, including using sign language. He had osteopenia with shortening of the proximal fibula, generalized aminoaciduria and nephrotic-range proteinuria, and recurrent episodes of epistaxis associated with the absence of platelet alpha-granules. The girl, who was born to Puerto Rican and Jualisco Mexican parents, was diagnosed with arthrogryposis and failure to thrive at 2 weeks of age. She had renal tubular dysfunction, mild cholestasis, hyperpigmented lichenified skin, bilateral hip dislocations, decreased muscle bulk, and sensorineural hearing loss. MRI at 14 months showed a thin corpus callosum and diffuse paucity of white matter. Additional features included weak dental enamel and easily chipped teeth.

Inheritance

Because of the exclusive involvement of males in early reports of this disorder and the finding in the family reported by Nezelof et al. (1979) of a large number of males on the mother's side of the family who had died at birth or shortly thereafter, this disorder had been classified as X-linked recessive. The occurrence of a female case and the universal occurrence of parental consanguinity is strong support for autosomal recessive inheritance.

Molecular Genetics

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 a homolog of the class C yeast vacuolar protein sorting protein, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.

Gissen et al. (2006) characterized molecular features of 62 individuals with ARCS from 35 families (11 of which had been previously reported). Germline VPS33B mutations were present in 28 of 35 families (48 of 62 individuals); heterozygosity was found in the VPS33B locus in some cases of ARCS, suggesting the possibility of a second ARC syndrome gene. Gissen et al. (2006) concluded that VPS33B analysis should replace organ biopsy as a first-line diagnostic test for ARC syndrome.

In a male infant, born of first-cousin Saudi Arabian parents, with contracture deformities and multiple bone fractures at birth, Taha et al. (2007) identified compound heterozygosity for the known R438X mutation (608552.0002) and a splice site mutation (608552.0004) in the VPS33B gene. The authors commented that presentation of ARC syndrome with osteopenia and fractures at birth is unusual and can be misleading during the neonatal period when other components of the syndrome may not be evident; they also noted that compound heterozygosity is a very rare finding in a child of consanguineous parents.

In an unrelated boy and girl with relatively mild ARCS, Smith et al. (2012) identified compound heterozygosity for a splice site mutation in the VPS33B gene (608552.0005) and 2 different frameshift mutations (608552.0006 and 608552.0007, respectively). In transfection studies with co-overexpression of VIPAR (613401) and a VPS33B missense mutation (L30P; 608552.0003) that is associated with a more severe ARCS phenotype, Smith et al. (2012) observed no colocalization; however, in studies of VIPAR and the VPS33B splice site mutation, there was evidence for aggregates containing both VPS33B and VIPAR, suggesting that some of the function of the VPS33B-VIPAR complex might be retained with the splice site mutation.