Arthrogryposis–renal dysfunction–cholestasis syndrome

Overview

Arthrogryposis–Renal Dysfunction–Cholestasis Syndrome (ARC Syndrome) is a rare, autosomal recessive multisystem disorder that affects the joints, kidneys, and liver. First described in the early 1980s, ARC syndrome is most commonly diagnosed in infancy and is characterized by a triad of features:

• Arthrogryposis – congenital joint contractures

• Renal dysfunction – primarily involving tubular defects

• Cholestasis – impaired bile flow causing liver dysfunction

ARC syndrome is severe and typically fatal within the first year of life. It is considered one of the lethal syndromes within the spectrum of congenital disorders of intracellular trafficking.

Causes

ARC syndrome is caused by mutations in one of the following genes:

• VPS33B – the most common cause

• VIPAS39 – associated with ARC2, a similar but less severe form

Both genes are involved in vesicle trafficking and protein sorting within cells, processes essential for normal liver, kidney, and joint development. The condition is inherited in an autosomal recessive pattern, meaning both copies of the gene (one from each parent) must carry mutations for the child to be affected.

Symptoms

The presentation of ARC syndrome is usually evident at birth or in early infancy and involves a combination of systemic abnormalities:

Musculoskeletal:

• Arthrogryposis multiplex congenita – stiffness and contractures in multiple joints

• Hip dislocations

• Clubfoot or other limb deformities

Renal (Kidney) Dysfunction:

• Renal tubular acidosis

• Proteinuria and glucosuria

• Nephrocalcinosis (calcium deposits in the kidney)

• Polyuria and dehydration

Hepatobiliary (Liver and Bile Ducts):

• Neonatal cholestasis (jaundice and pale stools)

• Low gamma-glutamyl transferase (GGT) cholestasis

• Hepatomegaly (enlarged liver)

Other Features:

• Sensorineural hearing loss

• Recurrent infections due to immune dysfunction

• Failure to thrive and poor feeding

• Bleeding tendency due to platelet dysfunction

• Ichthyosis (dry, scaly skin)

Diagnosis

Diagnosis of ARC syndrome is based on clinical evaluation, biochemical testing, and genetic confirmation:

• Physical examination: Identifies joint contractures and growth delay

• Blood and urine tests: Reveal signs of renal tubular dysfunction and cholestasis with low or normal GGT levels

• Liver biopsy: May show bile duct hypoplasia

• Imaging studies: Such as renal ultrasound, may reveal nephrocalcinosis

• Genetic testing: Confirms mutations in VPS33B or VIPAS39

Treatment

There is currently no cure for ARC syndrome. Treatment is supportive and focused on managing symptoms and improving quality of life:

Supportive and Symptomatic Care:

• Nutritional support: Special feeding regimens or parenteral nutrition

• Electrolyte management: Correction of metabolic acidosis and dehydration

• Liver support: Ursodeoxycholic acid to improve bile flow, vitamin supplementation

• Joint care: Physical therapy for joint contractures and orthopedic intervention as needed

• Infection prevention: Antibiotics for infections and regular monitoring due to immunodeficiency

Palliative Care:

• Due to the progressive and severe nature of the condition, palliative care is often introduced early to ensure comfort and dignity

Prognosis

The prognosis of ARC syndrome is poor. Most affected infants do not survive beyond the first year of life, primarily due to complications such as sepsis, liver failure, or severe electrolyte imbalances. In rare cases with milder mutations (especially involving VIPAS39), survival into childhood has been reported with intensive supportive care.

Genetic counseling is strongly recommended for affected families, especially in communities where consanguineous marriages are common.