Last updated:
3/15/2024
Years published: 2024
NORD gratefully acknowledges Alexis Poss, MS, Clinical Instructor, and Muge Calikoglu, MD, MPH, Associate Professor, Department of Pediatric Genetics and Metabolism, UNC School of Medicine and Gioconda Alyea, Brazilian MD, MS, National Organization for Rare Disorders, for the preparation of this report.
Arthrogryposis renal dysfunction cholestasis syndrome (ARC) is a very rare genetic condition. The condition is present at birth, but symptoms may not be noticed until later in a child’s life. The name of the condition describes the symptoms. Arthrogryposis comes from the Greek word for “bent” describing limbs that are difficult to straighten. Renal dysfunction refers to the kidneys not working. Cholestasis comes from the Greek word for “bile” referring to a problem with the flow of bile, a substance which normally helps the body digest fats.
There are two types of ARC, each caused by variants in a specific gene, but the signs and symptoms are similar for both types. ARC type 1 is caused by variants in the VIPAS39 gene. ARC type 2 is caused by variants in the VPS33B gene.
While it has been thought that babies affected with ARC do not survive beyond the first year of life, usually dying from infection (sepsis), dehydration or too much acid in body fluids (acidosis), we now know that there are “attenuated” or mild cases. There are children now enrolled in elementary school who are known to have ARC type 1.
People with ARC typically have:
ARC type 1 is caused by disease-causing variants in the VPS33B gene. ARC type 2 is caused by disease-causing variants in the VIPAS39 gene.
ARC is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parent is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
ARC affects males and females in equal numbers. ARC is very rare, affecting less than 1,000 people worldwide.
The diagnosis of ARC can be made when an infant has symptoms of arthrogryposis (limbs that are difficult to straighten), renal dysfunction (kidneys are not removing acid from the bloodstream) and cholestasis (bile is not flowing normally). When a diagnosis is suspected based on these clinical symptoms, genetic testing can be done to identify disease-causing variants in both copies of the VPS33B gene or the VIPAS39 gene.
The treatment of ARC is directed towards the specific symptoms that are present. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, dermatologists, nephrologists, hepatologists, physical therapists, feeding therapists, dieticians and other health care professionals may be needed for an individual’s treatment and to look for limb, kidney and skin problems and other internal organ problems. Families of children with complex medical needs may benefit from a case worker to navigate the healthcare system. Genetic counseling is recommended for families of individuals with ARC. Other treatments for this disorder are symptomatic and supportive.
Due to the contractures and thickened skin, fine motor skills (that would be required to communicate with sign language) are severely impaired.
Children have done well with hearing aids and cochlear implants to address hearing loss – enabling children to start speaking. Hearing aids amplify sounds so they may be detected by damaged ears. Cochlear implants bypass damaged portions of the ear and directly stimulate the auditory nerve.
A feeding tube managed by a dietician has been used successfully so children will have good nutrition and grow.
The itchy skin (pruritus) has responded to cutaneous biliary diversion. This procedure diverts bile from the gallbladder to a bag that is kept on the surface of the skin of the abdomen, with the bile being discarded.
Corrective surgery for hip dysplasia can enable children to start walking.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Linhares ND, Fagundes EDT, Ferreira AR, Queiroz TCN, da Silva LR, Pena SDJ. Mild phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome 1 caused by a novel VPS33B variant. Front Genet. 2022;13:796759. Published 2022 Feb 25. doi:10.3389/fgene.2022.796759
Smith H, Galmes R, Gogolina E et al. Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome. Human Mutation. 2012;33(12):1656-1664. Doi: 10.1002/humu.22155
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