Arthrogryposis-renal dysfunctional cholestasis Q89.7

Lutz-Richner and Landolt 1973

Arthrogryposis renal dysfunction cholestasis syndrome is a rare, apparently globally occurring, autosomal recessive inherited, multisystemic disease with the obligatory symptoms of neurogenic arthrogryposis multiplex congenita, renal tubulopathy and neonatal cholestasis with low activity of gamma glutamyl transferase in serum.

Worldwide < 100 patients have been described.

In most cases a homozygous mutation (c.178-3T>A) was found in the VPS33B gene (15q26.1). Furthermore, mutations in the VIPAS39 gene are described (Huang DG et al. 2017; Chai M et al. 2018). The VPS33B gene is involved in intracellular protein transport and membrane fusion.

The phenotype is variable, even in the same family, and because not all patients have all three major symptoms, the syndrome is not always recognized. Renal tubular dysfunction ranges from isolated renal tubular acidosis to full-blown Fanconi syndrome (polyuria, aminoaciduria, glycosuria, phosphaturia, and bicarbonate loss). Abnormalities of the liver include, in varying combination, cholestasis, hypoplasia of the intrahepatic bile ducts, and deposition of lipofuscin.

Other symptoms include: rather mild ichthyosis, flaccid skin, severe failure to thrive, platelet dysfunction (with possibly. severe bleeding), facial dysmorphia (low-set ears, high palatal arch, beak-shaped nose, small anterior fontanel), jaundice, diarrhea, susceptibility to infections with recurrent fevers, hypothyroidism, cardiac malformations, brain malformations, and sensorineural hearing loss (Ilhan O et al. 2016).

There is no specific therapy. Most infants have a life expectancy of < 1 year despite intensive treatment. Patients who survive longer have cirrhosis of the liver and are severely developmentally retarded.

1. Chai M et al (2018) Identification of genes and signaling pathways associated with arthrogryposis-renal dysfunction-cholestasis syndrome using weighted correlation network analysis. Int J Mol Med 42:2238-2246.
2. Huang DG et al (2017) Clinical features and VPS33B mutations in a family affected by arthrogryposis, renal dysfunction, and cholestasis syndrome. Zhongguo Dang Dai Er Ke Za Zhi 19:1077-1082.
3. Ilhan O et al (2016) Arthrogryposis-renal tubular dysfunction-cholestasis syndrome: a cause of neonatal cholestasis. Case report. Arch Argent Pediatr 114:e9-12.
4. Moon AT et al (2017) A Novel VPS33B Mutation in a Patient with Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome. Pediatric Dermatol 34:e171-e173.