An uncommon case of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and review of the renal involvement: Answers

Duong, Minh Dien; Rose, Chelsi M.; Reidy, Kimberly; Río, Marcela Del

doi:10.1007/s00467-019-04338-z

Cited by 5 publications

(9 citation statements)

References 14 publications

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“…Consequently, they were unable to fulfill their mission, i.e., to excrete bile acids, conjugated bilirubin, ALP, cholesterol, and other substances to the bile ducts [ 6 , 17 , 18 ]. In accordance with experimental findings and previously reported ARC patients, our patient developed elevated serum levels of conjugated bilirubin, bile acids, ALP, and triglycerides, and mildly elevated transaminases [ 8 , 10 – 12 , 19 – 23 ]. Normal of GGT is a constant finding in ARC-associated intrahepatic cholestasis and can be explained by the presence of normal bile ducts.…”

Section: Discussionsupporting

confidence: 93%

“…Additional comorbidities in our patient described previously in ARC patients include severe growth faltering despite adequate energy intake, stunting, neurodevelopmental delay, hypoplastic corpus callosum, dry and scaling skin, recurrent febrile episodes with or without evidence of infection, and increased serum triglycerides [ 8 , 10 – 13 , 19 , 23 – 25 , 30 ].…”

Section: Discussionmentioning

confidence: 97%

“…The unresponsiveness to desmopressin stimulation along with the normal MRI findings from hypophysis and hypothalamus excluded central diabetes insipidus suggesting NDI. NDI has been reported to occur in more than 50% of patients with ARC [ 8 – 13 ]. The effect of VPS33B dysfunction on collecting tubules is supported by experimental studies showing abnormal expression of membrane proteins and defective structure and function of the tight junctions of collecting duct cells in VIPAR- and VPS33B-deficient mouse [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, rare ARC cases with increased GGT caused by VPS 33 B mutations have also been reported [ 24 ]. In mild cases with long-term survival, progressive liver disease may ensue leading to cirrhosis [ 8 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

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A Novel Mutation of VPS33B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype

Agakidou

Agakidis

Kambouris

et al. 2020

Case Reports in Genetics

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Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations of the VPS33B encoding the vacuolar protein sorting 33B (VPS33B), which is involved in the intracellular protein sorting and vesicular trafficking. We report a rare case of ARC syndrome without arthrogryposis caused by a novel mutation of VPS33B. A female patient of Greek origin presented on the 14th day of life with renal tubular acidosis, Fanconi syndrome, nephrogenic diabetes insipidus, and cholestasis with normal gamma-glutamyl transpeptidase, without arthrogryposis and dysmorphic features. She was born to apparently healthy, nonconsanguineous parents. Additional features included dry and scaling skin, generalized hypotonia, hypoplastic corpus callosum, neurodevelopmental delay, failure to thrive, short stature, recurrent febrile episodes with and without infections, and gastrointestinal bleeding. DNA testing revealed that the patient was homozygous for the novel c.1098_1099delTG (p.Glu367Alafs∗17) mutation of exon 14 of VPS33B gene (NM_018668) on chromosome 15q26.1, leading to a nonsense frameshift variant of VPS33B with premature termination of translation. Her parents were heterozygous for the same VPS33B mutation. The prognosis was predictably poor in the context of the intractable polyuria necessitating long-term parenteral fluid administration via indwelling central catheter leading to catheter-related sepsis, to which she eventually succumbed at the age of 7 months. This is the first published VPS33B mutation in an ARC patient of Greek origin. The current case adds to the spectrum of ARC-associated VPS33B mutations and provides evidence supporting the existence of incomplete ARC phenotype. Increased awareness and early genetic testing for ARC are suggested in cases with isolated cholestasis and/or renal tubular dysfunction, even in the absence of arthrogryposis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A Novel Mutation of VPS33B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype

Agakidou

Agakidis

Kambouris

et al. 2020

Case Reports in Genetics

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“…There is a spectrum of phenotypes caused by VPS33B mutations. Patients with the c.1225 + 5G > C mutation in the VPS33B gene may have a mild phenotype and a longer lifespan [ 7 ]. Some patients do not present with all manifestations [ 6 , 8 ], and there are some cases that include high GGT [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

One case of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome featuring an incomplete and mild phenotype

Zhang

et al. 2022

BMC Nephrol

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Background Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare disease with a high mortality rate caused by VPS33B or VIPAS39 mutations. ARC syndrome typically presents with arthrogryposis, renal tubular leak and neonatal cholestatic jaundice, and most patients with this disease do not survive beyond one year. Case presentation Here, we report the case of a 13-year-old girl with ARC featuring an incomplete and mild phenotype with novel compound heterozygous mutations of VPS33B. The patient presented with arthrogryposis (claw-shaped limbs), ichthyosis, jaundice, and pruritus. Laboratory tests revealed highly evaluated levels of total bilirubin (TB), direct bilirubin (DB), and total bile acid (TBA) as well as normal levels of gamma-glutamyltransferase (GGT). However, signs of renal dysfunction, as well as other manifestations of ARC syndrome, including nervous system abnormalities, deafness, and failure to thrive, were not observed. The patient’s clinical symptoms of jaundice and pruritus were significantly alleviated by administration of ursodeoxycholic acid. Whole-exome sequencing (WES) revealed novel compound heterozygous mutations of VPS33B, c.1081 C > T (p.Q361X,257)/c.244 T > C (p.C82R). Both variants were predicted to be pathogenic in silico and have never been reported previously. To date, the patients’ cholestatic jaundice has been well controlled with continuous treatment of ursodeoxycholic acid. Conclusions We report the case of a Chinese female with ARC including novel compound heterozygous mutations of VPS33B and an incomplete and mild phenotype. Early diagnosis and suitable symptomatic therapies are critical for the management of ARC patients with mild manifestations and prolonged lifespan.

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Two novel mutations in the VPS33B gene in a Chinese patient with arthrogryposis, renal dysfunction and cholestasis syndrome 1: A case report

Yang¹,

Song²,

Guan³

et al. 2022

World J Clin Cases

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BACKGROUND The VPS33B (OMIM: 608552) gene is located on chromosome 15q26.1. We found a female infant with autosomal recessive arthrogryposis, renal dysfunction and cholestasis syndrome 1 (ARCS1) caused by mutation in VPS33B . The child was diagnosed with ARCS1 (OMIM: 208085) after the whole exome sequencing revealed two heterozygous mutations (c.96+1G>C, c.242delT) in the VPS33B gene. CASE SUMMARY We report a Chinese female infant with neonatal cholestasis disorder, who was eventually diagnosed with ARCS1 by genetic analysis. Genetic testing revealed two new mutations (c.96+1G>C and c.242delT) in VPS33B , which is the causal gene. The patient was compound heterozygous, and her parents were both heterozygous. CONCLUSION This study extends the mutational spectrum of the VPS33B gene to provide a molecular basis for the etiological diagnosis of ARCS1 and for genetic counseling of the family.

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An uncommon case of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and review of the renal involvement: Answers

Cited by 5 publications

References 14 publications

A Novel Mutation of VPS33B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype

A Novel Mutation of VPS33B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype

One case of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome featuring an incomplete and mild phenotype

Two novel mutations in the VPS33B gene in a Chinese patient with arthrogryposis, renal dysfunction and cholestasis syndrome 1: A case report

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