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Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 43-45

An infant with cholestasis and refractory electrolyte abnormalities

1 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Section of Pediatric Nephrology and Gastroenterology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
3 Department of Pediatrics, King Faisal Specialist Hospital and Research Center; Section of Pediatric Nephrology and Gastroenterology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

Date of Submission20-Oct-2021
Date of Decision07-Feb-2022
Date of Acceptance16-Feb-2022
Date of Web Publication28-Jun-2022

Correspondence Address:
Weiam Almaiman
Department of Pediatrics, King Faisal Specialist Hospital and Research Center, (MBC 58), P.O.B. 3354, Riyadh 11211
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajpn.ajpn_36_21

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Arthrogryposis-renal dysfunction-cholestasis (ARC) is a rare multisystem disorder caused by mutations in the VPS33B gene, which in turn lead to a premature truncation of the gene product. This autosomal recessive disease has variations in phenotype. We report an infant girl who had severe presentation in the form of dysmorphic features, abnormal hearing assessment and refractory electrolytes disturbances. She was a product of consanguineous marriage with family history of similar presentation. The child passed away at age of 6 months due to aspiration pneumonia.

Keywords: Cholestasis, children, renal tubular acidosis, tubulopathy, arthrogryposis

How to cite this article:
Alsubaie H, Kattan YS, Alshareef TA, Aldekhail W, Almaiman W. An infant with cholestasis and refractory electrolyte abnormalities. Asian J Pediatr Nephrol 2022;5:43-5

How to cite this URL:
Alsubaie H, Kattan YS, Alshareef TA, Aldekhail W, Almaiman W. An infant with cholestasis and refractory electrolyte abnormalities. Asian J Pediatr Nephrol [serial online] 2022 [cited 2022 Aug 18];5:43-5. Available from: https://www.ajpn-online.org/text.asp?2022/5/1/43/348529

This 3-month-old baby girl was admitted with failure to thrive, hypotonia, abnormal hearing assessment, and neonatal cholestasis. She was born at 37 weeks gestation to parents who were second-degree relatives through cesarean section due to breech presentation, with a birth weight of 3.5 kg. Mother had insulin-dependent gestational diabetes. She had 3 older healthy siblings. There was a family history of one elder sibling having died in the neonatal period at the age of 6 months, with neonatal jaundice and undiagnosed liver disease.

On examination, she was markedly jaundiced and dehydrated with dysmorphic features and abnormal skin texture. Dysmorphic features included microcephaly, high-arched palate, deformed feet, dry and lax skin with ichthyosis, and generalized hypotonia. Since the first day of admission, the patient showed normal anion gap metabolic acidosis, anemia, high creatinine, hyperbilirubinemia, and normal level of gamma-glutamyl transferase [Table 1]. Urinalysis showed glucosuria and 3 + proteinuria, random urine pH was 6.0, calcium/creatinine ratio was 0.5 mg/mg, and tubular reabsorption of phosphorus was 6.8%. She developed dehydration due to polyuria and refractory electrolyte disturbances with hypernatremia, hyperchloremia, hypocalcemia, hypophosphatemia, and hypomagnesemia. In addition, she had respiratory distress with tachypnea, nasal flaring, and subcostal retractions. The patient received multiple fluid boluses, in addition to continuous infusions of sodium bicarbonate, boluses of sodium phosphate, calcium carbonate, and magnesium gluconate.
Table 1: Laboratory values

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Genetic sequencing showed a homozygous pathogenic variation in VPS33B (NM_001289148: exon19: c. 1438C > T: p.R480x) that led to premature truncation of the gene product. In view of the presence of arthrogryposis, renal dysfunction, and cholestasis, a diagnosis of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome was made [Figure 1].
Figure 1: Infant with arthrogryposis, renal tubular dysfunction and cholestasis (ARC) syndrome. Note the ichthyosis

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Following a genetic diagnosis of ARC syndrome, caregivers were counseled regarding the disease pathogenesis and outcomes in a multidisciplinary meeting. Subsequently, the family decided to opt for a palliative care plan. The child succumbed to aspiration pneumonia 3 months following discharge from the hospital.

  Discussion Top

ARC syndrome is an autosomal recessive disease that was described to have several phenotypic variations.[1] The three cardinal features of arthrogryposis, renal tubular dysfunction, and cholestasis may be absent at presentation and may result in an underdiagnosis of cases. Cases were initially classified based on their hepatic histological findings, and patients were divided into either a group with intrahepatic biliary hypoplasia and giant cell hepatitis, or a group characterized by cholestasis and lipofuscin deposition. This remained the classification till Horslen et al. described a case presenting with both histological features, suggesting that all histological findings may be present in the same patient.[2],[3]

Our case presented with developmental delay, an abnormal hearing assessment, and arthrogryposis. She was found to have a homozygous pathogenic variation in VPS33B gene, which has a role in the apical recycling pathway through VPS33B-VIPAR complex to mediate vesicular membrane fusion in multiple organs, and also affects collagen maturation and keratinocyte differentiation. Therefore, defects in the gene may lead to structural and functional abnormalities in the kidney, liver, and skin.[4]

The feature arthrogryposis occurs secondary to the degeneration of the anterior motor neuron cells, resulting in reduced fetal movement and hypotonia. Decreased fetal movements also lead to the development of clubfoot and hip joint dislocation.[5],[6] Other central nervous system features that develop in ARC syndrome include developmental delay and sensorineural hearing loss.[7]

Renal tubular dysfunction is a cardinal feature of the syndrome. Presentation of the dysfunction ranges from isolated renal tubular acidosis to the complete Fanconi syndrome, occurring in the first few days or by 2–3 months of life. Patients with the ARC syndrome undergo a series of tests, including kidney ultrasound investigations. In most cases, dysplastic kidneys or nephrocalcinosis is evident, resulting in symptoms of renal tubular dysfunction.[5],[8] The present patient had refractory electrolytes disturbances with hypernatremia, hyperchloremia, hypocalcemia, hypophosphatemia, and hypomagnesemia due to proximal tubular dysfunction. Another defining feature associated with this syndrome is cholestasis and failure to thrive. These patients often present with failure to thrive, which is attributed to cholestasis leading to fat malabsorption, chronic diarrhea, and loss of nutrients from the gastrointestinal tract, as seen in the present patient.[6]

Patients with ARC syndrome show variable dysmorphic features, including flattened nasal bridge, low set ears, simian crease, and cryptorchidism.[9] Features including microcephaly, high-arched palate, deformed feet, and dry and lax skin with ichthyosis, were presented in our case. Careful history and physical examination, along with a high index of suspicion and genetic testing are required. For active cases, only supportive treatment is offered. Preimplantation diagnosis and prenatal counseling should be offered to all carrier parents.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bull LN, Mahmoodi V, Baker AJ, Jones R, Strautnieks SS, Thompson RJ, et al. VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: Incomplete ARC syndrome phenotype. J Pediatr 2006;148:269-71.  Back to cited text no. 1
Gissen P, Tee L, Johnson CA, Genin E, Caliebe A, Chitayat D, et al. Clinical and molecular genetic features of ARC syndrome. Hum Genet 2006;120:396-409.  Back to cited text no. 2
Horslen SP, Quarrell OW, Tanner MS. Liver histology in the arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC) syndrome: Report of three new cases and review. J Med Genet 1994;31:62-4.  Back to cited text no. 3
Cullinane AR, Straatman-Iwanowska A, Zaucker A, Wakabayashi Y, Bruce CK, Luo G, et al. Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. Nat Genet 2010;42:303-12.  Back to cited text no. 4
Deal JE, Barratt TM, Dillon MJ. Fanconi syndrome, ichthyosis, dysmorphism, jaundice and diarrhea – A new syndrome. Pediatr Nephrol 1990;4:308-13.  Back to cited text no. 5
Choi HJ, Lee MW, Choi JH, Moon KC, Koh JK. Ichthyosis associated with ARC syndrome: ARC syndrome is one of the differential diagnoses of ichthyosis. Pediatr Dermatol 2005;22:539-42.  Back to cited text no. 6
Abdullah MA, Al-Hasnan Z, Okamoto E, Abomelha AM. Arthrogryposis, renal dysfunction and cholestasis syndrome. Saudi Med J 2000;21:297-9.  Back to cited text no. 7
Abu-Sa'da O, Barbar M, Al-Harbi N, Taha D. Arthrogryposis, renal tubular acidosis and cholestasis (ARC) syndrome: Two new cases and review. Clin Dysmorphol 2005;14:191-6.  Back to cited text no. 8
Eastham KM, McKiernan PJ, Milford DV, Ramani P, Wyllie J, van't Hoff W, et al. ARC syndrome: An expanding range of phenotypes. Arch Dis Child 2001;85:415-20.  Back to cited text no. 9


  [Figure 1]

  [Table 1]


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