Investigations and Treatment:
Patient 1: Labs upon presentation showed fasting hypoglycemia and cholestatic hepatitis (Table 1). She was also found to have severe Vitamin D deficiency rickets based upon her labs and wrist X-rays. Abdominal ultrasound (US) showed hepatosplenomegaly as well as bilateral increased renal echogenicity surrounding the medullary pyramids. MRI brain revealed thin corpus callosum with overall decreased volume of cerebral white matter. MRI spine was normal. Renal tubular dysfunction was identified on labs that showed acidosis, proteinuria and glucosuria. She had a normal coagulation profile and negative infectious hepatitis panel Differential diagnosis initially included a genetic or metabolic syndrome given the vast array of findings. A clinical diagnosis of ARC syndrome was made that was later confirmed by genetic testing. A commercial genetic cholestasis panel was ordered that identified variants in VPS33B: c.1225+5G>C and c.1609del p. Asp538Metfs*17, with the c.1225+5 G>C previously described in association with a milder presentation of the disease. Another rare variant was positive, designated c.1609del, that has not been described in the literature or reported in a large population database. She was also found to have a heterozygous pathogenic variant in SERPINA1 (c. 863 A>T, p. Glu288Val) conferring a carrier state for alpha-1 antitrypsin (A1AT) deficiency. Her A1AT phenotype was MS with normal level.
Our patient’s vitamin D deficiency improved over time with supplementation and repeat labs showed normal Vitamin D, calcium, and phosphorus. Her acidosis improved with sodium citrate supplementation. She was started on ursodiol for cholestasis and her total and direct bilirubin levels also normalized.
Patient 2: Patient’s mother had undergone amniocentesis during pregnancy that confirmed biallelic pathogenic variants in VPS33B: c.1225+5G>C and c.1609del p. Asp538Metfs*17, which were also seen in her sibling (patient 1) confirming a diagnosis of ARC syndrome, as in patient 1. She did not have any additional mutations. Initial laboratory tests, including bilirubin and thyroid profile, were within normal range. Overtime, she also developed hepatitis and experienced fasting hypoglycemia, similar to her older sibling (Table 1). Abdominal ultrasound (US) revealed a congenital gallbladder anomaly (multiseptated gallbladder), without any associated hepatosplenomegaly or renal defects. MRI brain was normal. Renal tubular dysfunction was identified on labs that showed acidosis, proteinuria and glucosuria. She had a normal coagulation profile.
She was started on DEKA vitamins early on, and fortunately, did not develop Vitamin D deficient rickets, as seen in her sibling. She is now 11-month-old. For her failure to thrive, she is currently receiving supplemental enteral feeds via a gastrostomy tube, and she is on sodium citrate supplementation for her acidosis.