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.