Case Presentation: A 6mo female with GERD presented with poor weight gain. She was born full-term with a normal newborn screen. Family history was non-contributory. Since birth, she had poor weight gain despite medical therapy . She had large-volume spit ups shortly after eating, prompting GI evaluation. She was developmentally delayed, unable to sit without support or roll from front to back. She was dehydrated and at the 1st percentile for weight, head circumference, and length. Labs included Na 157, K 2.8, Cl 135, CO2 10, BUN 23, Cr 0.53, Ca 15.4, phos 3.1, albumin 4.7g/dL, lipase 25,537U/L, alk phos 143U/L, WBC 18.4, Hgb 13.1, plts 485, PTH <3.4, undetectable PTHrP, normal total vitamin D OH and low 1,25 OH vitamin D (8.1pg/ml). Urine studies: UK 41, UNa 17, UCl 16, UCa 4.7, UCr 4.4, UCa/UCr 1.1mg/mg (normal <0.8), Uosm 218, urine anion gap +42, urine pH 8.0. Renal ultrasound showed nephrocalcinosis and skeletal survey revealed beaten-copper appearance of the calvarium and delayed ossification and bone age. Two etiologies were considered – congenital distal renal tubular acidosis (dRTA) or primary hypercalcemia disorder with renal tubular calcium deposition and subsequent dRTA. She was started on bicarb replacement with improvement in her acidosis. She was also treated with calcitriol and bisphosphonate, but developed severe hypocalcemia requiring several months of supplementation. Intake improved with correction of her electrolytes and on follow-up, she was gaining weight and making developmental progress. Calcium normalized after correction of her acidosis. Genetic testing revealed two separate pathologic mutations in the ATP6V0A4 gene – deletion of exon 22 and deletion of exons 21-22. Mutations in this gene are known to cause congenital RTA.
Discussion: Many of our patient’s initial symptoms supported the diagnosis of congenital dRTA, including poor growth and osteoporosis, normal anion gap metabolic acidosis, positive urine anion gap, hypokalemia, and nephrocalcinosis. However, congenital dRTA is more commonly associated with hypocalcemia rather than hypercalcemia. There are case reports of hypercalcemia in dRTAs in patients less than 1 year old. The cause of hypercalcemia is believed to be acidosis-induced bone resorption. The immature renal tubules are unable to handle the increased calcium load due to decreased GFR. Calcium reabsorption may also increase in the proximal tubule in cases of dehydration, further compounding hypercalcemia. Correction of the acidosis typically resolves the hypercalcemia. The ATP6V0A4 gene encodes the α4 subunit of the H+-ATPase located in cells of the distal tubule. Mutations in this gene have been associated with dRTA and sensorineural hearing loss. There are few case reports of patients with ATP6V0A4 mutations and dRTA associated with hypercalcemia.
Conclusions: Hypercalcemia is rarely seen with dRTA and it is unclear what predisposes some patients to develop hypercalcemia compared to others. It will be interesting to see if specific mutations within the ATP6V0A4 gene are more commonly associated with hypercalcemia. Electrolyte abnormalities should resolve with correction of the acidosis, and medications to lower calcium are not typically needed, as severe hypocalcemia can develop with use of these medications.This case emphasizes that dRTA can be associated with hypercalcemia and should be considered in the differential of patients with a compatible clinical course.