Identification of AP2S1 mutation and effects of low calcium formula in an infant with hypercalcemia and hypercalciuria

J Clin Endocrinol Metab. 2013 Dec;98(12):E2022-7. doi: 10.1210/jc.2013-2571. Epub 2013 Sep 30.


Context: Although AP2S1 has recently been shown to be a causative gene for familial hypocalciuric hypercalcemia type 3 (FHH3), knowledge about FHH3 remains poor.

Objective: Our objective was to report AP2S1 mutation and effects of low calcium formula in a patient with hypercalcemia and hypercalciuria.

Patient: This Japanese female infant was found to have hypercalcemia by a routine laboratory test for poor weight gain on breast feeding. At 49 days of age, serum calcium (adjusted by Payne's formula) was 13.1 mg/dL, intact PTH 27 pg/mL, and urinary calcium-to-creatinine ratio 1.29 mg/mg. There was no evidence for hyperparathyroidism, PTHrP-producing neoplasm, and vitamin D excess. These data, except for hypercalciuria, appeared to be consistent with defective calcium-sensing receptor-mediated signaling. With use of low calcium formula containing 2.6 mg/dL of calcium, she showed catch-up growth, and serum calcium was decreased, as was urinary calcium-to-creatinine ratio. Furthermore, feeding with a mixture of low calcium formula and standard formula with a 2:1 ratio maintained serum calcium ∼12 mg/dL without markedly increasing serum PTH.

Results: Although no pathologic mutation was detected in CASR or GNA11, a presumably de novo heterozygous mutation (p.Arg15Leu), a previously reported causative mutation for FHH3, was identified in AP2S1 of this patient.

Conclusions: The results imply that lack of hypocalciuria does not necessarily argue against the presence of AP2S1 mutations. The early infantile age of this patient would have played a certain role in the occurrence of hypercalciuria, and low calcium formula is worth attempting in infants with FHH.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 2 / genetics*
  • Adaptor Protein Complex sigma Subunits / genetics*
  • Amino Acid Substitution
  • Calcium, Dietary*
  • Contraindications
  • Female
  • Humans
  • Hypercalcemia / diet therapy
  • Hypercalcemia / etiology
  • Hypercalcemia / genetics
  • Hypercalcemia / physiopathology
  • Hypercalcemia / prevention & control*
  • Hypercalcemia / urine
  • Infant
  • Infant Formula
  • Mutation*
  • Treatment Outcome


  • AP2S1 protein, human
  • Adaptor Protein Complex 2
  • Adaptor Protein Complex sigma Subunits
  • Calcium, Dietary

Supplementary concepts

  • Familial benign hypercalcemia, type 3