Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation.

Abstract

CONTEXT:

The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical features include congenital heart defects, facial dysmorphism, and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS.

CASE DESCRIPTION:

Our patient is a 16-year-old adolescent male with dysmorphic facial features and delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by fluorescence in situ hybridization. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. As a result of symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings.

CONCLUSIONS:

Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.

• Authors: Sirpa Tenhola, Geoffrey N Hendy, Helena Valta, Lucie Canaff, Bonnie S P Lee, Betty Y L Wong, Matti J Välimäki, David E C Cole, Outi Mäkitie
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 100 Issue 7 Pg. 2515-8 (Jul 2015) ISSN: 1945-7197 [Electronic] United States
• PMID: 25993639 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AP2S1 protein, human
• Adaptor Protein Complex 2
• Adaptor Protein Complex sigma Subunits
• Naphthalenes
• Cinacalcet

Topics

• Adaptor Protein Complex 2 (genetics)
• Adaptor Protein Complex sigma Subunits (genetics)
• Adolescent
• Base Sequence
• Cinacalcet
• DiGeorge Syndrome (complications, drug therapy)
• Humans
• Hypercalcemia (complications, congenital, drug therapy, genetics)
• Male
• Mutation, Missense
• Naphthalenes (therapeutic use)
• Pedigree