Infantile idiopathic hypercalcemia associated with heterozygous mutation of SLC34A1: a case series

Ozturk Ayse Pinar; Alina Oprea; Helen Jones; Laura Halpin; Alessandra Cocca

doi:10.1530/endoabs.110.P308

JOINT2997

Objective: Idiopathic infantile hypercalcemia (IIH) is a rare clinical disorder defined by hypercalcemia, typically presenting with symptoms such as failure to thrive, dehydration, vomiting, nephrocalcinosis, and elevated calcium levels. Mutations in SLC34A1, which encodes the sodium-phosphate cotransporter (NPT2A), lead to phosphate depletion and dysregulated production of 1, 25-dihydroxyvitamin D, resulting in subsequent hypercalcemia. Here, we present three cases of IIH associated with mutations in the SLC34A1 gene.

Methods: The clinical and laboratory findings of three patients with IIH were analyzed retrospectively.

Results: All patients were asymptomatic at presentation, and hypercalcemia was detected incidentally. The first two patients were twins, both presented with hypercalciuria and nephrocalcinosis. The third patient had hypercalciuria but did not show nephrocalcinosis. A targeted next-generation sequencing panel for nephrocalcinosis/nephrolithiasis was conducted to investigate the underlying aetiology. Genetic analysis revealed that the twins had compound heterozygous mutations in SLC34A1 (c. 644+1G>A/c. 398C>T p. (Ala133Val)), one of which was a pathogenic variant and the other variant of uncertain significance (VUS). The third patient had a monoallelic variant in SLC34A1 (c. 272_292del p. (Val91_Ala97del)), which was likely pathogenic (Table-1).


	Family-1		Family-2
	Patient-1	Patient-2	Patient-3
Sex	Female	Female	Male
Gestational-age, week	29+4	29+4	41+3
Birth-weight, gr	1174	1261	3445
Consanguinity	No	No	No
Family-history of renal calcification	No	No	No
Family-history of hypercalcemia	No	No	No
History of vitamin D application	600 U/day (from birth to 10w)	NA	400 U/day (from birth to 2 month)
Symptoms	Asymptomatic	Asymptomatic	Asymptomatic
Age at initial assessment, months	12	12	2
Initial assessmentAdjusted-Ca( mmol/l) (normal-range 2. 2-2. 7)	2. 91	2. 97	2. 71
Serum-Pi( mmol/l)	1. 26	1. 33	2
ALP(U/l)	192	213	1986
PTH(ng/l)(normal-range:15-63)	<3	<0. 5	10
25(OH)D3(nmol/l)	101	111	36
1, 25-dihydroxyvitamin D (pmol/l) (normal-range:48-192)	96		252
UrineCa/Cr( mmol/mmol) (normal-range:10. 05-1. 5)	2. 17	2. 33	3. 88
Renal-function	Normal	Normal	Normal
Imaging-examination
Nephrocalcinosis	+	+	-
Skeletal abnormality	-	-	-
Treatment	Potassium-citrate	Potassium-citrate	None
Gene-analysis	Compound-heterozygous mutation in SLC34A1 gene c. 644+1G>A/c. 398C>T p. (Ala133Val)		Heterozygous mutation in SLC34A1 gene c. 272_292del p. (Val91_Ala97del)

Conclusion: In the presence of hypercalcemia accompanied by hypercalciuria, DNA analysis for mutations in the SLC34A1 gene should be conducted. Heterozygous patients typically exhibit milder clinical symptoms compared to homozygous patients due to haploinsufficiency of NTP2A. Despite having a mild phenotype, they remain at risk for kidney damage and chronic kidney disease due to nephrocalcinosis and require close monitoring. Gaining a better understanding of the phenotypic and genotypic characteristics of this rare disease may help clarify its full spectrum over time.

Keywords: hypercalcemia, nephrocalcinosis, nephrolithiasis

Endocrine Abstracts

P308