Abstract
BackgroundInfantile hypercalcemia is an autosomal recessive disorder caused either by mutations in the CYP24A1 gene (20q13.2) or in the SLC34A1 gene (5q35.3). This disease is characterized by hypercalcemia, hypercalciuria and nephrocalcinosis in paediatric patients.Maternal uniparental disomy of chromosome 20 [UPD(20)mat], resulting in aberrant expression of imprinted transcripts at the GNAS locus, is a poorly characterized condition. UPD(20)mat patients manifest a phenotype similar to that of Silver-Russell syndrome and small for gestational age-short stature.Case presentationWe report here the genetic and clinical characterization of a male child with a phenotype of infantile hypercalcemia, postnatal growth retardation, and minor dysmorphic features. Genetic analysis using a next generation sequencing panel revealed a homozygous pathogenic variant of CYP24A1. The absence of the variant in the father led to microsatellite segregation analysis, suggestive of UPD. SNP-array revealed a large terminal copy neutral loss of heterozygosity leading to CYP24A1 homozygosity. SNP-array data of parent–child trio confirmed a UPD(20)mat responsible for both infantile hypercalcemia and Silver-Russell syndrome-like traits.ConclusionThis is the first report of uniparental disomy of chromosome 20 revealed by infantile hypercalcemia related to CYP24A1 biallelic homozygous variants, underlying the importance of controlling allelic segregation in cases of homozygosity.
Highlights
Infantile hypercalcemia is an autosomal recessive disorder caused either by mutations in the CYP24A1 gene (20q13.2) or in the SLC34A1 gene (5q35.3)
Single Nucleotid Polymorphisms (SNP)-array data of parent–child trio confirmed a Uniparental disomy (UPD)(20) mat responsible for both infantile hypercalcemia and Silver-Russell syndrome-like traits. This is the first report of uniparental disomy of chromosome 20 revealed by infantile hypercalcemia related to CYP24A1 biallelic homozygous variants, underlying the importance of controlling allelic segregation in cases of homozygosity
We present the first patient with UPD(20) mat revealed by phenotype of Infantile hypercalcemia (IH) related to CYP24A1
Summary
Infantile hypercalcemia is an autosomal recessive disorder caused either by mutations in the CYP24A1 gene (20q13.2) or in the SLC34A1 gene (5q35.3). Paternal uniparental disomy of chromosome 20, that includes the GNAS locus, has been identified in about 20 sporadic patients with pseudohypoparathyroidism 1B [6] whereas UPD(20)mat with normal karyotype (Mulchandani-Bhoj-Conlin syndrome, OMIM #617352) has been identified in 20 patients with pre- and post-natal growth failure, severe short stature with proportional head circumference and profound feeding difficulty phenotype [7,8,9,10] Those clinical features overlap with that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS) for which genetic bases are heterogeneous; the most frequent being imprinting anomalies of chromosomes 7 and 11 [11, 12]
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