ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2020 Jun 1;105(6):dgz260. Abstract: https://pubmed.ncbi.nlm.nih.gov/31821448/

In brief: In large kindred including five hypophosphatemic rickets (HR) patients with a pattern of autosomal dominant inheritance, a novel c.979–96 T>A variant in the SGK3 gene segregated perfectly with the phenotype, i.e. present in all 5 patients and in none of the healthy family members, providing strong support for its causation.

Comment: Hereditary hypophosphatemic rickets (HR) is a group of renal phosphate wasting disorders. X-linked HR, caused by genetic variant in the PHEX gene is the most common hereditary form of HR representing about 80% of all cases, while the rest are caused by variants in FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 genes.

The Index case was a 3-year-old female who was referred for short stature and bone deformities of the lower limbs. Mother, maternal grandmother, aunt, and a cousin were also affected with short stature and bone deformities. Biochemical and radiological investigations were confirmative of hypophosphatemic rickets with hypophosphatemia and reduced renal tubular phosphate reabsorption. Patients and their family members were negative for PHEX and FGF23 mutations. Exome sequencing was subsequently performed to identify novel candidate genes. No copy number variation was observed in the genome using CytoScan HD array analysis. Also, no mutations were found in DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 by exome sequencing.

A novel c.979–96 T>A variant in the SGK3 gene inherited in an autosomal dominant pattern was found in all 5 affected individuals and was absent in all unaffected family members that were tested. This gene codes for SGK3 (serum and glucocorticoid-regulated kinase 3), a serine/threonine kinase closely related to Akt. It has been shown to regulate renal tubular phosphate transport and bone density. The mutation is located 1 bp downstream of a highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids and therefore disruption of the protein tertiary structure and part of the protein kinase domain and is thus likely a loss-of-function variant.

The mechanism by which mutations in SGK3 cause phosphate wasting and hypophosphatemia is not fully elucidated. SGK3 has been shown to regulate renal tubular phosphate transport by increasing NaPi-2a activity, thus stimulating renal tubular phosphate reabsorption and bone mineralization (1). Consistently, Sgk3 knockout mice show phosphate wasting and have decreased bone density, likely related to reduced NaPi-2a activity (2). In addition, both plasma FGF23 and calcitriol (1,25(OH)2D3) concentrations were reduced in the Sgk3 knockout mice and the authors therefore speculated that SGK3 may participate in the regulation of calcitriol synthesis. In the index case, treatment for 5 years with 50 mg/kg/day phosphate sodium tablets, gradually increased to 75 mg/kg/day divided in 6 equal daily doses, and calcitriol at 40 ng/kg/day led to resolution of leg deformities and improvement in biochemical features of hypophosphatemic rickets.

In summary, this finding of a novel splice variant in the SGK3 gene that co-segregates perfectly within a 3-generation family with HR adds SGK3 to the list of genes in which mutations may cause hypophosphatemic rickets with an autosomal dominant inheritance.

Reference: 1. Trepiccione, F. and G. Capasso, SGK3: a novel regulator of renal phosphate transport? Kidney Int, 2011. 80(1): p. 13–5.2. Bhandaru, M., et al., Decreased bone density and increased phosphaturia in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase 3. Kidney Int, 2011. 80(1): p. 61–7.