A De Novo Mosaic PHEX Variant Causing Sporadic X-Linked Hypophosphatemic Rickets in a 2-Year-Old Girl

Abstract

Pathogenic variants in the PHEX gene are causative of X-linked hypophosphatemic rickets (XLH). We present a case of a 2-year-old girl with hypophosphatemic rickets with genu varum and short stature without any family history of XLH. Next generation sequencing of the PHEX gene identified a splice donor variant, NM_000444.6:c.1173 + 5G > A in intron 10. This variant had a mosaic pattern with only 22% of the sequence reads showing the variant allele and was not present in the girl's parents, both of whom had a normal phenotype. This is a sporadic case of a de novo mosaic splice-site variant in the PHEX gene.

Keywords

PHEX - X-linked hypophosphatemic rickets - mosaic

Publication History

Received: 08 January 2021

Accepted: 11 March 2021

Article published online:
01 June 2021

• References

• 1 Albright F, Butler AM, Bloomberg E. Rickets resistant to vitamin D therapy. Am J Dis Child 1937; 54 (03) 529-547
• 2 Levine BS, Kleeman CR, Felsenfeld AJ. The journey from vitamin D-resistant rickets to the regulation of renal phosphate transport. Clin J Am Soc Nephrol 2009; 4 (11) 1866-1877
• 3 Pavone V, Testa G, Gioitta Iachino S, Evola FR, Avondo S, Sessa G. Hypophosphatemic rickets: etiology, clinical features and treatment. Eur J Orthop Surg Traumatol 2015; 25 (02) 221-226
• 4 Beck-Nielsen SS, Mughal Z, Haffner D. et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J Rare Dis 2019; 14 (01) 58
• 5 Carpenter TO, Whyte MP, Imel EA. et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med 2018; 378 (21) 1987-1998
• 6 Goji K, Ozaki K, Sadewa AH, Nishio H, Matsuo M. Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait. J Clin Endocrinol Metab 2006; 91 (02) 365-370
• 7 Weng C, Chen J, Sun L. et al. A de novo mosaic mutation of PHEX in a boy with hypophosphatemic rickets. J Hum Genet 2016; 61 (03) 223-227
• 8 Lin Y, Xu J, Li X. et al. Novel variants and uncommon cases among southern Chinese children with X-linked hypophosphatemia. J Endocrinol Invest 2020; 43 (11) 1577-1590
• 9 Broseta JJ, López-Romero LC, Cerón JA, Mendizábal S, Hernández-Jaras J. Mosaicism in 2 cases of X-linked hypophosphatemia. Endocrinol Diabetes Nutr 2020; 67 (01) 70-71
• 10 Yang M, Kim J, Yang A. et al. A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets. Ann Pediatr Endocrinol Metab 2018; 23 (04) 229-234
• 11 Haffner D, Emma F, Eastwood DM. et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019; 15 (07) 435-455
• 12 Poon KS, Sng AA, Ho CW, Koay ES, Loke KY. Genetic testing confirmed the early diagnosis of X-linked hypophosphatemic rickets in a 7-month-old infant. J Investig Med High Impact Case Rep 2015; 3 (03) 2324709615598167
• 13 Zhang C, Zhao Z, Sun Y. et al. Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia. Bone 2019; 121: 212-220
• 14 Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37 (09) e67
• 15 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 16 Lin Y, Cai Y, Xu J. et al. 'Isolated' germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets. Eur J Endocrinol 2020; 182 (01) K1-K6