Ann Pediatr Endocrinol Metab.  2018 Dec;23(4):229-234. 10.6065/apem.2018.23.4.229.

A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets

• Yang M
• Kim J
• Yang A
• Jang J
• Jeon TY
• Cho SY
• Jin DK

• KMID: 2432276
• DOI: http://doi.org/10.6065/apem.2018.23.4.229

Abstract

X-linked hypophosphatemic rickets is caused by loss-of-function mutations in PHEX, which encodes a phosphate-regulating endopeptidase homolog. We report a 26-year-old man with X-linked hypophosphatemic rickets who showed decreased serum phosphate accompanied by bilateral genu valgum and short stature. He had received medical treatment with vitamin D (alfacalcidol) and phosphate from the age of 3 to 20 years. He underwent surgery due to valgus deformity at the age of 14 and 15. Targeted gene panel sequencing for Mendelian genes identified a nonsense mutation in PHEX (c.589C>T; p.Gln197Ter) and a mosaic pattern where only 38% of sequence reads showed the variant allele. This mutation was not found in his mother, who had a normal phenotype. This is a case of a sporadic nonsense mutation in PHEX and up to date, this is the first case of a mosaic mutation in PHEX in Korea.

Keyword

PHEX; Hypophosphatemic rickets; Mosaic mutation; Nonsense mutation

MeSH Terms

Adult
Alleles
Codon, Nonsense
Congenital Abnormalities
Familial Hypophosphatemic Rickets
Genu Valgum
Humans
Korea
Mothers
Phenotype
Rickets, Hypophosphatemic*
Vitamin D
Codon, Nonsense
Vitamin D

Figure

• 

  Fig. 1. (A, B) X-rays of the lower extremities in our patient at the age of 14 show coxa magna, coxa vara. (C, D) At the age of 26, follow-up X-rays show mild osteoarthritis in both hip joints and multiple old fractures in both femurs, tibias, and fibulas.

• 

  Fig. 2. Sanger sequencing of the proband and his mother: A novel nonsense mutation (c.589C>T; p.Gln197Ter) in PHEX was found in the patient. No mutations in the region were found in his mother.

Reference

References

1. Kim J, Yang KH, Nam JS, Choi JR, Song J, Chang M, et al. A novel PHEX mutation in a Korean patient with sporadic hypophosphatemic rickets. Ann Clin Lab Sci. 2009; 39:182–7.

2. Francis F, Strom TM, Hennig S, Böddrich A, Lorenz B, Brandau O, et al. Genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets. Genome Res. 1997; 7:573–85.

3. Kruse K, Woelfel D, Strom TM. Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation. Horm Res. 2001; 55:305–8.

4. Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodiumphosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006; 78:193–201.

5. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006; 38:1310–5.

6. Hasani-Ranjbar S, Amoli MM, Ebrahim-Habibi A, Dehghan E, Soltani A, Amiri P, et al. SLC34A3 intronic deletion in a new kindred with hereditary hypophosphatemic rickets with hypercalciuria. J Clin Res Pediatr Endocrinol. 2012; 4:89–93.

7. Brakemeier S, Si H, Gollasch M, Höffler D, Buhl M, Köhler R, et al. Dent's disease: identification of a novel mutation in the renal chloride channel CLCN5. Clin Nephrol. 2004; 62:387–90.

8. Song HR, Park JW, Cho DY, Yang JH, Yoon HR, Jung SC. PHEX gene mutations and genotype-phenotype analysis of Korean patients with hypophosphatemic rickets. J Korean Med Sci. 2007; 22:981–6.

9. Kang YE, Hong JH, Kim J, Joung KH, Kim HJ, Ku BJ, et al. A novel PHEX gene mutation in a patient with sporadic hypophosphatemic rickets. Endocrinol Metab (Seoul). 2014; 29:195–201.

10. Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y. A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res. 2005; 58:329–33.

11. Cheon CK, Lee HS, Kim SY, Kwak MJ, Kim GH, Yoo HW. A novel de novo mutation within PHEX gene in a young girl with hypophosphatemic rickets and review of literature. Ann Pediatr Endocrinol Metab. 2014; 19:36–41.

12. Holm IA, Nelson AE, Robinson BG, Mason RS, Marsh DJ, Cowell CT, et al. Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2001; 86:3889–99.

13. Popowska E, Pronicka E, Sułek A, Jurkiewicz D, Rowińska E, Sykut-Cegielska J, et al. X-linked hypophosphatemia in Polish patients. 2. Analysis of clinical features and genotype-phenotype correlation. J Appl Genet. 2001; 42:73–88.

14. Weng C, Chen J, Sun L, Zhou ZW, Feng X, Sun JH, et al. A de novo mosaic mutation of PHEX in a boy with hypophosphatemic rickets. J Hum Genet. 2016; 61:223–7.

15. 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; 91:365–70.

16. Jagtap VS, Sarathi V, Lila AR, Bandgar T, Menon P, Shah NS. Hypophosphatemic rickets. Indian J Endocrinol Metab. 2012; 177–82.

17. Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L, Guillaume-Czitrom S, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014; 3:R13–30.

18. Zhang X, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Ito T, et al. Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia. J Clin Pharmacol. 2016; 56:176–85.

19. Chen CP, Lin SP, Su YN, Chern SR, Su JW, Wang W. Prenatal diagnosis of recurrent autosomal dominant osteogenesis imperfecta associated with unaffected parents and paternal gonadal mosaicism. Taiwan J Obstet Gynecol. 2013; 52:106–9.