Ann Pediatr Endocrinol Metab.  2016 Sep;21(3):169-173. 10.6065/apem.2016.21.3.169.

Long-term clinical outcome and the identification of homozygous CYP27B1 gene mutations in a patient with vitamin D hydroxylation-deficient rickets type 1A

• Cho JH
• Kang E
• Kim GH
• Lee BH
• Choi JH
• Yoo HW

• KMID: 2366794
• DOI: http://doi.org/10.6065/apem.2016.21.3.169

Abstract

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A) is an autosomal recessively-inherited disorder caused by mutations in CYP27B1 encoding the 1α-hydroxylase enzyme. We report on a female patient with VDDR1A who presented with hypocalcemic seizure at the age of 13 months. The typical clinical and biochemical features of VDDR1A were found, such as hypocalcemia, increased alkaline phosphatase, secondary hyperparathyroidism and normal 25-hydroxyvitamin D3 (25(OH)D₃). Radiographic images of the wrist showed metaphyseal widening with cupping and fraying of the ulna and distal radius, suggesting rickets. A mutation analysis of the CYP27B1 gene identified a homozygous mutation of c.589+1G>A in the splice donor site in intron 3, which was known to be pathogenic. Since that time, the patient has been under calcitriol and calcium treatment, with normal growth and development. During the follow-up period, she did not develop genu valgum, scoliosis, or nephrocalcinosis.

Keyword

CYP27B1; Hypocalcemia; Vitamin D hydroxylation-deficient rickets type 1A

MeSH Terms

25-Hydroxyvitamin D3 1-alpha-Hydroxylase*
Alkaline Phosphatase
Calcifediol
Calcitriol
Calcium
Female
Follow-Up Studies
Genu Valgum
Growth and Development
Humans
Hyperparathyroidism, Secondary
Hypocalcemia
Introns
Nephrocalcinosis
Radius
Rickets*
RNA Splice Sites
Scoliosis
Seizures
Ulna
Vitamin D*
Vitamins*
Wrist
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Alkaline Phosphatase
Calcifediol
Calcitriol
Calcium
RNA Splice Sites
Vitamin D
Vitamins

Figure

• 

  Fig. 1 Radiographic images of the patient with vitamin D hydroxylation-deficient rickets type 1A. (A) Simple X-ray findings show fraying and cupping of the radius, ulnar, tibia and fibula, and metaphyseal widening at presentation. (B) Harrison sulcus and rachitic rosary were also observed (arrow). (C) After 2 years of treatment, marked improvement in widening and flaring of metaphysis of long bone were revealed.

• 

  Fig. 2 Mutation analysis of the CYP27B1 gene. Partial sequences of CYP21B1 show homozyous splicing mutation in intron 3 (c.589+1G>A).

• 

  Fig. 3 Growth curve of of the patient with vitamin D hydroxylation-deficient rickets type 1A. Mid parental height (arrow).

Reference

1. Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL, et al. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol. 1997; 11:1961–1970. PMID: 9415400.

2. Demir K, Kattan WE, Zou M, Durmaz E, BinEssa H, Nalbantoğlu Ö, et al. Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A. PLoS One. 2015; 10:e0131376. PMID: 26132292.

3. Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha, 25-dihydroxyvitamin D. N Engl J Med. 1973; 289:817–822. PMID: 4357855.

4. Babiker AM, Al Gadi I, Al-Jurayyan NA, Al Nemri AM, Al Haboob AA, Al Boukai AA, et al. A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report. BMC Res Notes. 2014; 7:783. PMID: 25371233.

5. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol. 2009; 160:491–497. PMID: 19095780.

6. Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, et al. Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab. 2007; 92:3177–3182. PMID: 17488797.

7. Kim CJ. Vitamin D dependent rickets type I. Korean J Pediatr. 2011; 54:51–54. PMID: 21503197.

8. Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, Portale AA, et al. Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am J Hum Genet. 1998; 63:1694–1702. PMID: 9837822.

9. Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin North Am. 2010; 39:333–346. PMID: 20511055.

10. Fu GK, Portale AA, Miller WL. Complete structure of the human gene for the vitamin D 1alpha-hydroxylase, P450c1alpha. DNA Cell Biol. 1997; 16:1499–1507. PMID: 9428799.

11. Monkawa T, Yoshida T, Wakino S, Shinki T, Anazawa H, Deluca HF, et al. Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D3 1 alpha-hydroxylase. Biochem Biophys Res Commun. 1997; 239:527–533. PMID: 9344864.

12. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, et al. Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med. 1998; 338:653–661. PMID: 9486994.

13. Durmaz E, Zou M, Al-Rijjal RA, Bircan I, Akçurin S, Meyer B, et al. Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. Clin Endocrinol (Oxf). 2012; 77:363–369. PMID: 22443290.

14. Kitanaka S, Murayama A, Sakaki T, Inouye K, Seino Y, Fukumoto S, et al. No enzyme activity of 25-hydroxyvitamin D3 1alpha-hydroxylase gene product in pseudovitamin D deficiency rickets, including that with mild clinical manifestation. J Clin Endocrinol Metab. 1999; 84:4111–4117. PMID: 10566658.

15. Miller WL, Portale AA. Vitamin D 1 alpha-hydroxylase. Trends Endocrinol Metab. 2000; 11:315–319. PMID: 10996526.

16. Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular basis of vitamin D-dependent rickets type I. Endocr J. 2001; 48:427–432. PMID: 11603564.

17. Kato S, Yoshizazawa T, Kitanaka S, Murayama A, Takeyama K. Molecular genetics of vitamin D-dependent hereditary rickets. Horm Res. 2002; 57:73–78. PMID: 12006701.

18. Glorieux FH, Pettifor JM. Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets. Bonekey Rep. 2014; 3:524. PMID: 24818008.

19. Akerström G, Hellman P, Hessman O, Segersten U, Westin G. Parathyroid glands in calcium regulation and human disease. Ann N Y Acad Sci. 2005; 1040:53–58. PMID: 15891005.

20. Cooper DN, Krawczak M, Antonaratis SE. The nature and mechanism of human gene mutation. In : Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill;1995. p. 259–291.