ESPE Abstracts (2019) 92 P1-176

Genotype and Phenotype Characterization of Turkish Patients with Vitamin D Dependent Rickets Type IA

Sare Betul Kaygusuz1, Pinar Ata2, Tarik Kirkgoz1, Zehra Yavas Abali1, Mehmet Eltan1, Busra Gurpinar Tosun1, Tuba Seven Menevse1, Didem Helvacioglu1, Tulay Guran1, Ahmet Arman2, Abdullah Bereket1, Serap Turan1

1Marmara University Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey. 2Marmara University Faculty of Medicine, Department of Medical Genetics, Istanbul, Turkey

Background: Vitamin D Dependent Rickets Type IA (VDDR-IA) is the most common type of VDDR and caused by mutations in CYP27B1. Here, we aimed to analyze the genotypic and phenotypic features of our VDDR-IA patients.

Materials and Methods: The patients with a clinical diagnosis of VDDR-IA were enrolled and analyzed for CYP27B1 gene mutations.

Results: 12 (5 males) patients from 9 unrelated families were evaluated. The mean age of diagnosis was 3.48±4.00 (median: 1.1 ; min-max: 0.75-11.6) years. Patients were initially misdiagnosed as nutritional (n:7) or hypophosphatemic rickets (n:3) before referral to our clinic. All had biochemical evidence suggestive of VDDR-IA (Table), except one with hypocalcemia and hyperphosphatemia (Ca: 6.4 mg/dL; PO4: 6.2 mg/dl; ALP: 710IU/L;PTH: 362 pg/ml; 25-OH vit D: 34 ng/ml), in whom pseudophypoparathyroidism (PHP) was excluded with normal GNAS gene sequencing and Gsα levels. Then, VDDR-IA was subsequently considered upon bone pain and the radiological findings of rickets on initial presentation. Six patients had a history of high dose vitamin D intake (300000-1500000 IU) and one had toxic level of 25[OH]D (250ng/ml). Mutation analysis of CYP27B1 gene revealed a homozygous frameshift mutation (p.Phe443Profs*24) in 6 patients from 4 unrelated families, and a homozygous missense mutation (p.Lys192Glu) in 3 patients from 2 unrelated families. Homozygous p.Phe443Profs*24 mutation leads to a truncated protein without enzymatic activity and the patients with this mutation presented to the clinic at an earlier age than the patients with p.Lys192Glu mutation (1.12±0.31 vs 10.13±1.40 years). A homozygous p.L380Afs*57 mutation was detected in one patient. Molecular analysis of two patients is still in progress .All mutations reported in our patients represent previously reported regional founders, which potentially facilitate genetic testing in VDRR-IA patients with same geographical origin.

Conclusions: Our results indicate a good genotype-phenotype correlation in patients with VDDR-IA and emphasize the importance of correct diagnosis in VDDR-IA for the proper management, and avoiding poor clinical outcomes.

Mean ± SDMin - MaxReference
7.69 ± 1.654.8 - 10.38,4-10,2
3.08 ± 1.082.2 - 6.22,4-10,4
2197 ± 2339219 - 925146-110
513 ± 323121 - 100615-65
86.5 ± 73.124 - 25020-100
33.3 ± 27.5<8 - 85.916-65