Genotype and phenotypic spectrum of vitamin D dependent rickets type 1A: our experience and systematic review

Abstract

Background Vitamin D dependent rickets type 1 (VDDR1) is a rare disease due to pathogenic variants in 1-α hydroxylase gene. We describe our experience with systematic review of world literature to describe phenotype and genotype. Methods Seven patients from six unrelated families with genetically proven VDDR1 from our cohort and 165 probands from systematic review were analyzed retrospectively. The clinical features, biochemistry, genetics, management, and long-term outcome were retrieved. Results In our cohort, the median age at presentation and diagnosis was 11(4–18) and 40(30–240) months. The delayed diagnoses were due to misdiagnoses as renal tubular acidosis and hypophosphatemic rickets. Four had hypocalcemic seizures in infancy whereas all had rickets by 2 years. All patients had biochemical response to calcitriol, however two patients diagnosed post-puberty had persistent deformity. Genetic analysis revealed two novel (p.Met260Arg, p.Arg453Leu) and a recurring variant (p.Phe443Profs*24). Systematic review showed that seizures as most common presentation in infancy, whereas delayed motor milestones and deformities after infancy. Diagnosis was delayed in 27 patients. Patients with unsatisfactory response despite compliance were >12 years at treatment initiation. Inappropriately normal 1,25(OH)2D may be present, however suppressed ratio of 1,25(OH)2 D/25(OH)D may provide a clue to diagnosis. Various region specific and hot-spot recurrent variants are described. Patients with truncating variants had higher daily calcitriol requirement and greatly suppressed ratio of 1,25(OH)2D/25(OH)D. Conclusion Delayed diagnosis may lead to permanent short stature and deformities. Truncating variants tend to have severe disease as compared to non-truncating variants. Diagnostic accuracy of 1,25(OH)2 D/25(OH)D ratio needs further validation.

An overview of CYP27B1 enzyme mutation and management: A case report and review of the literature

“…Of the 7 patients, 4 had episodes of hypocalcemic seizure. In 165 patients, seizures and motor-deformity were more common during infancy(11 of 31 infants) and post-infancy, respectively (38).…”

“…At the onset of radiographic changes, the calcitriol dose modified to 0.25-0.5 μg / day. They concluded that physiological doses of calcitriol (0.25-0.75 μg / day) could improve the clinical and laboratory profile of patients (38). Dhull et al considered doses of 30 ng/kg/day and 2 mmols/kg/day for calcitriol and phosphate, respectively, for both patients.…”

Alkaline phosphatase in clinical practice in childhood: Focus on rickets

“…As seen in 25-hydroxylase deficiency, the elevation of serum ALP levels is also typical of 1-alpha-hydroxylase deficiency (also defined as vitamin D-dependent rickets type 1 or VDDR1), a somewhat more common condition in which the genetic defect causes a defective conversion of 25OHD into the active form of vitamin D. In the case series published by Dodamani et al. ( 22 ), in which the authors reviewed the clinical features of a total of 165 probands affected by VDDR1 found in literature, the patients presented with markedly elevated ALP levels (on average 1480 IU/L). Ozden et al.…”

Osteomalacia Is Not a Single Disease

“…Some drugs such as antiepileptics and glucocorticoids may disrupt vitamin D metabolism and, in some cases, also cause decreased calcium absorption and increased renal losses, contributing to hypomineralization. The rare genetically determined disorders vitamin D-dependent rickets (VDDR) types 1A and 1B, caused by mutation in genes encoding cytochrome P450 family 27 subfamily B member 1, i.e., 1alpha-hydroxylase (CYP27B1) or cytochrome P450 Family 2 Subfamily R Member 1, i.e., 25-hydroxylase (CYP2R1), are included in the vitamin D-dependent forms of altered mineralization since they are cured with specific analogs of vitamin D, such as 1alpha-hydroxylated forms of vitamin D or 25-hydroxylated vitamin D, respectively [ 1 , 12 ].…”