A Previously Unreported Combination of Mutations and its Unexpected Outcome in a Patient with Type 1a Rickets: A Case Study

Background: Type 1a rickets is a rare autosomal recessive condition in which the enzyme 1-alpha-hydroxylase is not fully active. The result of this mutated enzyme is the inability to convert vitamin D from 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D. This form of rickets classically presents with low 1,25 (OH)2 vitamin D, hypocalcemia, elevated parathyroid hormone (PTH), and distinct radiographic findings such as bowing of the legs and widening of the growth plates1,2. There are a number of mutations of the CYPB27B1 gene that are known to cause impaired enzymatic activity. Individuals with homozygous and compound heterozygous mutations have been described. Correlations between specific mutations and varying degrees of enzymatic impairment have been made. Case Information: A 14-year-old male was referred to endocrinology after experiencing a pathologic femur fracture. His mobility was severely limited secondary to bowing of his legs and pain with weight bearing. He was 48.4” tall (z = -4.8). He had pronounced bowing of his extremities and wide wrists. Labwork revealed the following: serum Ca 6.3 mg/dL, serum Phos 4.4 mg/dL, PTH 265 pg/mL, 25-hydroxyvitamin D 29 ng/mL, and 1,25 (OH)2 vitamin D 33 pg/mL (19-83). He was then admitted to the inpatient endocrine service and treated with oral and IV calcium, ergocaliciferol, and calcitriol. Later, whole exome sequencing revealed compound heterozygous variants of the CYP27B1 gene: c1319_1325dupCCCACCC (p.P443fs) and c.1226C [greater than] T (p.T409l). The normal level of 1,25-(OH)2 vitamin D concentration was surprising, given that both of the mutations in this patient were previously believed to cause complete enzymatic inactivity. The P443fs variant has been found in combination with other mutations, resulting in phenotypic variability3. The T409l variant appears less frequently in the literature, but is also believed to cause complete enzymatic inactivity. The P443fs and T409l mutations, however, have not previously been described together. Conclusion: The normal 1,25 (OH)2 vitamin D concentration in this patient suggests that at least one of these two CYP27B1 variants does not universally cause complete enzymatic inactivity, which is a departure from the current evidence base. Further use of genetic testing in Type 1a Rickets may result in improved understanding of the connection between genotype and phenotype in this rare condition.