Hypocalcemic vitamin D-dependent rickets (ORPHA:289157)
A rare, genetic disorder of vitamin D metabolism characterized by severe hypocalcemia leading to osteomalacia and rachitic bone deformations, and moderate hypophosphatemia.
Epidemiology
The worldwide prevalence in the general population of hypocalcemic vitamin D-dependent rickets (VDDR) is unknown. In Denmark the prevalence among children under 15 years of age is estimated at 1/250,000.
Clinical description
The signs and symptoms vary depending on the severity of the disease. Symptoms can appear within the first year of life with manifestations of chronic hypocalcemia: hypotonia, tetany, seizures, muscle weakness, and poor growth. Progressively, patients present with signs and symptoms of rickets (bowed legs, rachitic rosary...).
Etiology
The disorder is commonly due to inactivating mutations in the CYP27B1 gene (12q14; disorder referred to as VDDR1A) which codes for the enzyme which converts the vitamin D precursor calcidiol to calcitriol. Less commonly, the disorder is due to variants in CYP2R1 (11p15.2; VDDR1B) resulting in decreased expression of vitamin D 25-hydroxylase enzyme which converts calciferol to calcidiol. These defects in the biosynthesis of active vitamin D leads to an impaired intestinal absorption of calcium and phosphate, consequently leading to hypocalcemia and abnormal bone mineralization.
Diagnostic methods
Diagnosis is based on biochemical and radiological findings. Classical radiological signs include rickets and/or osteomalacia and decreased bone mineralization. Biochemical findings include severe hypocalcemia, moderate hypophosphatemia and increase parathyroid hormone and alkaline phosphatase levels. In VDDR1A, additional biochemical anomalies include normal serum levels of calcidiol (25-hydroxyvitamin D) associated with low serum levels of calcitriol (1,25-dihydroxyvitamin D3). In VDDR1B, serum levels of calcidiol (25-hydroxyvitamin D) are undetectable and are associated with normal to high serum levels of calcitriol (1,25-dihydroxyvitamin D3). Diagnosis is confirmed by DNA analysis.
Differential diagnosis
Differential diagnosis includes nutritional vitamin D deficiency, vitamin D resistant rickets and bone dysplasia.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment aims at improving growth and restoring normal serum levels of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone and at healing/preventing skeletal deformities. It consists of daily administration of calcitriol (VDDR1A and VDDR1B). Patients with VDDR1B are also responsive to calcidiol. Nephrocalcinosis, hypercalciuria, and hypercalcemia can be observed as complications of the therapy. Regular monitoring (physical and biochemical examination, hand radiographs, renal ultrasound) is thus required.
Prognosis
With treatment, prognosis is good.

                            Last update: 
                            August 2022


                            - Expert reviewer(s): 
                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*


                                * European Reference Network