VDR MUTATION IN TWO SISTERS: PHENOTYPE VARIABILITY AND CLINICAL OUTCOME

Abstract

Objectives: Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disease secondary to the mutation of vitamin D receptor (VDR) gene. These children show an early onset of rickets and in some of them alopecia is associated. Methods: We describe clinical features and laboratory findings in two sisters affected by HVDRR, as well as their response to treatment. Results: The first born is now 4 years old and had a severe and resistant hypocalcaemia, with low response to high doses of calcium per os, the requirement of intravenous infusion of calcium for a prolonged period, hypocalcaemic seizures resolved with high doses of intravenous calcium and high doses of vitamin D. Clinical features were characterized by a typical rickets phenotype associated to alopecia and axial hypotonus. She presented hypocalcaemia, hypophosphatemia and high levels of PTH: 829 pg/ml. Genetic study of VDR revealed a homozygous novel mutation in the VDR gene (c.462+1G>A in the splicing locus of exon 6). The younger sister, 11 months old, was screened at birth, in the neonatal care unit, for hypocalcaemia, showing however normal values. She was called in our centre to further investigate her genetic status, showing the same mutation of the sister. At the age of 7 months she was further investigated and showed asymptomatic hypocalcaemia (6.7 mg/dl), low Ca++ (3.67 mg/dl), hypophosphatemia (3.2 mg/dl), high PTH (559 pg/ml). She was treated with calcium per os, and vitamin D, with a rapid normalization of calcaemia (Ca++: 4.31 mg/dl). She did not show skeletal manifestations of rickets, however she developed a mild alopecia. Conclusions: The two sisters showed a different clinical phenotype, probably in part linked to the precocious diagnosis of the younger sister.