Prenatal Diagnosis of Vitamin D-Dependent Rickets, Type II: Response to 1, 25-Dihydroxyvitamin D in Amniotic Fluid Cells and Fetal Tissues

Yosef Weisman, Niva Jaccard, Cyril Legum, Zvi Spirer, Gideon Yedwab, Lea Even, Samuel Edelstein, Alvin M. Kaye, Zeev Hochberg

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Vitamin D-dependent rickets type II (VDDR-II; hereditary resistance to 1, 25-dihydroxyvitamin D3 [1, 25(OH)2D3]), an autosomal recessive genetic disease that results from a failure to respond to 1, 25-(OH)2D3, is characterized by severe rickets, hypocalcemia, growth retardation, and high prevalence of alopecia. We used amniotic fluid cells in the 17th week of gestation to detect VDDR-II in fetuses at risk for the defect. First, we demonstrated in cells obtained from 15 control pregnancies the presence of a specific high affinity 1, 25-(OH)2D3 receptor (Kd = 0.3 × 10–11 mol/L; maximal number of binding sites, 6.1 fmol/ mg protein) and l, 25-(OH)2D3-induced 25-hydroxyvitamin D3-24-hydroxylase activity (up to 30-fold increase). Amniotic fluid cells from a woman who had already given birth to a child with VDDR-II contained receptors that bound [3H]1, 25-(OH)2D3 normally and responded to 1, 25-(OH)2D3 stimulation with a 10-fold increase in 24-hydroxylase activity. The fetus was, therefore, judged unaffected, and a normal baby girl was born. At the age of 16 months she did not demonstrate clinical or biochemical features of VDDR-II. Amniotic fluid cells from another mother of a child with VDDR-II were unable to bind [3H]1, 25-(OH)2D3, and the hormone failed to stimulate 24-hydroxylase activity. VDDR-II in this fetus was confirmed after termination of pregnancy by the total inability of 1, 25-(OH)2D3 to stimulate 24-hydroxylase activity in tissue explants and cell cultures prepared from the fetus’s kidney and skin. In contrast, tissues from dead control fetuses responded to stimulation by 1, 25-(OH)2D3 with a 3-to 10-fold increase in 24-hydroxylase activity. Fetal kidney and skin explants and cell cultures also synthesized a [3H]l, 25-(OH)2D3-like metabolite from [3H]25-OHD3 as early as the 17th week of gestation. 1, 25-OH)2D3 (10 nM) decreased the in vitro synthesis of the [3H]l, 25-(OH)2D3-like metabolite in tissues from dead control fetuses, but not from the affected fetus. Thus, human fetuses at midgestation already have the regulatory mechanisms responsive to 1, 25-(OH)2D3 present postnatally. The prenatal diagnosis of VDDR-II is now possible and is indicated in a high risk family.

Original languageEnglish
Pages (from-to)937-943
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
StatePublished - Oct 1990
Externally publishedYes


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