Prenatal diagnosis of vitamin D-dependent rickets, type II: response to 1,25-dihydroxyvitamin D in amniotic fluid cells and fetal tissues.
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 x 10(-11) mol/L; maximal number of binding sites, 6.1 fmol/mg protein) and 1,25-(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]1,25-(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]1,25-(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.
Weisman
Y
Y
Bone Disease Unit, Ichilov Hospital, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Jaccard
N
N
Legum
C
C
Spirer
Z
Z
Yedwab
G
G
Even
L
L
Edelstein
S
S
Kaye
A M
AM
Hochberg
Z
Z
D000328:Adult; D000653:Amniotic Fluid / Q000166:cytology*; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000175:diagnosis* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011296:Prenatal Diagnosis; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000378:metabolism*
D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D006899:Mixed Function Oxygenases; D002117:Calcitriol